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sumarioEditorial [Available in English]Currently role of premixed insulins in the treatment of type 2 diabetes

ReviewRole of metabolic endotoxemia in insulin resistance and obesity. The Buffering EfÞciency Hypothesis

Consensus documentEuropean Guidelines on Cardiovascular Disease Prevention in Clinical Practice.Spanish Version from the CEIPC 2008 (II/III)

Position document [Available in English]Position statement on continuous glucose monitoring

Seminars on diabetes [Available in English]

PrediabetesEpidemiology of prediabetes in SpainMain differences between impaired fasting glucose and impaired glucose tolerancePrevention of type 2 diabetes based on nutritional therapy and/or increase of physical activityPharmacologic interventions to prevent type 2 diabetes

Original articles [Available in English]Prevalence of tobacco use among diabetic patientsAggregation pattern and factorial analysis of cardiovascular risk factors included in the metabolicsyndrome in a Spanish non-diabetic population: the VIVA study

Clinical notes [Available in English]Treatment of severe diabetic neuropathy with spinal cord stimulation

Case report discussed by experts [Available in English]Insulin therapy in type 2 diabetes mellitus

New challenges in clinical practice [Available in English]Can be still admitted a target of HbA

1c<7%? Considerations about ACCORD,

ADVANCE and the new consensus from ADA-EASD

Historical perspectiveFrom pancreatic extracts to artiÞ cial pancreas: History, science and controversiesabout the discovery of the pancreatic antidiabetic hormone.II: Nicolae C. Paulescu: The discovery of pancreine

Pictures in clinical diabetes [Available in English]Differential diagnosis between foot osteomyelitis and acute Charcot arthropathy

Selected original articles analysed by expertsNews

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In the treatment of persons with T2D, the con-trol of hyperglycemia is one of the main objec-tives, and an effective way to reduce and delaythe onset of either microvascular or macrovas-cular impairments. At present, we count withseveral approaches, several drugs and differenttherapeutic antihyperglycemiant guidelines,which we have to adapt in a customized man-ner to each of the persons with T2D taking in-to account their age, the hyperglycemia level,the evolution of the disease, the associated co-morbidities and the social and personal situa-tion. Though the basis of the initial treatmentof the T2D is constituted by the changes in the life style that incorporate a nutritional treat-ment and the increase of physical activity, to-gether with the oral medication, in certain situ-ations the administration of insulin is required in order to achieve an adequate control.1

On one hand, the use of insulin is recommend-ed when a metabolic decompensation takesplace, if there are clear symptoms of hypergly-cemia or if the levels of glycemia or HbA1c arevery high. On the other hand, the insuliniza-tion will be necessary when the glycemic con-trol objectives are not achieved with the chang-

es of life style and other antihyperglycemicdrugs, avoiding unnecessary delays. Besidesthe fast and intermediate acting human insu-lins (NPH), there are at present synthetic ana-logues of insulin, both fast acting and slowacting. Likewise, there are insulin mixtures orpremixed insulins that contain a Þxed propor-tion of fast and intermediate insulins, or fastanalogues and intermediate insulin.

When the glycemic control target is notachieved with other treatments, the clinicalguidelines recommend the starting of insulintherapy adding a single dose of intermediateinsulin or slow analogue with later dose ad-justment. However, the use of two doses ofpremixed insulins proved to yield better resultsregarding the improvement of the HbA1c andthe postprandial glycemias.2 For this reason, itis recommended to consider the guideline oftwo injections of premixed insulin of 8.5-9%in these cases. Premixed analogues should beused rather if injections immediately beforethe meals are preferred, if the hypoglycemiasare an important risk for the patient or if thepostprandial ßuctuations of the glycemia arevery marked.

Moreover, starting insulin administration sug-gests starting a structured diabetes educationthat includes frequent self-analysis and self-control for an adequate adjustment of the dose.If after the beginning of the insulin therapywith slow or intermediate insulin and the laterincrease of the dose, the HbA1c objectives are

Editorial

Currently role of premixed insulinsin the treatment of type 2 diabetesPapel actual de las insulinas premezcladas en el tratamientode la diabetes tipo 2E. Ménendez TorreEndocrinology and Nutrition Service. Hospital Universitario Central de Asturias. Oviedo.

Date received: January 26th 2009Date accepted: January 28th 2009

Correspondence:E. Ménendez Torre, Endocrinology and Nutrition Service. HospitalUniversitario Central de Asturias. Julián Clavería, s/n. 33006 Oviedo.Email: [email protected]

List of acronyms quoted in the text:NPH: neutral protamine Hagedorn insulin.

EditorialPremixed insulins in type 2 diabetes. E. Menéndez Torre

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not achieved, there are two options in the insu-lin therapy intensiÞcation: to evolve to a basalbolus guideline, adding a dose of a fast ana-logue to the considered meals, or to change theguideline to premixed insulins in multi-doses, generally before breakfast and before dinner.This last guideline might be easy to under-stand and to carry out by the majority of thepatients with T2D with which an adequatecontrol is achieved in more than half of thecases,3 without differences as regards to thenumber of hypoglycemias or other adverse ef-fects. On the other hand, the guideline withpremixed insulins might provide a better lifequality compared to the basal bolus guideline.4

The usual guideline of two daily doses ofpremixed insulins before the breakfast anddinner might intensify itself if considered nec-essary adding a new dose before lunch, achiev-ing an improvement of the HbA1c, increasingthe risk of mild hypoglycemias only moderate-ly, which in any case are kept at low levels.5

The mixtures of insulin have also proved theirefÞcacy in hospitalized patients, achieving asimilar glycemic control to the basal bolusguideline without differences in the hypoglyc-emia’s incidence.6 At the hospital, they mightconstitute a very ßexible tool to reach an ade-quate metabolic control in changing situations,as the concomitant treatment with corticoids invariable doses.

To sum up, the premixed insulins are an efÞ-cient option, as well as safe and very useful inpatients with T2D who require insulin due to a

metabolic decompensation, or who need theintensiÞcation of the previous treatment guide-line with other antidiabetic drugs or with slowor intermediate insulin. ■

Declaration of potentialcon!ict of interestsE. Ménendez Torre received fees for teaching activ-ities through invitations of Sanofi-Avenits,Novonordisk and Lilly.

References1. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR,

Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193-203.

2. Qayyum R, Bolen S, Maruthur N, Feldman L, Wilson LM,Marinopoulos SS, et al. Systematic review: comparativeeffectiveness and safety of premixed insulin analogues in type 2 diabetes. Ann Intern Med. 2008;149:549-59.

3. Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H,Martin S. Advancing insulin therapy in type 2 diabetes previouslytreated with glargine plus oral agents: prandial premixed (insulinlispro protamine suspension/lispro) versus basal/bolus(glargine/lispro) therapy. Diabetes Care. 2008;31:20-5.

4. Masuda H, Sakamoto M, Irie J, Kitaoka A, Shiono K, Inoue G,et al. Comparison of twice-daily injections of biphasic insulin lispro and basal-bolus therapy: glycaemic control and quality-of-life of insulin-naïve type 2 diabetic patients. Diabetes ObesMetab. 2008;10:1261-5.

5. Clements MR, Tits J, Kinsley BT, Rastam J, Friberg HH,Lightelm RJ. Improved glycaemic control of thrice-dailybiphasic insulin aspart compared with twice-daily biphasic human insulin; a randomized, open-label trial in patients with type 1 or type 2 diabetes. Diabetes Obes Metab.2008;10:229-37.

6. Umpierrez GE, Hor T, Smiley D, Temponi A, Umpierrez D,Ceron M, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus NPH plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab. 2008.November 18 [Epub ahead of print].


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AbstractRecent studies have shown that elevated concentrations of plasmalipopolysaccharide (LPS) constitute a metabolic mechanism enoughfor triggering insulin resistance, obesity and type 2 diabetes in animalmodels, and that high fat diets lead to increased plasma LPS con-centrations through changes in the gut flora. We review here the LPSeffects in metabolic processes in vitro. In humans, an altered innateimmune system has also been associated with metabolic disorderssuch as insulin resistance, high endotoxemia markers (LBP, sCD14)and low LPS-neutralizing proteins (adiponectin, bactericidal perme-ability-increasing protein, αα-defensins and lactoferrin). In fact, insulinresistance is well known to be associated with inflammation, with adecrease in innate immune efficiency and a reduction in the produc-tion of antimicrobial proteins. In this revision, we propose a new viewaccording to which buffering efficiency of the innate immune systemcould prevent LPS-induced metabolic diseases.

Keywords: metabolic endotoxemia, endotoxemia markers, LPS-neutralizing proteins, insulin resistance, obesity.

IntroductionObesity is well known to be associated with a cluster ofmetabolic diseases, such as dyslipidemia, hypertension,insulin resistance, type 2 diabetes and atherosclerosis.1

Adipose tissue has an essential role as energy storage de-pot and for secreting adipokines inßuencing diverse tis-sue targets such as brain, liver, muscle, β cells, gonads,lymphoid organs, and systemic vasculature.2,3 Expres-sion analysis of macrophage and non-macrophage cellpopulations isolated from adipose tissue demonstratesthat adipose tissue macrophages are responsible for se-cretion of almost all of pro-inßammatory cytokines.4 Inrecent years, it has become evident that alterations in thefunction of the innate immune system are intrinsicallylinked to metabolic pathways in humans.5-7 Central tometabolic diseases is insulin resistance associated with alow-grade inflammatory status.8-11 The mechanismsthrough which proinßammatory cytokines, like tumornecrosis factor α (TNF-α), interleukin-6 (IL-6) and in-terleukin 1-beta (IL-1β) interact with cellular insulin sig-nal transduction cascades have been better understood inthe last few years.12-17 In vivo, a direct correlation be-tween increased circulating proinßammatory cytokinesand insulin resistance has been well-demonstrated.10,18

The origin of this increased inßammatory activity inobesity and type 2 diabetes is virtually unknown. Im-mune system homeostasis is challenged by continuousexternal insults, like saturated fatty acid-rich diets,19

pathogen associated molecular patterns (PAMP) like li-popolysaccharide (LPS)20 and advanced glycation end-products (AGEs),21 burden of infection22 and oxidativestress.23 These continuous insults could result in a chron-ic low level of inßammation associated with insulin re-sistance.

This revision is focused in the effects of metabolic con-centrations of plasma LPS in insulin resistance and other

Review

Role of metabolic endotoxemia in insulin resistanceand obesity. The Buffering Efficiency HypothesisJ.M. Moreno Navarrete, J.M. Fernández-RealDepartment of Diabetes. Endocrinology and Nutrition. Institut d’Investigació Biomèdica de Girona (IdIBGi).CIBER Fisiopatología de la Obesidad y Nutrición CB06/03/010. Girona (Spain)

Date received: 13th January 2009Date accepted: 30th January 2009

Correspondence:J.M. Fernández-Real, M.D., Ph.D. Unit of Diabetes, Endocrinology and Nutrition.Hospital de Girona «Dr. Josep Trueta». Ctra. França s/n, 17007 Girona (Spain).E-mail: [email protected]

Abbreviations: ADIPOQ: Adiponectin; AGEs: Advanced Glycation End-Products; BPI: Bactericidal/increasing protein permeability; CD14, CD14 molecule; DEFA1-3: Human α-Defensins; FABP4: Fatty Acid Binding Protein 4; GPD1: Glycerol-3-phosphateDehydrogenase 1 (soluble); GPI-linked protein CD14: Glycosylphosphatidylinositol-linked protein CD14; IKKβ: Inhibitor of NuclearFactor kappa B Kinase beta subunit; IL-6: Interleukin-6; IL-1β: Interleukin 1-β;LBP: Lipopolysaccharide Binding Protein; LPL: Lipoprotein Lipase; LPS: Bacterial Lipopolysaccharide or Endotoxin; LTF: Lactoferrin; MD-2: Myeloid Differentiation Protein-2; NF-κB: Nuclear Factor kappa-B DNA binding subunit; PAMP: Pathogenassociated Molecular Patterns; PKB: RAC-alpha serine/threonine-protein kinase;PI3K: Phosphatidylinositol 3-kinase; sTNFR1: Soluble tumor Necrosis Factor Receptor 1; sTNFR2: Soluble tumor Necrosis Factor Receptor 2; PPARγ:Peroxisome proliferator activated receptor gamma; TLR4: Toll-like Receptor4;TNF-α: Tumor Necrosis Factor α.

ReviewEndotoxemia and induced metabolic disturbances. J.M. Moreno Navarrete, et al.

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metabolic disorders associated with obesity, and the pos-sible role of an inefÞcient innate immune system re-sponding to this challenge.

Endotoxemia e"ects on obesityand insulin resistanceLPS is an important structural component of the outermembrane of Gram-negative bacteria. LPS consists ofthree parts: a lipid A, an oligosaccharide core, and an Oside chain.24 LPS is one of the best studied and most po-tent immunostimulatory components of bacteria whichinduces toxicity through increased signaling, triggeringsystemic inßammation.25 LPS leads to a strong stimula-tory release of several cytokines that are key inducers ofinsulin resistance which is a putative factor for the trig-gering of metabolic disorders. Lipid A is the main path-ogen associated molecular pattern of LPS and is acylatedwith saturated fatty acids. Removal of these fatty acidsresults in complete loss of endotoxic activity.26 LPS stim-ulation of mammalian cells occurs through series of in-teractions with several proteins including the LPS bind-ing protein (LBP), CD14, MD-2 and TLR4.27 LBP is asoluble shuttle protein which directly binds to LPS andfacilitates the association between LPS and CD14.28

CD14 is a glycosylphosphatidylinositol-anchored pro-tein, which also exists in a soluble form. CD14 facili-tates the transfer of LPS to the TLR4/MD-2 receptorcomplex and modulates LPS recognition.29 MD-2 is asoluble protein that associates non-covalently with TLR4but can directly form a complex with LPS in the absenceTLR4. MD-2 is associated with the extracellular domainof TLR4 and augments TLR4-dependent LPS responses in vitro being essential for correct intracellular distribu-tion and LPS-recognition of TLR4.30 The TLR4 receptorcomplex, recruits the adaptor protein, myeloid differen-tiation factor-88 (MyD88). MyD88 in turn recruits inter-leukin-1 receptor–associated kinase (IRAK) and, by ac-tivating IKKβ and NF-κB, ultimately induces theexpression of numerous inßammatory mediators.31 Fur-thermore, TLR4 can be activated with saturated free fat-ty acids, stimulating NF-κB signaling and expression ofinßammatory cytokine genes, such as TNF-α and IL-6 inadipocytes and macrophages.20,32,33

A recent article has demonstrated that metabolic concen-trations of plasma LPS are a sufÞcient molecular event totrigger insulin resistance, obesity and type 2 diabetes.34

This process was called metabolic endotoxemia, deÞned

as the association between metabolic concentration ofcirculating endotoxin (LPS) and inß ammation- and highfat diet-induced metabolic diseases. Metabolic concen-tration is the minimum LPS concentration to producemetabolic disorders, but not enough to produce acute en-dotoxemia. Interestingly, metabolic concentrations ofplasma LPS were increased by a high fat diet. The sameauthors reported new interactions between a high fat dietand the microbial gut ßora. They found that high fatfeeding changes microbial gut ßora (decreasing BiÞdo-bacterium spp.) and increases intestinal permeability,leading to increased LPS absorption, endotoxemia, in-ßammation and metabolic disorders.35 Selective increas-es of BiÞ dobacterium spp. in gut ßora improved high fatdiet-induced diabetes in mice and this was associatedwith decreased concentration of circulating LPS.36

In vitro, LPS induces nuclear factor-kappaB- and MAPK-dependent proinßammatory cytokine/chemokine expres-sion primarily in preadipocytes. These changes are asso-ciated with a decrease in adipogenic gene expression,lower ligand-induced activation of peroxisome prolifera-tor activated receptor (PPAR)-γ and decreased insulin-stimulated glucose uptake in adipocytes.37 PersistentLPS stimulus impaired adipocyte differentiation and de-creased the expression of lipogenic enzymes (FABP4,LPL), of different adipokines (adiponectin, resistin, vis-fatin, leptin) and of PPAR-γ.38 Thus, LPS stimulus leadto adipose tissue insulin resistance and to adipocyte dys-function usually found in the systemic metabolic disor-ders linked to obesity.

These Þndings in animal models are mirrored by differ-ent observations regarding endotoxemia markers andLPS-neutralizing proteins in humans, summarized below(table 1).

Table 1. Endotoxemia markers and LPS-neutralizingproteins

Endotoxemia markers LPS-neutralizing proteins

• Soluble CD14 (sCD14) • Adiponectin (ADIPOQ)

• Lipopolysaccharide binding • Bactericidal/permeabilityprotein (LBP) increasing protein (BPI)

• Human α-defensins (DEFA1-3)

• Lactoferrin (LTF)

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Endotoxemia markersand LPS-neutralizing proteinsEndotoxemia markersEndotoxemia markers are molecules of innate immunesystem which are produced by leukocytes (macrophagesand neutrophils), adipose tissue, liver, kidney, lung, thy-mus, small intestine and mammary tissue in response to LPS stimuli. This review is focused in the main endotox-emia markers soluble CD14 (sCD14) and lipopolysac-charide binding protein (LBP), two phase acute reactantsthat are released in response to LPS.

Soluble CD14 (sCD14)The earliest cell-mediated events following endotoxinrelease appear to involve the glycosylphosphatidyl-inosi-tol anchored protein CD14. Different lines of evidencesupport a central role for CD14 in LPS-mediated re-sponses. SpeciÞc monoclonal antibodies (mAb) againstCD14 inhibit the ability of LPS to stimulate monocytes.39

Transfection of CD14 into the 70Z/3 pre-B cell line en-hances the responsiveness of these cells to LPS by morethan 1000-fold.40 CD14 also exists in a soluble form(sCD14),41 and the levels are signiÞcantly raised in sep-tic patients.42

The physiological role of sCD14 is not yet completelyunderstood. sCD14 has been shown to inhibit the LPS-induced TNFα production in whole blood and mono-cytes,43,44 and in a mouse model of endotoxin shock,sCD14 has been shown to inhibit lethality as well.45

However, contrary to this inhibiting effect of sCD14 onLPS effects, sCD14 facilitates the activation of endothe-lial cells that do not express membrane CD14.46,47 Troel-stra et al reported that the effect of sCD14 on neutrophilresponse to LPS was a balance between activation andinhibition, depending on the concentration of circulatingLBP in serum.48 However, sCD14 could play a key roleas intermediate in the neutralization of LPS under physi-ological conditions. sCD14 accelerates the transfer be-tween LPS micelles and lipoproteins by acting as a car-rier. sCD14 also enhances the release of monocyte-boundLPS, transferring LPS into plasma and into lipoproteins and, thus, decreasing cellular responses to LPS, such asinduction of TNF-α and interleukin 6 synthesis.49,50

Recently, a direct relationship between sCD14 and en-dothelial function in type 2 diabetic subjects has beenfound in opposite to the inverse association of these pa-rameters in non-diabetic subjects.51 Furthermore, sCD14

was signiÞcantly and inversely associated with insulinresistance, waist to hip ratio, systolic and diastolic bloodpressure and inflammatory markers (sTNFR1 andsTNFR2), once fasting triglycerides and smoking wascontrolled.52 sCD14 could also be a marker of hepatic in-sulin resistance and dysfunction. In fact, decreased se-rum sCD14 concentration was associated with highercirculating alanine aminotransferase levels.53 These ap-parently protective associations of sCD14 with metabol-ic parameters (insulin sensitivity, blood pressure, hepaticinjury) are supported by the anti-inß ammatory activitiesof sCD14, neutralizing LPS effects in in vitro models.

Interestingly, genetic variations that lead to lower serumconcentration of sCD14 were associated with insulin re-sistance and the presence of increased inßammatorymarkers.52

Lipopolysaccharide Binding Protein (LBP)Lipopolysaccharide Binding Protein (LBP) is an impor-tant LPS marker. LBP is a 65-kDa protein present inblood at high concentrations (approximately 2-20 μg/mL).54 LBP is an acute-phase reactant, predominantly de-rived from the liver, and its plasma levels rise dramatical-ly after inßammatory challenge, including bacterial sep-sis.54 Although the molecular structure of LBP is notentirely known, LBP clearly binds LPS (and LPS sub-structures, such as lipid IVa) through the recognition oflipid A.55 The plasma protein LBP dramatically acceler-ates binding of LPS monomers from aggregates toCD14,56 thereby enhancing the sensitivity of cells to LPS.Furthermore LBP acts as a lipid transfer protein, a func-tion in correlation with its sequence homology to lipidtransferases (phospholipid transfer protein and cholester-ol ester transfer protein). LBP co-puriÞes with HDL par-ticles and additional studies have shown that LBP cantransfer LPS to lipoproteins,57 neutralizing LPS effects.58

Serum LBP reß ects the serum endotoxin (LPS) concen-tration and is negatively associated with insulin sensitiv-ity.59 Interestingly, serum LBP concentrations are in-creased in patients with type 2 diabetes.59

LPS-neutralizing proteinsSeveral naturally occurring proteins possess the capacityto bind to bacteria-associated LPS, resulting in reductionof bacterial viability. These LPS-neutralizing proteinsare adiponectin, bactericidal/permeability-increasingprotein (BPI), human α-defensins and lactoferrin.


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Adiponectin (ADIPOQ)Adiponectin (ADIPOQ) is almost exclusively producedby adipocytes and abundantly present in serum, where it circulates in two higher-order forms: a low-molecularweight dimers or trimers and a larger high-molecularweight complex of 12-18 subunits.60 ADIPOQ is knownto affect LPS-mediated inßammatory events. It inhibitsLPS-induced NF-κB activation and IL-6 production, andincreases PPARγ2 expression in adipocytes, while inmacrophages it suppresses both LPS-induced TNFα andIL-6 production. Peake et al suggested that adiponectinmay have anti-inßammatory potential by directly bind-ing to LPS.61

It is well known that adiponectin expression is reducedin obesity and insulin resistance states. Plasma levels ofadiponectin have also been reported to be signiÞcantlyreduced in obese/diabetic mice and humans, and in pa-tients with cardiovascular diseases, hypertension or met-abolic syndrome.62 A direct insulin-sensitizing effect ofadiponectin in vivo has been extensively reported. Themain mechanism of action of adiponectin in insulin-sen-sitizing actions are mediated through a reduction of tis-sue triglycerides content and activation of PPARα63 andAMP kinase,64,65 leading to the up-regulation of insulinsignaling. However, the anti-inßammatory effects of ad-iponectin and LPS neutralizing action cannot be forgot-ten, as two indirect ways to improve insulin sensitivity.Single nucleotide polymorphisms studies also supportthe role of adiponectin as a factor inßuencing the suscep-tibility to insulin resistance and type 2 diabetes.66,67

Bactericidal/increasing protein permeability (BPI)Bactericidal/increasing permeability protein (BPI) is lo-cated in the azurophilic granules of neutrophils. BPI isan approximately 55 kDa cationic protein with selectiv-ity towards Gram-negative bacteria, most likely due toits strong afÞnity for LPS.68 Besides its bactericidal ac-tivity, BPI also neutralizes the cytotoxic effects of LPS.Most of the antibacterial and LPS binding activity of ho-lo-BPI is found in 20-25 kDa N-terminal fragments/re-gions/domains of the protein.69 N-Terminal fragments/regions of BPI also inhibit LPS induced E-selectin ex-pression and reduce NF-κB activation in LPS-stimulatedendothelial cells.70 Furthermore, rBPI21, a recombinant21 kDa protein/peptide corresponding to amino acids 1-193of N-terminal human BPI in which a cysteine is replacedby an alanine at position 132), is bactericidal and bindsto and neutralizes endotoxin.71

Plasma BPI concentration was directly correlated withinsulin sensitivity and HDL-cholesterol concentrations,and inversely associated with metabolic parameters(waist-to-hip ratio, fasting triglycerides) and with serumLBP and LPS concentration. Genetic variations that leadto lower serum concentration of BPI were associatedwith insulin resistance and increased circulating inß am-matory markers.59

Human αα-defensins (DEFA1-3)Human α-defensins are arginine-rich peptides, contain-ing 29-35 amino acids. Their three disulÞde bridges con-nect cysteines 1-6, 2-4 and 3-5. Human α-defensins aresynthesized as 93-100 amino acid prepropeptides with a19-amino acid signal peptide and a 41-51 amino acid an-ionic pro-segment. α-defensins are predominantly foundin neutrophils (mainly DEFA1-3) and in small intestinePaneth cells. A stimulus-dependent release of pre-syn-thesized defensin-containing cytoplasmic granules con-tributes to the local antimicrobial response.72 Recently,significant positive associations among plasmaα-defensins (1-3) concentrations and non-atherogenic li-pid proÞle and vascular function in apparently-healthyCaucasian men have been reported.73

Lactoferrin (LTF)Lactoferrin is a pleiotropic glycoprotein of the innateimmune system that is involved in LPS buffering. Lacto-ferrin is a monomeric, 80 kDa glycoprotein, with a sin-gle polypeptide chain of about 690 amino acid residuesand two sialic acid molecules, that is produced by neu-trophils and several epithelia types. Lactoferrin is foldedinto homologous N- and C-terminal lobes, each compris-ing two domains that enclose a conserved iron bindingsite. This protein is positively charged in N-terminal re-gion (the Þrst 60 aminoacids) of N-lobe at physiologicalpH because it is rich in arginine.74 Lactoferrin is able tobind and buffer other pathogen associated molecular pat-terns in addition to LPS, viral DNA and RNA, CpG se-quences, and soluble components of the extracellularmatrix.75 This ability is associated with lactoferrin anti-inßammatory activity, as demonstrated in several stud-ies,76,77 in which lactoferrin down-regulates pro-inßamma-tory cytokine production in cell lines acting via NF-κB,78

decreasing the release of TNF-α and IL-6 in mice.

Circulating lactoferrin concentration was inversely asso-ciated with body mass index, waist-to-hip ratio, fastingtriglycerides and fasting glucose, and directly associated

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with HDL-cholesterol.79 Furthermore, circulating lactof-errin concentration was associated with vascular func-tion in obese subjects with altered glucose tolerance.Two non synonymous LTF gene polymorphisms thatproduce two aminoacid changes in the N-terminal regionwere associated with dyslipidemia according to glucose-tolerance status.79

The concentration of all these proteins and peptides withLPS-neutralizing effect were decreased in metabolic disor-ders associated with insulin resistance and obesity. Thus,the high LBP and endotoxin concentrations could be mark-ers of an unbalance of the innate immune system.

Bu" ering E#ciency HypothesisThe evidences reviewed here led us to propose the buff-ering efÞciency hypothesis (Þgure 1). LPS is an impor-tant factor that might produce insulin resistance andobesity in humans. Chronic low-grade inßammation andassociated insulin resistance might be viewed in the con-text of an unbalanced innate immune system. A de-creased production of anti-LPS proteins and peptideswere associated with insulin resistance, obesity, vasculardysfunction, hepatic dysfunction and dyslipidemia. Apartial lost in the buffering efÞciency of LPS could in-crease its negative effects on metabolism. Furthermore,insulin resistance might result in a decreased concentra-tion of those proteins that buffer LPS. It is well knownthat adiponectin production by the adipose tissue is de-creased under insulin resistance and inßammatory con-ditions. Neutrophils also lose antimicrobial efÞciency ininsulin resistant conditions, decreasing the production oflactoferrin, BPI and other antimicrobial proteins. Neu-trophil activity may be restored by controlling hypergly-cemia using insulin.80,81 Stegenga et al reported that hy-perglycemia impaired neutrophil degranulation inhumans after intravenous endotoxin administration.82

Impairment of neutrophil function was associated with apoor metabolic proÞle in subjects with type 2 diabetes,including a decreased neutrophil deformability and a highproduction of reactive oxygen species and proinßamma-tory cytokines.83-85 High PKB (a major downstream PI3Keffector) activity was found to promote neutrophil andmonocyte development/proliferation.86 In this sense, in-sulin resistance and a low grade inßammatory state po-tentiate each other, producing a vicious cycle, strength-ened by an unbalanced innate immune system.

ConclusionsThere is now strong evidence that type 2 diabetes and themetabolic syndrome are associated with a low-grade in-ßammatory state associated with an unbalanced innateimmune system. This low-grade inßammatory state istriggered by a continuous exposure to external insultssuch as reactive oxygen species (ROS), fatty acids, AG-Es and LPS. Metabolic concentrations of plasma LPSare associated with insulin resistance and obesity in ani-mal models, and this increase in plasma LPS could becaused by intestinal translocation of LPS from Gram-negative bacteria present in gut ßora. High fat diet couldcontribute to this increased LPS translocation from in-testine into the bloodstream.

LPS stimulates the release of antimicrobial proteins (by neutrophils and by epithelial cells from the lung, liverand adipose tissue) which also protect from other inju-ries such as reactive oxygen species and AGEs. A higherefÞciency (response and release) in this process could al-low a greater neutralizing effect of LPS. On the otherhand, insulin action is an important factor in the devel-

Figure 1. The effects of chronic activation of the innate immunesystem by external insults in LPS-neutralizing proteins and metabolic disorders


83

opment and maintenance of neutrophil function and efÞ-ciency. Thus, a continuous exposure to metabolic con-centrations of plasma LPS could begin a vicious cycle,weakening the innate immune system and increasingproinß ammatory cytokines and ROS due to a partial in-efÞciency of the innate immune system. As a conse-quence, the decreased protection in front of LPS chal-lenge would increase metabolic disturbances. Accordingto the buffering efÞciency hypothesis, an increased efÞ-ciency of the innate immune system attenuates metabol-ic endotoxemia, and decreases thereby the negative ef-fects of LPS on insulin sensitivity and metabolism.

Acknowledgements:CIBEROBN Fisiopatología de la Obesidad y Nutrición.This work was partially supported by research grantsfrom the Ministerio de Educación y Ciencia (SAF2008-0273). ■

Declaration of potential con!icts of interestNo disclosures.

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6. Festa A, D’Agostino R, Jr., Howard G, Mykkanen L, Tracy RP, Haffner SM.Chronic subclinical infl ammation as part of the insulin resistancesyndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102:42-7.

7. Fernandez-Real JM, Ricart W. Insulin resistance and chroniccardiovascular infl ammatory syndrome. Endocr Rev. 2003;24:278-301.

8.Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link betweeninsulin resistance, obesity and diabetes. Trends Immunol. 2004;25:4-7.

9.Hotamisligil GS. Inflammatory pathways and insulin action. Int J Obes RelatMetab Disord. 2003;27 Suppl 3:S53-5.

10. Marette A. Mediators of cytokine-induced insulin resistance in obesity andother infl ammatory settings. Curr Opin Clin Nutr Metab Care.2002;5:377-83.

11. Garg R, Tripathy D, Dandona P. Insulin resistance as a proinflammatorystate: mechanisms, mediators, and therapeutic interventions. Curr DrugTargets. 2003;4:487-92.

12. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces insulin resistancein 3T3-L1 adipocytes and is, like IL-8 and tumor necrosis factor-alpha,overexpressed in human fat cells from insulin-resistant subjects. J BiolChem. 2003;278:45777-84.

13. Stephens JM, Lee J, Pilch PF. Tumor necrosis factor-alpha-induced insulinresistance in 3T3-L1 adipocytes is accompanied by a loss of insulin receptor substrate-1 and GLUT4 expression without a loss of insulin receptor-mediated signal transduction. J Biol Chem. 1997;272:971-6.

14. Krogh-Madsen R, Plomgaard P, Moller K, Mittendorfer B, Pedersen BK.Infl uence of TNF-alpha and IL-6 infusions on insulin sensitivity andexpression of IL-18 in humans. Am J Physiol Endocrinol Metab.2006;291:E108-14.

15. Fasshauer M, Kralisch S, Klier M, Lossner U, Bluher M, Chambaut-GuerinAM, et al. Interleukin-6 is a positive regulator of tumor necrosis factor alpha-induced adipose-related protein in 3T3-L1 adipocytes. FEBS Lett.2004;560:153-7.

16. Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6 induces cellularinsulin resistance in hepatocytes. Diabetes. 2002;51:3391-9.

