glp 1 e seus análogos em terapia intesnsiva

review

article

Diabetes, Obesity and Metabolism 13: 118–129, 2011.© 2010 Blackwell Publishing Ltdreview article

The potential role of glucagon-like peptide-1 or itsanalogues in enhancing glycaemic control in critically illadult patients

J. Combes, S. Borot, F. Mougel & A. PenfornisDepartment of Endocrinology-Metabolism and Diabetology-Nutrition, Jean Minjoz Hospital, University of Franche-Comte, Boulevard Fleming, Besancon, France

Intravenous insulin therapy is the gold standard therapy for glycaemic control in hyperglycaemic critically ill adult patients. However,hypoglycaemia remains a major concern in critically ill patients, even in some populations who are not receiving infused insulin. Furthermore,the influence of factors such as glycaemic variability and nutritional support may conceal any benefit of strict glycaemic control on morbidity andmortality in these patients. The recently revised guidelines of the American Diabetic Association/American College of Clinical Endocrinologistsno longer advocate very tight glycaemic control or normalization of glucose levels in all critically ill patients. In the light of various concerns overthe optimal glucose level and means to achieve such control, the use of glucagon-like peptide-1 or its analogues administered intravenouslymay represent an interesting therapeutic option.Keywords: acute hyperglycaemia, exenatide, GLP-1 analogues, glycaemic control, insulin intensive management, intravenous insulin therapy,type 2 diabetes mellitus

Date submitted 3 January 2010; date of first decision 9 February 2010; date of final acceptance 26 September 2010

IntroductionThe prevalence of diabetes among hospitalized adults is poorlydocumented. In the USA, it is estimated to be between5 and 30–35% [1]. According to various reports, 19–27%of patients hospitalized for acute conditions [e.g. severeinfection, surgery or intensive care unit (ICU) admission withsignificant stress response] have documented type 2 diabetesmellitus (T2DM), whereas previously undiagnosed diabetesor stress hyperglycaemia is diagnosed at hospital admissionin an additional 12–18% [2–4]. This may be a significantunderestimation of the true incidence of T2DM or prediabetesin the heterogeneous critically ill population. Several studieshave shown the benefits of tight glycaemic control (TGC),i.e. maintaining glycaemia at normal levels between 80 and110 mg/dl (4.4–6 mmol/l), in certain situations of temporaryacute glycaemic imbalance in patients with T2DM or stresshyperglycaemia [5–14].

Continuous intravenous insulin therapy (IIT) representsa reasonable approach to achieve target blood glucose (BG)levels. However, several obstacles hamper the effective useof this therapy, particularly in ICUs, where IIT imposesmany constraints, as well as an extra workload, as it is timeconsuming [15]. Complex glucose management algorithms aredifficult to apply consistently in these settings, because of the

Correspondence to: Alfred Penfornis, Department of Endocrinology-Metabolism andDiabetology-Nutrition, Jean Minjoz Hospital, EA 3920, University of Franche-Comte,Boulevard Fleming, Besancon 25000, France.E-mail: [email protected]

instability of the patients, and the myriad examinations andtreatments that they require. Furthermore, the occurrence ofsevere hypoglycaemia, the main complication of IIT, is alsoproblematic [7,16,17].

In addition, there is some controversy as to whether thereis any direct benefit of insulin therapy on morbidity andmortality, independently of its effect on glycaemia. We cannotexclude from this debate the deleterious impact on mortalitysecondary to severe hypoglycaemia or excessive glycaemicvariability, which could overshadow the survival benefit ofthe insulin therapy [5,13,18–21]. Finally, other factors, suchas mode of nutritional support or the variability betweenglucose measurement methods also compound the difficulty ofobtaining TGC [22,23]. These factors constitute obstacles to theefficacious application of IIT and have probably contributedto the conflicting evidence about the benefits of TGC onmorbidity and mortality rates reported in several studies. Theissue of the risk/benefit ratio of TGC and methods to obtainit remain at the heart of the current controversy over idealglucose management in the ICU.

Glucagon-like peptide-1 (GLP-1) is one of a family ofintestinal factors named incretins, which stimulate insulinproduction in response to nutrient intake. Through itsmultiple glucose-regulating effects, GLP-1 plays an essentialrole in maintaining glucose homeostasis. GLP-1 administeredintravenously rapidly lowers glycaemia without the risk ofhypoglycaemia [24]. The use of GLP-1 or its analogues couldbecome a useful alternative or adjunct to IIT in the future inacute hyperglycaemic ICU patients.

DIABETES, OBESITY AND METABOLISM review articleIntravenous Insulin TherapySeveral studies have shown that continuous IIT is the optimalroute of administration in certain cases of transitory glycaemicimbalance in patients with T2DM or stress hyperglycaemia.Its effect on glycaemic control is more rapid, more stableand more reliable, and hypoglycaemia is less intensive andless frequent than after repeated subcutaneous injections ofinsulin [5]. However, IIT does pose some practical problemsin terms of feasibility and hypoglycaemia. BG measurement inthis setting requires reliable methods and nutritional supportcan complicate the task of reaching target BG levels [22,23]. Itremains debated whether there is currently sufficient benefitto IIT with the goal of normalization of glucose levels in thesetting of hyperglycaemia in the ICU. The factors that influencethese results warrant further exploration.

Feasibility

Meijering et al. [25] performed a literature review of manage-ment of patients with stress hyperglycaemia or T2DM using IITin certain acute situations. The severity of the initial glycaemicimbalance, the duration of the IIT, protocols for modificationof the insulin dosage, target glycaemic levels and the frequencyof BG monitoring, all varied considerably between studies,rendering pooled analysis of the results difficult to interpret.However, one common point was that many of these studiesbrought to light considerable difficulties in attaining target BGlevels, although the frequency of capillary BG monitoring, witha view to dose adaptation, ranged from once every 4 h to onceper hour. In two studies in patients with T2DM during theacute phase of myocardial infarction, the average glycaemiclevel obtained was reported to be 187 mg/dl (10.3 mmol/l)after 12 h [26] and 150 mg/dl (8.2 mmol/l) after 48 h [27] ofIIT, whereas the target range was between 70 and 140 mg/dl(4–8 mmol/l).

In another study of patients with T2DM hospitalizedfor acute medical conditions, average BG obtained after24 h was 183 mg/dl (10.1 mmol/l), [target 110–130 mg/dl(6–7 mmol/l)], despite hourly BG monitoring [28].

Finally, in a further study in patients with diabetes duringthe acute phase of stroke, 24% of patients had glycaemic levelsabove target values [<130 mg/dl (<7 mmol/l)] during the first24 h, despite BG monitoring every 2 h [29].

In their respective studies in this field, Kanji et al. [30],Goldberg et al. [7] and Barth et al. [31] showed that it is possibleto adequately control glycaemia and maintain BG within targetranges using standardized IIT protocols. However, all theseauthors underline the difficulty for the nursing staff to applysuch protocols, particularly in the intensive care setting. Theypropose four main reasons to explain these difficulties:

1 Hyperglycaemia is considered to be less important than thegravity of the initial disease.

2 Staff are not always aware of the necessity of maintainingappropriate BG levels.

3 They are not always experienced in applying IIT protocols,although this is changing with the increasing use of theseprotocols in the ICU setting [32,33].

4 Fear of hypoglycaemia leads staff to tolerate high BG levels.

Similarly, Goldberg et al. [7,33] estimate that the applicationof IIT protocols creates an extra workload of around 5 min/hfor nurses (hourly monitoring of BG, modification of insulindose, and data entry in the patient’s file) and this can beincompatible with the already high workload in certain ICUs.

Finally, patient testing and procedures, changes in feedingprotocols, evolution of the initial disease and the possiblepresence of co-morbidities combine to render problematic thepermanent and efficacious implementation of IIT protocols toreach TGC. Similarly, Wilson et al. [34] noted a wide variabilityin practice in this area and concluded that one standardprotocol might not be suitable for all patients. Accordingto Goldberg et al. [7], Kanji et al. [30] and Barth et al.[31],successful implementation of a protocol aiming at TGC withIIT requires a considerable investment of time in training,practice and evaluation, and in motivating the entire medicalstaff of the unit [33].