17. He J, Usui I, Ishizuka K, Kanatani Y, Hiratani K, Iwata M, et al. Interleukin-1alpha inhibits insulin signaling with phosphorylating insulin receptor substrate-1 on serine residues in 3T3-L1 adipocytes. Mol Endocrinol.2006;20:114-24.

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Practical considerations

• Elevated circulating endotoxemia markers (LBP)and decreased LPS-neutralizing proteins (BPIand LTF) could reflect metabolic endotoxemia as-sociated with insulin resistance.

• These markers may help to predict the develop-ment of type 2 diabetes and cardiovascular di-sorders. Also, an increased efficiency of the inna-te immune system is associated with aninsulin-sensitive profi le in healthy subjects.

• External administration of LPS neutralizing pepti-des (synthetic cationic peptides) may be helpfulto stop the inflammation-insulin resistance vicio-us cycle and to recover the efficiency of the inna-te immune system.

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24. Raetz CR, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem.2002;71:635-700.

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32. Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innateimmunity and fatty acid-induced insulin resistance. J Clin Invest.2006;116:3015-25.

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36. Cani PD, Neyrinck AM, Fava F, Knauf C, Burcelin RG, Tuohy KM, et al.Selective increases of bifi dobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia. Diabetologia. 2007;50:2374-83.

37. Chung S, Lapoint K, Martinez K, Kennedy A, Boysen Sandberg M,McIntosh MK. Preadipocytes mediate lipopolysaccharide-induced infl ammation and insulin resistance in primary cultures of newlydifferentiated human adipocytes. Endocrinology. 2006;147:5340-51.

38. Poulain-Godefroy O, Froguel P. Preadipocyte response and impairment ofdifferentiation in an infl ammatory environment. Biochem. Biophys. ResCommun. 2007;356:662-7.

39. van Furth AM, Verhard-Seijmonsbergen EM, Langermans JA, van DisselJT, van Furth R. Anti-CD14 monoclonal antibodies inhibit the productionof tumor necrosis factor alpha and interleukin-10 by human monocytes stimulated with killed and live Haemophilus infl uenzae or Streptococcuspneumoniae organisms. Infect Immunol. 1999;67:3714-8.

40. Lee JD, Kato K, Tobias PS, Kirkland TN, Ulevitch RJ. Transfection of CD14into 70Z/3 cells dramatically enhances the sensitivity to complexes of lipopolysaccharide (LPS) and LPS binding protein. J Exp Med. 1992;175:1697-705.

41. Bazil V, Strominger JL. Shedding as a mechanism of down-modulationof CD14 on stimulated human monocytes. J Immunol. 1991;147:1567-74.

42. Landmann R, Zimmerli W, Sansano S, Link S, Hahn A, Glauser MP,Calandra T. Increased circulating soluble CD14 is associated with highmortality in gram-negative septic shock. J Infect Dis. 1995;171:639-44.

43. Haziot A, Rong GW, Bazil V, Silver J, Goyert SM. Recombinant solubleCD14 inhibits LPS-induced tumor necrosis factor-alpha production by cells in whole blood. J Immunol. 1994;152:5868-76.

44. Schutt C, Schilling T, Grunwald U, Schonfeld W, Kruger C. Endotoxin-neutralizing capacity of soluble CD14. Res Immunol. 1992;143:71-8.

45. Haziot A, Rong GW, Lin XY, Silver J, Goyert SM. Recombinant solubleCD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide). J Immunol. 1995;154:6529-32.

46. Frey EA, Miller DS, Jahr TG, Sundan A, Bazil V, Espevik T, et al. SolubleCD14 participates in the response of cells to lipopolysaccharide. J ExpMed. 1992;176:1665-71.

47. Read MA, Cordle SR, Veach RA, Carlisle CD, Hawiger J. Cell-free poolof CD14 mediates activation of transcription factor NF-kappa B by lipopolysaccharide in human endothelial cells. Proc Natl Acad Sci USA.1993;90:9887-91.

48. Troelstra A, Giepmans BN, Van Kessel KP, Lichenstein HS, Verhoef J, VanStrijp JA. Dual effects of soluble CD14 on LPS priming of neutrophils.J Leukoc Biol. 1997;61:173-8.

49. Wurfel MM, Hailman E, Wright SD. Soluble CD14 acts as a shuttle in theneutralization of lipopolysaccharide (LPS) by LPS-binding protein and reconstituted high density lipoprotein. J Exp Med. 1995;181:1743-54.

50. Kitchens RL, Wolfbauer G, Albers JJ, Munford RS. Plasma lipoproteinspromote the release of bacterial lipopolysaccharide from the monocyte cell surface. J Biol Chem. 1999;274:34116-22.

51. Fernandez-Real JM, Lopez-Bermejo A, Castro A, Broch M, Penarroja G,Vendrell J, et al. Opposite relationship between circulating soluble CD14concentration and endothelial function in diabetic and nondiabetic subjects. Thromb Haemost. 2005;94:615-9.

52. Fernandez-Real JM, Broch M, Richart C, Vendrell J, Lopez-Bermejo A,Ricart W. CD14 monocyte receptor, involved in the inflammatory cascade,and insulin sensitivity. J Clin Endocrinol Metab. 2003;88:1780-4.

53. Fernandez-Real JM, Lopez-Bermejo A, Broch M, Vendrell J, Richart C,Ricart W. Circulating soluble CD14 monocyte receptor is associated withincreased alanine aminotransferase. Clin Chem. 2004;50:1456-8.

54. Myc A, Buck J, Gonin J, Reynolds B, Hammerling U, Emanuel D. The levelof lipopolysaccharide-binding protein is signifi cantly increased in plasma inpatients with the systemic infl ammatory response syndrome. Clin DiagnLab Immunol. 1997;4:113-6.

55. Tobias PS, Soldau K, Ulevitch RJ. Identification of a lipid A binding site inthe acute phase reactant lipopolysaccharide binding protein. J Biol Chem. 1989;264:10867-71.

56. Hailman E, Lichenstein HS, Wurfel MM, Miller DS, Johnson DA, Kelley M,et al. Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med. 1994;179:269-77.

57. Wurfel MM, Kunitake ST, Lichenstein H, Kane JP, Wright SD.Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med.1994;180:1025-35.

58. Fenton MJ, Golenbock DT. LPS-binding proteins and receptors. J LeukocBiol. 1998;64:25-32.

59. Gubern C, Lopez-Bermejo A, Biarnes J, Vendrell J, Ricart W, Fernandez-Real JM. Natural antibiotics and insulin sensitivity: the role of bactericidal/permeability-increasing protein. Diabetes. 2006;55:216-24.

60. Menzaghi C, Trischitta V, Doria A. Genetic influences of adiponectin oninsulin resistance, type 2 diabetes, and cardiovascular disease. Diabetes.2007;56:1198-209.

61. Peake PW, Shen Y, Campbell LV, Charlesworth JA. Human adiponectinbinds to bacterial lipopolysaccharide. Biochem. Biophys. Res Commun.2006;341:108-15.

62. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors.Endocrinol Rev. 2005;26:439-51.

63. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7:941-6.

64. Tomas E, Tsao TS, Saha AK, Murrey HE, Zhang Cc C, Itani SI, et al.Enhanced muscle fat oxidation and glucose transport by ACRP30 globular domain: acetyl-CoA carboxylase inhibition and AMP-activated protein kinase activation. Proc Natl Acad Sci USA. 2002;99:16309-13.


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66. Stumvoll M, Tschritter O, Fritsche A, Staiger H, Renn W, Weisser M, et al.Association of the T-G polymorphism in adiponectin (exon 2) with obesityand insulin sensitivity: interaction with family history of type 2 diabetes.Diabetes. 2002;51:37-4.

67. Menzaghi C, Ercolino T, Di Paola R, Berg AH, Warram JH, Scherer PE, et al.A haplotype at the adiponectin locus is associated with obesity and otherfeatures of the insulin resistance syndrome. Diabetes. 2002;51:2306-12.

68. Gazzano-Santoro H, Parent JB, Conlon PJ, Kasler HG, Tsai CM, Lill-Elghanian DA, Hollingsworth RI. Characterization of the structural elementsin lipid A required for binding of a recombinant fragment of bactericidal/permeability-increasing protein rBPI23. Infect Immunol. 1995;63:2201-5.

69. Capodici C, Chen S, Sidorczyk Z, Elsbach P, Weiss J. Effect oflipopolysaccharide (LPS) chain length on interactions of bactericidal/permeability-increasing protein and its bioactive 23-kilodalton NH2-terminal fragment with isolated LPS and intact Proteus mirabilis and Escherichia coli. Infect. Immunology. 1994;62:259-65.

70. Huang K, Fishwild DM, Wu HM, Dedrick RL. Lipopolysaccharide-inducedE-selectin expression requires continuous presence of LPS and is inhibited by bactericidal/permeability-increasing protein. Infl ammation.1995;19:389-404.

71. Horwitz AH, Leigh SD, Abrahamson S, Gazzano-Santoro H, Liu PS,Williams RE, et al. Expression and characterization of cysteine-modifi edvariants of an amino-terminal fragment of bactericidal/permeability-increasing protein. Protein Expr Purif. 1996;8:28-40.

72. Schneider JJ, Unholzer A, Schaller M, Schafer-Korting M, Korting HC.Human defensins. J Mol Med. 2005;83:587-95.

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75. Otsuki K, Yakuwa K, Sawada M, Hasegawa A, Sasaki Y, Mitsukawa K,et al. Recombinant human lactoferrin has preventive effects on

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Position document

Consensus statement on continuous glucose monitoring*Consenso sobre el uso de la monitorización continua de glucosaM. Ruiz de Adana, M. Rigla1

Hospital Universitario “Carlos Haya”, Málaga. 1Hospital de Sabadell. CSPT. CIBER-BBN. Sabadell (Barcelona); in representation of the Grupode Nuevas Tecnologías de la Sociedad Española de Diabetes (New Technologies Group of the Spanish Diabetes Society)

Others members of the work team:F.J. Ampudia-Blasco, Hospital Clínico (Valencia); R. Barrio, Hospital Ramón y Cajal (Madrid); C. de la Cuesta, Hospital VirgenMacarena (Sevilla); A. Chico, Hospital de la Santa Creu i Sant Pau (Barcelona); M. Giménez, Hospital Clínic (Barcelona);M.J. Goñi, Hospital de Navarra (Pamplona); A. Jara, Hospital Gregorio Marañón (Madrid); I. Levy, Hospital Clínic (Barcelona);P. Martín-Vaquero, Hospital La Paz (Madrid); F. Merino, Hospital La Fe (Valencia); M.J. Picón, Hospital Virgen de la Victoria(Málaga); J. Prieto, Hospital de Cabueñes (Gijón); M. Rodríguez-Rigual, Hospital Clínico Miguel Servet (Zaragoza); F. Vásquez, Hospital de Cruces (Bilbao); P. Vidal-Ríos, Endocrinology Center Dr. Pablo Vidal Ríos (A Coruña).

IntroductionTaking in account the extraordinary technological devel-opment that the continuous sensors of interstitial glucosehad during the last years, the New Technologies Groupof the Spanish Diabetes Society deemed it necessary todraw up a consensus document as regards to its possibleusefulness in the daily clinical practice. The continuousglucose monitoring system (CGMS) are exclusivelymentioned in this document, which measure the concen-tration of the latter in the interstitial ßuid of the subcuta-neous cell tissue.

Two types of systems are available at the Spanish marketat present: a) the micro-dialysis systems with externalsensor, as the GlucoDay® (Menarini Diagnostics, Flor-ence, Italy) and b) the subcutaneous in situ sensor sys-tems, as the CGMS (continuous glucose monitoring sys-tem), the Guardian®, the Guardian real time® or the

Paradigm RT® (Medtronic MiniMed, Northridge, CA);the monitor Navigator® (Abbott Laboratories, Alameda,CA) is pending of commercialization, probably for2009; Þnally, the Seven System® (Dex-Com Inc., San Di-ego, CA) is only available in the United States. All thesystems count with amperimetric sensors that quantifythe generation of sensors produced after the oxidation ofthe glucose by the glucose oxidase enzyme. These elec-trodes have a half-life of only 3-7 days, mainly due tothe enzymatic progressive degradation. The in situ sen-sor systems are the most used ones, and are cataloguedas “minimally invasive”. The sensor is usually insertedin the subcutaneous cell tissue of the abdominal wall, thearms or the thighs and the generated signal is collectedand processed in an external monitor. They require sev-eral calibrations daily (more than two), that are per-formed by means of the introduction of the capillary gly-cemia in the monitor.

None of the available sensors at present have the preci-sion of the usual capillary glucometers. This limitation isdue, in part, to the low concentration of glucose in theinterstitial ßuid, to the own dynamic of the glucose andthe inherent delays to the measurement system. For thisreason, at present they are approved as a complement tothe measurement of the capillary glycemia.

Basically, we can classify them in retrospective readingsystems (Holter type) and reading systems in real time:

Date received: January 5th 2009Date accepted: January 13th 2009*Published in Av Diabetol Published Ahead of Print February 13, 2009.Available at www.sediabetes.org

Correspondence:M. Ruiz de Adana. Endocrinology and Nutrition Service. Hospital Universitario“Carlos Haya”. Avda. Carlos Haya, s/n. 29010 Málaga. Email: [email protected]

List of acronyms quoted in the text:CGMS: continuous glucose monitoring systems; CSII: continuous subcutaneous insulin infusion; HbA1c: glycosylated hemoglobin.

Position documentContinuous glucose monitoring. M. Ruiz de Adana, et al.

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• Retrospective reading systems (Holter type). Theglucose data are downloaded at the end of the recordusing all the calibration points for its adjustment. Thecorrelation with the capillary glycemia values are in theregion of r= 0.8.1 The clinical precision estimated bymeans of the point & rate error grid analysis, offers usperfectly adequate information for the decisions taking,it is placed in the region on 70%.

• Reading systems in real time. The data are generatedas from an initial latency period and the Þrst calibration.They count with alarm systems for hypoglycemia andhyperglycemia and some models count with predictivealarms. In euglycemia situation, the means of the abso-lute difference between the differences of each pair ofvalues corresponding to the interstitial capillary-glucoseglycemia is in the region of 0.9 mmoL/L, suggesting arelative difference of 15%.2 The clinical precision esti-mated by means of point & rate error grid analysis is of75% for the Medtronic and Abbott systems, and be-tween 64 and 88% for the Menarini system.2,3

Clinical resultsTaking in account its recent development, we do notcount with sufÞcient clinical studies that prove the efÞ-ciency at mean-long term.

Retrospective reading systemsIn general, the clinical studies carried out with theCGMS® of Medtronic offer different results. Some au-thors observe relevant reductions of glycosylated hemo-globin (HbA1c) and others do not. It has to be taken intoaccount that the studies differ clearly regarding to the de-sign, frequency of use, duration, studied population, etc.,which difÞcult more the obtaining of consistent conclu-sions. Probably, the most relevant clinical study has beenrecently published. It shows a clear use beneÞt each 4weeks with CGMS in pregnant women with diabetes(T1D and T2D) as regards to the reduction of the HbA1c

and a lower incidence of macrosomy.4 However, its ef-fect on the presence of hypoglycemias did not show arelevant beneÞt and, moreover, a tendency to a highernumber of caesarean sections could be observed as well as newborns of low weight considering the gestationalage in the experimental group.4

Reading systems in real timeFour randomized studies have been published, whichhave successively provided the following conclusions: a)

the glucose sensors in real time might improve the levelsof HbA1c in children and adults with inadequate glyc-emic control,5 as they achieve a reduction of the HbA1c

concentrations when its use is equal or higher than 3-4days per week;6 b) they might reduce the hyperglycemiatimes (23%) and hypoglycemia times (21%), as well asthe night hypoglycemias (38%),7 and c) in the greatestpublished series performed in patients with a suboptimalmetabolic control, a reduction of the HbA1c has been in-formed of 0.5% in adults (>24 years of age), which how-ever was not observed in children, adolescents or adultsunder 24 yeas of age.8 Systems in real time were used in this study from three different industries (Medtronic,Abbott and DexCom) on a total of 322 patients distrib-uted in 10 sites and who were administered with insulin therapy both in multiple doses and in continuous subcu-taneous insulin infusion (CSII). There were no differenc-es in the number of serious hypoglycemias.

Possible uses of the continuous glucosemonitoring (CGMS)There are clinical situations in which the CGMS mightprovide valuable information to conÞrm a suspicion di-agnosis, or to be helpful in the therapeutic adjustment. Inthis paper we have chosen to list the clinical situations inwhich the use of the CGMS might have a special inter-est, since that every diabetic patient at some moment ofthe process might be an assessment subsidiary of contin-uous monitoring of interstitial glucose (table 1).

Recently, in its annual recommendations, the AmericanDiabetes Association (ADA) stated the following afÞrma-tions: a) the continuous glucose monitoring, togetherwith the intensive insulin treatment might be a useful toolto reduce the HbA1c more in screened adult patients (>25years of age) with T1D (evidence A level) b) though thereduction evidence of the HbA1c is lower in children, ado-lescents and young adults with diabetes, the CGMSmight also be useful in these patients, and the beneÞts arecorrelated with the level of systems use (evidence C lev-el) and c) the CGMS might suppose a complementarytool in patients with unnoticed hypoglycemias and/or fre-quent hypoglycemia events (evidence E level).9

ConclusionsThe glucose monitoring systems in subcutaneous tissueoffer the possibility of a continuous and dynamic assess-

Av Diabetol. 2009;25:96-8

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ment of the interstitial glucose levels. Even with less pre-cise systems than the capillary glycemia meters, theyhave proved certain beneÞts in the improvement of theglycemic control (HbA1c) and the reduction of the glyc-emic variability in patients with T1D under intensivetreatment. With the current scientiÞc evidence, betterclinical results are foreseen regarding to the glucosemonitoring systems in real time in motivated patients,adults and who have received a correct diabetologicaleducation for the use of these systems in order to avoid

inappropriate acts at discrepancy moments with the si-multaneously measured values of capillary glycemia.

Methodologically well set out clinical studies are stillnecessary to assess the impact of these systems on thecontrol level (HbA1c) and other metabolic variables, asthe frequency of the hypoglycemias, the glycemic vari-ability, the exposure time to the hyperglycemias, etc.,about the perception of the quality of life that might al-low us to carry out approaches to the cost-effectivenessand improve the knowledge about the range of possibleclinical indications. ■

Declaration of potential con!ict of interestsM. Ruiz de Adana received fees for conferences and/or consul-tancy by Abbott, Lilly, Medtronic, Roche, Novalab, Grupo ArsXXI de Comunicación and Servier, and has taken part in clini-cal trials totally or partially Þnanced by GSK, Novartis, PÞzerand sanoÞ-aventis. M. Rigla took part in clinical trials totallyor partially Þnanced by Novo Nordisk, PÞzer and sanoÞ-avent-is.

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Evaluating the clinical accuracy of two continuous glucose sensors using continuous glucose-error grid analysis. Diabetes Care. 2005;28:2412-7.

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Table 1. Clinical and experimental situations in whichthe continuous glucose monitoring systems present special interest

1. Diagnosis confirmation and hypoglycemia treatment:

• Unnoticed hypoglycemias

• Night hypoglycemias

• Hypoglycemias in the non-diabetic patient

2. Therapeutic adjustments in patients who do not achievethe glycemic control targets:

• Discrepancies between the glycosylated hemoglobin (HbA1c) andthe capillary glycemia values

• Help in the therapeutic decisions taking

• Pregestational diabetes

– Pregnancy preparation

– Ongoing pregnancy

3. As therapeutic education tool:

• Impact of additional intakes about the glycemic profile

• Practice of physical exercise

• Intercurrent situations

4. Diabetes and hospitalization:

• Treatment units of critical and/or coronary patients

• Pancreatic tissue transplant

5. In clinical investigation:

• Study of the glycemic profile variability

• Comparison of the effect on the glycemia of several therapeuticinterventions (drugs, education programs, etc.)

• Experimentation in closed loop systems


99

IntroductionType 2 diabetes mellitus (T2D), has become one of themost serious health problems of our times, and its pro-portions are already epidemic in most of the world.1

Therefore, there is an increasing interest in identifyingindividuals with high risk of diabetes in order to planprevention strategies, as several studies have demonstrat-ed that with changes in life style and/or medication it is possible to prevent or at least delay the onset of the dis-ease.2-5 The progression from the normoglycemia to thediabetes might take several years, which entails interme-

Seminars on diabetesPREDIABETES

Epidemiology of prediabetes in SpainEpidemiología de la prediabetes en EspañaS. Valdés,1 E. Delgado2

1Endocrinology and Nutrition Service. Hospital Univesitario “Carlos Haya”. Málaga, CIBER of Diabetes and Associated Metabolic Diseases (CIBERDEM).2Endocrinology and Nutrition Service. Hospital Universitario Central de Asturias. Oviedo

AbstractThis review analyses the prevalence of prediabetes in Spain, basedon various epidemiological cross-sectional studies conducted in ourcountry and the prospective data available on the incidence of T2Din these categories. The analysed data show a prevalence of im-paired glucose tolerance (IGT) between 10-17% and a prevalenceof impaired fasting glucose (IFG) between 6-12% in the Spanishpopulation, comparable as those reported in other European popula-tions or in USA. These prevalences apparently have been stable overthe last decade. By applying the revised criteria of the ADA 2003,IFG prevalence triples to 20-30%. Prospective studies have shownthe IGT and IFG are both highly predictive of diabetes and its effectis cumulative, being the risk maximum for individuals with combinedIGT-IFG. Only a single prospective study in our population has shownthat reducing the cut-off point for defining IFG as currently recom-mended by the ADA optimises the sensitivity-specificity balance inpredicting diabetes.

Keywords: prediabetes impaired fasting glucose, impaired glucosetolerance, epidemiology, prevalence, Spain.

ResumenEn esta revisión se analiza la prevalencia de prediabetes en Españautilizando varios estudios epidemiológicos transversales realizadosen nuestro país, así como los datos prospectivos disponibles de in-cidencia de diabetes tipo 2 en estas categorías. Los datos analiza-dos muestran unas prevalencias de intolerancia a la glucosa (ITG) deentre el 10 y el 17% y de glucemia basal alterada (GBA) de entre el6 y el 12% en la población española, comparables a las referidas enotras poblaciones europeas o en Estados Unidos. Estas prevalencias,aparentemente, se han mantenido estables en la última década. Alaplicar los criterios revisados de la American Diabetes Association(ADA) 2003, la prevalencia de GBA se triplica, hasta el 20-30%.Los estudios prospectivos han demostrado que tanto la ITG como laGBA son altamente predictivas de diabetes, y que su efecto es acu-mulativo, siendo el riesgo máximo en los individuos con GBA e ITGcombinadas. Sólo un estudio en nuestra población ha mostrado quereducir el punto de corte para definir la GBA según las recomenda-ciones actuales de la ADA optimiza el balance sensibilidad-especifi-cidad en la predicción de diabetes.

Palabras clave: prediabetes, glucemia basal alterada, intoleranciaa la glucosa, epidemiología, prevalencia, España.

Date received January 13th 2009 Date accepted: January 23rd 2009

Correspondence:S. Valdés. Endocrinology and Nutrition Service. Hospital Universitario«Carlos Haya». Plaza del Hospital Civil, s/n. 29009 Málaga. Email: [email protected]

List of acronyms quoted in the text:ADA: American Diabetes Association; CVD: cardiovascular disease; DECODE:Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe; EASD: European Association for the Study of Diabetes; IDF: International Diabetes Federation; IFG: Impaired fasting glycemia; IGT: impaired glucosetolerance; NHANES: National Health and Nutrition Examination Survey; OGOT:oral glucose overload test; T2D: type 2 diabetes mellitus; WHO: World HealthOrganization.

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diate phases of glycemia logically. Two diagnostic cate-gories are included here: the impaired fasting glucose(IFG) and the impared glucose intolerance (IGT).

“Prediabetes” is an old term that was coined by theWorld Health Organization (WHO) as a retrospective di-agnosis, that described the condition of a person previ-ous to the diabetes diagnosis.6 A radically different deÞ-nition has been recently introduced in the United Statesto describe jointly the individuals with IFG and / or IGT,stressing their high risk of developing diabetes in the fu-ture.7 Since then, the use of this term has been general-ized in the scientiÞ c literature.

The prediabetes prevalence, and the associated diabetesrisk, might vary widely in different populations,8 havingits particular study a special interest in the Spanish pop-ulation. In this review, we analyse the prediabetes preva-lence found in the different transversal epidemiologicalstudies performed in our country, as well as the availableprospective data as regards to the incidence of T2D inthese categories.

IFG and IGT. Concept and classi$ cationThe IGT, considered a “classic” prognosis factor of T2D,was introduced by the National Diabetes Data Group in1979 with the objective of deÞning an enhanced riskphase of progression to diabetes in which, however, thereversion to normality was also possible.9 The increasedrisk to develop a cardiovascular disease (CVD) in this in-termediate phase was also recognized. Moreover, thiscategory and its deÞnition are incorporated as clinicaldysglycemia class in the WHO classiÞcation of 1980.10

The term refers to the glycemia concentrations between 140 and 200 mg/dL, 2 hours after an oral glucose over-load (OGO), which are values that are clearly over thenormality but below the limit in order to deÞne diabetes.

The concept IFG was introduced in the report of theAmerican Diabetes Association (ADA) in 199711 withthe objective of deÞning the zone between the higherlimit for the normal baseline glycemia and the lowerlimit of the baseline glycemia associated to diabetes, asanalogue categories to the IGT for the baseline glyc-emia, deÞ ning it as a fasting glycemia concentration be-tween 110 and 126 mg/dL. This definition was alsoadopted in the WHO report of 1999.12 In the year 2003,the ADA decided to reduce the lower limit in order to de-

Þne the IFG to 100 mg/dL, optimizing its sensitivity andspeciÞcity to predict the diabetes in this way.13 This de-cision has been controversial, as it suggests an increaseranging between 2 to 4 times in the prevalence of IFG,which might lead to a “predibetes pandemia”.14 The Eu-ropean Diabetes Epidemiology Group (EDEG) – sub-group of the European Association for the Study of Dia-betes (EASD) – and a consultancy group of theInternational Diabetes Federation (IDF) / WHO havepublished reports recently recommending not to change the deÞnition of the IFG and to keep the original one(between 110 and 126 mg/dL),15,16 so at present there aretwo different deÞnitions for the IFG (table 1).

Prediabetes prevalence in SpainOGOT have been performed in several studies with apopulation basis to selected samples of the general pop-ulation with the main objective of assessing the T2Dprevalences. These studies have additionally added dataabout the prevalence of IFG and IGT (table 2).

In the transversal study performed in the province ofLeón through a clinical survey and OGO, in which 572individuals have been included, the IGT prevalence wasof 10.3%.17 In the study of Lejona (Vizcaya), in which862 individuals have been studied, older than 30 yearsand screened randomly, through OGO, the prevalence ofIGT was of 10.4%.18 In another population and transver-sal study performed in Aragón, with a sample screeningof 935 subjects between 10 and 74 years of age and inwhich OGO was carried out in all of them, except to the

Table 1. Values of plasmatic glycemia for thediabetes mellitus diagnosis and other disglycemia categories (WHO 1999;12 ADA 200313)

Category Test

Baseline Glycemia(mg/dL)

Glycemia after 2 hoursof the OGO (mg/dL)

Normal 110 WHO100 ADA

<140 WHO, ADA

IFG 110-125 WHO100-125 ADA

–

IGT – 140-200 WHO, ADA

DM >126 WHO, ADA >200 WHO, ADA

ADA: American Diabetes Association; DM: diabetes mellitus; IFG: impaired fastingglucemia: IGT: impaired glucose tolerance, WHO: World Health Organization; OGO:oral glucose overload.

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known diabetic patients, the IGT prevalence was of7.2%.19 In the study performed in Catalonia, which in-cluded 3839 subjects aged 30-89, 2214 underwent theOGOT, the IGT prevalence was 11.9%.20 In the Guíastudy performed in Gran Canaria, one of the highestprevalences of DM and IGT were found in the Caucasianpopulation. A total of 691 subjects older than 30 yearswere screened through a stratiÞed sampling by age andsex in the town of Guía; a survey was done to all ofthem, as well as an exploration and an OGO. The IFGand IGT were of 8.8 and 17.1%, respectively.21 In theSIRS (Spanish Insulin Resistance Study) 2949 patientswere included with ages ranging between 34 and 69,screened from seven Spanish cities (Arévalo, Talavera dela Reina, Guadalajara, A Coruña, Avilés, Vic, Alicanteand Mérida), resulting the global prevalences of IFG andIGT of 7.6 and 9.4%, respectively.22 In the Pizarra studydone at (Málaga), after studying 1,226 persons aged from18 to 65 through surveys, exploration and OGO in 982cases, the prevalence of IFG was of 12.4% and 11.5% ofIGT.23 In the Asturias study, carried out on 1034 individ-uals aged from 30 to 75 who have been screened throughtwo stage cluster samplings which include the wholepopulation of the Asturian community. The OGO wasapplied in all the cases except in the known diabetic pa-tients. The IGT prevalence was of 13.2% and the IFG of

7.6%.24 In a recent analysis, the effect of the criteriachanges for IFG of the ADA 2003 in this population wasevaluated, observing that the prevalence of the IFG wastrebled becoming 22.5%.25 In the city of Yecla (Murcia),286 persons were studied, from which 261 underwentthe OGOT , resulting an IGT prevalence of 13.2% whilethe isolated IFG was of 0.2%.26 In the province of Giro-na, a sample of 1748 persons were analysed aged 25 to74, representative of the general population, through de-termination of fasting glycemia in venous blood. An IFGprevalence of 8.6% was found.27 Finally, in the popula-tion study performed at Telde (Gran Canaria), which in-cluded 1030 individuals aged 30 to 82 who have beenscreened randomly and underwent a survey, explorationand OGO, the prevalences of IGT and isolated IFG wereof 11.4 and 2.8%, respectively.28 In this study, the predi-abetes prevalences with revised criteria of the ADA 2003have also been described, being the prevalence of theisolated IFG, isolated IGT and combined IFG and IGTof 14.6, 6.5 and 5.3%, respectively.29

In the XIX Congress of the Diabetes Spanish Society(SED), held in February 2008 at Sevilla, preliminary da-ta have been submitted on the diabetes prevalence stud-ies of Valencia and Madrid. The one done in Valencia isa transversal study performed in the twenty-two health

Table 2. Global prevalences of glucose intolerance (IGT) and impaired fasting glucemia (IFG) in the Spanish populationAge (years) n IGT

(%)IFG (%)

WHO criteria(110-125 mg/dL)

ADA criteria(100-125 mg/dL)

Franch Nadal et al.17 (León 1992) >18 572 10.3 – –

Bayo et al.18 (Lejona 1993) >30 862 10.4 – –

Tamayo et al.19 (Aragón 1997) 10-74 935 7.2 – –

Castell et al.20 (Catalonia 1999) 30-89 3,839 11.9 – –

De Pablos et al.21 (Guía 2001) >30 691 17.1 8.8 –

Lorenzo et al.22 (SIRS 2001) 34-69 2,949 9.4 7.6 –

Soriguer et al.23 (Pizarra 2002) >18 1,226 11.5 12.4 –

Botas et al.24,25 (Asturias 2003) 30-75 1,034 13.3 7.6 22.5

Martínez Candela et al.26 (Yecla 2004) >30 286 13.2 0.2* –

Masiá et al.27 (Girona 2004) 25-74 1,748 – 8.6 –

Boronat et al.28,29 (Telde 2005) 30-82 1,030 11.4 2.8* 19.9

Catalá et al.30 (Valencia 2008)** 18-88 668 10.8 – 29.7

Zorrilla et al.31(Madrid 2008)** >18 537 – 5.9 –

*Prevalences referred to isolated IFG. **Preliminary data.

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departments of the Community of Valencia. Results of2,092 subjects were presented. Applying the revised cri-teria of the ADA 2003: a prevalence of isolated IFG of23.3% is described as well as a prevalence of isolatedIGT of 4.4% and combined IFG and IGT of 6.4%.30 Inthe diabetes prevalence study of the Community of Ma-drid which included 2268 persons aged between 30 to 74from the databases of the health card of the Community of Madrid, using a two stage sampling clusters, a IFGprevalence of 5.9% has been documented from the fast-ing glycemia only (without OGO).31

Prospective studies of diabetesand prediabetes incidenceThe study of Lejona (Basque Country) has been duringseveral years the reference to evaluate the risk of devel-oping diabetes in subjects with prediabetes in Spain. Tenyears after this prevalence study performed in 1985, thesame population was evaluated again by using newOGOT (according to WHO criteria, 1985). The inci-dence of DM in individuals with IGT was 2%/year, be-ing this the most important diabetes prognostic factor inthis population (odds ratio: 4.17).32

Recently, a re-evaluation of the cohorts of Asturias andPizarra was completed (Málaga) (table 3). In the Astu-rias study, 700 subjects were included who took part inthe prevalence study of 1998-1999, who were re-as-sessed in 2004-2005 after a mean follow-up of 6.3 years.Only 630 subjects who did not have DM in the initialstudy had been screened in order to study the diabetesincidence, and the questionnaire was carried out again aswell as the exploration and the OGO with the obtainingof baseline venous blood and after 2 hours (WHO crite-ria 1999).

The diabetes incidences were. Five cases/1,000 inhabit-ants/year in individuals with normoglycemia. 21 cas-es/1,000 inhabitants/year in those with isolated IGT,34.7 cases/1,000 inhabitants/year in individuals with

IFG and 95.2 cases/1,000 inhabitants/year in individuals with combined IFG and IGT. In the multivariate logisticsregression analysis, the fasting glycemia and the glyc-emia 2 hours after the OGO were the most important di-abetes prognosis factors.33

In the Pizarra study, 824 individuals who took part in thetransversal study of 1997-1998, were re-evaluated (in theperiod 2003-2004) after 6 years of follow-up. The sam-ple for the incidence study included 714 subjects withinitial DM. In both studies, an OGO was performed de-termining basal glycemia and 2 hours after (WHO crite-ria 1999). The age and the presence of obesity, centralobesity and IFG and/or IGT in the initial study were rel-evant markers for the onset of T2D during the follow-up.The diabetes incidences in the different categories were: 10 cases/1,000 inhabitants/year in individuals with nor-moglycemia; 31.1 cases/1,000 inhabitants/year with iso-lated IGT, 38.1 cases/1,000 inhabitants/year with isolat-ed IFG and 66 cases/1,000 inhabitants / years in thosewith combined IFG and IGT.34

Evaluation of criteria change for IFGIn the Asturias study, the impact of the reduction of thecut point to deÞ ne the IFG to 100 mg/dL in the Spanishpopulation has been evaluated prospectively. The appli-cation of the ADA criterion for IFG (100-126 mg/dL)trebled the number of individuals with IFG. The diabetesincidence were of 3.8, 19.5 and 58.0 cases per 1,000 in-habitants / year in subjects with initial values of fastingglycemia <100 mg/dL, between 100 and 110 mg/dL and between 110 and 125 mg/dL, respectively. The inclusionof individuals with intermediate risk (in the zone 100-110 mg/dL) in the IFG deÞnition changed its prognosispositive value, as well as its speciÞcity and its sensitivityto predict diabetes of 36.5, 94.5 and 43.2% to 19.9, 77.3 and 75%, respectively. The analysis of the ROC curve,including all the levels of fasting glycemia from 64 to125 mg/dL, according to its capability to predict the dia-betes, showed that the closest point to the ideal one of

Table 3. Impacts of diabetes per 1,000 persons/year (CI of 95%) according to disglycemia clinical categories:WHO criteria 1999

Normoglycemia Isolated IGT Isolated IFG IGT + IFG

Asturias Study33 n= 630, mean follow-up 6.3 years 5.0 (2.8-8) 21 (10.9-40.4) 34.7 (14-71.5) 95.2 (54.1-167.7)

Pizarra Study34 N= 714, mean follow-up 6 years 10.0 (7.0-14.7) 31.1 (25.3-57.3) 38.1 (18.4-52.5) 66.0 (39.1-111.5)

IFG: impaired fasting glucemia; IGT: impaired glucose tolerance. WHO: World Health Organization.

Seminars on diabetesEpidemiology of prediabetes in Spain. S. Valdés, et al.

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100% of sensitivity and 100% of speciÞcity in all theglycemic range was the value 100 mg/dL. Therefore thestudy concluded that the reduction of the cut point to de-Þne the IFG optimized its capability to predict diabetesin this population25 (Þ gure 1).

ConclusionsThe different epidemiologic studies performed in ourcountry show prevalences of IGT between 10 and 17%and IFG between 6 and 12%. The values are comparableto those of the prevalence of IGT of 11.9% and IFG of10% that refer to the European population according tothe DECODE study (Diabetes Epidemiology Collabora-tive Analysis of Diagnostic Criteria in Europe), and alsoto the data of IGT prevalence of 14.9% and of 8.3% thatrefer to the population of the United States according to the national NHANES survey (National Health and Nu-trition Examination Survey) III.8 Unlike the T2D preva-lence, which seems to have increased in our country dur-ing the last decade,35 the prediabetes prevalence was keptstable apparently. This same tendency has been observedin the population of the United States.36

When applying the criteria revised by the ADA 2003, theIFG prevalence trebles up to 20-30%. The available pro-spective studies show: that both the IGT and the IFG arehighly predictive of diabetes and that its effect is cumu-lative, observing a maximum risk in the individuals with

combined IFG and IGT. The inclusion of both measure-ments allows a better stratiÞcation of the diabetes risk.Only a study showed that to reduce the cut point in orderto determine the IFG according to the ADA recommen-dations might optimize its sensitivity-speciÞcity in dia-betes prognosis in our population. By means of cohortsof bigger size and with higher representativeness in allthe Spanish population, these Þndings can be determinedbetter. ■

Declaration of potential con!ict of interestS. Valdés Hernández and E. Delgado Álvarez state that there areno conßicts of interest as regards to the content of this article.

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Parikka P, et al. Prevention of type 2 diabetes mellitus by changes inlifestyle among subjects with impaired glucose tolerance. N Engl J Med.2001;344:1343-50.

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Association. HHS, ADA warn Americans of “pre-diabetes”. Press release.27 Mar 2002. Washington, DC: DHHS, 2002. Available at: www.hhs.gov/news/press/2002pres/20020327.html (access January 8th 2009).


• Several epidemiologic studies in Spain have de-monstrated prevalence to impaired glucose tole-rance (IGT) and impaired fasting glucemia (IFG)of 10-17% and 6-12%, respectively, comparableto the one published for European and American populations.

• Both the IGTT and the IFG are highly predictableas regards to the diabetes development and itseffect is cumulative, therefore the presence ofboth increases the risk in a substantial manner.

• When applying the revised criteria of ADA 2003,the prevalence of IFG trebles up to 20-30%.However, at present there is no consensus if thisstrategy optimized the sensitivity and the specifi-city in the diabetes prognosis.

Figure 1. ROC Curve of basal glycemia in the diabetes prognosis in630 individuals aged 30-75. The closest point to the ideal one of 100%sensitivity and 100% specificity was of 100 mg/dL. Asturias Study25

Sensitivity

Speci city10

1

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

00.2 0.4 0.6 0.8

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100 mg/dL

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8. Unwin N, Shaw J, Zimmet P, Alberti KGMM. Impaired glucose tolerance andimpaired fasting glycaemia: the current status on defi nition and intervention.Diabet Med. 2002;19:708-23.

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14. Borch-Johnsen K, Colagiuri S, Balkau B, Glümer C, Carstensen B,Ramachandran A, et al. Creating a pandemic of prediabetes: the proposednew diagnostic criteria for impaired fasting glycaemia. Diabetologia. 2004;47:1396-402.

15. Forouhi NG, Balkau B, Borch-Johnsen K, Dekker J, Glumer C, Qiao Q, et al.The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group. Diabetologia.2006;49:822-7.

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19. Tamayo Marco B, Faure E, Roche Asensio MJ, Rubio Calvo E, Sánchez-Oriz E, Salvador Oliván JA. Prevalence of diabetes mellitus and impaired glucose tolerance in Aragon, Spain. Diabetes Care. 1997;20:534-6.

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21. De Pablos Velasco PL, Martínez Martín FJ, Rodríguez-Pérez F, Anía BJ,Losada A, Betancor P. The Guia Study. Prevalence and determinants ofdiabetes mellitus and glucose intolerance in Canarian Caucasian population: comparison of the ADA and the 1985 WHO criteria. Diab Med. 2001;18:235.

22. Lorenzo C, Serrano-Ríos M, Martínez-Larrad M, Gabriel R, Williams K,González-Villalpando C, et al. Was the historic contribution of Spain to theMexican gene pool partially responsible for the higher prevalence of type 2 diabetes in Mexican origin populations? The Spanish Insulin Resistance

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24. Botas P, Delgado E, Castaño G, Díaz de Greñu C, Prieto J, Díaz-CadórnigaFJ. Prevalencia de diabetes mellitus e intolerancia a la glucosa enpoblación entre 30 y 75 años en Asturias, España. Rev Clin Esp.2002;202:423-9.

25. Botas P, Valdés S, Delgado E, Álvarez F, Díaz-Cadórniga F. Does the newAmerican Diabetes Association defi nition for impaired fasting glucoseimprove its ability to predict type 2 diabetes mellitus in Spanish persons? “The Asturias Study”. Metabolism. 2008;57:399-403.

26. Martínez Candela J, Gallardo Martín A, Franch Nadal J, Romero Ortiz J,Cánovas Domíguez C, Gómez Marco R. Análisis de las alteraciones delmetabolismo hidrocarbonado en la población adulta de Yecla (Murcia).Aten Primaria. 2004;34:345-52.

27. Masiá R, Sala J, Rohlfs I, Piulats R, Manresa JM, Marrugat J; en nombrede los investigadores del estudio REGICOR. Prevalencia de diabetes mellitus en la provincia de Girona, España: estudio REGICOR. Rev Esp Cardiol. 2004;57:261-4.

28. Boronat M, Varillas VF, Saavedra P, Suárez V, Bosch E, Carillo A, et al.Diabetes mellitus and impaired glucose regulation in the Canary Islands (Spain): prevalence and associated factors in the adult population of Telde,Gran Canaria. Diabet Med. 2005;23:148-55.

29. Nóvoa FJ, Boronat M, Saavedra P, Díaz-Cremades JM, Varillas VF, LaRoche F, et al. Differences in cardiovascular risk factors, insulin resistance,and insulin secretion in individuals with normal glucose tolerance and in subjects with impaired glucose regulation: the Telde Study. Diabetes Care.2005;28(10):2388-93.

30. Catalá Bauset M, Catalá Pascual MJ, Dolz Domingo A, Lluch Verdú I, Costa E,Sáez E, et al. Prevalencia de diabetes en la Comunidad Valenciana. Datosepidemiológicos. Estudio Valencia. Av Diabetol. 2008;24 Suppl 1:45-112.

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36. Cowie CC, Rust KF, Ford ES, Eberhardt MS, Byrd-Holt DD, Li C, et al.A full accounting of diabetes and prediabetes in the US population, 1988-1994 and 2005-2006. Diabetes Care. 2008 Nov 18. [Epub ahead of print]


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IntroductionBoth the impaired fasting glucemia (IFG) as well as theimpaired glucose tolerance (IGT) make up the so-called“prediabetes”. However, in several epidemiologic stud-ies it has been proved that these two impairments corre-spond to different populations, with only a reducednumber of subjects that share both entities.1,4 This hap-pens because they have a different pathogenic mecha-nism, leading to the following differences as regards toits distribution within the population, the risk of develop-

Seminars on diabetes

Main differences between impaired fasting glucemiaand impaired glucose tolerancePrincipales diferencias entre glucemia basal alterada e intolerancia a la glucosaF.J. García SoidánCentro de Salud de Porriño (Pontevedra). Red-GEDAPS Group. Diabetes Group of SEMFYC

AbstractBoth impaired fasting glucose (IFG) as well as impaired glucose tol-erance (IGT) constitute what is known as prediabetes. Nevertheless,these two clinical situations are entities that differ significantly. Sub-jects with IFG manifest hepatic insulin resistance and a defect inearly-phase insulin secretion, whereas subjects with IGT manifestmuscle insulin resistance, accompanied by a greater defect in insulinsecretion since both early-phase and late-phase insulin secretion areaffected. IFG is more frequent in men and young people, whereasIGT is more frequent in women and its prevalence increases as agerises. Both IFG and IGT are useful for the identification of subjects ata high risk of developing type 2 diabetes, although the subjectsidentified with each of them are different. Finally, many studies haveshown that both IFG as well as IGT are associated with an increasedcardiovascular risk. Nevertheless, IGT involves a higher risk and is astronger risk predictor than IFG.

Keywords: impaired oral glucose tolerance, impaired fasting glu-cose, prediabetes, diabetes mellitus.

ResumenTanto la glucemia basal alterada (GBA) como la intolerancia a la glu-cosa (ITG) conforman la llamada «prediabetes». Sin embargo, estasdos situaciones clínicas son entidades con grandes diferencias. Lossujetos con GBA presentan una resistencia hepática a la insulina yun déficit en la fase precoz de su secreción, mientras que en la ITGexiste una resistencia muscular a la insulina, acompañada de un dé-ficit más acusado de insulina, ya que se ven afectadas tanto la se-creción precoz como la tardía. La GBA es más frecuente en varonesy en personas jóvenes, mientras que la ITG es más habitual en mu-jeres y su prevalencia se incrementa a medida que aumenta la edad.La GBA y la ITG son útiles para identificar a sujetos con elevado ries-go de desarrollar diabetes tipo 2, aunque los individuos identifica-dos con cada una de ellas sean diferentes. Finalmente, en numero-sos estudios se ha demostrado que tanto la GBA como la ITG tienenun riesgo cardiovascular aumentado. Sin embargo, la ITG conlleva unriesgo más elevado y es un mejor factor pronóstico del riesgo quela GBA.

Palabras clave: intolerancia oral a la glucosa, glucemia basal al-terada, prediabetes, diabetes mellitus.

Date received: January 8th 2009 Date accepted: January 15th 2009

Correspondence:F.J. García Soidán. Centro de Salud de Porriño. Fernández, Areal, s/n. 36400Porriño (Pontevedra). Email: javier@garciasoidán.jazztel.es

List of acronyms quoted in the text:ADA: American Diabetes Association; CVR: cardiovascular risk; GIP: glucose-dependent insulin tropic polypeptide; GLP-1: glucagon-like peptide-1; IFG: impaired fasting glucemia; IGT: impaired glucose tolerance; NGT: normal glucosetolerance; OGO: oral overload with 75 g of glucose; WHO: World HealthOrganization.

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ing type 2 diabetes, the cardiovascular risk, the risk ofdeveloping complications and the mortality. In the fol-lowing paragraphs, we will proceed to analyse these dif-ferences.

PathogenesisThe IFG is characterized by a deÞcit in the early secre-tion phase of the insulin and by an increase of the hepat-ic resistance to the action of such hormone, which can beunderstood as an increase of the hepatic glycogen.1-7

When an oral overload with 75 g of glucose (OGO) isdone in these patients, it can be observed from the verybeginning that the glycemia values are high, and thatthey remain high after 30 and 60 minutes, with higherlevels than those of the individuals with IGT and thosewith normal glucose tolerance (NGT). However, after120 minutes the glycemia is reduced up to practicallynormal values (Þgure 1). As regards to the insulin levelsduring OGO in these same subjects, it can be observedthat there is a reduced response at an initial phase, withlower levels than those of the individuals with IGT orNGT, though this secretion is similar than the secretionof subjects with normal glucose tolerance5 (Þgure 2) af-ter 60 minutes.

On the other hand, the IGT is characterized by an in-crease of the peripheral resistance to the insulin action in

the muscle, as well as by a deÞcit of insulin secretion,both in the early and late-phase. When an OGO is per-formed to these patients, it can be observed that theyshow normal glycemia levels at the beginning. However,after 60 minutes their levels are raised relevantly and arekept high after 90-120 minutes (Þgure 1). As regards tothe insulin levels in the OGO, it can be observed thatthey are slightly reduced after 30-60 minutes and fromthat moment they increase, but not sufÞciently to reducethe levels of glycemia that remain high, due to the greatmuscular resistance to the insulin action5 (Þgure 2).

Therefore, in subjects with IFG there is a hepatic resist-ance to the insulin and a deÞcit in the early phase of itssecretion, whereas in the IGT there is a muscular resist-ance to the insulin accompanied by a remarked insulindeÞcit, as the early and late-phase are affected. The indi-viduals with the combination of both impairments (IFG+ IGT) shall take part of the physiopathologic impair-ments of both processes.

Recently, a study has been published that analysed thephysiopathologic differences between the IFG and theIGT at other levels, and in this way it has been objec-tiÞ ed that they also show a different response in relationto the release of the intestinal peptides after the intake,so the patients with IGT have a reduced GIP (glucose-dependent insulino-tropic polypeptide) response, where-

Figure 1. Glycemia levels during the oral glucose overload in individuals with impaired fasting glucemia (IFG), impaired glucose tolerance (IGT) and normal glucose tolerance (NGT)

Glyc

emia

(mg/

dL)

120

Time (min)

90600 30

200

160

120

80

IFGIGTNGT

Figure 2. Insulinemia levels during oral glucose overload in subjects with impaired fasting glucemia, glucose intolerance and normal glucose tolerance

Insu

linem

ia(μ

U/m

L)

120

Time (min)

90600 30

150

120

90

60

30

0

IFGIGTNGT

Seminars on diabetesImpaired fasting glycemia and glucose intolerance. F.J. García Soidán

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as those with IFG show an increase in the GLP-1 (gluca-gon-like peptide-1).8 This might explain, at least in part,the higher deÞcit in the insulin secretion that is shown bythe individuals with IGT.

Population distributionThe distribution of the IFG and the IGT is different con-sidering age and sex of the individuals, whereas the IFGis more frequent in men and in young persons, statingtheir prevalence while the age of the patients rises. Con-trary, the IGT is more frequent in women and its preva-lence increases while the age rises, so it is more frequentin elderly persons.9-13 This fact led to the recommenda-tion, in individuals over 65 years of age, to take into ac-count the use of OGO as systematic diagnosis methodfor the detection of impairments in the metabolism ofcarbohydrates.13

Risk of developing diabetesThere is no doubt about the higher risk of developing di-abetes that both the individuals with IFG and IGT show,being even higher the risk in those who suffer the com-bination of both impairments. Up to date, in most of the studies aimed to determine the differences between both entities, the diagnosis criteria recommended by theWorld Health Organization (WHO) in 1999 have beenused (IFG: baseline glycemia between 110 and 125 mg/

dL; IGT: glycemia after 2 hours from the OGO between140 and 199 mg/dL).14 Only a few studies have used theAmerican Diabetes Association (ADA) criteria of 2003, in which the lower diagnosis level of IFG was reducedfrom 110 to 100 mg/dL, leaving the rest of the criteriathe same.15 This is relevant as the results that have beenobtained are substantially different.

The risk of developing T2D in patients with IGT or IFG(WHO 99) is similar (and it is assessed that it is 4-5times higher than in the subjects with normal toleranceto glucose), with an annual diabetes development rateof 5-10%. In those persons that have IFG + IGT, therisk is approximately the double than with any of themin an isolated manner.16-20 Considering the WHO-99criteria, the prevalence of diabetes in subjects with IGTis almost the double than in those with IFG, the IGT re-sults more sensitive, though slightly less speciÞc, thanthe IFG in order to identify persons who might developdiabetes.

As we have already mentioned, in 2003 the ADA re-duced the diagnosis value of the IFG from 110 up to 100mg/dL with the intention of improving its sensitivityand equal it to the IGT, and in this way eliminate theneed to undergo an OGO. However, in practice, in spiteof having equalled the sensitivity of the IFG and theIGT with the new criteria (ADA 2003), the speciÞcityhas been remarkably reduced and the positive prognosisvalue of the IFG to detect subjects in risk, increasing in4 the number of individuals with IFG. Notwithstanding,it persists the identiÞcation of different individuals bythe IFG and the IGT, as it happened with the previouscriteria (WHO 99).16-20

In view of the above, we can conclude that both entities(IFG and IGT) are useful to identify subjects with highrisk to develop diabetes, and the individuals identiÞedwith each of the criteria are different, so it has to do withtwo complementary strategies (and not excluding) withthe same aim.

Cardiovascular riskIn several studies, it has been demonstrated that both theIFG and the IGT imply an increased cardiovascular risk(CVR). However, the IGT entails a higher risk and is abetter prognosis factor of the CVR than the IFG.13,21,22

These differences might be due, at least in part, to the

Figure 3. Relative risk of cardiovascular and total mortality of individuals with impaired fasting glucemia, glucose intolerance and diabetes.Results of the DECODE study24

Relat

iveris

k

Cardiovasculardisease

Diabetes IGT IFG

2

1.75

1.5

1.25

1Coronary

heart diseaseStroke Any cause

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fact that the IGT is associated mainly to the existence ofother factors of CVR, and that the affected patients showhigher levels of triglycerides and arterial pressure valuesthan in the IFG.7,23 However, it could be stated that thesedifferences in the CVR of both entities persisted afterthe adjustment, taking into account the remaining CVRfactors.

These differences are even more evident as regards tothe cardiovascular mortality, as it could be demonstrat-ed in the DECODE study (Þgure 3).24 In this study, itcould be observed that the increased glycemia Þguresafter 2 hours of the OGO were associated to an increaseof the total mortality and cardiovascular risk, regard-less of the fasting glycemia value, not being the highfasting glycemia sufÞcient to predict the mortality byits own. It could also be observed that the highernumber of deaths took place in the group of subjectswith IGT, but with a normal fasting glycemia. Thesesame results were obtained in Asiatic population in theDECODE study.25

ConclusionsTherefore, we can conclude that the IGT has a pathogen-ic mechanism and a population distribution differentfrom the IFG ones, as it implies a risk of cardiovascularand mortality events higher than the one of the IFG.Both entities determine a higher risk of suffering diabe-

tes; however, they detect different groups of individuals,constituting two complementary entities to identify indi-viduals with a high cardiovascular risk. ■

Declaration of potential con!icts of interestF.J. García Soidán states that there are no conßicts of interestas regards to the content of this article.

References1. Weyer C, Bogardus C, Pratley R. Metabolic characteristics of individuals

with impaired fasting glucose and/or impaired glucose tolerance. Diabetes.1999;48:2197-203.

2. Schianca GPC, Rossi A, Sainaghi PP, Maduli E, Bartoli E. The significanceof impaired fasting glucose versus impaired glucose tolerance: importance of insulin secretion and resistance. Diabetes Care. 2003;26:1333-7.

3. Hanefeld M, Koehler C, Fuecker K, Henkel E, Schaper F, Temelkova-Kurktschiev T. Impaired Glucose Tolerance for Atherosclerosis and Diabetesstudy. Insulin secretion and insulin sensitivity pattern is different in isolatedimpaired glucose tolerance and impaired fasting glucose: the risk factor in Impaired Glucose Tolerance for Atherosclerosis and Diabetes study.Diabetes Care. 2003;26:868-74.

4. Festa A, D’Agostino R, Hanley A, Karter AJ, Saad MF, Haffner SM.Differences in insulin resistance in nondiabetic subjects with isolated impaired glucose tolerance or isolated impaired fasting glucose. Diabetes.2004;53:1549-55.

5. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA.Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans AdministrationGenetic Epidemiology Study. Diabetes. 2006;55:1430-5.

6. Meyer C, Pimenta W, Woerle HJ, Van Haeften T, Szoke E, Mitrakou A,et al. Different mechanisms for impaired fasting glucose and impairedpostprandial glucose tolerance in humans. Diabetes Care.2006;29:1909-14.

7. Miyazaki Y, Akasaka H, Ohnishi H, Saitoh S, DeFronzo RA, Shimamoto K.Differences in insulin action and secretion, plasma lipids and blood pressure levels between impaired fasting glucose and impaired glucose tolerance in Japanese subjects. Hypertens Res. 2008;31:1357-63.

8. Faerch K, Vaag A, Holst JJ, Glümer C, Pedersen O, Borch-Johnsen K.Impaired fasting glycaemia vs impaired glucose tolerance: similar impairment of pancreatic alpha and beta cell function but differential roles of incretin hormones and insulin action. Diabetologia. 2008;51:853-61.

9. Dunstan DW, Zimmet PZ, Welborn TA, De Courten MP, Cameron AJ,Sicree RA, et al. The rising prevalence of diabetes and impaired glucosetolerance: the Australian Diabetes, Obesity and Lifestyle Study. DiabetesCare. 2002;25:829-34.

10. DECODE Study Group. Age and sex-specific prevalences of diabetes andimpaired glucose regulation in 13 European cohorts. Diabetes Care.2003;26:61-9.

11. Qiao Q, Hu G, Tuomilehto J, Nakagami T, Balkau B, Borch-Johnsen K, et al.DECODA Study Group. Age- and sex-specific prevalence of diabetes andimpaired glucose regulation in 11 Asian cohorts. Diabetes Care.2003;26:1770-80.

12. Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM, Engelgau MM,et al. Prevalence of diabetes and impaired fasting glucose in adults in the US population: National Health and Nutrition Examination Survey 1999-2002. Diabetes Care. 2006;29:1263-8.

13. Meigs JB, Nathan DM, D’Agostino RB, Wilson PWF. Fasting andpostchallenge glycaemia and cardiovascular disease risk: the Framingham Offspring study. Diabetes Care. 2002;25:1845-50.

14. Alberti KG, Zimmet PZ. WHO. Definition, diagnosis and classification ofdiabetes mellitus and its complications. Report of a WHO Consultation,


• The impaired fasting glucemia (IFG) and the im-paired glucose tolerance (IGT) imply differentphysiopathology impairments. The hepatic insu-lin resistance and the early impairment of the in-sulin secretion prevail in the IFG, whereas themuscular resistance in the IGT prevails and theinsulin secretion is more affected, both in theearly and late-phase.

• Both entities are associated to 4-5 high fold riskto develop diabetes than the subjects with nor-mal tolerance to the glucose, though the IGTturns out to be more sensitive and slightly morespecifi c than the IFG.

• Both the IFG and the IGT are also associated toan increase of cardiovascular risk, which is hig-her in the case of the IGT.

Seminars on diabetesImpaired fasting glycemia and glucose intolerance. F.J. García Soidán

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Part 1: Diagnosis and classification of diabetes mellitus. Diabet Med.1998;15:539-53.

15. Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, et al. ExpertCommittee on the Diagnosis and Classifi cation of Diabetes Mellitus.Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care.2003;26:3160-7.

16. Shaw JE, Zimmet PZ, De Courten M, Dowse GK, Chitson P, GareebooH, et al. Impaired fasting glucose or impaired glucose tolerance. Whatbest predicts future diabetes in Mauritius? Diabetes Care.1999;22:399-402.

17. De Vegt F, Dekker JM, Jager A, Hienkens E, Kostense PJ, Stehouwer CD,et al. Relation of impaired fasting and postload glucose with incident type 2 diabetes in a Dutch population: The Hoorn Study. JAMA.2001;285:2109-13.

18. Qiao Q, Lindström J, Valle TT, Tuomilehto J. Progression to clinicallydiagnosed and treated diabetes from impaired glucose tolerance and impaired fasting glycaemia. Diabet Med. 2003;20:1027-33.

19. Rasmussen SS, Glümer C, Sandbaek A, Lauritzen T, Borch-Johnsen K.Determinants of progression from impaired fasting glucose and impairedglucose tolerance to diabetes in a high-risk screened population: 3 yearfollow-up in the ADDITION study, Denmark. Diabetologia. 2008;51:249-57.

20. Nichols GA, Hillier TA, Brown JB. Progression from newly acquiredimpaired fasting glucose to type 2 diabetes. Diabetes Care.2007;30:228-33.

21. Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship betweenglucose and incident cardiovascular events. A metaregression analysis ofpublished data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care. 1999;22:233-40.

22. Levitzky YS, Pencina MJ, D’Agostino RB, Meigs JB, Murabito JM, Vasan RS,et al. Impact of impaired fasting glucose on cardiovascular disease: the Framingham Heart Study. J Am Coll Cardiol. 2008;51:264-70.

23. Blake DR, Meigs JB, Muller DC, Najjar SS, Andres R, Nathan DM.Impaired glucose tolerance, but not impaired fasting glucose, isassociated with increased levels of coronary heart disease risk factors:results from the Baltimore Longitudinal Study on Aging. Diabetes.2004;53:2095-100.

24. DECODE Study Group, the European Diabetes Epidemiology Group.Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch Intern Med. 2001;161:397-405.

25. Nakagami T. DECODA Study Group. Hyperglycaemia and mortality from allcauses and from cardiovascular disease in fi ve populations of Asian origin.Diabetologia. 2004;47:385-94.


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IntroductionThe diabetes mellitus (DM) is a metabolic disorder char-acterized by a deÞcit of insulin secretion or its peripher-

al action, or both. The T2D affects more than 7% of thepopulation. The incidence is increasing especially in the developing countries and between the young popula-tions. Such increase is very much related to the “westernlifestyle”, in other words, with inadequate diet habitsand physical inactivity. The impaired glucose tolerance(IGT) and the impaired fasting glucose (IFG) are consid-ered intermediate phases between the normal glucosetolerance (NGT) and the DM. The IGT and the IFGshould be considered as risk factors for the developmentof DM, more than an entity in itself. The IGT term1 wasintroduced in 1979 and reßects a peripheral resistance tothe insulin action. The IFG term,2 introduced in 1997,expresses an increase of the glucose hepatic synthesisand a defect in the early insulin secretion.


Prevention of type 2 diabetes based on nutritional therapyand/or increase of physical activityPrevención de la diabetes tipo 2 basada en la terapia nutricional y/o el aumentode la actividad físicaS. Artola MenéndezCentro de Salud Hereza. Leganés (Madrid)

Abstract The increasing incidence of type 2 diabetes is associated with thewestern lifestyle. Intervention programs oriented to increasing exer-cise combined with an adequate nutrition therapy have a protectiveeffect against the development of type 2 diabetes in people at risk.These results are even better than with the pharmacologic approach.Prevention of diabetes with lifestyle intervention is cost-effectivefrom a health care point of view. It is important to detect people athigh risk to develop type 2 diabetes to prevent progression of hyper-glycemia. There are not enough data with exercise alone neither ondiabetes prevention nor in morbidity and mortality. There is a needfor studies exploring the effect of interventions with exercise alone orcombined with nutrition therapy on cardiovascular morbidity andmortality.

Keywords: diabetes, prevention, diet, exercise.

ResumenEl aumento de la incidencia de diabetes tipo 2 está asociado al es-tilo de vida occidental. Los programas de intervención dirigidos aaumentar el ejercicio, combinados con una alimentación adecuada,son capaces de retrasar el desarrollo de este tipo de diabetes ensujetos de riesgo. Los resultados son incluso mejores que con elabordaje farmacológico. La prevención de la diabetes mediante laintervención sobre la modificación del estilo de vida es coste-efec-tiva desde la perspectiva de un sistema público de salud. Es impor-tante identificar a los individuos con alto riesgo de desarrollar diabe-tes para prevenir el progreso de la hiperglucemia. No hay datossuficientes sobre la prevención de la diabetes sólo con ejercicio, nisobre el efecto en la morbimortalidad. Parece necesario realizar es-tudios que analicen los beneficios del ejercicio, solo o combinadocon la dieta, en la morbilidad y mortalidad cardiovascular.

Palabras clave: diabetes, prevención, dieta, ejercicio.