Benefit of TGC with IIT in Different ICU Populations

The effect of TGC in the ICU has been investigated invarious clinical settings, such as patients with myocardialinfarction, stroke, septicaemia, trauma, neurosurgical andcardiac surgical patients, and the heterogeneous medical andsurgical population. Results have been conflicting and, to date,it has not been possible to establish with certainty that TGC isbeneficial in any particular disease setting.

The meta-analysis by Wiener et al. included 29 randomizedstudies totalling 8432 patients hospitalized in intensive careand showed that TGC with IIT is not associated with a signif-icant mortality benefit. Conversely, Griesdale et al. [20], in ameta-analysis of 26 studies, concluded that patients in surgicalICU yield a benefit from TGC [relative risk (RR) 0.63 (95% CI0.44–0.91)] among the 14 trials that reported hypoglycaemia.This meta-analysis did not include all the studies reviewedin Wiener’s analysis, but did include the Normoglycemia inIntensive Care Evaluation-Survival Using Glucose AlgorithmRegulation (NICE-SUGAR) data. In a previous meta-analysisincluding 38 randomized studies and published prior to thoseof Griesdale and Wiener, Pittas et al. [35] also observed a reduc-tion in mortality in the surgical ICU with TGC [RR 0.58 (95%CI 0.22–0.62)]. Taken together, these data show conflicting evi-dence and remain difficult to interpret, in view of the numerousbiases and the wide variations in methodology between studies.

Impact of the Existence of Documented Diabeteson Morbidity–Mortality Outcomes and on the Benefitsof TGC in the ICU

When interpreting the results of the studies mentioned above,it should be noted that there is a potential bias, in that there mayhave been a number of patients with undiscovered diabetes atadmission, who were considered as having stress hypergly-caemia. In a meta-analysis of 15 studies in the setting of myocar-dial infarction in the cardiac ICU, Capes et al. [36] showed thatthe relative risk of in-hospital death in patients without knowndiabetes and with elevated glucose levels was 3.9-fold higherthan that of patients without diabetes and with lower glucoseconcentrations. Among patients with known diabetes, for those

Volume 13 No. 2 February 2011 doi:10.1111/j.1463-1326.2010.01311.x 119

review article DIABETES, OBESITY AND METABOLISM

who had BG concentrations above 180 mg/dl (10 mmol/l), therisk of in-hospital death was moderately increased (RR 1.7)compared to patients with diabetes and normal glycaemia. Theretrospective Cooperative Cardiovascular Project study [37]included 141 680 patients admitted to the ICU for myocardialinfarction, of whom 30.4% had known diabetes. This studyshowed that elevated BG levels were significantly associatedwith mortality at 30 days in patients without known diabetesvs. those with diabetes. The risk of death began to increase whenglycaemia exceeded 110 mg/dl (6.1 mmol/l) in patients withoutknown diabetes, whereas the threshold was higher for patientswith diabetes. Similarly, Krinsley [38] and Whitcomb et al. [39]also retrospectively noted a relationship between hypergly-caemia at admission and survival in patients with diabetes inboth medical and surgical ICUs. In Krinsley’s study, the lowesthospital mortality (9.6%) was observed among patients withmean glucose values between 80 and 99 mg/dl, and increasedprogressively as glucose values increased, reaching 42.5%among patients with mean glucose values exceeding 300 mg/dl.In the study by Whitcomb et al., the association between hyper-glycaemia on ICU admission and in-hospital mortality was notuniform in the study population; hyperglycaemia was an inde-pendent risk factor only in patients without the history ofdiabetes in the cardiac, cardiothoracic and neurosurgical ICUs.

The HI-5 study [40] compared the benefit of IIT inmyocardial infarction in 116 patients with known diabetesand 128 patients with admission glycaemia above 140 mg/dl(7.8 mmol/l) but without documented diabetes. IIT was notassociated with a reduction in mortality. However, amongpatients with diabetes, there was a significant reduction inthe risk of re-infarction after >72 h (0 vs. 7.7%, p = 0.04),and a lower occurrence of the composite endpoint combiningdeath and any major cardiac event at 3 months (21.9 vs. 40.4%,p = 0.03).

In a study performed in surgical ICU patients, Van denBerghe et al. [14] found that IIT aiming at TGC reduced mortal-ity in critically ill patients, regardless of the existence of knowndiabetes or hyperglycaemia. However, the effect was more pro-nounced in hyperglycaemic patients without known diabetes.The mortality rates were 8.4 vs. 4.7% in the conventional treat-ment vs. intensive IIT groups, respectively, in patients withoutdiabetes, compared to 5.8 vs. 4% in patients with diabetes. Ina further study in 2006, Van den Berghe et al. [13] pooled thedata from their two prospective randomized studies in medicaland surgical ICUs [target glycaemia range of 80–110 mg/dl(4.4–6.1 mmol/l) in the IIT group]. Among the 2748 patientsincluded, there were 200 patients with diabetes in the conven-tional therapy group and 207 in the intensive therapy group.Contrary to the findings observed in patients without diabetes,intensive IIT showed no benefit on mortality in the subgroup ofpatients with diabetes. Furthermore, risk of death mirrored thatof patients without diabetes for all strata of BG control, witha non-significant increase in risk among patients with diabeteswhen average BG was below 110 mg/day (6.1 mmol/day).

In a single-centre retrospective cohort study, Krinsley [41]compared the outcome in patients admitted to surgical andmedical ICUs before and during the era of TGC with IIT.Patients with diabetes represented 1110 of the 5365 patients

included (532 before and 578 after implementation of TGC withIIT). A significant reduction in mortality was observed amongpatients without diabetes between the historical era and the eraof TGC (18.7 vs. 13.5%), whereas there was a non-significantreduction among patients with diabetes (22.6 vs. 19.2%).Conversely, in a case-control study of 7285 patients undergo-ing IIT in medical and surgical ICUs, Rady et al. [42] observeda twofold higher mortality in patients without diabetes vs.controls. It is noteworthy that, in these last three studies,hyperglycaemic patients without diabetes included those withundiagnosed diabetes or a prediabetic condition. Thus, thismay reflect part of what Umpierrez et al. [3] observed in generalhospital patients who were hyperglycaemic, but undertreatedand/or not known to have T2DM on admission, but who hadit nonetheless.

More recently, subgroup analysis in the NICE-SUGARstudy [43] did not reveal any significant difference in thetreatment effect between patients with and without diabetes.

Although results are disparate, it appears that patientswithout diabetes yield greater benefit from intensive glucosecontrol with IIT in medical and surgical ICUs than patientswith diabetes, whereas in the setting of cardiac ICU, patientswith diabetes seem to obtain the greatest benefit.

Impact of Glycaemic Variability on Glycaemic Controlin the ICU

The benefit of TGC in the ICU setting with intensive IIThas been assessed in some reports by the variation in themean BG levels [44]. Glucose variability may confer an adverserisk of mortality, independent of absolute glucose level andindeed is a stronger risk factor for mortality than averageglucose levels [44,45]. In a study of 5728 patients over 3 yearsin a medical-surgical ICU, Hermanides et al. [46] studiedglycaemic variability using the absolute variation in meanhourly BG, as well as the standard deviation of mean BG,which is the usual parameter used to analyse glycaemicvariability. IIT was initiated with a target BG range of72–126 mg/dl (4–6.9 mmol/l). This study showed that elevatedglycaemic variability was associated with a significant increasein mortality, while low glycaemic variability exerted a protectiveeffect, even when mean BG remained high.

In a cohort of >66 000 ICU patients, Bagshaw et al. [47]observed glycaemic variability [defined as the occurrence ofhypoglycaemia <80 mg/dl (4.5 mmol/l) or hyperglycaemia>220 mg/dl (12 mmol/l) within 24 h of admission] in 2.9%of patients. This early glycaemic variability was associated witha significant increase in the risk of ICU or hospital death.

Patients with glycaemic variability are generally older withmore co-morbidities, particularly heart failure and renaldysfunction. They also usually present with the most severeforms of disease and undergo the most aggressive therapy. Thesepredisposing factors raise the question of whether glycaemicvariability is a marker of disease severity or rather a risk factorfor morbidity and mortality.

Similarly, Egi et al. [45] retrospectively analysed 168 337 BGmeasures in 7049 ICU patients and concluded that glycaemicvariability (s.d. of mean BG) was independently associated with

120 Combes et al. Volume 13 No. 2 February 2011

DIABETES, OBESITY AND METABOLISM review articlelonger ICU stay and higher ICU and hospital mortality. Thisrelation was not observed among the subgroup of 728 patientswith known diabetes.

In a prospective study of glycaemic variability in 191 patientsadmitted to the ICUs for sepsis or septic shock, patients under-went intensive IIT to maintain BG between 80 and 140 mg/dl(4.4–7.7 mmol/l) [48]. Results showed that a standard devia-tion of BG levels >20 mg/dl (1.1 mmol/l) was associated withsignificantly higher mortality than among patients with a stan-dard deviation <20 mg/dl (24 vs. 2.5%, p = 0.0195). Similarresults were observed by Ali et al. [49] in a retrospective studyof patients with sepsis. It would thus appear that glycaemic vari-ability has a negative impact on outcome. Strategies to limit gly-caemic variability should be an integral part of management ofhyperglycaemia in the ICU setting in the future. However, it is ofnote that, in the study by Van den Berghe et al. [13], in patientshospitalized in mixed medical/surgical ICUs, the IIT did notconfer any major impact on improving glucose variability.

Impact of Nutritional Support on BG Control in the ICU

The effects of enteral or parenteral nutritional support on BGcontrol in ICU patients have been widely studied, but the resultshave been discordant. Briefly, it would appear that both formsof nutritional support are equivalent, and the most appropriatemethod should be chosen taking into account the advantagesand disadvantages in a given clinical situation. It has been shownthat parenteral nutrition is used in 12–71% of patients, whileenteral nutrition is used in 33–92% of ICU patients requiringnutritional support [50–55]. Several factors may explain thiswide variability in the use of enteral and parenteral nutrition,such as local practices, cost issues, nutritional status of thepatient, the type and severity of the underlying pathology andtype of surgery.

In a meta-analysis of 13 studies, Gramlich et al. [56] showedthat there was no difference in mortality between enteral andparenteral nutrition in critically ill patients. However, they didobserved a significant reduction in infectious complicationsin patients receiving enteral nutrition. The higher infectiousrisk observed with parenteral nutrition could be secondary tothe higher incidence of hyperglycaemia with this method, ascompared with enteral feeding [56,57].

The influence of nutritional support on BG control hasbeen less extensively studied among patients receiving IIT inthe ICU. Van den Berghe et al. [58] showed, in a prospective,randomized study among 1548 ICU patients, that the benefit ofstrict BG control was similar regardless of whether nutritionalsupport was enteral, parenteral or mixed. Dan et al. [57]observed similar findings in a retrospective study of a mixedmedical–surgical ICU.

Van den Berghe et al. [58] observed that with similar levels ofnutritional support, the insulin doses required to normalize BG[target 80–100 mg/dl (4.4–6 mmol/l)] were 26% higher whennutritional support was by the parenteral route, as comparedto the enteral route, because of the incretin effects. Accordingto Van den Berghe, parenteral nutrition incurs a higher risk ofhyperglycaemia through insufficient or delayed adaptation ofinsulin doses. These same authors also indicate that the benefitof early initiation of enteral nutrition observed in certain studies

could be explained by a lower risk of hyperglycaemia. Thus,early enteral nutrition is all the more recommended when IITis initiated in the ICU to treat hyperglycaemia, in order toallow better insulin dose adjustment. Van den Berghe et al.also underlined that caloric uptake is the main determiningfactor in deciding to adjust insulin doses, and in 62% of cases,hypoglycaemia results from non-adjustment of the dose ofinsulin when nutritional support is interrupted.

Vriesendorp et al. [59] also purport that non-adjustmentof insulin doses, when nutritional support (be it parenteral,enteral or mixed) is reduced or temporarily interrupted, is oneof the main factors predisposing patients to hypoglycaemia (in11% of hypoglycaemia cases).

In a retrospective analysis of data from a subset of 211patients included in the ‘Glucontrol’ trial and 393 patients fromthe Specialized Relative Insulin Nutrition Titration (SPRINT)initiative, Suhaimi et al. [60] showed that glycaemic variabilityis greater when insulin protocols do not take into accountcarbohydrate administration. Thus, it would appear that nutri-tional support, particularly when it is modified or interrupted,may create a favourable environment for the occurrence ofhypoglycaemia and greater glycaemic variability, through inad-equate adjustment of IIT. This in turn can have a negativeimpact on glycaemic control in the ICU.

In the two studies by Van den Berghe carried out in themedical [13] and surgical [14] ICU settings, patients initiallyreceived a high dose of glucose by the parenteral route (average160 g/24 h) in the first few days, contrary to subsequentstudies, whose results were more equivocal. For example,in the NICE-SUGAR study, average glucose administeredintravenously was approximately 22 g/24 h.

In a systematic review of trials that studied the impact ofTGC, Marik and Preiser [61] showed a significant relationshipbetween the treatment effect of TGC on 28-day mortality andthe proportion of calories provided parenterally. Conversely,lack of early parenteral nutrition in such situations wouldeven appear to be associated with an increase in the numberof deaths. Marik and Preiser hypothesize that the differencebetween the positive results of Van den Berghe’s two studiesand the conflicting results observed thereafter could be at leastpartially explained by the use of early parenteral nutrition highin glucose.

Increased glucose turnover and insulin resistance may allowthe body to provide sufficient supplies of the glucose thatis vital to certain organs. However, the initiation of IITwithout administration of additional glucose, by suppressingthe body’s adaptive response, could have a deleterious effect onprognosis [62]. Future studies are needed to identify the impactof nutritional support on the effect of strict glycaemic controlin the ICU and to elucidate whether there is a benefit fromearly parenteral high-glucose nutritional support associatedwith intensive IIT.

Hypoglycaemia

In intervention studies among patients with diabetes invarious acute situations where IIT aiming at TGC is used,hypoglycaemia is not always reported [9,25,26]. When it isrecorded, the incidence varies widely from one study to another,



ranging from 0 to 17.7% [40,63–71]. Analysis and comparisonof these figures are difficult, as the duration of therapy,glycaemia targets and insulin protocols differ significantlybetween studies.

The diabetes and insulin–glucose infusion in acute myocar-dial infarction (DIGAMI) 1 and DIGAMI 2 studies, whichincluded a large number of T2DM patients during the acutephase of myocardial infarction, used robust methodology toillustrate that even with staff who are well trained in the applica-tion of IIT protocols, and despite average BG results often abovetarget levels with frequent monitoring, hypoglycaemia remainsfrequent [11,66]. In DIGAMI 1 [66], 46 of the 306 patients withT2DM (15%) in the group treated by IIT in the first 24 h werereported to have hypoglycaemia, although BG monitoring wasperformed every 1 or 2 h, target levels were between 130 and180 mg/dl (7–10 mmol/l) and average BG in the first 24 h was174 ± 60 mg/dl (9.6 ± 3.3 mmol/l). In DIGAMI 2 [11], in thetwo groups of T2DM patients (n = 474 and 473, respectively)treated by IIT during the first 24 h, with the same target BGlevels and the same monitoring frequency as above, the rateof hypoglycaemia was 12.7 and 9.6%, respectively. Average BGduring the first 24 h was 165 mg/dl (9.1 mmol/l). In the twostudies by Van den Berghe et al. in the surgical [14] and med-ical [13] ICU setting, hypoglycaemia was reported to occur in5.1 and 18.7%, respectively. Two multicentre studies, namelythe Efficacy of Volume Substitution and Insulin Therapy inSevere Sepsis (VISEP) [18] and Glucontrol [72] studies, wereprematurely stopped. In both these studies, the target glycaemialevels were the same as those used in the two Van den Berghestudies, that is, 80–110 mg/dl (4.4–6.1 mmol/l) [13,14]. TheVISEP study included 537 patients, of whom 163 had dia-betes [18]. The trial was stopped because of the increased rate ofsevere hypoglycaemia in the group receiving intensive insulintreatment (12.1 vs. 2.1% in the conventional therapy group,p < 0.01) and there was no significant difference betweengroups in terms of morbidity and mortality at 28 and 90 days.The Glucontrol study [72] was prematurely stopped after theinclusion of 1101 patients because of a high rate of unintendedprotocol violations (based on the evaluation of available BGmeasures). Although ICU mortality was similar in the twogroups (15.3% in the intermediate BG control group vs. 17.2%in the intensive IIT group), higher rates of severe hypoglycaemiawere observed in the intensive therapy arm.