Date received: January 15th 2009 Date accepted: January 22nd 2009

Correspondence:S. Artola Menéndez. Centro de Salud Hereza. J. Haddad Blanco, 2. 28914Leganés (Madrid). Email. [email protected]

List of acronyms quoted in the text:ADA. American Diabetes Association; BMI: body mass index; CDQDPOS: ChinaDa Qing Diabetes Prevention Outcomes Study; CDQDPS: China Da Qing Diabetes Prevention Study; DM: diabetes mellitus; DPP: Diabetes Prevention Project. DPS: Finnish Diabetes Prevention Study; IDF: International Diabetes Federation; IDPP:Indian Diabetes Prevention Programme; IFG: impaired fasting glucemia; IGT:impaired glucose tolerance; LM: lifestyle modifications; NNT: number needed totreat; NGT: normal glucose tolerance; OGTT: oral glucose tolerance test; RRR:relative risk reduction; T2D: type 2 diabetes mellitus.

Seminars on diabetesPrevention of type 2 diabetes with diet plus exercise. S. Artola Menéndez

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Can diabetes be prevented?There are two strategies to reduce the development of di-abetes: 1) interventions on the lifestyle, and 2) pharma-cological treatment. In this chapter, we will develop theevidences and recommendations about the prevention ofT2D based on the nutritional therapy and/or the increaseof the physical activity. Intervention studies have beenpublished during the last years that have evidenced clear-ly positive results.

The great studies developed in China, Europe and theUnited States have demonstrated clearly that the conver-sion of IGT to T2D can be avoided or delayed at least. Itis conÞrmed that the loss of weight is the determining

factor in the prevention of diabetes. In table 1, the stud-ies on the prevention of diabetes are depicted with non-pharmacological measures.

Intervention studiesMalmö Study3

It was one of the Þrst intervention studies in which mod-iÞcations of the lifestyle have been used for the preven-tion of DM. It was performed on men between 47 and49 years of age of the population of Malmö (Sweden).Some subjects with IFG and all those who had NGT per-formed a “usual follow-up”. The patients with T2D andthose with IGT have been randomized to a program in

Table 1. Main studies on non-pharmacology intervention for the prevention of diabetes

Study Country Publication Year

Design Education Intervention

Size Mean follow-up

Results* (%)

Comments

Malmö Preventive Trial3

Sweden 1991 Non randomized intervention in acohort group

Diet treatment and/or increase of exercise.Intervention of 6months with annual follow-up

n= 222 (from acohort of 6956).Men with incipient T2D (41) or IGT (181)

6 years >50 After 12 years (in 1998), the groupwith IGT on which the intervention took place was still without increasing mortality

China Da Qing IG and Diabetes Study (CDQPDS)4

China 1997 Clinical trial after screening of IGT in general population

Diet and/orexercise.Individual and group intervention. weekly,1 month, monthly3 months, andquarterly follow-up with half-yearly evaluation

n= 530Men (283)And women (247)

with IGT

6 years 31-46 Diet only, exerciseonly, or diet andexercise have been effective in similar level

Finnish Diabetes Prevention Study (DPS)5

Finland 2001 Randomized clinical trial and partially blind

Quarterly intensive intervention with customized advice on diet and exercise.Annual medical revision with OGTT

n= 522Men (172) and women (350) between 40 and 65 years of age with BMI >25 kg/m2 andprevious diagnosis of IGT

3.2 years 58 The prevention ofthe diabetes was obtained with modest reductions of weightNNT= 22(or 5 in 5 years)

Diabetes Prevention Program (DPP)8

United States

2002 Change of habits

Intensive course of 16 sessions to reduce the weigh in 7% by means of diet and exercise.Monthly reinforcement and six months - control

n= 3234Men (1043) and women (2191) >25 years and with IFG and IGT

2.8 years 58 NNT= 7

*Reduction of the progression towards diabetes mellitus. BMI: body mass index; IFG: impaired fasting glucemia; IGT: impaired glucose tolerance; NNT: number needed to treat;OGTT: oral glucose tolerance test with 75 g of glucose.

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lifestyle change that consisted of exercise and diet dur-ing 6 months. At the end of the study it could be provedthat the IGT group in which the intervention was donehas a lower incidence of T2D. After 12

years of follow-up, the patients with IGT who receivedan intensive program on lifestyle showed the Þrst mor-tality rates than those with NGT and less than half ofmortality than those with IGT who had performed a“usual follow-up”.

The China Da Qing Diabetes Prevention Study(CDQPDS)4

This study analysed the effect of one intervention of 6years with diet plus exercise in 577 subjects of Chineserace that showed IGT and had a mean age of 45. Theparticipants were randomized to one of the three groups of active treatment (a: only diet, b: only exercise and c:diet plus exercise) or to the control group. The incidenceof T2D after 5 years was of 67.7% (CI 95%, 59.8-75.2)in the control group, versus 43.8% (CI 95%: 35.3-52.3)in the diet group, and 41.1% (CI 95% 33.4-49.4) in theexercise group and 46% (CI 95%: 37.3-54.7) in the dietplus exercise group (p <0.05). After the adjusted analysisaccording to the baseline differences in the body massindex (BMI) and the baseline glycemia, the diet, the ex-ercise and the diet plus exercise, showed a respective re-duction of 31% (p <0.03), 46% (p <0.0005) and 42% (p <0.005). Surprisingly, the double intervention achieveda lower reduction than the one observed with the isolatedexercise.

The Finnish Diabetes Prevention Study (DPS)5,6

In this study, 522 subjects with overweight / obesity andIGT, a mean age of 55 years and 66% of women, wererandomized to a program of intensive lifestyle modiÞca-tions (LM) versus a conventional follow-up during 3.2years. The intensive treatment consisted of 7 sessionswith a nutritionist during the Þrst year and, then, four an-nual sessions together with a physical exercise program.The control group received usual recommendations ondiet plus exercise. The reduction of 5% of weight ob-served in the intervention group reduced the incidence ofdiabetes from 23 to 11%, with a relative risk reduction(RRR) of 58%. Each of the Þve intervention compo-nents (loss of weight, increase of the physical activity orat least 30 min/day, reduction of 30% of the intake of to-tal fats, reduction of 10% of the saturated fats and in-crease of the Þbre intake) contributed to the risk reduc-

tion. It has to be pointed out that the 21% of theparticipants reached four of the Þve objectives and thatonly 6% did not achieve any. From the subjects whoreached the Þve objectives of lifestyle, none of them de-veloped diabetes. Among those who did not achieve anyof the objectives, a 35% developed diabetes.

The Japanese studyThe study of Kosaka et al.7 included 458 men with IGTwho were randomized, with a ration 4:1, to standard in-tervention (n= 356) or intensive (n= 102). The objectivewas to keep a BMI <24 kg/m2 in the control group, anda BMI <22 kg/m2 in the group of active intervention bymeans of diet plus exercise. In the intervention group,the recommendations on diet and physical activity on anactive basis each 3-4 months was repeated. The accumu-lated incidence of T2D after 4 years was of 9.3% in thecontrol group and 3% in the intervention group. The lossof weight resulted to be of 0.39 kg in the control groupversus 2.18 kg in the intervention group (p <0.001). Theintensive treatment was associated with a 67.4% of riskreduction of T2D (p <0.001).

The Diabetes Prevention Project Study (DPP)8

This is one of the clinical trials with a higher number ofsubjects. It included 3234 individuals of the UnitedStates with IFG and IGT, from which 68% were womenand 45% corresponded to ethnic minorities. The meanage was of 51 and the BMI of 34 kg/m2. The study com-pared three intervention branches, a) control group,b) pharmacological intervention (metformin) and c) LM,during almost 3 years of follow-up. The DM incidencewas of 11, 7.8 and 4.8 per 100 persons and year, respec-tively, in each group. The intervention on the lifestylereached a 7% of reduction in weight and reduced the in-cidence of DM from 29 to 14% (RRR= 58%, CI 95%:48-66). The DM incidence in the metformin group wasreduced in a 31% (CI 95%: 17-43). The number of sub-jects that needed to be treated (NNT) for LM was of 6.9(CI 95%: 5.4-9.5) versus 13.9 (CI 95%: 8.7-33.9) formetformin. A later analysis9 of the data corresponding tothis study concluded that the physical activity helps tokeep the weight and to reduce the risk of developing dia-betes, even in subjects who do not lose weight.

The Indian Diabetes Prevention Programme Study(IDPP)10

This study might be considered a reproduction of theDPP study in the Indian population. The progression to


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diabetes of the subjects who showed IGT was even high-er than in the European or American studies. The inten-sive intervention both with LM and metformin reducedrelevantly the diabetes incidence (RRR= 28.5 and26.4%, respectively) without detecting any improvementwith the addition of both interventions (28.2%).

Persistence of the e"ectsof the long-term interventionOne of the most discussed aspects is if the beneÞcialeffects persist at long-term once the active interventionis discontinued. In the trials with different drug groups,fast risk parity can be proved with the subject who hadnot received any sort of treatment, whereas in the trialswith LM the conclusions are more optimistic after ex-tended follow-ups. Thus, in the DPS11 follow-up, theeffect on the reduction of the diabetes incidence waskept for at least 4 years after the intervention ended.The number of cases with T2D after 7 years of totalfollow-up (4 years of intervention plus 3 years of fol-low-up) was of 75 in the intervention group versus 110in the control group. The incidence rate was of 4.3 (CI95%: 3.4-5.4) and 7.4 (CI 95%: 6.1-8.9) per 100 per-sons and year in the intervention and control groups,respectively. The hazard ratio was of 0.57 (CI 95%:0.43-0.76) with NNT of 22 subjects per year (Þgure 1).The risk reduction to develop T2D was kept in 43%during the 3 years of follow-up. Though the value islower than 58%, observed after 4 years of active inter-vention, this is an important datum from the healthpublic point of view. These Þndings show that the realbeneÞt as regards to the prevention of the diabetes hasto be focused through the LM more than in the pharma-cological treatments, whose effects are extinguishedwhen the intervention is interrupted. The high inci-dence of DM, even in the intervention group, suggeststhat the strategies on LM should be set out in all thehigh-risk subjects, even before they develop IGT.

The China Da Qing Diabetes Prevention OutcomesStudy (CDQDPOS)12 carried out a follow-up during 20years after the intervention of 6 years with LM. Thesubjects under LM had a 51% less of DM incidence(reduction of the hazard ratio of 0.49; CI 95%: 0.33-0.73) and in this group it was kept a 43% less of DMincidence (reduction of the hazard ratio of 0.57; CI95%: 0.41-0.81) during the later 20 years of follow-up(Þgure 2).

In 2005, a systematic revision was published13 of the Co-chrane Library about the structured interventions of en-couraging the physical activity and the diet in order toreduce the risk of developing diabetes. The interventiongroups with LM reduced the T2D incidence after a yearin approximately 50% (risk reduction: 0.55; CI 95%:0.44-0.69) compared to the control groups.

In 2007 a meta-analysis was published14 that evaluat-ed the efÞcacy of the interventions with pharmacolog-ical treatments and LM in order to prevent or delayT2D in persons with IGT. The accumulated effects forall the types of intervention in the lifestyles reached arisk reduction of 0.51 (CI 95%: 0.44-0.60: p <0.001),indicating a RRR to develop DM of 49%, without im-portant differences to analyze separately the threegroups of diet, exercise and diet plus exercise. For theantidiabetic drugs, the risk reduction was of 0.7 (CI95%: 0.62-0.79; p <0.001) and for orlistat, a drug forobesity of 0.44 (CI 95%: 0.28-0.69; p <0.001). Theauthors concluded that both the intervention on the LMand the pharmacological intervention reduce the pro-gression rate to DM in persons with IGT, but the Þrst

Figure 1. Development of T2D in each intervention group of DPS11 study during the 8 years follow-up. The diabetes incidence was of 4.3(3.4-5.4) and 7.4 (6.1-8.9) cases per 100 persons/year in the intervention and control groups, respectively. The reduction of DM riskwas of 43%. The follow-up was interrupted after 8 years because thenumber of participants was very low starting from the seventh year

Prob

abilit

yofr

emain

ingwi

thou

tdiab

etes

8Years

7430 2

1.00

0.75

0.50

0.25

0.00

InterventionControl

1 65

Hazard ratio: 0,57 (IC 95%: 0,43-0,76)

Cases at riskControl 265 261 250 238 228 214 191 174 118Intervention 257 251 231 209 192 176 157 140 91

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ones seem to be more efÞcacious than the treatmentwith drugs.

In July 200815 a new revision of the Cochrane Librarywas published. The screening criteria have been random-ly studied with interventions on the diet and/or the exer-cise for a minimum of 6 months that detected the T2Dincidence in subjects at special risk of developing it.Eight studies have been included that performed a jointintervention (diet plus exercise) (n= 2,241) versus a con-trol group (n= 2,509) and two studies with only diet in-tervention (n= 167) and only exercise (n= 178). The du-ration of the studies ranged between 1 and 6 years.Globally, the diet intervention plus exercise reduced therisk of developing diabetes in 37% (RR= 0.63; CI 95%:0.49-0.79). Such intervention showed beneÞts associatedto the reduction of weight, the BMI and the abdominalperimeter. The beneÞt was modest in blood lipids. How-ever, the intervention on the lifestyle improved indeedthe control of the arterial pressure, with a reduction ofthe systolic pressure of –4 mmHg (CI 95%: [–5]-[–2]) andthe diastolic pressure of –2 mmHg (CI 95%: [–3]-[–1])No relevant effects were observed in the diabetes inci-

dence when the interventions of only exercise versuscontrol were compared or only diet. None of the studies provided relevant data in relation to the diabetes and car-diovascular morbimortality, nor lifestyle.

Should diabetes be prevented?The epidemic increase of the diabetes and its conse-quences at long term justify the efforts to prevent itsonset. In the two intervention studies with diet and ex-ercise that perform cost-effectiveness analysis (DPP8

and IDPP10), it is pointed out that the prevention of thediabetes through the intervention on the LM is cost-ef-fective from the health public system point of view. Itis important to identify the individuals at high risk ofdeveloping diabetes in order to prevent the worseningof the hyperglycemia. The recommended screening forthe general population would be performed in the formof a validated questionnaire based on parameters suchas age, family diabetic history, previous hyperglycemiahistory, the physical inactivity and the BMI or waistmeasure. In subjects at special risk, the performanceof the oral glucose tolerance test (OGTT) should beconsidered.

Therefore, it is necessary to make a double effort: on onehand, to identify the patients at higher risk both of devel-oping diabetes and of showing cardiovascular diseases(IGT, metabolic syndrome), and on the other hand, to in-tervene with programs of exercise, diet and weight con-trol. If in the meta-analysis of Gillies et al.14 the authors concluded that the intervention on LM was at least as ef-fective than the pharmacological intervention to preventthe onset of T2D, in the Cochrane Library15 revision of2008 it is conÞ rmed that the combination of diet and ex-ercise has a favorable effect not only on the preventionof T2D but also in the reduction of weight and waist pe-rimeter and in the reduction of the systolic and diastolic pressure. Any improvement in the cardiovascular riskfactors is accompanied by a lower onset of cardiovascu-lar events. On the other hand, the diet and the exercisehad a very modest effect in the lipid proÞ le.

Recommendationsof the clinical practice guidelinesThe American Diabetes Association (ADA),16 issued aconsensus document on the approach of the prediabetesstages. The association between obesity and diabetes

Figure 2. Accumulated incidence of T2D during the follow-up of the Da Qing Study (CDQDPOS).12 During the 20 years of follow-up, theaccumulated incidence of DM was of 80% in the intervention group and 93% in the control group. The reduction of the risk to develop DMwas of 51% after 6 years of intervention, and after 20 years of follow-up, it was kept at 43%

Cases at riskIntervention 135 105 69 48 40 37 34 27 27 23 14Control 428 387 314 250 230 206 192 161 147 136 114

(%)

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161080 6

100

90

80

70

60

50

40

30

20

10

0

InterventionControl

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Intervention during 6 years,Hazard ratio 0,49 (IC 95%: 0,33-0,73)

Follow-up after 20 years,Hazard ratio 0,57 (IC 95%: 0,41-0,81)

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obliges to determine, as Þrst priority, the control of theoverweight with modifications of the lifestyle ad-dressed to losses of 5-10% of the body weight, and aminimum exercise of 30 minutes daily (table 2). Thegroup of experts recommends the performance ofOGTT if it is foreseen that the IFT/IGT stages detec-tion in the subject might be beneÞted from the treat-ment with metformin. Moreover, it does not indicatethe performance of OGTT in those individuals whowill only follow recommendations on lifestyle. In itslast update of 2009,17 the ADA asserts that the patientswith IGT (evidence A) and IFT (evidence B) should re-ceive advice in order to reduce the risk of developingdiabetes and should be referred to a structured programin order to lose 5-10% of body weight, as well as to in-crease the physical activity up to 150 minutes weeklyof moderate exercise, as walking.

The International Diabetes Federation (IDF),18 proposes,in a recent consensus document, a strategy in order toprevent the diabetes addressed to two groups of subjects:a) the individuals at high risk of developing diabetes andb) the general population.

The Canadian Guideline19 incorporates the performanceof a structured program of LM that includes a moderateloss of weight as well as regular physical activity, in or-der to reduce the T2D development in subjects with IGT(recommendation of grade A, level 1A) and in those withIFT (recommendation of grade D).

ConclusionsThe several discussed studies on intervention suggestthat at present it seems possible to prevent diabetes, or atleast to delay its onset. The option approach should bethe changes of lifestyle, taking in account that anychange, regardless of how small it is, provides relevantresults. The increase of physical exercise together with abalanced diet reduces the T2D incidence in subjects withIGT or metabolic syndrome. There is not sufÞcient dataabout the prevention of diabetes only with exercise, norabout its effect on the morbimortality. It seems to be nec-essary to develop studies that analyse the exercise andthe diet beneÞts on the morbidity and cardiovascularmortality. ■

Declaration of potential con!ict of interestS. Artola Menéndez states that there are no conß icts of interestas regards to the content of this article.

References1. National Diabetes Data Group. Classification and diagnosis of diabetes

mellitus and other categories of glucose intolerance. Diabetes.1979;28:1039-57.

2. Report of the Expert Committee on the Diagnosis and Classification ofDiabetes Mellitus. Diabetes Care. 1997;20:1183-97.

3. Eriksson K, Lindgrade F. Prevention of type 2 (non-insulin-dependent)diabetes mellitus by diet and physical exercises. Diabetologia.1991;34:891-8.

4. Pan X, Li G, Hu Y, Wang J, Yang W, An Z. Effects of diet and exercise inpreventing NIDMM in people with impaired glucose tolerance. The Da QingIGT and Diabetes Study. Diabetes Care. 1997;20:537-44.

5. Tuomilehto J, Lindstrom J, Eriksson J, Valle T, Hamalainen H. Prevention oftype 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-50.

6. Lindstrom J, Louheranta A, Mannelin M, Rastas M, Salminen V, ErikssonJ. The Finnish Diabetes Prevention Study (DPS): lifestyle intervention and

Table 2. Recommendations for individualswith IFG / IGT16 or both

Population Treatment

IFG or IGT Modifications of lifestyle (reduction of 5-10% of weight and moderate activity during 30 min/day)

IFG and IGT plus at least one of the following:

• <60 years• BMI ≥35 kg/m2

• Family history of firstgrade of diabetes

• High triglycerides• Low HDL• Arterial hypertension

• HbA1C >6.0%

Modification of lifestyle and/or metformin (850 mg twice daily)

BMI: body mass index; HbA1C: glycosylated hemoglobin; HDL: high-density lipopro-teins; IFG: impaired fasting glucemia; IGT: impaired glucose tolerance.


• An adequate diet and the increase of physicalexercise might delay the T2D development in pa-tients at high risk

• The beneficial effects of the lifestyle modifica-tions seem to extend themselves once the inter-vention therapy ended, whereas the benefits ofthe pharmacological treatments are extinguishedafter their interruption.

• The modifications on the lifestyle are cost-effec-tive; therefore they should be set out in all thepatients at high risk, even before they developglucose intolerance.

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3-year results on diet and physical activity. Diabetes Care.2003;26:3230-6.

7. Kosaka K, Noda M, Kuzuya T. Prevention of type 2 diabetes by lifestyleintervention: a Japanese trial in IGT males. Diabetes Res Clin Pract.2005;67:152-62.

8. Knowler W, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM.Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

9. Hamman R, Wing R, Edelstein S, Lachin J, Bray G, Delahanty L, et al. Effectof weight loss with lifestyle intervention on risk of diabetes. Diabetes Care.2006;29:2102-7.

10. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar A, Vijay V.The Indian Diabetes Prevention Programme shows that lifestylemodification and metformin prevent type 2 diabetes in Asian Indiansubjects with impaired glucose tolerance (IDPP-1). Diabetologia.2006;49:289-97.

11. Lindstrom J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson J, Hemio K.Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet.2006;368:1673-9.

12. Li G, Zhang P, Wang J, Gregg E, Yang W, Gong Q, et al. The long-termeffect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study. Lancet. 2008;371:1783-9.

13. Yamaoka K, Tango T. Efficacy of lifestyle education to prevent type 2diabetes. A meta-analysis of randomized controlled trials. Diabetes Care.2005;28:2780-6.

14. Gillies CL, Abrams KR, Lambert PC, Cooper NJ, Sutton AJ, Hsu RT, et al.Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ. 2007;334:299-302.

15. Orozco LJ, Buchleitner AM, Giménez-Pérez G, Roqué I, Figuls M,Richter B, et al. Exercise or exercise and diet for preventing type 2diabetes mellitus (Review). Cochrane Database Syst Rev.2008;(3):CD003054.

16. Nathan DM. Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R,et al. Impaired fasting glucose and impaired glucose tolerance. Consensusstatement. Diabetes Care. 2007;30:753-9.

17. American Diabetes Association. Standards of Medical Care in Diabetes2009. Diabetes Care. 2009;32 Suppl 1:S16.

18. Alberti KG, Zimmet P, Shaw J. International Diabetes Federation: aconsensus on type 2 diabetes prevention. Diabet Med.2007;24:451-63.

19. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Canadian Diabetes Association 2008 clinical practiceguidelines for the prevention and management of diabetes in Canada. Can J Diabetes. 2008;32 Suppl 1:S17.


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IntroductionDiabetes mellitus (DM) is a metabolic disorder charac-terized by the presence of chronic hyperglycemia togeth-er, in a greater or lesser extent, with the impairments incarbohydrate, protein and lipid metabolism.1,2 Taking in-to account the statistics that characterize the T2D, thissuggests at present a health and socio-economic problemof great magnitude. Moreover, even in the better previ-sions, these values will obtain an overtone of real epi-demic in the near future worldwide.3 We are facing a po-tentially serious and asymptomatic disease, that isunknown by the patient in most of the cases, which fre-quently comes together at the moment of diagnosis bythe presence of chronic disorders (micro and macro vas-


Pharmacological interventions to prevent type 2 diabetesPrevención de la diabetes mellitus tipo 2 basada en la intervención farmacológicaM. Giménez Álvarez, I. Conget DonloEndocrinology and Diabetes Service. Hospital Clínic i Universitari, IDIBAPS (Institut d´Investigacions Biomèdiques August Pi i Sunyer).CIBER of Diabetes and Related Metabolic Diseases (CIBERDM). Barcelona

AbstractConsidering the results from the largest studies in type 2 diabetesprevention, there’s no doubt that the first treatment option in thissubset of patients should be promoting lifestyle changes. However,assuming what the large trials defined as lifestyle changes, the ques-tion is if these measures are reliable to be applied in the generalpopulation. Nevertheless, lifestyle changes are so effective in diabe-tes prevention that any change, even modest, could derive in posi-tive results. There’s also no consensus about what drug should beused first, in which patients and how long. The recent success ofsome of them, forced that in 2007 three scientific societies proposethe use of two of these drugs (metformin or acarbose) in subjects athigh risk, in which lifestyle changes didn’t achieve the expectedgoals. Considering that there’s a chance for preventing type 2 diabe-tes, we are still waiting for the results of upcoming studies which willconfirm or complement what is known up-to-date on diabetes pre-vention.

Keywords: type 2 diabetes, prevention, lifestyle changes, acarbose,metformin.

ResumenSi nos basamos en los resultados de los grandes estudios sobreprevención de diabetes, no cabe duda de que la aproximación inicialde elección debería ser efectuar cambios saludables en el estilo devida. Uno se pregunta si la implementación de los protocolos de es-tos estudios es extensible a la práctica cotidiana. Sin embargo, laeficacia que han demostrado en cuanto a prevención de diabetes estan grande, que cualquier pequeño cambio en el estilo de vida po-dría ofrecer resultados significativos. No existe consenso a la horade decidir si debemos o no utilizar fármacos cuando estas medidasno son suficientes. Durante los últimos años, han aparecido múltiplesestudios que han utilizado fármacos con este propósito. En 2007, seposicionaron por primera vez tres sociedades científicas que con-templaron la utilización de algunos de ellos en personas de altoriesgo en las que los cambios en el estilo de vida se consideran, apriori, ineficaces. Con la certeza inicial de que podemos prevenir ladiabetes tipo 2 (DM2), deberemos esperar a la aparición de nuevosestudios en los próximos años que intentarán corroborar y comple-mentar lo que hasta la fecha conocemos.

Palabras clave: diabetes tipo 2, prevención, cambios en el estilode vida, acarbosa, metformina.

Date received: January 7th 2009 Date accepted: January 13th 2009

Correspondence:M. Giménez Álvarez. Endocrinology and Diabetes Service. Hospital Clínic iUniversitari. IDIBAPS (Institut d´Investigacions Biomèdiques August Pi i Sunyer).Villarroel, 170. 08036 Barcelona. Email: [email protected]

List of acronyms quoted in the text:BMI: body mass index; DM: diabetes mellitus; DPP: Diabetes Prevention Program; DREAM: Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication; IDDP-1: Indian Diabetes Prevention Program 1; IFG: impaired fasting glucemia; ONTARGET: Ongoing Telmisartan Alone andin Combination with Ramipril Global Endpoint Trial; PIPOD: Pioglitazone in theprevention of Diabetes; Reduced: reduced oral glucose tolerance OGT;STOP-NIDDM: Study to Prevent non Insulin Dependent Diabetes Mellitus; TRIPOD: Troglitazone in prevention of Diabetes; T2D: type 2 diabetes mellitus;XENDOS: Xenical in the Prevention of Diabetes in Obese Subjects Study.

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cular). It has not to be forgotten, moreover, that the inter-mediate situations between normality and DM are notonly evident risk situations for the development of thisdisease. There are a lot of epidemiologic evidences thatshow that the risk of showing some cardiovascular dis-ease events (CVE) are substantially increased in thosesituations that undergo glycemias between normalityand diabetes.4 If we take into account that the disor-ders in the tolerance to glucose are part and appear fre-quently together with other components of the so-called metabolic syndrome, these Þndings are easily under-standable.

There is no doubt that, when DM prevention studies areevaluated, the initial approach of choice would be theimplementation of healthy changes in the lifestyle. It istrue that, when it is analysed what is understood and isapplied as “intensive changes in the lifestyle” in thegreat prevention studies, one asks oneself if these proto-cols are extendible to the daily routine. Nevertheless, ifwe take into account such considerable efÞciency thatthey have showed, any change, as small as it can be, of-fers us clinically relevant results. At present, there is noconsensus as regards to the use or not of drugs in casethat the previously mentioned measures are not sufÞ-cient. There is neither consensus about which drug to useÞrst, on which sort of patient and for how long.

Diabetes prevention studieswith pharmacology interventionsThough there were previous studies directly leading toprevent the T2D and other studies that, in post hoc anal-ysis, have stopped as regards to this subject, it was notuntil 2001 when, successively, the results of four studiescame forth, randomized and controlled, in subjects with reduced oral glucose tolerance (reduced OGT) and im-paired fasting glucemia (IFG), whose primary objectivewas to evaluate different strategies addressed to preventT2D. The four studies included the essential number ofpatients that ensures a high reliability of the obtained re-sults. Moreover, almost simultaneously, the results ofother great studies were published in which, though thepresence of reduced OGT, which was not a requirement,different strategies for the prevention of the disease wereevaluated in individuals with high risk to suffer it. Theresults of these last studies were the Þnal support to con-vince that T2D is a disease that can and must be prevent-ed (table 1).

Several drugs have been studied in order to evaluate theprevention of new cases of DM in subjects with inter-mediate stages between normality and T2D. Amongthese drugs, some stand out that usually is used to treatthe DM per se (metformin, ascarbose and glitazones)and others used as drugs for the reduction of weight(orlistat).

MetforminThis drug is undoubtedly the most studied one as re-gards to the prevention of DM. The most numerous co-horts of patients that have been evaluated in interven-tion studies with this drug are the one included in theDiabetes Prevention Program (DPP)5 study. The sub-jects included in the study represented the Americanpopulation and those of different origins: mean age50.6, approximately 70% were women, 57% were menand 73% of the women were obese (body mass index[BMI]: >30 kg/m2, 70% had family history of T2D and305 of arterial hypertension, and approximately a thirdpart of them had lipid metabolic disorders. Moreover,the fasting glycemia had to be between 95 and 125 mg/dL.

Table 1. Characteristics and results of the maintudies on the prevention of T2D with pharmacological intervention in subjects with OGRT

Study n Intervention Intervention effect (NNT)

DPP5 3,234 Placebo

Metformin

Lifestyle changes

–31%/14

–58%/7

I-DPP-17 531 Placebo

Metformin

Lifestyle changes

Combination of both

–26.4%/6.9

–28.5%/6.4

–28.2%/6.5

STOP-NIDDM8 1,429 Placebo

Acarbose –25%/11

XENDOS10 3,304 Placebo + lifestyle changes

Orlistat + lifestyle changes –37%/36

TRIPOD11 236 Placebo

Troglitazone –58%/6

DREAM14 5,269 Placebo

Rosiglitazone –62%/7

NNT: number of individuals needed to be treated in order to prevent a case;reduced OGT: reduced oral glucose tolerance.

Seminars on diabetesPharmacological interventions to prevent type 2 diabetes. M. Giménez Álvarez, et al.

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To sum up, these were individuals with high risk of re-duced OGT.

The 3234 patients were distributed randomly in threetypes of intervention: a) a group at intensive lifestylechanges (open study, 1,079 individuals); b) a group atplacebo (1,082 subjects) and c) a third group to receivemetformin 850 mg/12 h (these two last ones, doubleblind: 1073 subjects). Considering the obtained results,the follow-up period of the DPP study was interrupted ayear before what has been stated in the initial protocol,and ended with a mean follow-up period of 2.8 years.The therapeutic compliance with metformin was excel-lent during the study and in spite of the foreseeable gas-trointestinal effects and the drug dosage; it reduced therelative DM risk in 31% versus placebo.

While the ethnic origin and the sex of the subjects didnot have a relevant inßuence in the results of the inter-ventions performed in the DPP study, the effects of thepatients’ age, the BMI and the baseline glycemia valuedeserve a separate comment. In the youngest individuals(especially in those ≤44 years of age) metformin was aseffective as the measures on lifestyle (44 and 48% of re-duction, respectively), while the beneÞts obtained in thesubjects over 60 years of age were not so important.Higher beneÞts with metformin were also observed inthose individuals with a level II obesity (51% of reduc-tion compared to placebo). As regards to the inßuence ofthe fasting glycemia Þgures, it has to be pointed out thatthe highest reduction in the onset of T2D with metform-in occurred in those individuals with glycemia between110 and 125 mg/dL (48%), quite similar to 63% ob-tained by the lifestyle changes.6 To sum up, metformin isespecially useful in young and obese patients and thosethat have IFG.

Recently, the results of two studies have been publishedin India and China, in which similar results have beennotiÞ ed using 250 mg of metformin (2 or 3 times a day).The Indian Diabetes Prevention Program 1 (I-DPP-1)7

states, for the Þrst time, that the combination of met-formin and lifestyle changes is not more effective thanthe single use of these last ones. In second place, itshows that, at least in the Indian population, the use ofmetformin in doses lower than those used in the DPP isas effective as the healthy changes in the lifestyle. And inthird and last place, this study suggests that the efÞcien-cy in the lifestyle changes in this type of population is

lower than the one observed in other studies (reductionof the new cases of T2D in 28%).