In the NICE-SUGAR study, a significantly higher rateof hypoglycaemia was also observed in the group receivingintensive IIT as compared to the conventional therapy group(6.8 vs. 0.5%, p < 0.001) [43].

The incidence of hypoglycaemia is reportedly similarly inmedical and surgical ICU patients [59] and hypoglycaemiaremains an independent risk factor for mortality in ICUpatients. Certain predisposing factors for hypoglycaemia inthe ICU have been identified. Vriesendorp et al. [59] analyseddata from a cohort of 2272 patients admitted to the ICU,and identified the following predisposing factors: reduction ofnutrition without a corresponding adjustment of insulin ther-apy, documented diabetes, sepsis, use of inotropic medicationor octreotide and venovenous haemofiltration with bicarbonatesubstitution fluid.

In a retrospective study, Krinsley and Grover [73] alsoidentified diabetes and sepsis as predisposing factors for hypo-glycaemia, but further observed that mechanical ventilation,renal insufficiency and severity of illness were also risk factorsfor hypoglycaemia.

Heightened awareness of the predisposing factors forhypoglycaemia, combined with more frequent BG controlsin the population at risk, could help to reduce the incidence ofhypoglycaemia.

However, in a retrospective multicentre cohort studyincluding 7820 patients hospitalized with acute myocardialinfarction and who were hyperglycaemic on admission, whilehypoglycaemia was associated with increased mortality, thisrisk was confined to patients who developed hypoglycaemiaspontaneously [74]. In contrast, iatrogenic hypoglycaemia afterinsulin therapy was not associated with higher mortality risk.

Benefit of TGC by IIT on Morbidity and Mortality inIntensive Care

The meta-analysis by Wiener et al. [19], published in 2008,included 29 randomized studies totalling 8432 patientshospitalized in intensive care and showed that TGC by IITis not associated with a significant reduction in mortality, but isassociated with a significantly increased risk of hypoglycaemia.The recently published randomized NICE-SUGAR study [43]included over 6000 patients in intensive care and showed asignificant increase in cardiovascular and all-cause mortalityat 90 days in the group with intensive BG control [target81–108 mg/dl (4.4–5.9 mmol/l)] compared to the controlgroup [target 180 mg/dl or less (10 mmol/l)]. This findingwas also observed in the subgroups of patients hospitalized inmedical and surgical ICUs. The results of the NICE-SUGARstudy are at odds with those observed in previous studies incritical care [14], surgery [13] and the paediatric setting [75].This discrepancy in the results could be explained by differencesin parameters such as inclusion criteria, the methods used tomeasure BG, staffing ratios, patient populations, incidenceof diabetes and, in particular, the intervention itself, that is,the method used to obtain strict BG control. In addition,the results of the single-centre randomized controlled trial ofintensive IIT by Van den Berghe et al. in 2001 have given rise tosome debate. This unblinded study concluded that ‘intensiveinsulin therapy to maintain BG at or below 110 mg/dl reducesmorbidity and mortality among critically ill patients in thesurgical ICU’. Among the several limitations of this studythat have been raised [76], it is of note that the study wasstrongly biased towards postoperative cardiothoracic surgicalpatients, and mainly showed benefits for patients in the ICU for>5 days. Furthermore, all patients initially received a high doseof glucose by the parenteral route, followed by initiation ofeither total parenteral nutrition, enteral feeding or combinedfeeding, which is a highly unusual practice. A recent meta-analysis [20] including 26 randomized studies, with a total of13 567 patients in intensive care, including the NICE-SUGARdata, showed, as in Wiener’s meta-analysis, that intensive IITincreases the risk of hypoglycaemia sixfold, without any benefiton mortality, except in the subgroup of patients admitted tosurgical intensive care.


DIABETES, OBESITY AND METABOLISM review articleIn light of the NICE-SUGAR data, the American Diabetes

Association (ADA) and American Association of ClinicalEndocrinologists (AACE) [77] recently revised their guidelineson inpatient glycaemic control. Although the previousADA guidelines advocated initiation of insulin infusion forICU patients in the aim of maintaining BG <140 mg/dl(7.7 mmol/l), and if possible <110 mg/dl (6 mmol/l) forpatients in surgical intensive care, the revised guidelinesnow recommend that for critically ill patients, BG shouldbe maintained between 140 and 180 mg/dl (7.7–9.9 mmol/l),aiming preferably to approach the lower end of this range.Lower BG levels may be appropriate in selected patients. In therecent revision of the ‘Surviving Sepsis’ guidelines, initiationof glycaemic control is recommended, targeting BG levels<150 mg/dl after initial stabilization for the management ofpatients with severe sepsis or septic shock [78]. However,target BG <110 mg/dl (<6 mmol/l) is not recommended inany circumstances.

We cannot exclude the hypothesis that a certain proportionof deaths may be caused by unidentified severe hypoglycaemia(such as in patients with consciousness disorders, oftenunder sedation and whose mechanisms of hormonal counter-regulation are altered). Such an excess could mask the benefitof TGC on mortality [13,18–21,59].

In addition, the practical obstacles associated with the useof IIT outlined above underline how difficult it is to obtainappropriate and stable BG control. Indeed, in the NICE-SUGAR study, even with a complex and computerized IITprotocol, investigators reported that, on average, patient BGlevels were within the target range only 40% of the time [43].

Therefore, it would seem that, at present, the benefit ofTGC for patients in intensive care may be concealed by thelack of reliable tools for IIT that can effectively maintaintarget BG levels without danger of excess hypoglycaemia. TheCGAO-REA study (impact of computerized glucose control incritically ill patients), which is currently ongoing, may providenew information in this setting.

Incretin–GLP-1Physiological Data

GLP-1 is a gut hormone produced by the proglucagon gene inthe L-cells located predominantly in the distal small intestine.It is secreted in response to nutrient intake (figure 1). Themain circulating form in humans is the GLP-1(7-36) amide(figure 2). The half-life of GLP-1 is extremely short (1–2 min)because it is rapidly inactivated by the ubiquitous, non-specific enzyme dipeptidyl peptidase-4 (DPP-4), leading tothe formation of its inactive metabolite (figure 1) [79,80].

GLP-1 Possesses Several Important Pharmacodynamic Properties.It stimulates insulin secretion in a dose-dependent manner,but this effect disappears when BG levels are below 80 mg/dl(4.4 mmol/l) as the insulinotropic activity of GLP-1 is strictlyglucose-dependent [79]. On top of the insulinotropic effects,GLP-1 stimulates insulin production and exerts a trophic effecton β cells (differentiation of progenitor cells, reduction ofapoptosis and proliferation of β cells) (figure 3) [81].

Figure 1. Glucagon-like peptide-1 (GLP-1) secretion and metabolism.Bioactive GLP-1(7-36) amide and GIP (1–42) are released from thesmall intestine after meal ingestion and enhance glucose-stimulatedinsulin secretion (incretin action). Dipeptidyl peptidase-4 (DPP-4) rapidlyconverts GLP-1 to its inactive metabolite GLP-1(9-36) in vivo. Inhibitionof DPP-4 activity prevents GLP-1 degradation, thereby enhancing incretinaction. GIP (glucose-dependent insulinotropic polypeptide) is anotherincretin. Adapted with permission from Ref. [107].

Figure 2. Chemical structure of native human glucagon-like peptide-1.Adapted with permission from Ref. [108].

• GLP-1 dose dependently inhibits glucagon secretion, butwithout preventing hormonal counter-regulation at BG levelsbelow 65 mg/dl (3.5 mmol/l).

• It slows gastric emptying, reduces intestinal peristalsis andreduces secretory activity in the upper digestive tract throughmechanisms initiated by the vagal nerve and the autonomicnervous system [82].

• Finally, GLP-1 promotes satiety, which can lead to reducedfood intake and weight loss [83]. This effect could bemediated by vagal afferent activity or could result from adirect action of circulating GLP-1 on areas of the centralnervous system with receptors that are not protected by theblood–brain barrier.



Figure 3. Glucagon-like peptide-1 (GLP-1) action in peripheral tissues. The majority of the effects of GLP-1 are mediated by direct interaction withGLP-1 receptors on specific tissues. However, the actions of GLP-1 in liver, fat and muscle most probably occur through indirect mechanisms. Adaptedwith permission from Ref. [107].

GLP-1 in the Treatment of T2DM

GLP-1 possesses two essential characteristics that enhanceits potential as a treatment for T2DM. First, the majorityof its effects are exerted very rapidly in the presenceof hyperglycaemia and cease as soon as BG returns tonormal levels. Second, in patients with T2DM, secretion ofGLP-1 may be diminished, but sensitivity to GLP-1 remainsunchanged. These particular characteristics combine to makeGLP-1 a focus of research for the treatment of T2DM insituations of acute hyperglycaemia. However, in the caseof ICU patients, hyperglycaemia is often stress-induced andpatients are not known to have T2DM. Also, with counter-regulatory hormones potentially altered during critical illnessand altered gluconeogenesis or glycogenolysis (e.g. in thosewith decompensated liver or relative starvation), the globalpotential of GLP-1 remains to be elucidated through furtherresearch.

Subcutaneous Injection of GLP-1

Subcutaneous injection of high doses of GLP-1 (1.5 nmol/kg)makes it possible to rapidly normalize BG levels in patientswith T2DM. However, the effect is of short duration, becauseof the rapid inactivation of GLP-1, and therefore regularsubcutaneous injections every 2 h are required to maintainBG levels within the normal range [84].

Intravenous (IV) Administration of GLP-1

Efficacy. Several studies have shown that continuous IVinfusion of GLP-1 makes it possible to normalize fastingand postprandial (PP) glycaemia in patients with T2DMsuffering from moderate to severe glycaemic imbalance (apartfrom episodes of acute decompensation) [85,86]. Similarefficacy is observed regardless of whether patients wereinitially treated with sulphonylurea [86,87], metformin [88]or pioglitazone [89]. Normalization of fasting BG in T2DMpatients can be obtained within approximately 4 h after thestart of GLP-1 infusion. When fasting glycaemia is above270 mg/dl (15 mmol/l), normalization may take longer [90].

Dosage and Side Effects. In most studies, the most efficaciousand best tolerated dose of GLP-1 when administered by infusionis from 1 to 1.2 pmol/kg/min. This does not increase the risk ofhypoglycaemia [85,86,91–95]. There exists a dose-dependentrelationship between the dose of GLP-1 administered anddeceleration of gastric emptying which may cause digestive sideeffects after food intake. Higher doses improve BG levels consid-erably, but also significantly increase the rate of side effects [87].However, Meier et al. [91] showed in a recent study that nor-malization of fasting and PP glycaemia (test meal of 250 kcal)in patients with T2DM was not dose-dependent at doses lowerthan 1.2 pmol/kg/min. GLP-1 administered at doses of 0.4, 0.8or 1.2 pmol/kg/min by overnight infusion, or started 1 h before


DIABETES, OBESITY AND METABOLISM review articlea meal, normalized BG levels in the same manner both in thefasting state and 4 h after the meal. However, unlike the lowerdoses of GLP-1, gastric emptying was almost completely inhib-ited 4 h after meal intake at the 1.2 pmol/kg/min dose. Theseadverse effects of GLP-1 activity on intestinal motility and diges-tive secretions may compound the reduction in gastric empty-ing frequently observed in ICU patients. This renders the use ofGLP-1 difficult in medical–surgical patients with gastrointesti-nal or pancreatic diseases as well as in patients with diabetic gas-troparesis. Whether GLP-1-based therapies might increase therisk of aspiration and alter gastrointestinal tract caloric intake,because of the changes they can induce in gastric emptying andfood absorption, should be closely monitored in these criticalsituations. However, Deane et al. [96] have shown, in criticallyill mechanically ventilated patients, without known diabetes,that exogenous GLP-1 slows gastric emptying only when the lat-ter is normal, but not when it is already spontaneously delayed.

Continuous or Discontinuous Infusion. Infusion of 1 pmol/kg/min of GLP-1 for 4 h in patients with T2DM in the fasting state,with average initial BG of 210 ± 16 mg/dl (11.7 ± 0.9 mmol/l),normalizes glycaemia at the end of infusion [87 ± 7 mg/dl(4.8 ± 0.4 mmol/l)] and for up to 4 h afterwards if patientsremain fasting [92,93]. If food is given after the interruptionof GLP-1 infusion, then BG rises within 1 h to levels similar tothose observed after the infusion of placebo [95]. However, iffood is ingested while maintaining an infusion of GLP-1, BGremains normal [91,94].

In patients with poorly controlled T2DM and normal foodintake of 3 meals/day, only a continuous infusion of GLP-1made it possible to maintain normal BG levels over a 24-hperiod. Interruption of the infusion for 6 h during the nightresulted in elevated fasting BG levels, similar to those observedunder 24-h placebo infusion. The beneficial effect on BG levelscan persist for up to 1 week if continuous IV infusion of GLP-1is maintained [87].

Continuous Subcutaneous Infusion of GLP-1

The therapeutic use of GLP-1 for the long term is hamperedby the necessity of IV administration. In this context, studieshave been carried out to test continuous subcutaneous pumpinfusion over periods ranging from 48 h [90] to 3 months [97].Administration by the subcutaneous route achieves circulatingGLP-1 concentrations that are more or less equivalent to thoseobtained by the IV route by radio-immunological dosing, butfor reasons that remain to be identified, the therapeutic efficacyand the side effects are less. Thus, doses of 2.4–4.8 pmol/kg/minare necessary by subcutaneous administration, compared todoses of 0.4–1.2 pmol/kg/min by the IV route to obtain asignificant therapeutic effect [90,97,98].

In a parallel group study of 20 patients with poorlycontrolled T2DM [HbA1c 9.2 ± 1.8% (77 ± 17 mmol/mol)],Zander et al. showed that GLP-1 administered by subcutaneousinfusion at a dose of 4.8 pmol/kg/min for 6 weeks lowered fast-ing BG from 261 to 183 mg/dl (14.4–10.1 mmol/l), and averageplasma BG as assessed by an 8-h profile of BG concentrationswas reduced by 100 mg/dl (5.5 mmol/l). These effects were

observed from week 1 and persisted till 6 weeks, with a reduc-tion of 1.3% (12 mmol/mol) in HbA1c. At this dose, BG levelswere thus not normalized, but tolerance was good [98].

Over a period of 3 months, subcutaneous administration ofGLP-1 in elderly patients (75 ± 2 years) with T2DM at a doseof 2.4 pmol/kg/min was shown to be as efficacious as treatmentby oral antidiabetic agents (metformin and/or sulphonylureatreatment) to maintain HbA1c at 7% (53 mmol/mol), withgood tolerance and without the risk of hypoglycaemiaobserved with secretagogues [97]. However, it is unlikelythat subcutaneous administration, whether continuous ornot, would be a viable option for ICU patients, because ofthe absorption difficulties linked to the frequent presence ofvasoconstriction or peripheral oedema, and the potential forhaematoma or infection in or around the sites of recurrentsubcutaneous infusions or injections in frail patients.

Controlled Intervention Studies

Although it has been shown that continuous IV infusion ofGLP-1 at doses of 1–1.2 pmol/kg/min makes it possible torapidly normalize fasting and PP BG levels with good tolerancein diabetic patients with severe, transitory glycaemic imbalance(apart from episodes of acute decompensation), there is apaucity of controlled intervention studies in this setting. Inparticular, data are lacking about the use of GLP-1 in the highlycomplex, dynamic and often unstable ICU patient who mayhave little hepatic or pancreatic reserve.

In a randomized study of eight patients with T2DM,Schmoelzer et al. [99] observed that GLP-1 infusion at a doseof 1.2 pmol/kg/min over 8 h normalized BG to the same extentas IIT, with a more rapid effect, without dose adaptation andwithout hypoglycaemia.