AcarboseThe alpha-glycosidase inhibitor, ascarbose, has alsobeen evaluated in several studies for the prevention ofDM. The most outstanding one is the Study to Prevent NonInsulin Dependent Diabetes Mellitus (STOP-NIDDMtrial).8 It is an international study (Canada, Spain, Ger-many, Austria, Israel and Scandinavian), multicenter, ran-domized and placebo controlled that assessed the useful-ness of ascarbose when preventing or delaying theconversion of reduced OGT to T2D. For this, 1429 indi-viduals were included (mean BMI: 31 kg/m2, mean age:55; 50% women) with reduced OGT and that besides,had fasting glycemia of >100 mg/dL. The use of acar-bose reduced the onset of T2D in 25% during a meanfollow-up period of 3.3 years. The number of patients to treat during 3 years in order to prevent T2D was of 11.Likewise, it increased the normalization rate of the oralglucose tolerance. It is necessary to point out that thebeneÞcial effects of acarbose have been obtained in allthe included age groups (40-70 years of age), in bothsexes and in any BMI value. Though the adverse effects(gastrointestinal mainly) were more frequent in thegroup of patients who received acarbose, no serious ad-verse effect could be observed in any case.

On the other hand, taking into account that the cardio-vascular events are the main cause of death of the pa-tients with T2D and that to a great extent these deathsjustify the excess of cost that represents for the healthsystems, it is logic that the possibility of preventing T2Dmakes us look for the reduction in the incidence of CVD.Most of the studies addressed to prevent the disease havedemonstrated that this prevention is associated to an im-provement in other cardiovascular risk factors. However,only the STOP-NIDDM proved (in a secondary objec-tive of the study, indeed) a reduction of 49% in the onsetof any cardiovascular event and of a heart attack up to91% associated to the use of acarbose.9

Agents for the reduction of weight: orlistatIn Xenical in the Prevention of Diabetes in Obese Sub-jects Study (XENDOS)10 3305 patients with a BMI ≥30kg/m2 have been included. Randomly, they have beendistributed to an intervention arm with lifestyle changes and orlistat (120 mg/3 times a day) or to the use of suchlifestyle changes together with placebo. The 79% of the

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included patients had a normal oral glucose tolerance,and 21% had a reduced OGT. After 4 years of treatment,the accumulated incidence of T2D in the patients whoreceived placebo was of 9% while in those who receivedorlistat was of 6.2%. These data suggest a risk reductionof 37.3%. The use of orlistat was associated to a meanreduction in the weight of 5.8 kg compared to 3 kg ob-tained in the group that only undertook lifestyle changes.The data of the XENDOS study indicate, once more, the close existing relation between the presence of obesityand the risk of developing T2D.

GlitazonesThe insulin sensibilizing properties of glitazones gener-ated a general enthusiasm from the beginning consider-ing a possible role in the prevention of DM. In the Tro-glitazone in Prevention of Diabetes (TRIPOD)11 study,the use of troglitazone was assessed for the preventionof DM in 266 patients of Hispanic-American originwith previous gestation diabetes history. Troglitazoneor placebo was administered to the patients randomly(400 mg/day). During 30 months of follow-up (mean),the annual incidence of T2D was of 12.1% in the place-bo group and 5.4% in the group of women who receivedtroglitazone. In other words, the use of the drug reducedthe onset of T2D in 51%. It has to be mentioned that the troglitazone was withdrawn from the market due to itshepatotoxic effects.

Recently, this same group and those patients who endedthe TRIPOD study without T2D (89 women) decided touse pioglitazone in an open, observational study, withthe aim of assessing its effects in pancreatic beta-cellfunction, as well as in the sensitiveness to the insulin andin the incidence of T2D. It is the Pioglitazone in the Pre-vention of Diabetes (PIPOD) study.12 With the cautionwith which the results have to be considered as regardsto a study of these characteristics, the authors demon-strated beneÞcial effects on those parameters involved inthe pathogeny of the T2D.

Afterwards, the Diabetes Reduction Assessment study withRamipril and Rosiglitazone Medication (DREAM)13,14

included 5,269 participants (24,872-screened subjects)of origin population of four of the Þve continents tocompare rosiglitazone and ramipril simultaneously. It is astudy with a design of 2 × 2 factors, placebo controlled,multicenter and of international participation (21 coun-tries), that included patients with reduced oral glucose

tolerance and/or fasting altered glycemia. This study as-sessed the efÞciency of ramipril and rosiglitazone in aprimary target made up of the T2D onset and death forany reason. As it was expected in a study of these char-acteristics, a series of secondary objectives were also in-cluded, among which the cardiovascular and renal events.The sort of participants was similar to those included inprevious studies of this class: patients between 50 and 60years of age, with overweight or obesity and with thefrequent presence of arterial hypertension, dyslipedemiaand other features that make up the so-called “metabolicsyndrome”.

In the case of the ramipril effectiveness, and in a cleardiscrepancy with what could be expected by the resultsof the previous studies, the use of this anti-hypertensivedrug did not reduce the onset of new T2D cases. In anycase, it has to be pointed out that ramipril had beneÞ-cial effects on the carbohydrate metabolism that haveto be taken into account. The case of rosiglitazone wascompletely opposite. The use of this glitazone reducedthe T2D onset and the death incidence (primary objec-tive) in 60% and the incidence of new isolated T2Dcases in 62%. In other words, a reduction of the samemagnitude to the one obtained by the lifestyle changesin previously published studies. It is worth to mentionthat this effect took place both in men and women inthe same way, regardless to the age, the origin conti-nent, the glucose tolerance impairment, the weight andthe localization of the adiposity of the subjects. In theconglomerate of cardiovascular events that made up thesecondary objective, there were no relevant results.However, it has to be mentioned that in the group thatreceived rosiglitazone 14 cases were observed withcongestive heart failure, versus only 2 in the placebogroup.

Other drugsThe post hoc analysis of different studies has suggestedthe possible beneÞt of the angiotensin-converting en-zyme inhibitors in the DM prevention. Ramipril was as-sessed in the DREAM study with negative results on thisregard, as it has already been mentioned. In the sameline, a secondary target of the ONTARGET study15 as-sessed again the effectiveness of ramipril and telmisartanin patients with vascular disease or high risk of DM. Inthis sub-study, 5,427 patients were included of the grouptreated with ramipril, 5,294 of the telmisartan group and 5,280 of the combined treatment group. However, none


121

of the drugs in neither monotherapy nor the combinationof both was associated to a lower incidence of new DMcases during the mean follow-up of 56 months.

Also in a post hoc way, the West of Scotland CoronaryPrevention Study16 suggested that the use of pravastatinmight have a potential beneÞt in the prevention of DM.However, this hypothesis has not been assessed by anyrandomized clinical trial.17-19

Finally, preliminary in vitro studies which used newtherapies for the treatment of T2D, such as the GLP-1analogues (exenatide) or the DPP-IV inhibitors, suggestthat these therapies do not only improve the insulin se-cretion, but also boost up the proliferation of the betacells.20 In this way, there is a possibility that these agentsmight also be useful on this regard, though we have towait for speciÞcally designed new clinical trials to replythis question.

Final considerationsThere is no doubt that at present we do not make anymistakes if we assert that we are able to delay the onset of T2D with the combination of health lifestyle habitsand some drugs.21 Nevertheless, it has to be pointed outthat this beneÞ cial effect has been demonstrated in veryspeciÞc population groups, as subjects with overweight /obesity, approximately of 50 years of age and with inter-mediate impairments of oral glucose tolerance. The ex-tension of these results to other populations cannot bedone without due care.

Though for some persons this is only a “semantic” dis-cussion, it is true that none of the interventions used upto date levels the curve of T2D incidence in the preven-tion studies performed in individuals with reduced OGT.In other words, the natural history of the disease, thoughslowed down, progresses inexorably. Moreover, the factof using drugs used in the treatment of T2D once it hasbeen diagnosed complicates the discussion more. It has tobe pointed out that, though it is mentioned repeatedlythat the positive effects of the glitazones when prevent-ing the onset of T2D in the group of Hispanic women re-main even when the drug is withdrawn (TRIPOD study),the number of individuals included and the minimumnumber of new T2D cases does not allow to determine adeÞnitive conclusion on this regard.11A total of 1,274 pa-tients of the DPP study randomized to placebo or met-

formin took part in a “wash-out period” at the end of thestudy. After two weeks of leaving both treatments, thecondition of carbohydrate tolerance was assessed inthese subjects. The conversion rate of reduced OGT toT2D after considering the study and wash-out periodswas still relevantly lower in the metformin group.22 Inconclusion; only one part of the “preventive” effect ob-tained with metformin might be attributed to its purelypharmacological effects on the glycemia. In the STOP-NIDDM and DREAM studies, the results obtained inthis sense were quite similar. In other words, once thedrug was withdrawn, its effect was reduced and thephysiopathologic process that underlies starts again at itsusual speed.

Opinion of the scienti$c societiesThere is no doubt that the initial approach of choice inthe prevention of T2D based on the results of the men-tioned studies is to perform healthy changes in life-style.23 Even so, it is also true when analysing what isunderstood and is applied as intensive changes of life-style in the great prevention studies, one has to ask one-self if these protocols are extendible to the daily practice.However, its effectiveness is such that any change, assmall as it might be, might offer us clinically relevant re-sults. In any case, there is no consensus as regards to theuse or not of drugs in case that the previously mentioned measures are not sufÞcient, and to which drug to useÞrst, on whom and during how long.24

In 2007, the International Diabetes Federation pub-lished for the Þrst time a consensus document about theprevention of T2D. A proposal of a plan based on thecontrol of modiÞable risk factors in persons with highrisk to develop T2D and in the general population wasstated. Regardless of the risk group, measures of pro-gressive use are stated as well as the use of drugs (met-formin and acarbose) in those persons of high risk inwhich the lifestyle changes are considered inefÞcient.25

For some years, the American Diabetes Association inits general recommendations states in a similar mannerand includes the use of metformin as feasible.26 Finally,in the consensus of 2008 between the American Asso-ciation of Clinical Endocrinologist and the AmericanCollege of Endocrinology, the pharmacological inter-vention is considered in similar situations by using sev-eral drugs, as follows: metformin, acarbose, orlistat orglitazones.27

Av Diabetol. 2009;25:117-23

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ConclusionsWith the initial certainty that we have to and can preventthe T2D, during the following years we will expect thepublication of several studies that shall prove and com-plement what we know up to date about T2D prevention.In most of them there has been a substantial change asregards to the problem approach, speciÞcally, the pre-vention of the cardiovascular disease included as prima-ry objective. The NAVIGATOR study that uses nategli-nide and valsartan, the ORIGIN study, with insulinglargine, the CANOE study that uses rosiglitazone andmetformin, and the ACT-ON study that analyses the ef-fects of pioglitazone, are some of them. ■

Declaration of potential con!ict of interestM. Giménez gave conferences for Glaxo-Smith-Kline andMerck-Sharp-Dhome. I. Conget gave conferences for Glaxo-Smith-Kline, Merck-Sharp-Dhome, Novartis, SanoÞ-Aventisand Eli-Lilly and has been part of the Direction Committee of the STOP-NIDDM and DREAM studies.

References1. Conget I. Diagnosis, classification and pathogenesis of diabetes mellitus.

Rev Esp Cardiol. 2002;55:528-38.2. Alberti KG, Zimmet PZ. Definition, diagnosis and classification of diabetes

mellitus and its complications. Part 1: diagnosis and classification ofdiabetes mellitus provisional report of a WHO consultation. Diabet Med. 1998;15:539-53.

3. King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025:prevalence, numerical estimates, and projections. Diabetes Care.1998;21:1414-31.

4. Glucose tolerance and mortality: comparison of WHO and AmericanDiabetes Association diagnostic criteria. The DECODE study group.European Diabetes Epidemiology Group. Diabetes Epidemiology:

Collaborative analysis Of Diagnostic criteria in Europe. Lancet.1999;354:617-21.

5. Knowler WC, Barret-Connor E, Fowler SE, Hamman RF, Lachin JM, WalkerEA, et al. The Diabetes Prevention Program Research Group. Reduction inthe incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.

6. Conget I, Pellitero S. Metformina y prevención de la diabetes mellitus.Actualización de metformina en el síndrome metabólico. Med Clin (Barc).2004;5:23-7.

7. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V.Indian Diabetes Prevention Programme (IDPP). The IDPP shows thatlifestyle modifi cation and metformin prevent type 2 diabetes in Asian indiansubjects with impaired glucose tolerance. Diabetologia. 2006;49:289-97.

8. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M.Acarbose can prevent the progression of impaired glucose tolerance to type2 diabetes mellitus: the STOP-NIDDM Trial. Lancet. 2002;359:2072-7.

9. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M.Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA. 2003;290:486-94.

10. Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in theprevention of diabetes in Obese Subjects (XENDOS) study: a randomised study of Orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care. 2004;27:155-61.

11. Azen SP, Peters RK, Berkowitz K, Kjos S, Xiang A, Buchanan TA. TRIPOD(TRoglitazone In the Prevention Of Diabetes): a randomized, placebo-controlled trial of troglitazone in women with prior gestational diabetes mellitus. Control Clin Trials. 1998;19:217-31.

12. Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, et al. Effectof pioglitazone on pancreatic beta-cell function and diabetes risk in Hispanicwomen with prior gestational diabetes. Diabetes. 2006;55(2):517-22.

13. Bosch J, Yusuf S, Gerstein HC, Pogue J, Sheridan P, Dagenais G, et al.The DREAM trial investigators. Effect of ramipril on the incidence ofdiabetes. N Engl J Med. 2006;114:1551-62.

14. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, et al.The DREAM trial investigators. Effect of rosiglitazone on the frequencyof diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet. 2006;368:1096-105.

15. Yusuf S, Teo KK, Poque J, Dyal L, Copland I, Schumacher H, et al. TheONTARGET trial investigators. Telmisartan, ramipril, or both in patientsat high risk for vascular events. N Engl J Med. 2008;358:1547-59.

16. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, et al.Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary PreventionStudy. Circulation. 2001;103:357-62.

17. Collins R, Armitage J, Parish S, Sleigh P, Peto R. Heart Protection StudyCollaborative Group. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5,963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-16.

18. Keech A, Colquhoun D, Best J, Kirby A, Simes RJ, Hunt D, et al. Secondaryprevention of cardiovascular events with long-term pravastatin in patients with diabetes or impaired fasting glucose: results from the LIPID trial. Diabetes Care. 2003;26:2713-21.

19. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al.Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-LipidLowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.Drugs. 2004;64:43-60.

20. Meece J. Pancreatic islet dysfunction in type 2 diabetes: a rational target forincretin-based therapies. Curr Med Res Opin. 2007;23:933-44.

21. Padwal R, Majumdar SR, Johnson JA, Varney J, McAlister FA. A systematicreview of drug therapy to delay or prevent type 2 diabetes. Diabetes Care.2005;28:736-44.


• The initial option approach in the prevention ofT2D is to undertake healthy lifestyle changes.Provided its efficiency, any small change mightoffer clinically relevant results.

• At present, some scientific societies as IDF, ADAor the ACE/AACE, consider the use of drugs (me-tformin, acarbose) in those persons at high risk inwhich the lifestyle changes are considered ineffi-cient.

• Metformin is especially useful in young patients,obese subjects and those with IFG, though only apart of the obtained “preventive” effect is attribu-ted to the effects on glycemia.


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22. Effects of withdrawal from metformin on the development of diabetes in the diabetes prevention program. Diabetes Care. 2003;26:977-80.

23. Lindström J, Ilanne-Parikka P, Peltonen M, Aunola S, Eriksson JG, Hemiö K,et al. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet.2006;368:1673–79.

24. Costa A, Conget I, Gomis R. Impaired glucose tolerance. Is there a casefor pharmacological intervention? Treat Endocrinol. 2002;1:205-10.

25. Alberti KGMM, Zimmet P, Shaw J. International diabetes federation: aconsensus on type 2 diabetes prevention. Diabet Med. 2008;24:451-63.

26. American Diabetes Association. Standards of Medical Care in Diabetes-2008. Diabetes Care. 2008;31:S12-S54.

27. Jellinger PS, Davidson JA, Blonde L, Einhorn D, Grunberger G, HandelsmanY, et al. Road maps to achieve glycemic control in type 2 diabetes mellitus:ACE/AACE Diabetes Road Map Task Force. Endocr Pract.2007;13(3):260-8.


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IntroductionSmoking increases the cardiovascular risk both in thediabetic population and in the non-diabetic.1 However,considering that the persons with diabetes mellitus (DM)have already an increased cardiovascular risk due to thedisease,2,3 increasing it more by the consumption of to-bacco constitutes a dangerous behavior. The complica-tions risk associated to the consumption of tobacco

added to the diabetes is 4 times higher than smoking orhaving diabetes when it is considered separately.4

Besides this increase of cardiovascular risk, there areworks that refer that some of the products that are inha-led when smoking, as nicotine, might determine a reduc-tion of the insulin sensitivity,5 therefore the consumptionof tobacco might be related both to an increase of theDM risk in the smoking population and to an increase of the micro/macro vascular complications in this popula-tion.6,7

Thus, tobacco and diabetes constitute a “dangerous com-pany”, which is why the measures addressed to reducethe consumption of tobacco are a comprehensive part of

AbstractIntroduction: Nicotinism is a cardiovascular risk factor that increas-es the risk of both macrovascular as well as microvascular complica-tions in the diabetic population. Material and method: A total of440 patients were studied and a survey was used to assess theirtobacco use, its relationship to age and gender, the degree of nico-tine dependence, the level of motivation to stop smoking and thephase of tobacco cessation. Results: the rate of nicotinism in the dia-betic population was 17%, and it was highest among people withdiabetes under the age of 50 (47.6%). The women had a higherrate of prevalence of nicotinism under the age of 40 (45.4%), whilefor men the rate was highest between the ages of 40 and 50(57.9%). Conclusions: Although the nicotine dependence is minor,the desire among diabetic patients to stop smoking is very limited.Therefore, health professionals involved in the treatment of diabeticpatients must pursue an active policy to control nicotinism with thesame determination with which other cardiovascular risk factors arecontrolled in this population.

Keywords: diabetes mellitus, nicotinism, Fagerström test, Rich-mond test, cardiovascular risk.

ResumenIntroducción: El tabaquismo constituye un factor de riesgo cardio-vascular que incrementa el riesgo de complicaciones, tanto macrovas-culares como microvasculares, en la población diabética. Material ymétodo: Se estudió a un total de 440 pacientes y se valoró median-te encuesta su hábito tabáquico, su relación con la edad y el sexo, elgrado de dependencia nicotínica, el grado de motivación para dejar defumar y la fase de abandono tabáquico. Resultados: La tasa de ta-baquismo en la población diabética fue del 17%, y era mayor en laspersonas con diabetes antes de los 50 años (47,6%). Las mujerestenían una prevalencia mayor de tabaquismo antes de los 40 años(45,4%), mientras que los varones la tenían entre los 40 y los50 años (57,9%). Conclusiones: Aunque la dependencia nicotínicaes leve, el interés de los pacientes diabéticos por dejar de fumar esescaso. Es necesario llevar a cabo una política activa por parte de losprofesionales implicados en el tratamiento de los pacientes diabéticos,con el objetivo de controlar el tabaquismo con el mismo empeño quelos otros factores de riesgo cardiovascular en esta población.

Palabras clave: diabetes mellitus, tabaquismo, test de Fagerström,test de Richmond, riesgo cardiovascular.

Date received: January 27th 2009Date accepted: January 18th 2009

Correspondence:M.A. Saavedra Blanco. CEP «Hermanos Sangro». c/ Peña Prieta, 4. 28038 Madrid.Email: [email protected]

Original article

Prevalence of tobacco use among diabetic patientsPrevalencia del hábito tabáquico en pacientes diabéticosM.A. Saavedra Blanco,1 R. Garrido Martínez,1 E. León Carralafuente,1 P. Vaquero Lozano,2 S. Solano Reina2

1Endocrinology Service. 2Anti-tobacco Unit. Centro de Especialidades “Hermanos Sangro”. Hospital “Virgen de la Torre”. Madrid

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the treatment of the patients with DM. Notwithstanding, there are only a few programs to stop smoking that havebeen focused on this risk group.

The objective of this work is to register the tobacco habitof the diabetic population assisted in a specialized areaconsultation, and set out the withdrawal of the tobaccoconsumption as control objective for the cardiovascularrisk factors in the diabetic patient. In order to make outthis study, we count with the collaboration of the anti-to-bacco unit of our center.

Material and method440 patients have been studied who attended to the endo-crinology outpatient consultation during the period com-prised between May and December 2007. The following aspects have been assessed: age, type of DM, years sincediagnosis, metabolic control, associated cardiovascularrisk factors (central distribution obesity, hypertensionand hyperlipemia), complications (micro/macro vascu-lar), sleep apnea and chronic obstructive pulmonary di-sease. The data related to the patient’s tobacco habit ha-ve also been collected: if the patient was a smoker, thedaily consumption of cigarettes, the level of physical de-pendence (simpliÞ ed Fagerström test, a validated surveydescribed in Annex 1)16 and the level of motivation tostop smoking (Richmond test, a validated survey descri-bed in Annex 1);17 if the patient was not a smoker, sincewhen and the level of tobacco consumption previous tostop smoking.

The smoker patients were informed about the dangerthat entails the consumption of tobacco for them, andwere invited to stop smoking, assessing the abandon-ment phase at that moment. If the patient had a Þrm pur-pose (preparation phase or action phase) and a high mo-tivation (Richmond test equal or higher than 8), thepatient was referred to the anti-tobacco unit of the center.

This is a descriptive study in which the absolute and re-lative frequencies are determined by the qualitative va-riables and the arithmetic mean, the mean and the stan-dard deviation for the quantitative variables.

ResultsFrom the 440 studied patients, 44 were diagnosed withT1D (21 women and 23 men) and 396 had T2D (231 wo-

men and 165 men). The gestational diabetes cases wereexcluded. The characteristics of the study diabetic popu-lation are depicted in table 1.

According to the distribution per genders, 252 were wo-men and 188 men; 75 were smokers (17%) and 365 we-re not smokers (83.0%) and from these, 163 (44.6%) we-re ex-smokers.

According to the distribution of smokers per ages, 26(34.7%) were over 61 years old, 18 (24%) were between51 and 60 years old 20 (26.7%) between 41 and 50, and only 11 (14.7%) were under 40 years old. The details aredescribed in table 2.

Table 3 depicts the distribution per ages correspondingto the ex-smokers group.

Considering the age of the patients with DM, in thegroup under 40 years old, 44% are smokers and 28% are ex-smokers; in the group of 41-50 years old , 44.4%smoke and 28.9% are ex-smokers; in the group of 51-60years old , 22.2% smoke and 45.7% are ex-smokers, and inthe group over 60 years old , 9% are smokers and 36.3%are ex-smokers.

Table 1

Mean Standard deviation Range

Age 64.2 13.2 21-90

Weight (kg) 77.3 14.8 39-136.9

Waist (cm) 104 14.2 70-146

Body mass index (kg/m2) 30.2 5.5 16.6-50.6

Years sincediagnosis

12.8 9.7 0-50

Glycosylated hemoglobin (%)

7 1.4 4-12.8

Table 2

Age (years)

Totalpopulation (n)

Smokers (n)

Women(n)

Men (n)

<40 25 11 5 6

41-50 45 20 9 11

51-60 81 18 9 9

>61 289 26 11 15

Total 440 75 34 41

Original articlePrevalence of tobacco use among diabetic patients. M.A. Saavedra Blanco, et al.

127

Considering the distribution per genders, 45.4% of thewomen smoke and 42.8% of men under 40 years old; inthe group of 41-50 years old , 34.6% of the womensmoke and 57.9% of the men; in the group 51-60 yearsold 21.4% of the women smoke and 23.1% of the men,and in the group over 60 years old , 6.4% of the wo-men smoke and 12.9% of the men. Table 4 depicts thisanalysis.

Taking into account the type of diabetes, the rate ofsmokers in patients with T1D is of 45.5%, while in thepatients with T2D it is of 13.9%.

Among the smokers, 69 of them consume cigarettes and the other 6 consume cigars. The mean consumption ofcigarettes is 24 per day and 5 cigars during a week.

In relation to the tobacco abandonment phase, the33.3% of the diabetic subjects (25 patients) are underthe pre-contemplation phase (they do not have the in-tention to stop smoking for the next 6 months), 28%(21 patients) under contemplation phase (are thin-king of stopping smoking in the next 6 months), 24%(18 patients) under preparation phase (shall try to stopsmoking during the next month) and 14.7% (11 pa-tients) under the action phase (withdrawal of less than6 months).

As regards to the nicotine dependence measured by theFagerström test, a mean ± standard deviation (SD) of 3.5± 2.3 was obtained and in the motivation to stop smo-king measured by the Richmond test the mean ± SD wasof 5.5 ± 2.5.

DiscussionThe tobacco constitutes an important modiÞ able cardio-vascular risk factor that increases the micro/macro vas-cular risk in the diabetic population.4 The withdrawal ofthe tobacco consumption shall constitute a target in thetreatment of this population, as the different treatmentguidelines include for the diabetic patients.8,9

In this work, the tobacco habit prevalence between ourdiabetic population is of 17%, similar to the one referredby other authors,10,11 and lower to the tobacco habit ratein the Spanish population according to the last health na-tional survey, placed at 27%.12

Considering the distribution per ages, we Þnd that, this isin relation with the distribution of the diabetes in ourpopulation, whose mean age is of approximately 65years old though the group with higher number ofsmokers is the one of >50 years old. However, we Þndthe higher rate of tobacco habit in the youngest diabetic subjects; thus, 44.3% smoke among those under 50 yearsold and 11.9% of the diabetic population among thoseover such age; similar percentages than those of the ge-neral population and of other diabetic series, where theyoungsters have higher rates of tobacco habit.10-12

Besides the smokers rate, the exposure to tobacco in dia-betic patients in some stage of their life is very high inour population; thus, in the non-smoker population the44.4% has been in some stage of their life, and this per-centage is higher than 80% in men.

Table 3

Age (years)

Ex smokers (n)

Women(n)

Men (n)

<40 7 3 4

41-50 13 7 6

51-60 37 11 26

>61 105 22 83

Total 162 43 119

Table 4

Age (years)

Total population(n)

Smokers (n)

Women(n)

Smokers’ women as regardsto the total of women (%)

Men (n)

Smokers’ men as regardsto the total of men (%)

<40 25 11 5 45.4 6 42.8

41-50 45 20 9 34.6 11 57.9

51-60 81 18 9 21.4 9 23.1

>61 289 26 11 6.4 15 12.9

Total 440 75 34 13.5 41 21.8

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It seems that the higher tobacco habit takes place in sub-jects aged 50 and from that moment the rate of ex-smokers increases, what makes us think that from thisage the diabetic patient starts to stop smoking.

We can think that the diabetes diagnosis is a motivationto stop smoking in our population and, therefore, the pa-tients stop smoking as from 50 years old. However, thisis unlikely, as we observe that the nicotinism rate in pa-tients with T1D is much higher than in patients with T2Dand this is in relation with the mean lower age of the Þrstones; in other words, the diabetic subjects, as the generalpopulation, smoke at early ages.

Considering the gender, a 50% of the women less than40 years old smoke, while the men smoke more fre-quently between 40 and 50 years, with a rate of 57.9%.This distribution per gender is also similar than the onereßected in the National Health Survey of 2006, issuedby the National Institute of Statistics.12

Transversal and prospective studies show a higher risk ofmacro/micro vascular disease in the diabetic population,with an increase of the early mortality in the smoker dia-betic population,3,4,13 moreover, there are evidences thatthe nicotine reduces the insulin sensitivity and increases the diabetes risk.4,5 In spite of all these data, the numberof diabetic persons is high, and in some series it doesnot differ from the non diabetic population.14 In our se-ries, the percentage of smokers is lower than the one ofthe National Health Survey of 2006, but suggests a per-centage of 17% with an increase in the younger groupsand in women. Moreover, the exposition to the tobaccoconsumption is very high, with more than 44% of ex-smokers, with the repercussion that it might have on thepossible diabetic complications.

The abandonment of tobacco habit implies an evident re-duction in the risk of vascular events, with a reduction ofthe risk in 36% of all the causes of mortality related wi-th diabetes.15 In spite of these evidences, a few strategiesperformed in order to reduce the consumption of tobac-co have been focused in this population and notwithstan-ding, the tests indicate that the active planning addressedspeciÞcally to the diabetic patients resulted in a reduc-tion of the smoker population of this group.10

The nicotinism is a cardiovascular risk factor that has tobe controlled in the diabetic population; therefore the re-

cord on the tobacco consumption is a datum that cannotbe missed in the revisions of these patients. In each re-vision, the patients have to be reminded about the addi-tional vascular risk that supposes tobacco consumption,recommending them the abandonment of such habit and facilitating them the treatments available in order to getabandon of tobacco habit.

From the 75 smokers of the study, 69 (92%) consume ci-garettes, with a mean of 24 per day. The 6 remainingconsume cigars in a mean quantity of 5 per week. Mo-reover, more than 33% of these smokers has not set outthe possibility of stop smoking, though all of them refer knowing the risk that this supposes for them, in spite of the fact that the nicotine dependence is light, with a sco-re in the Fagerström test of 3.5 (scores ≤4 indicate a lightdependence).18 All this states the need of a procedureaddressed to reduce the tobacco consumption in the dia-betic population, consistent in motivating the patientwho is not predisposed (in this population the motivationis scarce: Richmond test of 5.5; it is considered that inorder to include a smoker in a program to get abandon tonicotinism it is necessary that this test shows values bet-ween 9 and 10 points),18 to help the motivated patient toperform an attempt to stop smoking and to achieve thatthose who have tried can keep it and become an ex-smoker.

For this objective, we count with the collaboration of theanti-tobacco unit at our center, where we refer the pa-tients under preparation or action phase with a Rich-mond test of ≥8. The patients with an abandonment ex-pectation higher than a month, they are offered acustomized anti-tobacco advice, proposing them the re-duction of 50% in the current consumption of cigarettes and leaving all our help open for the moment in whichthe patient decides to face the total abandonment of to-bacco.

These data allow concluding that the prevalence of to-bacco habit in our diabetic population (17%), lower thanthe general population, is higher in patients less than 50 years old and in patients with T1D. The women smokemore in early ages (<40 years old) and the men between 40 and 50 years old.

The nicotine dependence is not high, but the motivationto stop smoking is scarce, therefore it is necessary to ca-rry out an active strategy by the professionals in charge

Original articlePrevalence of tobacco use among diabetic patients. M.A. Saavedra Blanco, et al.

129

Annex 1. Fagerström test and Richmond testSIMPLIFIED FAGERSTRÖM TEST

Physical dependence measurementAssesses the nicotine dependence level in a scale from 0 to 10 points.How much time passes since you wake up and smoke your Þrst cigarette?

Within 5 minutes............................................................................................................................................... 3 points6 to 30 minutes ................................................................................................................................................. 2 points31-60 minutes ................................................................................................................................................... 1 pointAfter 60 minutes .............................................................................................................................................. 0 points

Do you Þ nd it difÞcult not to smoke in places where it is forbidden?Yes .................................................................................................................................................................... 1 pointNo ..................................................................................................................................................................... 0 points

Which cigarette would difÞcult to give up?The Þ rst one in the morning ............................................................................................................................. 1 pointAny other .......................................................................................................................................................... 0 points

How many cigarettes do you smoke per day?Less than 10 cigarettes ...................................................................................................................................... 0 pointsBetween 11 and 20 cigarettes ........................................................................................................................... 1 pointBetween 21 and 30 cigarettes ........................................................................................................................... 2 pointsMore than 30 cigarettes .................................................................................................................................... 3 points

Do you smoke more during the Þ rst hours after waking up?Yes .................................................................................................................................................................... 1 pointNo ..................................................................................................................................................................... 0 points

Do you smoke if you are so ill that you have to be in bed?Yes .................................................................................................................................................................... 1 pointNo ..................................................................................................................................................................... 0 points

TOTAL.......................................... POINTS

Score lower or equal than 4: low nicotine dependenceScore with values between 5 and 6: mean dependenceScore equal or higher than 7: high nicotine dependence

RICHMOND TESTMotivation level measurement to stop smoking

Assesses the motivation to stop smoking in a scale from 0 to 10 points.Would you like to quit smoking if you could do it easily?