In a study among eight patients with T2DM who hadundergone major surgery, Meier et al. [24] observed that withinfusion of GLP-1 over 8 h at a dose of 1.2 pmol/kg/minbetween the second and eighth postoperative day, anormoglycaemic fasting BG range was reached within 150 min,with good tolerance and without hypoglycaemia. In arandomized study of GLP-1 IV infusion vs. placebo in 20patients during the postoperative phase, Sokos et al. showedthat in the 12 h preceding and the 48 h following coronaryartery bypass graft surgery, GLP-1 at a dose of 1.5 pmol/kg/minachieved better glycaemic control, with less frequent use of IIT,and 45% less insulin was required to obtain the same glycaemiccontrol compared to when IV insulin was used. Furthermore,GLP-1 achieved comparable haemodynamic recovery, withless use of inotropic and anti-arrhythmic medication [100].These beneficial effects are in line with the GLP-1-inducedimprovements in left ventricular ejection fraction in micesubjected to ischaemia–reperfusion [101].

In another randomized study of GLP-1 IV infusion vs. IITamong 20 patients with T2DM over the 12 h following coronaryartery bypass graft surgery, GLP-1 at a dose of 3.6 pmol/kg/minobtained normalized glycaemia levels as efficaciously as IIT,with good tolerance and no reported hypoglycaemia [102].A further study showed that infusion of GLP-1 over 4 hmakes it possible to normalize BG levels in severely ill patientshyperglycaemic during total parenteral nutrition [103].



Finally, Deane et al. [104] assessed the effect of exogenousGLP-1 on the glycaemic response to enteral nutritionin patients with critical illness-induced hyperglycaemia. Inthis randomized double-blind placebo-controlled crossoverstudy, seven mechanically ventilated critically ill patients,not previously known to have diabetes, received two IVinfusions of GLP-1 (1.2 pmol/kg/min) and placebo over270 min, while a mixed nutrient liquid was infused viaa postpyloric feeding catheter. Acute, exogenous GLP-1infusion markedly attenuated the glycaemic response to enteralnutrition in all these critically ill patients, with reduced overallglycaemic response during enteral nutrient stimulation andreduced peak BG [GLP-1 (10.1 ± 0.7 mmol/l) vs. placebo(12.7 ± 1.0 mmol/l); p < 0.01]. The same authors, in a similarstudy design, showed that exogenous GLP-1 lowers PPglycaemia in 25 critically ill patients after intragastric feeding.This may occur, at least in part, by reducing the rate ofcarbohydrate absorption [96].

GLP-1 AnaloguesAs the therapeutic use of GLP-1 is considerably limited by itsvery short half-life, GLP-1 receptor agonists (GLP-1 analogues),which are active for longer, have been developed.

Exendin-4 or exenatide (Byetta®, Amylin PharmaceuticalsInc., San Diego, CA, USA) is the first GLP-1 mimetic to beapproved for the treatment of T2DM. The approved dose forexenatide is 5–10 μg, twice daily, by subcutaneous injection.A subcutaneous injection of 5–10 μg of exenatide exerts itsbiological effects for a duration of 5–7 h [105].

A recent study in 13 patients with diabetes with BG withinnormal range {[HbA1c at 6.1% (43 mmol/mol)], plasma BGbetween 70 and 101 mg/dl (4.4 and 5.6 mmol/l)} and receivingglucose infusion showed that IV infusion of exenatide at adose of 25 ng/min augmented first- and second-phase insulinsecretion and brought BG down from 300 mg/dl (16.5 mmol/l)to initial values in less than 3 h with excellent tolerance [106].

Results of ongoing longer-term studies with exenatide by IVinfusion in T2DM patients with acute glycaemia imbalance arekeenly awaited.

ConclusionGLP-1 administered by IV infusion makes it possible to rapidlynormalize and stabilize BG in hyperglycaemic patients withdiabetes. GLP-1 therapy, at a dose of 1–1.2 pmol/kg/min, iswell tolerated, without the risk of hypoglycaemia, and reducesthe frequency of capillary BG testing. GLP-1 therapy showsgreat promise as a new therapeutic alternative to intensive IITin situations of glycaemic imbalance in patients with T2DM.Administration of GLP-1 receptor agonists by the IV routecan compensate for the current difficulties in access to GLP-1therapy. Treatment with GLP-1 or its analogues needs tobe explored further through larger-scale studies to confirmencouraging results from preliminary studies. Remainingareas of concern that require clarification include tolerance(particularly gastrointestinal tolerance in ICU patients beingtube fed or in postoperative patients at high risk for ileus),

the apparently inferior efficacy as compared to insulin and theneed for insulin–GLP-1 combination therapy in some patients.Intervention studies with exenatide are currently ongoing[see http://clinicaltrials.gov: IV exenatide (Byetta®) for thetreatment of perioperative hyperglycaemia, NCT00882050; IVexenatide in coronary ICU patients, NCT00736229], which mayanswer some of these outstanding questions and subsequentlyhelp evaluate the potential benefit of GLP-1 therapy onmorbidity and mortality.

AcknowledgementWe would like to thank Fiona Ecarnot for translation andeditorial assistance.

Conflict of InterestJ. C. and A. P. took the decision to write this review and wereresponsible for writing the manuscript. All authors contributedto the research and analysis of literature and drafting andrevising the manuscript. Prof. Penfornis reports receiving aninvestigator-initiated research grant and honoraria for speakingengagements from Eli Lilly. No other potential conflicts ofinterest relevant to this review were reported.

References1. Cowie CC, Rust KF, Ford ES et al. Full accounting of diabetes and pre-

diabetes in the U.S. population in 1988–1994 and 2005–2006. DiabetesCare 2009; 32: 287–294.

2. Pili-Floury S, Mitifiot F, Penfornis A et al. Glycaemic dysregulation innondiabetic patients after major lower limb prosthetic surgery. DiabetesMetab 2009; 35: 43–48.

3. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi AE.Hyperglycemia: an independent marker of in-hospital mortality inpatients with undiagnosed diabetes. J Clin Endocrinol Metab 2002; 87:978–982.

4. Wexler DJ, Nathan DM, Grant RW, Regan S, Van Leuvan AL, Cagliero E.Prevalence of elevated hemoglobin A1c among patients admitted to thehospital without a diagnosis of diabetes. J Clin Endocrinol Metab 2008;93: 4238–4244.

5. Clement S, Braithwaite SS, Magee MF et al. Management of diabetesand hyperglycemia in hospitals. Diabetes Care 2004; 27: 553–591.

6. Furnary AP, Gao G, Grunkemeier GL et al. Continuous insulin infusionreduces mortality in patients with diabetes undergoing coronary arterybypass grafting. J Thorac Cardiovasc Surg 2003; 125: 1007–1021.

7. Goldberg PA, Siegel MD, Sherwin RS et al. Implementation of a safeand effective insulin infusion protocol in a medical intensive care unit.Diabetes Care 2004; 27: 461–467.

8. Hermans G, Wilmer A, Meersseman W et al. Impact of intensive insulintherapy on neuromuscular complications and ventilator dependency inthe medical intensive care unit. Am J Respir Crit Care Med 2007; 175:480–489.

9. Lazar HL, Chipkin SR, Fitzgerald CA, Bao Y, Cabral H, Apstein CS. Tightglycemic control in diabetic coronary artery bypass graft patientsimproves perioperative outcomes and decreases recurrent ischemicevents. Circulation 2004; 109: 1497–1502.

10. Malmberg K. Prospective randomised study of intensive insulin treatmenton long term survival after acute myocardial infarction in patients withdiabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion inAcute Myocardial Infarction) Study Group. BMJ 1997; 314: 1512–1515.


DIABETES, OBESITY AND METABOLISM review article11. Malmberg K, Ryden L, Wedel H et al. Intense metabolic control by means

of insulin in patients with diabetes mellitus and acute myocardialinfarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J2005; 26: 650–661.

12. Scalea TM, Bochicchio GV, Bochicchio KM, Johnson SB, Joshi M, Pyle A.Tight glycemic control in critically injured trauma patients. Ann Surg2007; 246: 605–610; discussion 10–12.

13. Van den Berghe G, Wilmer A, Milants I et al. Intensive insulin therapyin mixed medical/surgical intensive care units: benefit versus harm.Diabetes 2006; 55: 3151–3159.

14. Van den Berghe G, Wouters P, Weekers F et al. Intensive insulin therapyin the critically ill patients. N Engl J Med 2001; 345: 1359–1367.

15. Aragon D. Evaluation of nursing work effort and perceptions about bloodglucose testing in tight glycemic control. Am J Crit Care 2006; 15:370–377.

16. Bode BW, Braithwaite SS, Steed RD, Davidson PC. Intravenous insulininfusion therapy: indications, methods, and transition to subcutaneousinsulin therapy. Endocr Pract 2004; 10(Suppl. 2): 71–80.

17. Egi M, Bellomo R, Stachowski E et al. Hypoglycemia and outcome incritically ill patients. Mayo Clin Proc 2010; 85: 217–224.

18. Brunkhorst FM, Engel C, Bloos F et al. Intensive insulin therapy andpentastarch resuscitation in severe sepsis. N Engl J Med 2008; 358:125–139.

19. Wiener RS, Wiener DC, Larson RJ. Benefits and risks of tight glucosecontrol in critically ill adults: a meta-analysis. JAMA 2008; 300: 933–944.

20. Griesdale DE, de Souza RJ, van Dam RM et al. Intensive insulin therapyand mortality among critically ill patients: a meta-analysis includingNICE-SUGAR study data. CMAJ 2009; 180: 821–827.

21. Gandhi GY, Murad MH, Flynn DN et al. Effect of perioperative insulininfusion on surgical morbidity and mortality: systematic review andmeta-analysis of randomized trials. Mayo Clin Proc 2008; 83: 418–430.

22. Martindale RG, McClave SA, Vanek VW et al. Guidelines for the provisionand assessment of nutrition support therapy in the adult critically illpatient: Society of Critical Care Medicine and American Society forParenteral and Enteral Nutrition: executive summary. Crit Care Med2009; 37: 1757–1761.

23. Rice MJ, Pitkin AD, Coursin DB. Review article: glucose measurement inthe operating room: more complicated than it seems. Anesth Analg2010; 110: 1056–1065.

24. Meier JJ, Weyhe D, Michaely M et al. Intravenous glucagon-like peptide1 normalizes blood glucose after major surgery in patients with type 2diabetes. Crit Care Med 2004; 32: 848–851.

25. Meijering S, Corstjens AM, Tulleken JE, Meertens JH, Zijlstra JG, LigtenbergJJ. Towards a feasible algorithm for tight glycaemic control in critically illpatients: a systematic review of the literature. Crit Care 2006; 10: R19.

26. Davies RR, Newton RW, McNeill GP, Fisher BM, Kesson CM, Pearson D.Metabolic control in diabetic subjects following myocardial infarction:difficulties in improving blood glucose levels by intravenous insulininfusion. Scott Med J 1991; 36: 74–76.

27. Hendra TJ, Yudkin JS. An algorithm for tight glycaemic control in diabeticinfarct survivors. Diabetes Res Clin Pract 1992; 16: 213–220.

28. Bonnier M, Lonnroth P, Gudbjornsdottir S, Attvall S, Jansson PA. Valida-tion of a glucose-insulin-potassium infusion algorithm in hospitalizeddiabetic patients. J Intern Med 2003; 253: 189–193.

29. Scott JF, Robinson GM, French JM, O’Connell JE, Alberti KG, Gray CS.Glucose potassium insulin infusions in the treatment of acute strokepatients with mild to moderate hyperglycemia: the Glucose Insulin inStroke Trial (GIST). Stroke 1999; 30: 793–799.

30. Kanji S, Singh A, Tierney M, Meggison H, McIntyre L, Hebert PC. Stan-dardization of intravenous insulin therapy improves the efficiency and

safety of blood glucose control in critically ill adults. Intensive Care Med2004; 30: 804–810.

31. Barth MM, Oyen LJ, Warfield KT et al. Comparison of a nurse initiatedinsulin infusion protocol for intensive insulin therapy between adultsurgical trauma, medical and coronary care intensive care patients. BMCEmerg Med 2007; 7: 14.

32. Furnary AP, Wu Y. Clinical effects of hyperglycemia in the cardiac surgerypopulation: the Portland Diabetic Project. Endocr Pract 2006; 12(Suppl.3): 22–26.

33. Studer C, Sankou W, Penfornis A et al. Efficacy and safety of an insulininfusion protocol during and after cardiac surgery. Diabetes Metab 2010;36: 71–78.

34. Wilson M, Weinreb J, Hoo GW. Intensive insulin therapy in critical care: areview of 12 protocols. Diabetes Care 2007; 30: 1005–1011.

35. Pittas AG, Siegel RD, Lau J. Insulin therapy for critically ill hospitalizedpatients: a meta-analysis of randomized controlled trials. Arch InternMed 2004; 164: 2005–2011.

36. Capes SE, Hunt D, Malmberg K, Gerstein HC. Stress hyperglycaemia andincreased risk of death after myocardial infarction in patients with andwithout diabetes: a systematic overview. Lancet 2000; 355: 773–778.

37. Kosiborod M, Rathore SS, Inzucchi SE et al. Admission glucose andmortality in elderly patients hospitalized with acute myocardial infarction:implications for patients with and without recognized diabetes.Circulation 2005; 111: 3078–3086.

38. Krinsley JS. Association between hyperglycemia and increased hospitalmortality in a heterogeneous population of critically ill patients. MayoClin Proc 2003; 78: 1471–1478.

39. Whitcomb BW, Pradhan EK, Pittas AG, Roghmann MC, Perencevich EN.Impact of admission hyperglycemia on hospital mortality in variousintensive care unit populations. Crit Care Med 2005; 33: 2772–2777.

40. Cheung NW, Wong VW, McLean M. The hyperglycemia: Intensive InsulinInfusion in Infarction (HI-5) study: a randomized controlled trial of insulininfusion therapy for myocardial infarction. Diabetes Care 2006; 29:765–770.

41. Krinsley JS. Glycemic control, diabetic status, and mortality in aheterogeneous population of critically ill patients before and duringthe era of intensive glycemic management: six and one-half yearsexperience at a university-affiliated community hospital. Semin ThoracCardiovasc Surg 2006; 18: 317–325.

42. Rady MY, Johnson DJ, Patel BM, Larson JS, Helmers RA. Influence ofindividual characteristics on outcome of glycemic control in intensivecare unit patients with or without diabetes mellitus. Mayo Clin Proc2005; 80: 1558–1567.

43. Finfer S, Chittock DR, Su SY et al. Intensive versus conventional glucosecontrol in critically ill patients. N Engl J Med 2009; 360: 1283–1297.

44. Krinsley JS. Glycemic variability: a strong independent predictor ofmortality in critically ill patients. Crit Care Med 2008; 36: 3008–3013.

45. Egi M, Bellomo R, Stachowski E, French CJ, Hart GK. Variability of bloodglucose concentration and short-term mortality in critically ill patients.Anesthesiology 2006; 105: 244–252.

46. Hermanides J, Vriesendorp TM, Bosman RJ, Zandstra DF, Hoekstra JB,Devries JH. Glucose variability is associated with intensive care unitmortality. Crit Care Med 2010; 38: 838–842.

47. Bagshaw RJ, Bellomo R, Jacka MJ et al. The impact of early hypoglycemiaand blood glucose variability on outcome in critical illness. Crit Care 2009;13: R91.

48. Waeschle RM, Moerer O, Hilgers R, Herrmann P, Neumann P, Quintel M.The impact of the severity of sepsis on the risk of hypoglycaemia andglycaemic variability. Crit Care 2008; 12: R129.



49. Ali NA, O’Brien JM Jr, Dungan K et al. Glucose variability and mortality inpatients with sepsis. Crit Care Med 2008; 36: 2316–2321.

50. De Jonghe B, Appere-De-Vechi C, Fournier M et al. A prospective surveyof nutritional support practices in intensive care unit patients: What isprescribed? What is delivered? Crit Care Med 2001; 29: 8–12.

51. Heyland DK, Schroter-Noppe D, Drover JW et al. Nutrition support in thecritical care setting: current practice in Canadian ICUs—opportunities forimprovement? JPEN J Parenter Enteral Nutr 2003; 27: 74–83.