No ..................................................................................................................................................................... 0 pointsYes .................................................................................................................................................................... 1 point

How interested are you to quit smoking?Not at all ........................................................................................................................................................... 0 pointsA little ............................................................................................................................................................... 1 pointA lot .................................................................................................................................................................. 2 pointsVery interested .................................................................................................................................................. 3 points

Will you try to stop smoking in the following two weeks?DeÞ nitively not ................................................................................................................................................. 0 pointsPerhaps .............................................................................................................................................................. 1 pointYes .................................................................................................................................................................... 2 pointsDeÞ nitively yes ................................................................................................................................................. 3 points

How likely are you to be a non-smoker in the following six months?DeÞ nitively not ................................................................................................................................................. 0 pointsPerhaps .............................................................................................................................................................. 1 pointYes .................................................................................................................................................................... 2 pointsDeÞ nitively yes ................................................................................................................................................. 3 points

TOTAL.......................................... POINTS

Av Diabetol. 2009;25:125-30

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of the treatment of the diabetic population, rendering thesame attention to the treatment that to other cardiovascu-lar risk factors that are present in these patients. The ob-jective is to achieve the withdrawal of such consump-tion. The anti-tobacco advice and the therapeuticsavailable to abandon the consumption are a usual prac-tice in the handling and treatment of the patient withdiabetes. ■

Declaration of potential con!ict of interestM.A. Saavedra Blanco, R. Garrido Martínez, E. León Carrala-fuente, P. Vaquero Lozano and S. Solano Reina state that thereare no conß icts of interest as regards to the content of this arti-cle.

References1. Mynt PK, Welch AA, Bingham SA, Luben RN, Wareham NJ, Day NE, et al.

Smoking predicts long-term mortality in stroke: the European Prospective into Cancer (EPIC) Norfolk prospective population study. Prev Med.2006;42:128-31.

2. Tapp RJ, Balkau B, Shaw JE, Valensi P, Cailleau M, Eschwege E.Association of glucose metabolism, smoking and cardiovascular risk factorswith incident peripheral arterial disease: the DESIR study. Atherosclerosis.2007;190:84-9.

3. Mulnier HE, Seaman HE, Raleigh VS, Soedamah-Muthu SS, Colhoun HM,Lawrenson RA. Mortality in people with type 2 diabetes in UK. Diabet Med. 2006;23:516-21.

4. Wen CP, Cheng TYD, Tsai SP, Hsu HL, Chan HT, Hsu CC. Exploring therelationships between diabetes and smoking: with the development of «glucose equivalent» concept for diabetes management. Diabetes Res Clin Pract. 2006;73:70-6.

5. Meisinger C, Döring A, Thorand B, Löweln H. Association of cigarettesmoking and tar and nicotine intake with development of type 2 diabetes

mellitus in men and women from the general population: the Monica/Kora Augsburg Cohort Study. Diabetologia. 2006;49:1770-6.

6. Saito K, Sone H, Kawai K, Tanaka S, Kodama S, Shu M, et al. Riskimparted by various parameters of smoking in Japanese men with type 2 diabetes on their development of microalbuminuria. Diabetes Care.2007;30:1286-8.

7. Mühlhauser I, Bender R, Bott U, Jörgens V, Grüsser M, Wagener W, et al.Cigarette smoking and progression of retinopathy and nephropathy in type 1 diabetes. Diabet Med. 1996;13:536-43.

8. American Diabetes Association: clinical practice. Standars of Medical Carein Diabetes 2006. Diabetes Care. 2006;29:20S.

9. Documento 2005 de consenso entre varias sociedades científicassobre pautas de manejo del paciente diabético tipo 2 en España. Abordaje de otros factores de riesgo cardiovascular. Av Diabetol.2005;21:34-44.

10. Mollet C, Gray J, Saxena S, Netuveli G, Majeed A. Impact of pay-for:performance incentive on support for smoking cessation and smoking prevalence among people with diabetes. CMAJ. 2007;176:1705-10.

11. López-Guzmán A, Lozano JE, Álvarez C, Andía VM, Fraile AL. Hábitotabáquico y diabetes mellitus. Av Diabetol. 2006;22:223-7.

12. Encuesta Nacional de Salud. Ministerio de Sanidad y Consumo.Disponible en: www.msc/estadEstudios/estadisticas/encuestaNacional/encuesta 2006

13. De Cosmo S, Lamacchia O, Rauseo A, Viti R, Gesualdo L, Pilotti A, et al.Cigarette smoking is associated with low glomerular fi ltration rate in malepatients with type 2 diabetes. Diabetes Care. 2006;29:2467-70.

14. Gulliford M, Sedgwick J, Pearce A. Cigarette smoking, health status,socio-economic status and access to health care in diabetes mellitus: a cross-sectional study. BMC Health Serv Res. 2003;3:1-9.

15. Critchley J, Capewell S. Smoking cessation for a secondary prevention ofcoronary heart disease. Cochrane Library. 2007;4:1-52.

16. Balfour D, Fagerström K. Pharmacology of nicotine and its therapeutic usein smoking cessation and neurodegenerative disorders. Pharmacol Ther.1996;10:1-30.

17. Richmond R, Kehoe L, Webster I. Multivariate models for predictingabstention following intervention to stop smoking by general practitioner.Addiction. 1993;88:1127-35.

18. Barrueco M, Hernández M, Torrecilla M. Manual de prevención ytratamiento del tabaquismo. Madrid: Ergon, 2003.


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AbstractAims: The aim of this study is to describe the most frequent cardio-vascular risk factors (CVRF) clustering related to the metabolic syn-drome (MS) in a non-diabetic Spanish population sample. Test by fac-torial analysis if the CVRF in the MS can be considered manifestationsof a unique common factor. Materials and methods: Observational,multicenter, transversal epidemiologic study. 2583 subjects aged 30-65 were randomly assigned from nine population registries. Exclusiveaggregations were considered. Correlation among the MS variableswas analyzed using factorial analysis. Results: In order of frequencythe prevalence of conventional CVRF was: dyslipidemia: 34% (CI95%:32-35.5); hypertension: 32% (CI95%: 30.2-33.8); obesity: 27%(CI95%: 25.3-28.7); hyperglycaemia: 23% (CI95%: 21.6-25).22% of the population showed 2 CVRF and 11% 3 CVRF. The most

common CVRF aggregations were hypertension-obesity (5.3%;CI95%: 4.4-6.2) and hypertension-obesity-hyperglycaemia(4.1%; CI95%: 3.3-5). MS specific risk variables tended to aggregatein three factors: factor 1 (BMI, waist circumference and basal glycae-mia), factor 2 (insulin, glycaemia 2h, and arterial blood pressure), fac-tor 3 (total cholesterol/HDL, triglycerides). Conclusions: There is ahigh prevalence of CVRF and MS in the population studied. Analysis ofthe metabolic syndrome does not contribute with additional informationto predict cardiovascular risk in susceptible patients, as compared tothe clustering of CVRF. Factorial analysis do not confirm the existenceof a unifying factor to explain MS.

Keywords: cardiovascular risk factors, metabolic syndrome, facto-rial analysis.

Date received: January 8th 2009Date accepted: March 16th 2009

Correspondence:R. Gabriel Sánchez. Investigation Unit, Hospital Universitario “La Paz”. Paseo dela Castellana, 261. 28046 Madrid. Email: [email protected]

Work financed with charge to the projects: FIS: 95/0029; PI06/90270,ERICE: G03/065, PI05/1464 and RECAVA: RD06/014/0015.

List of acronyms quoted in the text:AHT: arterial hypertension; BMI: body mass index; CVD: cardiovascular diseases;CVRF: cardiovascular risk factors; DAP: diastolic arterial pressure; HDL: high density lipoproteins; HOMA: Homeostasis Model Assessment; MAP: mean arterial pressure; MS: metabolic syndrome; NCEP-ATP III: National Cholesterol Education Program-Adult Treatment Panel III; SAP: systolic arterial pressure; TC/cHDL: totalcholesterol/Cholesterol bond to high density lipoproteins; VIVA: Variability ofInsulin with Visceral Adiposity; WC: waist circumference; WHO: World HealthOrganization.

Original article

Aggregation pattern and factorial analysis of cardiovascularrisk factors included in the metabolic syndrome in a Spanishnon-diabetic population: the VIVA study*Patrón de agregación y análisis factorial de los factores de riesgo cardiovascularintegrantes del síndrome metabólico en población española no diabética: estudio VIVAR. Gabriel,1 M. Alonso,1 J. Parra,2 J.M. Fernández-Carreira,3 G. Rojo-Martínez,4 C. Brotons,5 A. Segura,6 J, Cabello,7, J, Muñiz,8 S. Vega,9 J. Gómez-Gerique,10 M. Serrano-Ríos,11 on behalf of the Cooperation Group of VIVA StudyInvestigation Unit-Clinical Epidemiology. Red RECAVA. 1Hospital Universitario La Paz. Madrid. 2Hospital de Mérida. Badajoz. 3Hospital San Agustín. Avilés. 4Hospital Carlos Haya. Málaga. 5Hospital General de Vic. Barcelona. 6Instituto de Ciencias de Salud. Talavera de la Reina. Toledo.7Hospital General de Alicante. 8Instituto Universitario de Ciencias de la Salud. Universidad de La Coruña and Red RECAVA. Hospital Juan Canalejo.9Centro de Salud de Arévalo (Ávila) and Red RECAVA. 10Fundación Jiménez Díaz. Madrid. 11Hospital Clínico San Carlos. Madrid

*Cooperation Group of VIVA Study:Hospital Universitario La Princesa-La Paz, Madrid: R. Gabriel, G. Fernández,M. Alonso, F. Rodríguez Salvanés; Instituto Universitario de Ciencias de la Salud,Universidad de La Coruña y Centro de Salud Begonte (Lugo): J. Muñiz, I. López, Á.F. Lorenzo, C. Otero, E. Pardo, C. Pardo, J.M. Rábade, L. Sánchez, T. Pérez;Hospital de Vic (Barcelona): M. Pladevall, C. Blay, J. Espiñas, A. Ledesma, J. Oliva,A. Planas, A. Punete, R.M. Salla, J. Verdera, C. Brotons; Centro de Salud deArévalo (Ávila): S. Vega, L. de la Rosa, C. Gómez, L. López, M.P.Marques, C. Vian,M.N. García; Hospital General Universitario de Guadalajara: P. Horcajo, F. Carballo,J.R. Conejo, M.J. Gaspar, C.Martínez de Pancorbo, F.J. Mauleón, I. de la Villa;Centro Regional de Salud Pública, Talavera de la Reina (Toledo): A. Segura,B. Blanco, P. de Diego, C. Hernández, A. de Lucas; Hospital General Carlos Haya,Málaga: F. Soriguer, I. Esteva, G.Rojo-Martínez; Hospital General de Alicantey Centro de Salud San Vicente del Raspeig (Alicante): J. Cabello, C. Gisbert; Hospital General de Avilés: J.M. Fernández Carreira, J. Ferreiro, A.J. González,D. Pérez, A.M. Arias; Hospital General de Mérida: J. Parra. P. Sáenz de Aranzubia;Hospital Clínico de San Carlos, Madrid: M. Serrano-Ríos, M.T. Fernández Larrad;Fundación Jiménez Díaz, Madrid: J. Gómez-Gerique, A. Porres.

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ResumenObjetivos: Describir las agregaciones más frecuentes de los factoresde riesgo cardiovascular (FRCV) que integran con el síndrome metabó-lico (SM) en una muestra de población española no diabética. Compro-bar mediante análisis factorial si los diferentes FRCV considerados en el SM son manifestaciones de un posible único factor común. Material ymétodos: Estudio poblacional transversal, multicéntrico, realizado en2.583 sujetos de 30-65 años elegidos al azar de 9 registros poblacio-nales. Para el cálculo de la frecuencia de cada uno de los FRCV y de susagregaciones se utilizaron las definiciones clásicas de cada factor.Las agregaciones de factores se calcularon de forma excluyente. Lacorrelación entre los FRCV se realizó mediante análisis factorial. Resul-tados: De mayor a menor, la prevalencia de los distintos FRCV clásicosconsiderados en la defi nición del SM según el NCEP ATP III fue: dislipe-mia 34% (intervalo de confianza [IC] del 95%: 32-35,5); hipertensión32% (IC del 95%: 30,2-33,8); obesidad 27% (IC del 95%: 25,3-28,7) e hiperglucemia 23% (IC del 95%: 21,6-25). Se observan dife-rencias significativas entre sexos: predominaba la dislipemia en hombresy la obesidad en mujeres. El 22% de la población mostraba agregaciónde dos FRCV y el 11% de tres FRCV. Las agregaciones más frecuentesfueron: hipertensión-obesidad, 5,3% (IC del 95%: 4,4-6,2), e hiperten-sión-obesidad-hiperglucemia, 4,1% (IC del 95%: 3,3-5). Los FRCVconsiderados tienden en general a formar tres conglomerados: 1) índicede masa corporal, diámetro sagital abdominal y glucemia; 2) insulina,glucemia a las 2 horas y presión arterial, y 3) razón colesterol total/co-lesterol unido a las lipoproteínas de alta densidad y triglicéridos. En loshombres pueden identificarse hasta cuatro conglomerados de FRCV,mientras que en las mujeres éstos pueden reducirse hasta dos. Conclu-siones: La prevalencia de los distintos FRCV clásicos integrantes delSM según el NCEP ATP III es alta en la población española no diabética.La agregación obesidad-hipertensión arterial es la más frecuente. El aná-lisis factorial no demuestra la existencia de un único factor unificador quepermita explicar el conglomerado de factores que defi ne el SM. Se ob-serva una agrupación de FRCV distinta en función del sexo.

Palabras clave: factores de riesgo, síndrome metabólico, análisisfactorial.

IntroductionThe cardiovascular diseases (CVD) are a public healthproblem presenting high prevalence and because theyconstitute cause of death in the adult population in most of the countries.1 The knowledge of the main modiÞablecardiovascular risk factors (CVRF) allow to deÞne andintroduce cardiovascular prevention strategies, the deter-mination of the aggregation patterns of the differentCVRF among them are every day more important for the

evaluation and the cardiovascular risk factor.2 In fact, ithas been proved that the different CVRF interact posi-tively, so the cardiovascular risk arisen from the simulta-neous exposure to some of them is higher than the oneexpected from the simple addition of the risk corre-sponding to each one.3 At present, the need to treat thesubjects intensively who show multiple abnormalities inthe CVRF stand out, even in those who show minimallyaltered values.4 On the other hand, the contribution of thedifferent CVRF and the way in which they aggregateshow a great variability as regards to the different fac-tors, among which the gender has a relevant role, there-fore the strategies tend to be more customized everyday.5

All these facts are related directly to the onset of themetabolic syndrome (MS) entity, which was initially de-Þned as a risk factor in itself for the development of thecardiovascular disease (CVD) and T2D,6 and in whichthe insulin resistance or the glucose altered metabolismwas a main component. Then, the National CholesterolEducation Program-Adult Treatment Panel III (NCEP-ATP III) developed a more clinical proposal of the MS,7

based on the deÞnition of the World Health Organization(WHO), but in which the MS was considered an aggre-gation of individual factors that constituted a global en-tity, where the concurrence of three or more abnormali-ties in the values of its components was a mainrequirement for the diagnosis. Some later epidemiologic studies validated the existence of this aggregation ob-serving a higher frequency in the association of these ab-normalities than the per se random one.5 Subsequently,other deÞnitions have been developed,8 on which con-sensus was achieved regarding to the principal factorsthat deÞne the MS (glucose intolerance, obesity, hyper-tension and dyslypidemia) that, when observed thor-oughly, they coincide with the classic CVRF but in earlyphases, therefore the cut points are lower and its assess-ment form has been improved. In fact, the componentsof the MS can be assessed easily in the clinical practice, thus, the MS becomes a very efÞcient tool for the evalu-ation and prevention of the potential cardiovascular risk.However, it has to be clariÞed how these components in-teract among them, and if there is a physiological inter-relation that allows considering them as manifestationsof a unique entity.

The objectives of this study are to describe the aggrega-tion patterns of the main conventional CVRF that make

Original articleAggregation of cardiovascular risk factors in non-diabetic population. R. Gabriel, et al.

133

up the deÞnition of the MS in the adult non-diabeticSpanish population and to study if there are differencesbetween men and women. Secondly, to determine,through factorial analysis, the possible correlationsamong the different CVRF that are considered in theMS, how they interrelate among them and if they can beconsidered manifestations of a unique common factor.

Material and methodPopulationThe VIVA Project is an epidemiologic, transversal andmulticenter study, performed in 9 geographic zones inSpain: Arévalo (Ávila), Talavera de la Reina (Toledo),Guadalajara, Begonte (Lugo), Vic (Barcelona), Avilés(Asturias), San Vicente del Raspeig (Alicante), Mérida(Badajoz) and Pizarra (Málaga). In 1998, a stratiÞed ran-domized sample was collected by age and gender of2,959 subjects aged 35-64, among the population regis-tered at the municipal records of each of the involvedsites. Finally, the analysis was done on a total of 2583patients (87.3%) from the 2,959 polled who had com-plete information for all the considered variables andwho complied with the inclusion criteria: non-diabeticsubjects and non-pregnant women (Þ gure 1).

Procedures and determinationsThe methods employed for the determination of allconsidered variables are described widely in another

previous work.9 Brießy, the biochemical parameters(total cholesterol [TC] and cholesterol bound to highdensity lipoproteins [cHDL], triglycerides, glucose andinsulin) have been determined in a standard mannerand have been measured in a unique central laboratory(Fundación Jiménez Díaz of Madrid), qualiÞed by theSpanish Society of Clinical Chemistry; the measure-ments of the anthropometric variables (weight, heightand waist circumference [WC]) have been measuredwith mercury sphygmomanometer in the right arm,with the subject sitting and after 5 minutes of rest. Themeasures have been validated in a sample of partici-pants and three different persons have compared theobtained results.

Definitions of the cardiovascular risk factorsand metabolic syndromeThe CVRF included in the analysis are those that consid-er the MS deÞnition of the NCEP ATP III.7 The deÞni-tions that have been used to describe its frequency, dis-tribution and aggregation were: hypertension (AHT)≥140/90 mmHg or anti-hypertensive treatment;10 impair-ment of the glucose metabolism (plasmatic fasting glyc-emia ≥110 mg/dL, and/or 140-199 mg/dL after 2 hoursof oral glucose overload);11 obesity (body mass index(BMI) ≥30) and abdominal obesity (PC >102/88 cm,men/women);12 dyslipidemia (ratio CT/cHDL ≥ 5 mg/dLor hypoglycemiant treatment).7

The diagnosis of the MS was done considering the deÞ-nition of the NCEP ATP III, according to which the sub-jects shall comply with at least three of the following cri-teria: 1) WC >102/88 cm (men / women); 2) plasmaticfasting glycemia ≥110 mg/dL; 3) cHDL >40/50 mg/dL(men / women); 4) triglycerides ≥150 mg/dL; 5) systolicarterial pressure (SAP) ≥130 mmHg or diastolic arterial pressure (DAP) ≥85 mmHg.7

Statistical analysisThe variables with continuous distribution aresummed up through means and conÞdence intervals(CI) and those of discrete distribution through fre-quency charts. The statistical comparisons were per-formed by χ2 test for the discrete variables and theStudent t test for the continuous variables. For the as-sessment of the frequency of the different aggrega-tions of the CVRF, the aggregations were consideredin an exclusive manner. An exploration factorial anal-ysis was performed in order to determine the correla-

Figure 1. Flow of the VIVA transversal study population

Excluded n= 205

Random sampleAged 35-64 surveyed

n= 2,959

n= 2,754

Total analyzedn= 2,583

Incomplete data= 171

Inclusion criteriafor the analysisNon-Diabetic

Non-Pregnant

NO

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tions and the lowest number of factors that might ex-plain the MS. We used the Kaiser-Meyer-Olkin(KMO) index to determine the sample adequacy level.The mean arterial pressure (MAP) has been used toreduce the co-linearity in the EFA instead of the SAPand DAP. The method of maximum probability hasbeen used for the extraction of a factor that comparesthe adjustment goodness of the model of a factor withthe possible multifactorial model found in the EFA,separately for men and women.13

ResultsSocio-demographic characteristicsand clinic of the sampleThe socio-demographic and clinic characteristics of theentire study population and by genders are depicted intable 1. For all the studied parameters, except for SAPand BMI, the male population showed relevantly highervalues compared to women. The women had values rel-evantly higher regarding to the BMI than men (p <0.05)and there have not been differences between genders asregards to the SAP.

Prevalence of the cardiovascular risk factorsThe dyslipidemia was the most frequent risk factor(34%, CI of 95%: 32-35.5) in the entire population, fol-lowed by the AHT (32%; CI of 95%: 30.2-33.8), obesity(27%: CI of 95%: 25.3-28.7) and the alteration of the

glucose metabolism (23%; CI of 95%: 21.6-25). Whenwe analyzed the differences between genders, we ob-served that the men showed a relevantly higher preva-lence of dyslipidemia (p <0.05) and lower regarding toobesity compared to women (table 2). The prevalence ofMS, according to the criterion of NCEP- ATP III, in thesample as a whole was of 15% (CI of 95%: 13.8-16.6),relevantly higher (p <0.01) in men (19.5%) than in wom-en (14.7%). The prevalence of abdominal obesity was of27.3% (CI of 95%: 22-29) in the sample as a whole andrelevantly higher (p <0.01) in women (33.8%) than inmen (17.1%).

Aggregation number and patternof the cardiovascular risk factorsMost of the subjects of the population did not show anyCVRF (33%) or only one (32.5%). However, most of themen (35%) showed a CVRF, while most of the women(38%) did not show any (table 3).

22% of the population showed aggregation of twoCVRF: AHT-obesity (5.3%; CI of 95%: 4.4-6.2); AHT-dyslipidemia (4.1%; CI of 95%: 3.3-5) and obesity-dys-lipidemia (3.8%; CI of 95%: 3.1-4.6).

The principal aggregation patters in men are dyslipi-demia-AHT (6.4%) and dyslipidemia-hyperglycemia(6.1%), while the aggregation pattern AHT-obesity(6.8%) prevails in women.

Table 1. Socio-demographic and clinical characteristics of the sample

Variable Total Men Women p

N (%) 2,583 1,175 (45.5) 1,408 (54.5)

Age (years) 49 (48-49) 49 (48-49) 49 (48-49) 0.861

Tobacco consumption (yes/no) 794 (30.7) 533 (45.4) 261 (18.5) <0.001

SAP (mmHg) 126 (125-127) 126 (125-127) 126 (125-127) 0.918

DAP (mmHg) 79 (78-80) 80 (79-81) 78.5 (77.8-79.1) <0.05

BMI (kg/m2) 27.6 (27.5-27.8) 27.4 (27.1-27.6) 27.9 (27.6-28.2) <0.05

WC (cm) 94.7 (94.2-95.1) 95.6 (95.1-96.2) 93.8 (93.2-94.5) <0.001

Capillary glycemia (mg/dL) 96.9 (96.4-97.4) 99.3 (98.6-100.1) 94.9 (94.3-95.6) <0.001

HOMA Index 2.8 (2.7-2.9) 2.8 (2.7-3.0) 2.8 (2.6-2.9) 0.405

Total cholesterol (mg/dL) 221.4 (219.8-223) 223.9 (221.5-226.3) 219.3 (217.2-221.4) 0.005

Cholesterol HDL (mg/dL) 51 (50.5-51.6) 46.3 (45.5-47.1) 55 (54.3-55.7) <0.001

Triglycerides (mg/dL) 115.4 (112.6-118.2) 134.3 (129.4-139.2) 99.8 (99-102.5) <0.001

BMI: body mass index; DAP: diastolic arterial pressure; HOMA: Homeostasis Model Assessment; SAP: systolic arterial pressure; WC: waist circumference.Qualitative variables: n and %, quantitative variables: mean and confidence interval, statistical tests: χ2 and Student t.


135

11% of the population showed aggregation of threeCVRF: AHT-obesity-hyperglycemia (4.1%; CI of 95%:3.3-5), which is the most frequent aggregation both inmen and women. The aggregation of the four consideredfactors, hyperglycemia-AHT-obesity-dyslipidemia wasonly found in 1.9% of the sample (table 4).

Factorial analysis of the cardiovascular risk factorsconsidered in the metabolic syndromeIn a general manner, the considered CVRF tend togroup in three factor clusters that explain up to 61% ofthe variable. The Þrst cluster is constituted by the basalglycemia and the obesity. The second one includes theglycemia after 2 hours, the insulin and MAP. The MAPis superimposed with the Þrst cluster, therefore it canalso be considered as a component. The third clustercomprised blood lipids (CT/cHDL and triglycerides)(table 5).

On this regard, in men, the CVRF tend to group in fourclusters that explain up to 70% of the variable (factor 1:basal glycemia and triglycerides, factor 2: BMI and sag-ittal abdominal diameter; factor 3: glycemia after 2 hoursand insulin, CT/cHDL; factor 4: MAP).

In turn, in women, only two factors might explain up to59.1 of the variable (factor 1: BMI, sagittal abdominaldiameter, MAP; basal glycemia and after 2 hours and in-sulin; factor 2: triglycerides and CT/cHDL). The adjust-ment goodness of the test showed a value of p <0.001,

Table 3. Number of cardiovascular risk factorsfor the total population and per gender

Number of cardiovascularrisk factors

Total(n= 2,583)

Men (n= 1,175)

Women(1,408) p

0 853 (33) 324 (27.6) 529 (37.6)

<0.001

1 840 (32.5) 416 (35.4) 424 (30.1)

2 562 (21.8) 296 (25.2) 266 (18.9)

3 280 (10.8) 114 (9.7) 166 (11.8)

4 48 (1.9) 25 (2.2) 23 (1.6)

p= difference between men and women considering the number of factors. The total number of patients is depicted and between brackets the percentage that represents the sample in each category.

Table 4. Most frequent aggregations of the risk factorper gender and categories

Two risk factors n= 2,583 (%) Men Women

AHT-obesity 136 (5.3) 40 (3.4) 96 (6.8)

AHT-dyslipidemia 106 (4.1) 75 (6.4) 31 (2.2)

Obesity-dyslipidemia 98 (3.8) 68 (5.8) 30 (2.1)

Hyperglycemia-dyslipidemia 97 (3.8) 72 (6.1) 25 (1.8)

AHT-hyperglycemia 75 (2.9) 28 (2.4) 47 (3.3)

Three risk factors

AHT-hyperglycemia-obesity 106 (4.1) 45 (3.8) 61 (4.3)

AHT-hyperglycemia-dyslipidemia

91 (3.5) 35 (3) 56 (4)

AHT-hyperglycemia-obesity 42 (2.8) 17 (1.5) 25 (1.8)

Hyperglycemia-obesity-dyslipidemia

41 (2.7) 17 (1.5) 24 (1.7)

Four factor risks

Hyperglycemia-AHT-dyslipidemia-obesity

48 (1.9) 25 (2.1) 23 (1.6)

AHT: arterial hypertension.

Table 2. Prevalence of cardiovascular risk factors according to the gender and the presence of metabolic syndrome(NCEP- ATP III criteria)

Risk factors Total (n= 2,583) Men (n= 1,175) Women (n= 1,408)

Arterial hypertension (≥140/90 mmHg, treatment) 826 (32) 360 (30.6) 466 (33.1)

Hyperglycemia (fasting glycemia >110 mg/dL and/or 140-199 mg/dL after 2 h)

601 (23.3) 263 (22.4) 489 (24)

Obesity: BMI ≥30 (kg/m2)

Abdominal obesity: waist circumference >102/88 cmin men/women

698 (27)

1,196 (27.3)

271 (23.1)

275 (17.1)

427 (30.3)*

915 (33.8)*

Dyslipidemia (CT/cHDL ≥5) or treatment 871 (33.7) 556 (47.3) 315 (22.4)*

BMI: body mass index; TC/cHDL: total cholesterol/cholesterol bond to high-density lipoproteins. *Variables that show statistical meaning for the χ2 test (p<0.05). The total numberof patients is indicated and between brackets the percentage of the sample in each category.

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both for men and for women, and the null hypothesis ofexistence is rejected as regards of a unique factor as un-derlying.

DiscussionDuring the last decades we are considering an increasein the CVRF prevalence, as the hyperglycemia, the dys-lipidemia, the AHT or the obesity.14-16 In our case, theanalysis performed in the general non-diabetic Spanishpopulation places the dyslipidemia as the most prevalentof the considered CVRF (34%), followed by the AHT(32%), the obesity (27%) and the alterations in the glyc-emia (23%). These results are slightly different than the data described in other epidemiologic studies performed in our Þeld, that reveal that the prevalence of the AHTreaches 40% in mean life ages and the obesity approxi-mately 20%.17-19 This can be explained in part becauseour study is focused on the general population aged 35-64 (does not include elder population, in which the AHT is very high) and non-diabetic population (once excludedfrom the analysis the cases detected of diabetic patients),in which it is known that the prevalence of AHT is alsovery high.20 This can also be related with the differencesbetween sexes as regards to the prevalence and the meannumber of CVRF, since the menopausal and post-meno-pausal female population has an obesity and dyslipi-demia pattern that is similar to the men’s pattern than tothe young adult woman.21,22

When evaluating the repercussion of the CVRF on thecardiovascular risk, it is important to consider that the

different factors interact in a multiplying form amongthem; therefore the risk derived from the simultaneousexposure to some of them is higher than the one thatmight be expected from the simple addition of the cor-responding risk to each one. However, when analyzingthe physiopathology of the different CVRF aggrega-tions, it is more efÞcient to consider only the excludingaggregations (pure) among the factors. On this regard,the most usual aggregation in the whole of the samplewas the AHT-obesity with a global prevalence of 6%.Such aggregation of CVRF was also more frequent inwomen, but the aggregation AHT-dyslipidemia pre-vailed on men.

During the last decades, the appearance of the “meta-bolic syndrome” concept as cluster of several factors isgetting more importance in the clinical practice and theidentiÞcation of the individuals with MS provides op-portunities to intervene early in the processes that pre-dispose the development of CVD. The MS is integratedby several abnormalities that in an isolated manner donot constitute a deÞned disease, but in a concomitantmanner they make an associated clinical entity with ahigh risk of CVD. We have considered the deÞnition ofthe NCEP-ATP III for our study, which is the most usedone in clinical and in epidemiologic studies, and a goodoperative deÞnition, as it does not affect the involvedfactors. According to the criteria of NCEP ATP III, theprevalence of MS found in this study (15%) is slightlyhigher than the one assessed for the active Spanishworking population (10.2%)23 and lower to the one de-scribed in the American (25%)24 and European popula-

Table 5. Exploratory factorial analysis of the main CVRF in the population as a whole and per gender

FactorsTotal (60.6%) Men (69.6%) Women (59.1%)

Factor 1 Factor 2 Factor 3 Factor 1 Factor 2 Factor 3 Factor 4 Factor 1 Factor 2

Body mass index 0.810 0.226 0.846 0.273 0.731 0.378

Waist circumference 0.798 0.141 0.219 0.831 –0.245 0.747 0.197

Basal glycemia 0.629 0.213 0.118 0.701 –0.167 0.405 0.682 0.223

Glycemia after 2 h 0.148 0.799 0.757 0.136 0.526 0.131

Fasting insulin 0.503 –0.246 0.168 0.506 0.687

Mean arterial pressure 0.464 –0.194 0.542 0.906 0.689

Total cholesterol quotient/cHDL 0.856 0.247 0.442 0.676 –0.305 0.157 0.913

Triglycerides 0.314 0.809 0.825 0.168 0.155 –0.101 0.175 0.898

The values in bold represent the correlation quotients that are bound relevantly among them within each factor, making up an independent cluster of factors. The values betweenbrackets show the percentage of the total variable explained by the group of factors identified for the total of the sample (3 factors) for men (4 factors) and for women (3 factors).


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tion.25 However, it matches with the one described inthe international25 and national23 literature as regards toa higher frequency of MS in men than in women. Re-garding to the relation among the different componentsof the MS, it has been proved what is described in thegeneral population in relation to the association amongthe glycemia variables, obesity and MAP. Thus, the MScan be understood as a true reßection of the cardiovas-cular risk phenotype aggregations in the population.This study ensures the results of other studies,26,27 thatleave on record that it is frequent to Þnd physiological,metabolic factors in the population as well as strictlycardiovascular and states the inexistence of a commonuniÞer factor.

Moreover, it can be observed a different cluster in menand women that state what has been described in otherprevious works28,29 regarding the difference between sex-es in the factor involved in the MS. It seems to be a cen-tral nucleus bond to glucose metabolism, which in wom-en is closely related with the fat distribution in the bodyand with the AP, while in men it is related to lipid metab-olism and atherogenic index. These results support thetendencies that consider that the clinical approach shouldbe addressed to detect the CVRF in a customized man-ner.30 Therefore, the MS would pass to be a “primary ob-jective” in the prevention of the CVD in the therapeuticplans of patients at risk and not secondary, as other au-thors set out.31,32 So the efforts of future investigationsshall be addressed to optimize the prevention strategiesand the early detection of the factors that make such MSin the population at risk.

As conclusion, we point out that the prevalence of theCVRF in the general population is high. From them,the dyslipidemia is the most frequent one in the popu-lation as a whole, but the AHT is the most commonfactor present in all the aggregations. There are greatdifferences regarding to the prevalence and the aggre-gation of the CVRF in men and women. This can beproved by using factorial analysis that indicates a cor-relation between glucose metabolism and lipid param-eters in men and with obesity and AP parameters inwomen.

AcknowledgementsTo Ana Isabel Ortega for her help in the orthographiccorrection and the manuscript style. ■

Declaration of potential con!ict of interestR. Gabriel, M. Alonso, J. Parra, J.M. Fernández-Carreira,G. Rojo-Martínez, C. Brotons, A. Segura, J. Cabello, J. Muñiz,S. Vega, J. Gómez-Gerique, and M. Serrano-Ríos state thatthere are no conßicts of interest as regards to the content of thisarticle.

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2005;366:1512-4.2. Eckel RH, Kahn R, Robertson RM, Rizza RA. Preventing cardiovascular

disease and diabetes: a call to action from the American Diabetes Association and the American Heart Association. Diabetes Care.2006;29:1697-9.

3. Stern MP, Williams K, González-Villalpando C, Hunt KJ, Haffner SM. Doesthe metabolic syndrome improve identification of individuals at risk oftype 2 diabetes and/or cardiovascular disease? Diabetes Care.2004;27:2676-81.

4. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, et al.Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 1999;100:1134-46.

5. Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS, et al.Prevalence of obesity, diabetes, and obesity-related health risk factors.JAMA. 2003;289:76-9.

6. WHO consultation. Definition, diagnosis and classification of diabetesmellitus and its complications (I): diagnosis and classifi cation of diabetesmellitus. Non-communicable disease surveillance. Genève: World HealthOrganization, 1999.

7. Executive Summary of the Third Report of the National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).JAMA. 2001;285:2486-97.

8. Alberti KG, Zimmet P. Metabolic syndrome; a new world-wide definition.A Consensus Statement from the International Diabetes Federation. Diabet Med. 2006;23:469-80.

9. Balkau B, Charles MA, Drivsholm T, Borch-Johnsen K, Wareham N, YudkinJS, et al. (EGIR): frequency of the WHO metabolic syndrome in Europeancohorts, and an alternative definition of an insulin resistance syndrome.Diabetes Metab. 2002;364-76.

10 Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr,et al.; National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee onPrevention, Detection, Evaluation, and Treatment of High Blood Pressure.The JNC 7 Report. JAMA. 2003;289:2560-72.

11. American Diabetes Association. Report of the Expert Committee on theDiagnosis and Classifi cation of Diabetes Mellitus. Diabetes Care. 2003;26Suppl 1:5-20.

12. World Health Organization. Measuring obesity. Classification and descriptionof anthropometric data. Report on a WHO consultation on the epidemiology of obesity. Copenhague: WHO, 1988.

13. Álvarez R. Estadística multivariante y no paramétrica con SPSS. Aplicación a lasciencias de la salud. Capítulo 7: Componentes principales. Análisis factorial.El procedimiento factor. Madrid: Díaz de Santos, 1989; 231-63.

14. Marrugat J, Solanas P, D’Agostino R, Sullivan L, Ordovas J, Cordón F, et al.Estimación del riesgo coronario en España mediante la ecuación de Framingham calibrada. Rev Esp Cardiol. 2003;56:253-61.

15. Recommendations of the Second Joint Task Force of European and otherSocieties on Coronary Prevention. Prevention of coronary heart disease in clinical practice. Eur Heart J. 1998;19:1434-503.

16. Sánchez-Chaparro M, Román-García J, Calvo-Bonacho E, Gómez-Larios T,Fernández-Meseguer A, Sáinz-Gutiérrez J, et al. Prevalencia de factores de

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riesgo vascular en la población laboral española. Rev Esp Cardiol. 2006;59:421-30.

17. Gutiérrez-Fisac J, Royo-Bordonada M, Rodríguez-Artalejo F. Riesgosasociados a la dieta occidental y al sedentarismo: la epidemia de obesidad. Gac Sanit. 2006;20:48-54.

18. Aranceta J, Pérez Rodrigo C, Serra Majem L, Ribas Barba L, QuilesIzquierdo J, Vioque J, et al. Prevalencia de la obesidad en España:resultados del estudio SEEDO 2000. Med Clin (Barc). 2005;125:460-6.

19. Medrano Albero JM, Cerrato E, Delgado Rodríguez M, Boix Martínez R.Factores de riesgo cardiovascular en la población española: metaanálisisde estudios transversales. Med Clin (Barc). 2005;124:606-12.

20. Wingard DL, Barrett Connor E. Heart diasease and diabetes. Diabetes inAmerica. Washington, DC: US Govt Printing Office (NIH publ. n.º 95-1468), 1995;429-48.

21. Matthews KA, Kuller LH, Sutton-Tyrrell K, Chang YF, Tietjen GE, Brey RL.Changes in cardiovascular risk factors during the perimenopause and postmenopause and carotid artery atherosclerosis in healthy women editorial comment: premenopausal risk continuum for carotid atherosclerosis after menopause. Stroke. 2001;32:1104-11.

22. Bonithon-Kopp C, Scarabin PY, Darne B, Malmejac A, Guize L.Menopause-related changes in lipoproteins and some other cardiovascular risk factors. Int J Epidemiol. 1990;19:42-8.

23. Alegría E, Cordero A, Laclaustra M, Grimac A, León M, Casasnovas J, et al.Prevalencia del síndrome metabólico en población laboral española: registro MESYAS. Rev Esp Cardiol. 2005;58:797-806.

24. Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic syndromeamong US adults: findings from the Third National Health and NutritionExamination Survey. JAMA. 2002;287:356-9.

25. Matthews KA, Kuller LH, Sutton-Tyrrell K, Chang YF, Tietjen GE, Brey RL.Changes in cardiovascular risk factors during the perimenopause and postmenopause and carotid artery atherosclerosis in healthy women editorial comment: premenopausal risk continuum for carotid atherosclerosis after menopause. Stroke. 2001;32:1104-11.

26. Lempiainen P, Mykkanen L, Pyoralak K, et al. Insulin resistance syndromepredicts coronary heart disease events in elderly nondiabetic men. Circulation. 1999;100:123-8.

27. Meigs JB, D’Agostino RB Sr, Wilson PW, et al. Risk variable clustering inthe insulin resistance syndrome. The Framingham Offspring Study.Diabetes. 1997;46:1594-600.

28. Poulsen P, Vaag A, Kyvik K, Beck-Nielsen H. Genetic versus environmentalaetiology of the metabolic syndrome among male and female twins.Diabetologia. 2001;44:537-43.

29. Regitz-Zagrosek V, Lemkuhl V, Weickert MO. Gender differences in themetabolic syndrome and their role for cardiovascular disease. Clin ResCardiol. 2006;95:136-47.

30. Sakkinen PA, Wahl P, Cushman M, et al. Clustering of procoagulation,inflammation, and fibrinolysis variables with metabolic factors ininsulin resistance syndrome. Am J Epidemiol. 2000;152:897-907.

31. Bruno G, Merletti F, Biggeri A, Bargero G, Ferrero S, Runzo C, et al.Metabolic syndrome as a predictor of all-cause and cardiovascular mortality in type 2 diabetes: the Casale Monferrato Study. Diabetes Care.2004;27:2689-94.

32. Murray C, López A. Alternative projections of mortality and disability bycause 1990-2020: Global Burden of Disease Study. Lancet.1997;349:1498-504.


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Case descriptionThe neuropathic pain associated to the diabetes mellitus (DM) is sometimes so serious that the conventional the-rapies are not sufÞcient; therefore technical procedureshave to be used in order to improve the quality of life.

We present the case report of a male aged 52, with allergyto beta lactamases history, DM over 20 years of evolutionunder treatment with insulin, temporary hyperparatiroi-dism, high blood pressure (HBP) under treatment with an-giotensin-converting enzyme inhibitors (ACEI), chronicpancreatitis and previous events of nephritic spasms.

The patient was referred due to a serious neuropathicpain in the upper limbs (ULL) and lower limbs (LLLL),described as electric, burning pain with associated fe-eling disorders in hands and feet bilaterally, of 3 years ofevolution. The patient did not show visual or vascularimpairments. The pain interfered in the night rest. Thepatient associated back and cervical osteoarthrosic dege-nerative phenomena and the surgical approach.

AbstractDiabetes mellitus (DM) is a widespread disease among the generalpopulation which, because of the damaging effect of hyperglycemiaon the nervous or vascular structures, may lead to complicationswhich in many cases are difficult to treat. In general, neurologicaldisorders secondary to DM cause severe, painful processes. A greatmany clinical practice guidelines are available providing recommen-dations about different drugs to be used as a monotherapy or incombination, with varying degrees of evidence. Nevertheless, certainclinical situations show no response to pharmacological therapiesand, therefore, other resources have to be found and implementedto achieve analgesia. We present a case that was resistant to tradi-tional pharmacological treatments, in which analgesic control wasachieved through spinal cord stimulation systems.

Keywords: diabetic neuropathy, spinal cord stimulation, polyneu-ropathy.

ResumenLa diabetes mellitus (DM) es una patología ampliamente extendidaen la población general que, por el efecto perjudicial que ejerce lahiperglucemia sobre estructuras nerviosas o vasculares, puede ge-nerar complicaciones, en muchas ocasiones difíciles de tratar. Laalteración nerviosa secundaria a la DM ocasiona, por lo general, pro-cesos dolorosos graves. Existen multitud de guías de práctica clínicaque realizan recomendaciones sobre el uso de diferentes fármacosen monoterapia o combinados, con distintos grados de evidencia.Sin embargo, hay situaciones clínicas en las que no se produce res-puesta a las terapias farmacológicas, por lo que se buscan otrosrecursos para obtener la analgesia. Presentamos un caso resistenteal tratamiento convencional farmacológico, en el que se obtiene elcontrol analgésico mediante sistemas de estimulación medular.

Palabras clave: neuropatía diabética, estimulación medular, poli-neuropatía.

Clinical note

Treatment of severe diabetic neuropathy with spinal cordstimulationTratamiento de la neuropatía diabética grave mediante estimulación medularV.L. Villanueva Pérez,1 M.V. Silva Cedeño,2 L. Vaquer Quiles,2 J.A. de Andrés Ibáñez3

1Specialist in Family and Community Medicine. Multidisciplinary Unit of Pain Treatment. Consorcio Hospital General Universitario de Valencia.2Resident Physician in Anaesthesiology. Hospital Clínico de Valencia. 3Head of the Anaesthesia, Resucitation and Pain Therapeutic Service.Head of the Multidisciplinary Unit of Pain Treatment. Consorcio Hospital General Universitario de Valencia. Associate Professor of Health Sciences.Facultad de Medicina de Valencia.

Date received: January 19th 2009Date accepted: February 19th 2009

Correspondence:V.L. Villanueva Pérez. Multidisciplinary Unit of Pain Treatment. Avda. Tres Cruces,s/n. 46014 Valencia. Email: [email protected]

List of acronyms quoted in the text:ACEI: angiotensin-converting enzyme inhibitors; DM: diabetes mellitus; EMG: electromyography; HBP: high blood pressure; LLLL: lower limbs; ULL: upper limbs; SCS: spinal cord stimulation.

Av Diabetol. 2009;25:139-41

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The exploration showed a bilateral hypoesthesia in ULL/LLLL, with mild skin excoriations and impairment ofthe osteotendinous reßex. The patient showed a reduc-tion of touch feeling with monoÞlament and the vibra-tion with tuning fork. The diagnosis was performed, af-ter ruling out other causes by means of imaging, analyticstudies and electromyography (EMG) of the ULL/LLLL,which was informed as diabetic mixed polyneuropathy(sensory-motor), following the recommendations of theConsensus Guideline of the Clínica Mayo.1

The previous treatment for this process indicated byother specialists (traumatology, endocrinology) havebeen taken into account in the therapeutic proposal, aspregabalin, gabapentin, oxcarbazepine or duloxetine, allof them up to maximum doses, associated to level 2analgesics of the World Health Organization (tramadol,codeine). Considering the scarce response, a stimulationprotocol was started and the indication of a double spinalcord stimulation (SCS), cervical and lumbar.

After the evaluation by the psychologist, the patient wasinformed accordingly about the complete form techni-que, and was included in the waiting list. The patient un-derwent surgery on April 19th 2005 and a cervical andstimulation of posterior spinal cords system was implan-ted, Synergy Model (Medtronic Neurological Inc., Min-neapolis, United States). An electrode Pisces Quad Com-pact 3890 (Medtronic Neurological Inc, Minneapolis,United States) with electrode point was placed betweenthe spinal body of C4-C5 for ULL, and an electrode Pis-ces Quad 3890 (Medtronic Neurological Inc, Minneapo-lis, United States) with electrode point was placed in thespinal body D10-D111 for LLLL.

After 2 months from the implant, the patient recognizedan improvement superior to 80%, he perceived paresthe-sia in the affected zone, and the pain was reduced to ba-seline levels if he put the stimulator off. In November2006, he showed a worsening, with an intense pain in thewaist, especially on the left side and numbness in the le-ft groin. After revising the stimulation system, a breaka-ge of the lumbar electrode has been determined. The pa-tient underwent surgery on April 26th 2007 in order towithdraw the broken electrode and implantation of a newone with point in T9, with stimulation in LLLL. Sincethen, the patient keeps pain control, together with adju-vant medication (pregabalin 150 mg/12 h, tramadol 150mg/day and clonazepam, 3 drops in night doses).

DiscussionThe DM is the most common cause of neuropathy in oc-cidental countries. It is described in 20-24% of the dia-betic patients and affects especially the patients withlong evolution DM (15-20 years).1

Antidepressant drugs (duloxetin, amitriptyline) are re-commended in most of the clinical practice guidelines aswell as anticonvulsants (pregabalin, gabapentin, oxcar-bazepine) as Þrst line treatment of the diabetic polyneu-ropathy, and the opioids as tramadol and oxycodone assecond line.1 In general, the pregabalin and the duloxeti-ne are considered a Þrst choice and event the joint use ofthem.1,2

If the patients do not respond to standard treatment sche-mes, the invasive measures might be indicated. Thus, theneuro-modulation techniques, as the SCS, used in otherpathologies (eg. post-surgical spine pain and syndromeof complex regional pain) or even in advanced therapiesin coccygodynia, might be useful in the treatment of the-se patients.

The SCS is based in the “gate control theory” of Mel-zack and Wall,3 which states that the painful stimulationmight be blocked by an electric or tactile stimulation,mediated by the nervous A-beta, myelinic and fast con-duction Þbers. From the neuro-chemical point of view, itmight act restoring the GABA levels in the posterior spi-nal horn and probably on the release of adenosine, redu-cing the neuropathic pain.4

A few studies have been performed with spinal stimula-tion in patients with diabetic neuropathy. The work ofTesfaye et al.5 has been published in 1996 in which tendiabetic patients were studied and who were implantedwith spinal stimulators. Neuro-stimulators were implan-ted in 5 patients and placebo stimulators in the rest. Thetolerability of the exercise on the treadmill after 3 mon-ths has been evaluated. At the end of the study it couldbe observed that both groups improved the pain compa-red to the baseline pain, but with a greater difference inthe patients with active stimulator (1.5-31.3; p= 0.002)compared to the placebo group (15.5-56.3; p= 0.005),which were related with an improvement in the bloodßow in the peripheral nerves by a dorsal stimulation ofthe A-beta Þbers an inhibition of the C Þbers. The au-thors recommend the performance of more studies aboutthe diabetic neuropathy, as the safety and efÞcacy of the

Clinical noteTreatment of severe diabetic neuropathy with spinal cord stimulation. V.L. Villanueva Pérez, et al.

141

SCS has been determined in the chronic pain of differentetiology, though not in diabetic patients.

Petrakis and Sciaccia6 conducted a study in 60 diabeticpatients classiÞed as Fontaine III or IV phases (28 withdiabetic neuropathy), who underwent SCS after havingreceived a conservative or non efÞcacious treatment. Thetranscutaneous oxygen pressure (TcpO2) was measuredin patients before and after 2 and 4 weeks of the implant.A pain improvement was found in 35 patients, while 12showed a partial relief, within 6 months after the implan-tation. Only 3 from the 28 patients with neuropathy ob-tained a beneÞt at long term. As conclusion of this study,it is stated that in patients with a relevant increase of theTcpO2 post-stimulation, with a relief during a period of2 weeks, the treatment with SCS might be beneÞcial atlong term, unless the neuropathy is an advanced phase,as it has been observed that it was related inversely to thetherapy success.

The SCS7 is minimal invasive and reversible techniquethat since it has been used for the Þrst time in 1967 byShealy, showed a great efficiency and safety in thetreatment of the especially neuropathic chronic pain andin other processes, as the ischemic cardiopathy. However,it is not a technique free of possible complications (heada-che, infection, bruises, hygroma, opening of the surgicalwound and displacement or breakage of the electrode).

In conclusion, we believe that the presentation of this ca-se opens an innovative possibility in the therapeuticapproach of the serious neuropathic pain in the diabeticpatients. ■

Declaration of potential con!ict of interestsV.L. Villanueva Pérez, M. V. Silva Cedeño, L. Vaquer Quilesand J. A. de Andrés Ibáñez state that there are no conßicts ofinterests as regards to the content of this article.

References1. Argoff CE, Backonja MM, Belgrade MJ, Bennett GJ, Clark MR, Cole BE,

et al. Consensus guidelines; assesment, diagnosis and treatment of diabetic peripheral neurophatic pain. Mayo Clin Proc. 2006;81(4):512-25.

2. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm forneuropathic pain treatment: an eveidence based proposal. Pain.2005;118(3):289-305.

3. Melzack R, Wall PD. Pain mechanisms: a new theory. Science.1965;150:971-9.

4. Meyerson BA, Linderoth B. Mode of action of spinal cord stimulationin neuropathic pain. J Pain Symptom Manage. 2006;31 Suppl 4:6-12.

5. Tesfaye S, Watt J, Benbow SJ, Pang KA, Miles J, MacFarlane IA. Electricalspinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet.1996;348(9043):1698-701.

6. Petrakis IE, Sciacca V. Epidural spinal cord electrical stimulation in diabeticcritical lower limb ischemia. J Diabetes Complications. 1999;13(5-6):293-9.

7. Cruccu G, Aziz TZ, García-Larrea L, Hanson P, Jensen TS, Lefaucheur JP,et al. EFNS guidelines on neurostimulation therapy for neurophatic pain. Eur J Neurol. 2007;14;952-70.


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Case report discussed by experts

Insulin therapy in type 2 diabetes mellitusInsulinoterapia en la diabetes mellitus tipo 2

M ale aged 58, with T2D of 14 years of evolution, who showed an HbA1c of 8.2% in the last analytic, he was alsocontrolled with levels that did not exceed 7.5% and does not know what changed, as there have not been re-

cent incidences in his life.

Personal historyDiagnosed of glaucoma, hyperuricemia, mixed hyperlipidemia and diffuse proliferative glomerulonephritis with arte-riolar hyalinosis, proteinuria and arterial hypertension since 1993. He underwent a treatment with metformin 2550mg/day and repaglinide 3 mg, distributed in three daily intakes, night NPH insulin in doses of 14 IU, simvastatin andezetimibe in doses of 10 mg/day, irbestartan 300 mg/day and acetylsalicylic acid 100 mg/day.

Data corresponding to the last revisionWeight 85 kg, height 174 cm; arterial pressure 143/92 mmHg, abdominal waist 98 cm. No vascular peripheral dis-order can be observed nor signs of peripheral neuropathy. In the differed analytic appear the following results: cre-atinine 1.1 mg/day, basal glycemia 184 mg/dL, glycosylated hemoglobin 8.2%, uric acid 7.4 mg/dL, total cholester-ol 229 mg/dL, triglycerides 167 mg/dL, cholesterol bond to high density lipoproteins 37 mg/dL and proteinuria2.8 g/24 h. There is no other pathologic biochemical datum. As regards to the outpatient control, he carries out aglycemic profi le of 4 points per week and a measuring of the AP.

Anamnesis

Which modi$cations would youdo to this patient’s hypoglycemianttreatment?We Þnd ourselves in front of a patient with multiple car-diovascular risk factors. One of them is the T2D, of longevolution, that at present is inadequately controlled dueto non-evident reasons, in principle.

We speak about inadequate control as the recommendationsof the American Diabetes Association and of the EuropeanAssociation for the Study of Diabetes (ADA-EASD) updatedin 20091 are to achieve values of glycosylated hemoglobin(HbA1c) lower than 7% and for this the pre-prandial capillaryglycemias shall be kept between 70 and 130 mg/dL, whilethe postprandial glycemias shall not exceed 180 mg/dL.

Date received: February 11th 2009 Date accepted: March 10th 2009

Correspondence:C. Casanova García. Centro de Salud Barrio del Pilar. Finisterre, 18.28029 Madrid. Email: [email protected]

List of acronyms quoted in the text:ABPM: ambulatory blood pressure monitoring; ADA: American DiabetesAssociation; AP: arterial pressure; BMI: body mass index; cLDL: cholesterol bond to low-density lipoproteins; EASD: European Association for the Study of Diabetes: HbA1c: glycosylated hemoglobin; NPH: neutral protamine Hagedorninsulin.

Answer of Dr. Carlos Casanova

Case report discussed by expertsInsulin therapy in T2D. C. Casanova García, J.C. Padillo Cuenca

143

In this case we do not know the importance of therelative contribution of the pre/postprandial glucoseto the HbA1c value, as the patient’s glycemia profilesresults are not available. If we based ourselves on theassessments of the fasting glycemia relative contri-bution and the postprandial glycemia of the HbA1c ofMonier et al.2 in this case for a HbA1c of 8.2 mg/dL,both would range the 50% of relevance, therefore weshould treat both the fasting glycemia and the post-prandial glycemia with the same effort. Before un-dertaking any modification to the treatment, it wouldbe convenient to count with several glycemia pro-files, with previous values and 2 hours after the threemain meals of the day. Basing ourselves on the rec-ommendations of the ADA-EASD consensus, thefirst modification of the patient’s treatment would bein increasing the doses of the used drugs. We wouldadjust the night neutral protamine Hagedorn insulin(NPH) increasing it up to 18 IU, with the aim of im-proving the basal glycemia. We would increase thedoses in 2 IU each three days until achieving valuesof basal glycemia <130 mg/dL. In case of night hy-poglycemias, we would assess to replace the NPHinsulin for a slow insulin analogue, as the glargine orthe detemir.

For the adjustment of postprandial glycemias, we canintensify our treatment of secretagogues doubling thedose of repaglinide previous to the meals that need it,basing ourselves in the patient’s glycemia proÞles. Incase of not achieving the control targets with thesemeasures, we would have the option to add a third drugby oral route. At present, we could choose the glita-zones, as the use of the gliptines (sitagliptine, vild-agliptine) in combination with insulin has not been ap-proved yet.

As alternative, or considering the failure of this thera-py, we should intensify the insulin treatment. After as-sessing the patient’s glycemia before lunch, before din-ner or when going to bed, a second dose could beadded, starting with 4 IU and adjusting 2 IU each 3days. Should the glycemia before lunch exceed the 150mg/dL, we would add fast insulin before breakfast.Should the glycemia before dinner exceed the 150 mg/dL, we would add NPH insulin before breakfast or fastinsulin before lunch. Should the glycemia before goingto bed exceed 150 mg/dL, we would add fast insulinbefore dinner.

Would you do any changeto the treatment of the rest of thecardiovascular risk factors,as the hypertension, the lipids and theuric acid?The treatment for any patient shall be considered in acomprehensive manner. If our aim is to prevent the mor-bidity and increase the survival, all the cardiovascularrisk factors should be treated as a whole. In this case,there is not only an inadequate control of the glycemiavalues, but the lipid, arterial pressure (AP) and weightare out of our objectives.

After the evidences showed in studies as the HPS,3

ASCOT-LLA4 or CARDS,5 it is clear the importance ofcontrolling the lipids in the diabetic patient. Our control objective is to achieve a cholesterol bound to low densitylipoproteins (cLDL) <100 mg/dL.

Given that this patient has cLDL of 158.6 mg/dL, wewould need to pass to atorvastatin 40 mg to achieve a re-duction, because if we consider the reduction of 6% dou-bling the dose of simvastatin, we would reach a cLDLbetween 134 and 140 mg/dL when achieving the doselimit of this statin.

In the case of the AP control, both the HOT6 and theUKPDS7 study showed that an intensive treatment is as-sociated to a lower incidence of cardiovascular compli-cations in the diabetic patients. There is consensus con-sidering that the diabetic patients with hypertension haveto keep the AP values below 130/80 mmHg and thesevalues have to be reduced a bit more in patients with ne-phropathy, as long as they tolerate it. In this case, I con-sider that the best option might be to add a blocker of thecalcium channels. Though the use of a diuretic is also agood option, I would rule it out at Þrst due to the possi-ble increase of the hyperuricemia.

The increase of the uric acid of the patient might be con-sidered mild and asymptomatic, in possible relation withthe treatment in low doses of acetylsalicylic acid. Iwould only intervene advising a protein restriction to0.8 g/kg of weight/day, as this would improve the valueof the uric acid in blood, which is also necessary to im-prove the renal function of our patient.

The patient’s weight, that shows a body mass index of28.1, is in the overweight range, therefore he needs a re-

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duction of at least 10% of his body weight. In order toachieve this, I would try to introduce a customized bal-anced diet, together with an increase of regular aerobicexercise that the patient undergoes.

Which is the number of glycemic andpressure controls you considerappropriate for the patient to undergo?Following the recommendations of the ADA-EASD con-sensus and the International Diabetes Foundation,8 it isaccepted that the self-monitoring of the blood glucose is useful in patients with T2D under insulin treatment. Inthe case of our patient, and since he is undergoing thedosage change of insulin and the intensiÞcation of theoral antidiabetic doses, until achieving the Þxed objec-tives, I would perform a complete proÞle of six controlseach 3 days, and once the glycemia targets are reached,a weekly complete proÞ le.

As regards to the AP control of the patient, I believe itconvenient not to give up the weekly control that he wasdoing, though the recommendations are not so exhaus-tive, a control during the follow-up visits would beenough. In this case, I consider it convenient to performan outpatient control of the arterial pressure, in order torule out the presence of a non-dipper pattern, which ismore frequent in diabetic hypertensive patients and inhypotensive patients with renal disorder, as the patientherein described. This pattern, besides its prognosis in-volvement, entails the possibility of customizing the op-timal moment of treatment administration in order to re-state the physiological circadian profile as much aspossible.

Would you do any complementary test?Within the evaluation protocol of the diabetic patient, itis recommended to perform a diabetic retinopathyscreening; therefore a funduscopy with pupillary dilata-tion should be done once a year, or at least each 2-3

years if one or more examinations are normal. Should itbe necessary, this can be done more frequently.

An electrocardiogram should be performed in order torule out any asymptomatic heart disease. It is necessaryto perform a thorough examination of the foot of everypatient with diabetes, which should include the use ofmonoÞ lament, turning fork, palpation and visual exami-nation. ■

Declaration of potential con!ict of interestC. Casanova states that there is no conßict of interests as re-gards to the content of this manuscript.

References1. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R,

et al. Medical management of hyperglycemia in type 2 diabetes: a consensusalgorithm for the initiation and adjustment of therapy. A consensus statementof the American Diabetes Association and the European Association for theStudy of Diabetes. Diabetes Care. 2009;32:193-203.

2. Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandialplasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c. Diabetes Care.2003;26:881-5.

3. Collins R, Armitage J, Parish S, Sleigh P, Peto R. Heart Protection StudyCollaboration Group. MRC/BHF Heart Protection Study of cholesterol-lowering in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet. 2003;361:2005-16.

4. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al.Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-LipidLowering Arm (ASCOT-LLA): a multicentre randomized controlled trial.Lancet. 2003;361:1149-58.

5. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,Livingstone SJ, et al. Primary prevention of cardiovascular disease withatorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomized placebo-controlled trial. Lancet. 2004;364:685-96.

6. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al.Effects of intensive blood pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) trial. Lancet. 1998;351:1755-62.

7. UKPDS. Intensive blood-glucose control with sulphonylureas or insulincompared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-53.

8. Global Guideline for Type 2 Diabetes. IDF Task Force on Clinical Guidelines,International Diabetes Federation, 2006. Available at: http://www.idf.org


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Which modi$cations would you do to thispatient’s hypoglycemiant treatment?The patient shows T2D of long evolution, with a recentinadequate control. At present, he receives treatmentwith metformin in maximum doses, fast acting secreta-gogues in each meal and night intermediate action insu-lin in low doses. It is necessary to intensify the currenttreatment, and for this it would be convenient to under-take self-controls of capillary glycemia in order to obtaininformation about the glycemic levels during the day(before and 2 h after the meals gradually and on differentdays). In Guerci et al. study, the group of patients whounderwent self-monitoring of the capillary glycemia (sixweekly controls on 3 different days, included the pre/postprandial) had a mean glycosylated hemoglobin(HbA1c) relevantly lower after 5 months as regards to theconventional group.1

Since the HbA1c values of our patient, high pre-prandialglycemias can be suspected. In case of fasting hypergly-cemias, the NPH insulin should be increased (neutralprotamine Hagedorn) 2 IU each 3 days, in order toachieve an optimal glycemic control. On the contrary, ifthere is a hyperglycemia before dinner, the replacementof NPH insulin should be chosen for 2 doses of premixedinsulin during breakfast and dinner (leaving the repagli-nide only for lunch), or replace it for a dose of basal in-sulin (glargine or determir, 1-2 doses). According to theconsensus algorithm of ADA-EASD (American Diabe-tes Association and European Association for the Studyof Diabetes),2 it would be added in this case a seconddose of NPH at breakfast, though this could increase the hypoglycemia risk with another injection without con-trol of the postprandial glycemias. Both the Treat-to-Tar-get3 and the Hermansen et al.4 conÞ rm a lower incidenceof hypoglycemia without differences in the glycemiccontrol with the insulin glargine and determir, respec-

tively, compared to NPH. Moreover, in this last study alower weight gain was found with insulin detemir, with-out differences in the glycemic control. The LANMETstudy showed also a lower incidence of hypoglycemiaswith glargine insulin compared to NPH in diabetic pa-tients treated with metformin previously.5

In case of using a dose of insulin detemir at night with anadequate control of the fasting glycemia and high pre-prandial glycemias at dinner and / or lunch, a seconddose of insulin detemir should be added at breakfast.Both analogues of basal insulin, glargine and detemir,have been compared in a trial performed by Rosenstocket al., who considered that these analogues share a com-parable efÞciency in the glycemic control (with detemirespecially in two injections daily) and that the weightgain is lower with detemir (especially with a daily injec-tion).6

If hypoglycemias occur at dawn, the dose of 4 IU NPHinsulin could be reduced or a 10% of the dose or changethe NPH insulin for glargine or detemir. If the pre-pran-dial glycemias are controlled and the HbA1c is ≥7%, thepostprandial glycemias could be determined. If they arehigh, the dose of repaglinide should be increased to amaximum of 4 mg in each meal. In case of no adequatepostprandial glycemias are achieved, the repaglinideshould be replaced for prandial insulin, preferably ana-logues of fast insulin (lispro, aspart or glulisine) as partof the basal bolus therapy at breakfast and dinner and, ifnecessary, analogues of fast insulin at lunch.

Studies have been published that compare the effective-ness on the metabolic control among the analogues ofbasal insulin and the analogues of biphasic insulin, with different results. In the Holman et al. trial, a better glyc-emic control was achieved with two injections of bipha-

Answer of Dr. José Carlos Padillo Cuenca

Date received: December 12th 2008 Date accepted: January 7th 2009

Correspondence:J.C. Padillo Cuenca. Endocrinology and Nutrition Service. Hospital Santa Bárbaraof Puertollano. Malagón, s/n. 13500 Ciudad Real. Email: [email protected]

List of acronyms quoted in the text:ABPM: ambulatory blood pressure monitoring; ACEI: angiotensin-converting enzyme inhibitors; ADA: American Diabetes Association; AP: arterial pressure;ARA II: agiotensin II receptor antagonists; cHDL: cholesterol bond to high densitylipoproteins, cLDL: cholesterol bond to low density lipoproteins; EASD: European Association for the Study of Diabetes; ESC: European Society of Cardiology; ESH: European Society of Hypertension; GLP-1: glucagon-like peptide 1; HbA1c:glycosylated hemoglobin; IDF: International Diabetes Federation; NCEP-ATP III: National Cholesterol Education Program-Adult Treatment Panel III; NPH: neutralprotamine Hagedorn insulin.

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sic insulin aspart 70/30 and with three doses of prandial insulin (aspart) than with detemir, though the incidenceof hypoglycemias and the weight gain were higher.7

Raskin et al. have also proved a higher effectiveness ofthe biphasic insulin aspart 70/30 compared to insulinglargine on the reduction of the HbA1c below the controlobjectives (6.5 and 7%) in patients previously treatedwith metformin alone or in combination with other drugsand the weight gain and the incidence of hypoglycemiaswere much higher with premixed insulin.8 Likewise, thestudy Robbins et al. obtained similar results comparingtwo treatment groups, one with biphasic insulin lispro50/50 and the other with insulin glargine, combined bothwith metformin, thus the mean HbA1c, the pre-prandialglycemias (except for the fasting glycemias) and thepostprandial glycemias were lower in the Þrst treatmentgroup.9 Malone et al. have also detected a better post-prandial glycemic control (at breakfast and dinner), alower HbA1c and a discrete increase of the hypoglyc-emia’s (not at night) in the biphasic lispro 25/75 group,compared to the glargine group, both with metformin.10

However, in the trial of Janka et al. it was more effectiveto add insulin glargine in inadequate controlled patients, treated with glimepiride and metformin, than replacingthe oral antidiabetics for human premixed insulin 30/70, and the incidence of hypoglycemia was lower in the ba-sal insulinization group.11

Finally, the basal or premixed insulin dose should beadjusted increasing 2 units each 3 days in order toachieve optimal pre-prandial glycemias without hy-poglycemia risk. The metformin should be kept if thepatient shows a better tolerance, as this would avoid aponderal gain increase with the intensiÞcation of theinsulin therapy. Moreover, the insulin requirementswould be lower without an increase of the hypoglyc-emia incidence. These adjustments would be done each3 months according to the self-controls and the HbA1c;this is an intensiÞcation indicator of the hypoglycemi-ant therapy if it is ≥7%.2

The beneÞ t on the cardiovascular results of the improve-ment in the glycemic control of the diabetic patient hasnot been ratiÞed in the studies ADVANCE, ACCORDand VADT.12-14 However, Þnally the study UKPDS15 con-cluded stating the positive effect that causes the intensi-Þcation of the treatment, either with insulin or with oralantidiabetics (sulphonylureas and metformin), on thecardiovascular events and on mortality.

Would you do any change to thetreatment of the rest of thecardiovascular risk factors,as the hypertension, the lipidsand the uric acid?The Steno-2 study shows an important beneÞt of theintensive treatment of the diabetes mellitus, the hyper-tension and the dyslipidemia on the macro vascularand micro vascular events, through changes in thelifestyle and the pharmacological treatment.16 Our pa-tient shows, besides diabetes mellitus, an inadequatecontrolled arterial hypertension, a slightly increasedtotal cholesterol, lower levels of cholesterol bound tohigh density lipoproteins (cHDL) (<40 mg/dL) and adiscrete asymptomatic hyperuricemia, so he complieswith all the metabolic syndrome criteria of the Inter-national Diabetes Federation (IDF)17 (table 1) andfour of the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III)18 criteria(table 2).

The cholesterol bound to low density lipoproteins(cLDL), assessed though the Friedewald19 formula(cLDL= total cholesterol – [cHDL + triglycerides/5],gives us a value of 158.6 mg/dL, which is higher than theadvised reference value (<100 mg/dL) in the patientwith diabetes or with cardiovascular disease as statedby the NCEP-ATP III guideline. The HPS (Heart Pro-tection Study) showed that a reduction of 30 mg/dL ofthe cLDL reduces the cardiovascular risk in 30%, re-gardless of the basal level of cLDL.20 The triglyceri-demia is lower than the recommended target in the dia-betes, lower than 150 mg/dL.

The intensiÞcation of the hypolipemiant treatment, ad-dressed to achieve an optimal lipid proÞle in our pa-tient, should consist to ensure a diet compliance with ascarce intake of cholesterol (<300 mg/day) and in-crease the dose of simvastatin to reduce the cLDL upto Þgures lower than 100 mg/dL. Should this not belike this, atorvastatin 40 mg/day could be changed,which achieves a mean reduction of cLDL of almost50%. Once the cLDL target has been reached, it isquite probable that our patient might reduce the levelof triglycerides below 150 mg/dL. In case of keepinga triglyceridemia >177 mg/dL, a Þbrate or nicotinicacid should be added to the hypolipemiants treatmentin order to achieve the optimal objective of non-HDLcholesterol.


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The advisable control targets on the arterial pressure ofthe diabetic patient match with lower values than 130/80 mmHg, according to the ESH-ESC (European Societyof Hypertension and European Society of Cardiology)and ESC-EASD of 2007 guidelines.21-22 The control ofarterial pressure (AP) should be performed in an outpa-tient form or with measurements at home following therecommendations of the ESH-ESC guidelines. If valuessimilar to the AP are conÞ rmed in our patient, we are inthe presence of grade I arterial hypertension. In order toachieve optimal values lower than 130/80 mmHg, atiazidic diuretic can be added to irbesartan through theirbesartan 300/hydrochlorotizide 25 mg daily associa-tion, following in this way the recommendations of theESH-ESC once the “white coat”21 effect has been ruledout (Þgure 1). For this, it would be convenient to countwith self-monitoring determinations of the AP or the am-

bulatory blood pressure monitoring (ABPM). Moreover,our patient shows a secondary proteinuria to a doubleetiology nephropathy, both hypertensive and diabetic.Though the albuminuria is not speciÞ ed, which we sup-pose high, the treatment of the renin-angiotensin-aldos-terone axis after its determination, adding an angi-otensin-converting enzyme inhibitors (ACEI) to theagiotensin II receptor antagonists (ARA II) already indi-cated as complementary treatment should be reinforced, though there is no sufÞcient evidence on this therapeuticeffect.

The hyperuricemia is asymptomatic and discrete, so it isindicated to adopt measures related to the lifestyle. A di-et poor in purines (red meats, entrails, seafood, etc.)might reduce the levels of the uric acid in blood below7 mg/dL, as a mean reduction of the uricemia is achieved

Table 1. Definition of metabolic syndrome accordingto the IDF17 criteria

Central obesity defined as waist circumference >94 cm for men and >80 for Caucasian women (with specific values for other ethnic groups), besides two of the following factors:

• Increase of triglycerides ≥150 mg/dL (1.7 mmol/L),or specific treatment for this lipid impairment

• Reduction of cHDL ≤40 mg/dL (1.0 mmol/L) in men and≤50 mg/dL (1.3 mmol/L) in women, or specific treatmentfor this lipid impairment

• High AP: systolic AP ≥130 mmHg or diastolic AP ≥85 mmHg,or previous antihypertensive treatment

• Increase of the plasmatic fasting glucose ≥100 mg/dL(5.6 mmol/L) or previously diagnosed T2D

AP: arterial pressure.

Table 2. Definition of metabolic syndrome accordingto the NCEP-ATO III18 criteria

At least three of the following conditions have to be complied with:

• Abdominal obesity defined as waist circumference ≥102 cm inmen and ≥88 cm in women

• Triglycerides ≥150 mg/dL

• cHDL ≤40 mg/dL in men and ≤50 mg/dL in women

• Arterial pressure ≥130/85 mmHg

• Plasmatic fasting glucose ≥110/mg/dL

The American Diabetes Association recommends lowering the limit of plasmatic fasting glucose to 100 mg/dL.

Figure 1. Pharmacological treatment strategies of the arterial hypertension according to the clinical practice guidelines of ESH-ESC (2007)21. AP: arterial pressure; CV: cardiovascular

Marked increaseof the AP

High / very highCV risk

Lower control targetsof AP

Choose between

Drug in monotherapy at low doses

Combination oftwo drugs at

low doses

Previous drug at maximum

doses

Add another drug at

low doses

Previouscombination atmaximum doses

Add a thirddrug withlow doses

If the AP target has not been achieved

If the AP target is not achieved

Combination of two or three

drugs at maximum doses

Monotherapy and maximum

doses

Combination of two or threedrugs at maximum doses

Mild increase of APLow/Moderate CV Risk

Conventional objective of

antihypertensive treatment

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between 0.6 and 1.4 mg/dL. Moreover, the alcoholicwithdrawal would be recommended.

The patient shows a body mass index of 28, with a cen-tral distribution of the adiposity according to his waistcircumference. This Þgure matches with a level II over-weight, so he would beneÞt himself with lifestyle modi-Þcation measures. The modiÞcations would include abalanced diet with scarce intake of saturated fats andrich in Þbers, a Mediterranean diet rich in monounsatu-rated fatty acids (better for the glycemic control) or a di-et with a mild reduction in the proportion of carbohy-drates (better for the lipid proÞle), being the latter themost effective for the ponderal weight.23 The mild andregular aerobic exercise during 30-60 minutes, 5 daysper week, would be beneÞcial, according to the currentrecommendations of the ADA.24

Which is the number of glycemic andpressure controls you considerappropriate for the patient to undergo?When the diabetes pharmacological treatment includesoral antidiabetics that do not cause hypoglycemia, asmetformin, glitazones and analogues of the GLP-1 (glu-cagon-like peptide-1), the monitoring by means of theself-measurement of the capillary glycemia is not neces-sary. The intensiÞcation of the treatment would dependon the HbA1c in these cases. The frequency of the con-trols depends on the glycemic control level and on thetreatment. When the treatment is based on drugs thatshow hypoglycemia risk (sulphynuloreas, glinides andinsulin), the monitoring should be more frequent. In caseof variable controls and an inadequate metabolic control(HbA1c ≥7) the frequency shall also be higher. Six week-ly controls are advised in these cases at least, distributed on two different days and including pre/postprandial lev-els of capillary glycemia, as the improvement of the gly-cemic control is achieved in this way.1

The monitoring frequency of the AP by the patient de-pends on the control level and the need of intensifyingthe treatment. If there is an inadequate control of the AP and the treatment has been started, or has been startedwith combined therapy, a higher number of determina-tions is necessary to adjust such intervention. Thisnumber of determinations can be from once a week ormonthly, up to one or more every day, distributed ac-cording to the AP rising pattern of each patient, which

can be described by the ABPM. This patient, especially,should perform between one or two determinationsweekly, and one on alternate days, until reaching the op-timal control of the AP after intensifying the treatment;then the frequency of the controls can be spaced to oneeach 2-4 weeks.

Would you do any complementary test?Funduscopy or retinographyThis is patient with T2D of long evolution, with diabetic-hypertensive nephropathy; therefore a diabetic retinopa-thy has to be ruled out as microangiopathic screeningprotocol through funduscopy or retinography.

Urinary and hepatic biochemistryThe determination of the albuminuria of morning sampleshall also be appropriate to characterize the nephropathybetter, to support the intensiÞcation of the treatment andto allow the monitoring of the treatment efÞcacy withACEI/ARA II. The determination of the transaminasem-ia shall be appropriate to rule out a hepatic steatosis, asthe patient complies to metabolic syndrome criteria.

ElectrocardiogramAn electrocardiogram should be performed in order torule out asymptomatic repolarization disorders, asischemia or silent infarction.

Arterial Doppler of lower limbsSince the absence of peripheral vascular and neuropathicsymptomatology, it is not indicated to determine “initial-ly” the ankle/arm index by using the Doppler techniqueto rule out a peripheral vascular pathology, nor an elec-tromyography of the lower limbs to rule out a diabeticpolyneuropathy. ■

Declaration of potential con!ict of interestJ.C. Padillo Cuenca states that there is no conßict of interestsas regards to the content of this manuscript.

References1. Guerci B, Drouin P, Grangé V, Bougneres P, Fontaine P, Perlan V, et al.

Self-monitoring of blood glucose signifi cantly improves metabolic control inpatients with type 2 diabetes mellitus: the Auto-Surveillance Intervention Active (ASIA) study for the ASIA group. Diabetes Metab. 2003;29:587-94.

2. Nathan DM, Buse JB, Davidson MB, Ferranini E, Holman RR, Sherwin R, etal. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care.2008;31:1-11.


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3. Riddle MC, Rosenstock J, Gerich J. The Treat-to-Target Trial. Diabetes Care.2003;26:3080-6.

4. Hermansen K, Davies M, Derezinski T, Martínez G, Clauson P, Home P.A 26-week, randomized, parallel, treat-to-target trial comparing insulindetemir with NPH insulin as add-on therapy to oral glucose-lowering drugs ininsulin-naïve people with type 2 diabetes. Diabetes Care. 2005;28:254-9.

5. Yki-Järvinen H, Kauppinen-Mäkelin R, Tükkainen M, Vähätalo M, VirtamoH, Nikkilä K, et al. Insulin glargine or NPH combined with metformin in type2 diabetes: the LANMET study. Diabetologia. 2006;49:442-51.

6. Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G.A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia. 2008;51:408-16.

7. Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul S, et al.Addition of biphasic, prandial, or basal insulin to oral therapy in type 2diabetes. N Engl J Med. 2007;357:1716-30.

8. Raskin P, Allen E, Hollander P, Lewin A, Gabbay RA, Hu P, et al. Initiatinginsulin therapy in type 2 diabetes. Diabetes Care. 2005;28:260-5.

9. Robbins DC, Beisswenger PJ, Ceriello A, Goldberg RB, Moses RG,Pagkalos EM, et al. Mealtime 50/50 basal + prandial insulin analoguemixture with a basal insulin analogue, both plus metformin, in theachievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison. Clin Ther.2007;29:2349-64.

10. Malone JK, Kerr LF, Campaigne BN, Sachson RA, Holcombe JH.Combined therapy with insulin lispro mix 75/25 plus metformin or insulin glargine plus metformin: a 16-week, randomized, open-label, crossover study in patients with type 2 diabetes beginning insulin therapy. Clin Ther.2004;26:2034-44.

11. Janka HU, Plewe G, Riddle MC, Kliebe-Frisch C, Schweitzer MA,Iki-Järvinen H. Premixed insulin as initial insulin therapy for type 2 diabetes.Diabetes Care. 2005;28:254-9.

12. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al.;ADVANCE Collaborative Group. Intensive blood glucose control and

vascular outcomes in patients with type 2 diabetes. N Engl J Med.2008;358(24):2560-72.

13. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al.Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med.2008;358(24):2545-59.

14. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al.Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129-39.

15. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-upof intensive glucose control in type 2 diabetes. N Engl J Med.2008;359(15):1577-89.

16. Pedersen O, Gaede P. Intensified multifactorial intervention andcardiovascular outcome in type 2 diabetes: the Steno-2 study. Metabolism.2003;52 Suppl 1:19-23.

17. Available at: http://www.sochob.cl/pdf/sindrome_metabolico/The%20IDF%20consensus%20worldwide%20defi nition%20of%20the%20Metabolic%20Syndrome.pdf

18. Available at: http://www.nhlbi.nih.gov/guidelines/cholesterol/atp3full.pdf19. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of

low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem. 1972;18:499-502.

20. Collins R, Armitage J, Parish S, Sleigh P, Peto R. Heart protection study ofcholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361:2005-16.

21. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G,et al. 2007 ESH-ESC Practice guidelines for the management of arterial hypertension. J Hypertens. 2007;25:1751-62.

22. Rydén L, Standl E, Bartnik M, Vand den Berghe G, Betteridge J, De BoerM, et al. Guidelines on diabetes, pre-diabetes, and cardiovascular diseases.Eur Heart J. 2007;28:88-136.

23. Shai I, Schwarzfuchs D, Henkin Y, Shahar DR, Witkow S, Greenberg I, et al.Weight loss with a low-carbohydrate, Mediterranean, or low-fat diet. N EnglJ Med. 2008;359:229-41.

24. American Diabetes Association. Standards of medical care in diabetes2008. Diabetes Care. 2008;31:12S-54S.


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The American Diabetes Association (ADA) and the Eu-ropean Association for the Study of Diabetes (EASD)have recently published (December 2008) a “new” con-sensus1 for the pharmacological treatment of T2D. Agroup of experts of both societies proposed a new algo-rithm that roused certain controversy and that positionsitself clearly stating debatable priorities among the avail-able drugs. The most outstanding contributions of thisnew document, which its intention is to integrate the newdata provided by the studies ACCORD, ADVANCE,VADT and UKPDS-PTM, in follow-up phase open 10years after the study was communicated, might be sum-marized in two points:1

• A glycemic control objective is kept under 7% ofHbA1c.

• As regards to the new proposed algorithm, it is insistedin starting the treatment with quality life changes andmetformin, and to change early to new therapeutic re-gimes in the patients who can not achieve the men-tioned objectives, especially guidelines with sulphony-lureas and insulin. Moreover, it states clearly theexclusion of the rosiglitazone and, however, it placesthe use of pioglitazone in a second therapeutic level(“less well validated therapies”); an extremely careful

posture is adopted as regards to the DPP-4 inhibitors(vildagliptin, sitagliptin), seeking protection in the car-diovascular safety lack of knowledge at long term, butthe use of exenatide (GLP-1 analogue) is surprisinglyprioritized.

The Þrst point, which constitutes the main objective ofthis consideration, is not excessively controversial, as itis kept within the previous recommendations,2 based onthe well-established beneÞts of reducing the micro andmacro-vascular complications (which reduce the quality of life in patients considerably), without trying to go be-yond the HbA1c target <7% as other guidelines defend.3,4

The data of DCCT5 (in T1D) and of UKPDS6 (in T2D)are clear and unquestionable. The new data of AD-VANCE also ratify a reduction of renal damage with areduction of the HbA1c over than 7% though withoutgreat achievements in macrovascular events. As the 2008was a proliÞc year as regards to the spreading of greatstudies results (ACCORD,7 ADVANCE,8 VADT9) thathave tried to explain if the intensive control (HbA1c of6.5% versus standard control of >7%) might reduce themacrovascular complications. The results in this sense,well known at that time, do not reduce the HbA1C exces-sively as general rule beyond 7%, but admit certain nu-ances. More than reduction levels of HbA1C, the studiescompare different therapeutic strategies among ones andother studies, though the set out HbA1C objective isachieved. Moreover, the general patients evaluated had avery advanced disease.10

There is a clear suggestion of beneÞt in diabetic patientsof relative short evolution, of lower risk and/or without

New challenges in the clinical practice

Can be still admitted a target of HbA1c of <7%? Considerations about ACCORD, ADVANCEand the new consensus from ADA-EASD¿Puede admitirse todavía un objetivo de hemoglobina glucosilada inferior al 7%?Reflexiones sobre el ACCORD, el ADVANCE y el nuevo consenso ADA-EASDP. ContheInternal Medicine Department. Hospital General Universitario “Gregorio Marañón”. Madrid

Date received: January 20th 2009Date accepted: Janaury 24th 2009

Correspondence:P. Conthe Gutiérrez. Internal Medicine Department Head. Hospital GeneralUniversitario “Gregorio Marañón”. Dr. Esquerdo, 46. 28007 Madrid.Email: [email protected]

List of acronyms quoted in the text:ADA: American Diabetes Association; ACCORD: Action to Control CardiovascularRisk in Diabetes; EASD: European Association for the Study of Diabetes; HbA1C:glycosylated hemoglobin; UKPDS: UK Prospective Diabetes Study.

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determined cardiovascular disease. On the contrary, ithas been noted to the serious hypoglycemia as possibleand valid neutralizing cause of the beneÞt, especially inpatients with determined cardiovascular disease.9-11 Thefollow-up data in open phase of the UKPDS study sug-gest that the macrovascular beneÞt, the clinic events andthe cardiovascular mortality seem to require more timeof glycemic control in order to show its beneÞcial ef-fects. Possibly, the most preventive role of the strict gly-cemic control is achieved before the clinical cardiovas-cular disease is developed.12

In view of the above, once more, and as it happens inother Þelds of the cardiovascular therapeutics, it is aneed to individualize the patients, treatment, having toconsider the existence of hypoglycemia history and/orrisk of showing them as fundamental factors, as well asthe years of the evolution of the diabetes and the pres-ence of determined vascular disease. Many patients witha more benign or early proÞle of the disease might takebeneÞt of a more intensive control, especially the young-er patients, without a determined disease and with lowrisk of hypoglycemia. On the contrary, it is valid that inolder patients with determined disease (often advancedatherosclerosis) and who show a greater tendency to se-rious hypoglycemias with higher lesion risk, the inten-sive control (HbA1C of 6.5% or less) implies more risksthan beneÞts.8,10,11 In any case, the current controversyshould not be extrapolated to the patients with an inade-quate glycemic control (>8%), which is the real settingin the usual clinical practice in our environment,13 andeven in sites of excellence,14 as it might be perverse tolead to a greater therapeutic nihilism/inertia and to giveup the achievement of glycemic objectives within an in-tegrator approach of the disease.

As regards to the second point object of this comment–the new proposal of algorithm– admits a higher level ofcontroversy and especially it has to be object of a rea-soned criticism. First, it is more arguable to provide anew concrete algorithm (displacing the one spread dur-ing the last year, with several options in a second step af-ter the metformin);15 when there are scarce evidences inresults “body to body” among different drugs and evenamong different therapeutic strategies, at least as regardsto the “hard” targets of clinical events or cardiovascularmortality. Secondly, the proposed strategy after met-formin in the Þrst step does not seem to take into accountthe capital importance of minimizing hypoglycemias,

the higher value of the DPP4 inhibitors and the worseadverse effect of the sulphonylureas, not even the con-venience of avoiding the weight increase, the constantadverse effect of the glitazones, the sulphonylureas andinsulin, when all of them are elements that have to bepresent when determining a therapeutic strategy. In thissense, it cannot be clearly stated why the pioglitazonecan be in a second therapeutic step (“Less well validatedtherapies”) if it has known adverse effects (bone frac-tures),16 or because it can be especially prioritized as re-gards to other therapeutic groups. Likewise, neither thefrequent digestive effects nor the necessary parenteraladministration of the GLP-1, introduced in the UnitedStates in 2005 and recently in our environment, seem tobe object of unfavorable consideration in spite of thedoubtful tolerability and difÞculty of acceptance of thistreatment modality in our environment.

Therefore, the criteria that have led to this new therapeu-tic algorithm proposed for the treatment of the patientwith T2D by a group of experts deserve an open discus-sion. As the authors state, the therapeutic individualiza-tion has always to prevail. The proposal presents, prob-ably, a certain load of subjectivity and a focused view inthe economic considerations and in the clinical experi-ence obtained with some hypoglycemiant drugs on theother side of the Atlantic Ocean. ■

Declaration of potential con!ict of interestsP. Conthe stated that there are no conßicts of interest as regardsto the content of this article.

References1. Nathan D, Buse B, Davidson M, Ferrannini E, Holman R, Sherwin R,

et al. Medical management of hyperglycemia in type 2 diabetes:a consensus algorithm for the initiation and adjustment of therapy.A consensus statement of the American Diabetes Association and theEuropean Association for the Study of Diabetes. Diabetes Care.2008;31:1-11.

2. American Diabetes Association: Standards of medical care in diabetes-2008. Diabetes Care. 2008;31(Suppl. 1):S12-S54.

3. Canadian Diabetes Association. 2008 Clinical practice guidelines for theprevention and management of diabetes in Canada. Can J Diabetes.2008;32(Suppl. 1). (Disponible en: http://www.diabetes.ca/for-professionals/resources/2008-cpg/).

4. Guías de práctica clínica sobre prevención de la enfermedadcardiovascular: versión resumida. Cuarto Grupo de Trabajo Conjunto de laSociedad Europea de Cardiología y otras Sociedades sobre Prevención de la Enfermedad Cardiovascular en la Práctica Clínica. Rev Esp Cardiol. 2008;61:e1-e49.

5. Diabetes Control and Complications Trial Research Group. The effect ofintensive treatment of diabetes on the development and progression

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of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med. 1993;329:977-86.

6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854-65.

7. Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse JB, et al.,and the Action to Control Cardiovascular Risk in Diabetes Study Group.Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med.2008;358:2545-59.

8. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al.,and the ADVANCE Collaborative Group. Intensive blood glucose control andvascular outcomes in patients with type 2 diabetes. N Engl J Med.2008;358:2560-72.

9. Duckworth W, Abraira C, Moritz T, Reda D, Emannele N, Reaven PD, etal. Intensive glucose control and complications in American veteranswith type 2 diabetes. N Engl J Med. 2008, December 17 [Epub aheadof print].

10. Skyler J, Bergenstal R, Bonow R, Buse J, Deedwania P, Gale E, et al.intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials. A positionstatement of the American Diabetes Association and a scientifi c statement

of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32:187-92.

11. Pérez A. Implicaciones clínicas de los estudios ACCORD, ADVANCE y VADT.Av Diabetol. 2008;24:279-82.

12. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med.2008;359:1577-89.

13. De la Calle H, Costa A, Díez-Espino J, Franch J, Goday A. Evaluation onthe compliance of the metabolic control aims in outpatients with type 2 diabetes mellitus in Spain. The TranSTAR study. Med Clin (Barc).2003;120:446-50.

14. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of amultifactorial intervention on mortality in type 2 diabetes. N Engl J Med.2008;358:580-9.

15. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R,et al. Management of hyperglycaemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: update regarding the thiazolidinediones. Diabetologia. 2008;51:8-11.

16. Meier C, Kraenzlin M, Bodmer M, Jick S, Jick H, Meier CR. Use ofthiazolidinediones and fracture risk. Arch Intern Med.2008;168:793-5.


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CommentMale aged 58, with metabolic syndrome history, as wellas level 2 obesity of abdominal predominance (BMI 37kg/cm2, abdominal circumference 101 cm), arterial hy-pertension, mixed dyslipidemia and T2D of more than10 years of evolution, under combined treatment withpremixed insulin aspart/aspart protamine 30/70 (0.69 IU/kg/day distributed in 2 doses) and oral agents (vildaglip-tine-metformin, 500/1.000 mg, 2 tablets per day). Themetabolic control was usually inadequate (HbA1c of10.5%) due to the lack of diet compliance. As known mi-cro vascular complications of his diabetes, he showed di-abetic nephropathy, non-proliferative retinopathy anderectile dysfunction, which have been treated Þnallywith the implant of a penile prosthesis. As concomitantdiseases, he showed a Barrett’s esophagus secondary to gastroesophageal reßux disease (GERD) and a sleep ap-nea-hypopnea syndrome (SAHS) under CPAP nighttreatment.

Clinically, the patient referred a progressive edematiza-tion of foot and left ankle of 6 months of evolution, withpain, dysesthesias like tingling with numbness and par-esthesia of night predominance. He had no fever, or gen-eral condition affectation. He did not refer previous trau-matic lesions in the foot, or apparent tetanus as injuriesor excoriations. He did not show either previous clinic ofintermittent lameness or other symptomatology. In theclinical exploration, a hard edema could be observed in

the foot and left ankle, up to the third part of the leg,with erythema and a discrete increase of local tempera-ture, associated to a great deformity with loss of arch ofthe foot. He showed interdigital and bilateral nail myco-sis, without any other lesions. The propioceptive sensi-tivity explored with monoÞlament and calibrated tuningfork was clearly reduced bilaterally, with distribution “insock”, though it was more intense in the left lower limb.Moreover, a reduction of the kneecap osteotendinous re-ßex and Achilles heel in both legs could be observed.The peripheral pulses, back extensor digitorum brevisand tibial posterior muscles were palpable in the rightfoot, but were reduced in the left foot. The right ankle-arm index was normal (1.1) and it was not able to ex-plore in the left lower limb due to the presence of ede-matization. The indicative biological parameters ofinßammation were within normality (leukocytes 7.2 3

103/µL with normal formula; hemoglobin 12.2 mg/dL;platelets 202 3 103/µL, C-reactive protein 4.9 mg/dL; Þ-brinogen 4.1 mg/dL, ferritin 49 mg/dL).

In the x-ray of the left foot (Þgure 1), it could be statedthe destruction of the joints between the wedges and the basis of the metatarsians, together with impairments inthe head of the second and third metatarsians; Þndingsthat are compatible with the Charcot arthropathy, withpredominance in the Lisfranc joint. Taking in accountthe symptomatology persistence, it was decided to per-form a magnetic resonance imaging (MRI) of the foot inorder to proceed with the differential diagnosis with os-teomyelitis, notwithstanding that the clinical and biolog-ical data were not indicative of an infectious process.

The MRI showed a collapse of the foot vault withdesestructuration of the mesofoot, inflammatory

Date received: January 23rd 2009Date accepted: January 28th 2009

Correspondence:M. Molina. Reference Diabetes Unit, Endocrinology and Nutrition Service.Hospital Clínico Universitario de Valencia. Avda. Blasco Ibáñez, 17.46010 Valencia. Email: [email protected]

Pictures in clinical diabetes

Differential diagnosis between foot osteomyelitisand acute Charcot arthropathyDiagnóstico diferencial entre osteomielitis de pie y artropatía de Charcot agudaM. Molina, J. García Jodar, R. Aliaga,1 F.J. Ampudia-Blasco, J.T. Real, R. CarmenaReference Diabetes Unit, Endocrinology and Nutrition Service; Hospital Clínico Universitario de Valencia.1Magnetic Resonance Imaging Unit (ERESA). Radiology Service. Hospital Clínico de Valencia

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changes with bone edema in the back foot and meso-foot bones and affectation of the soft parts, compati-ble with the presence of osteomyelitis (Þgure 2). Con-sidering the acute osteomyelitis diagnosis in diabeticfoot, intravenous combined antibiotherapy was startedwith ciprofloxacin and clindamycin, together withfoot discharge. The patient showed a favorable evolu-tion with reduction of pain at rest and progressive re-duction of the external inßammatory signs. After 3

months of treatment, the patient is asymptomatic,though a deformity in the back part of the foot stillpersists and certain difÞculty for the ßexo-extensionof the ankle. ■

Figure 2. Uppermost part: sagittal T1 sequence of the foot for the anatomic assessment of its structures. Lower part: sagittal STIRsequence in the same level than the previous one, which allowsassessing the presence of inflammatory changes, as cellulitis, myositisand bone edema

Figure 1. Simple x-ray of left foot

avances en diabetología · currently role of premixed insulins in the treatment of type 2 diabetes...

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