52. Hill SA, Nielsen MS, Lennard-Jones JE. Nutritional support in intensivecare units in England and Wales: a survey. Eur J Clin Nutr 1995; 49:371–378.

53. Lipman TO. Grains or veins: Is enteral nutrition really better thanparenteral nutrition? A look at the evidence. JPEN J Parenter EnteralNutr 1998; 22: 167–182.

54. Payne-James JJ, De Gara CJ, Grimble GK et al. Artificial nutrition supportin hospitals in the United Kingdom—1991: second national survey. ClinNutr 1992; 11: 187–192.

55. Preiser JC, Berre J, Carpentier Y et al. Management of nutrition inEuropean intensive care units: results of a questionnaire. Working Groupon Metabolism and Nutrition of the European Society of Intensive CareMedicine. Intensive Care Med 1999; 25: 95–101.

56. Gramlich L, Kichian K, Pinilla J, Rodych NJ, Dhaliwal R, Heyland DK. Doesenteral nutrition compared to parenteral nutrition result in betteroutcomes in critically ill adult patients? A systematic review of theliterature. Nutrition 2004; 20: 843–848.

57. Dan A, Jacques TC, O’Leary MJ. Enteral nutrition versus glucose-based orlipid-based parenteral nutrition and tight glycaemic control in critically illpatients. Crit Care Resusc 2006; 8: 283–288.

58. Van den Berghe G, Wouters PJ, Bouillon R et al. Outcome benefit ofintensive insulin therapy in the critically ill: insulin dose versus glycemiccontrol. Crit Care Med 2003; 31: 359–366.

59. Vriesendorp TM, van Santen S, DeVries JH et al. Predisposing factors forhypoglycemia in the intensive care unit. Crit Care Med 2006; 34: 96–101.

60. Suhaimi F, Le Compte A, Preiser JC et al. What makes tight glycemiccontrol tight? The impact of variability and nutrition in two clinicalstudies. J Diabetes Sci Technol 2010; 4: 284–298.

61. Marik PE, Preiser JC. Toward understanding tight glycemic control in theICU: a systematic review and metaanalysis. Chest 2010; 137: 544–551.

62. Losser MR, Damoisel C, Payen D. Glucose metabolism in acute criticalsituation. Ann Fr Anesth Reanim 2009; 28: e181–e192.

63. Dazzi D, Taddei F, Gavarini A, Uggeri E, Negro R, Pezzarossa A. Thecontrol of blood glucose in the critical diabetic patient: a neuro-fuzzymethod. J Diabetes Complications 2001; 15: 80–87.

64. Gonzalez-Michaca L, Ahumada M, Ponce-de-Leon S. Insulin subcuta-neous application vs. continuous infusion for postoperative blood glucosecontrol in patients with non-insulin-dependent diabetes mellitus. ArchMed Res 2002; 33: 48–52.

65. Jaspers CA, Elte JW, Olthof G. Perioperative diabetes regulation with thehelp of a standard protocol. Neth J Med 1994; 44: 122–130.

66. Malmberg K, Ryden L, Efendic S et al. Randomized trial of insulin-glucoseinfusion followed by subcutaneous insulin treatment in diabetic patientswith acute myocardial infarction (DIGAMI study): effects on mortality at1 year. J Am Coll Cardiol 1995; 26: 57–65.

67. Malmberg KA, Efendic S, Ryden LE. Feasibility of insulin-glucose infusionin diabetic patients with acute myocardial infarction. A report from themulticenter trial: DIGAMI. Diabetes Care 1994; 17: 1007–1014.

68. Markovitz LJ, Wiechmann RJ, Harris N et al. Description and evaluation ofa glycemic management protocol for patients with diabetes undergoingheart surgery. Endocr Pract 2002; 8: 10–18.

69. Pezzarossa A, Taddei F, Cimicchi MC et al. Perioperative managementof diabetic subjects. Subcutaneous versus intravenous insulin admin-istration during glucose-potassium infusion. Diabetes Care 1988; 11:52–58.

70. Stefanidis A, Melidonis A, Tournis S et al. Intensive insulin treatmentreduces transient ischaemic episodes during acute coronary events indiabetic patients. Acta Cardiol 2002; 57: 357–364.

71. Watts NB, Gebhart SS, Clark RV, Phillips LS. Postoperative managementof diabetes mellitus: steady-state glucose control with bedside algorithmfor insulin adjustment. Diabetes Care 1987; 10: 722–728.

72. Preiser JC, Devos P, Ruiz-Santana S et al. A prospective randomised multi-centre controlled trial on tight glucose control by intensive insulin therapyin adult intensive care units: the Glucontrol study. Intensive Care Med2009; 35: 1738–1748.

73. Krinsley JS, Grover A. Severe hypoglycemia in critically ill patients: riskfactors and outcomes. Crit Care Med 2007; 35: 2262–2267.

74. Kosiborod M, Inzucchi SE, Goyal A et al. Relationship between sponta-neous and iatrogenic hypoglycemia and mortality in patients hospitalizedwith acute myocardial infarction. JAMA 2009; 301: 1556–1564.

75. Vlasselaers D, Milants I, Desmet L et al. Intensive insulin therapy forpatients in paediatric intensive care: a prospective, randomised controlledstudy. Lancet 2009; 373: 547–556.

76. Bellomo R, Egi M. Glycemic control in the intensive care unit: why weshould wait for NICE-SUGAR. Mayo Clin Proc 2005; 80: 1546–1548.

77. Moghissi ES, Korytkowski MT, DiNardo M et al. American Association ofClinical Endocrinologists and American Diabetes Association consensusstatement on inpatient glycemic control. Diabetes Care 2009; 32:1119–1131.

78. Dellinger RP, Levy MM, Carlet JM et al. Surviving Sepsis Campaign:international guidelines for management of severe sepsis and septicshock: 2008. Crit Care Med 2008; 36: 296–327.

79. Holst JJ, Vilsboll T, Deacon CF. The incretin system and its role in type 2diabetes mellitus. Mol Cell Endocrinol 2009; 297: 127–136.

80. Nauck MA. Unraveling the science of incretin biology. Am J Med 2009;122: S3–S10.

81. Farilla L, Hui H, Bertolotto C et al. Glucagon-like peptide-1 promotes isletcell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology2002; 143: 4397–4408.

82. Little TJ, Pilichiewicz AN, Russo A et al. Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthysubjects: relationships with postprandial glycemic and insulinemicresponses. J Clin Endocrinol Metab 2006; 91: 1916–1923.

83. Williams DL, Baskin DG, Schwartz MW. Evidence that intestinal glucagon-like peptide-1 plays a physiological role in satiety. Endocrinology 2009;150: 1680–1687.

84. Nauck MA, Wollschlager D, Werner J et al. Effects of subcutaneousglucagon-like peptide 1 (GLP-1 [7–36 amide]) in patients with NIDDM.Diabetologia 1996; 39: 1546–1553.

85. Meneilly GS, McIntosh CH, Pederson RA et al. Effect of glucagon-likepeptide 1 on non-insulin-mediated glucose uptake in the elderly patientwith diabetes. Diabetes Care 2001; 24: 1951–1956.

86. Nauck MA, Sauerwald A, Ritzel R, Holst JJ, Schmiegel W. Influence ofglucagon-like peptide 1 on fasting glycemia in type 2 diabetic patientstreated with insulin after sulfonylurea secondary failure. Diabetes Care1998; 21: 1925–1931.

87. Larsen J, Hylleberg B, Ng K, Damsbo P. Glucagon-like peptide-1 infusionmust be maintained for 24 h/day to obtain acceptable glycemia in type 2diabetic patients who are poorly controlled on sulphonylurea treatment.Diabetes Care 2001; 24: 1416–1421.


DIABETES, OBESITY AND METABOLISM review article88. Zander M, Taskiran M, Toft-Nielsen MB, Madsbad S, Holst JJ. Additive

glucose-lowering effects of glucagon-like peptide-1 and metformin intype 2 diabetes. Diabetes Care 2001; 24: 720–725.

89. Zander M, Christiansen A, Madsbad S, Holst JJ. Additive effects ofglucagon-like peptide 1 and pioglitazone in patients with type 2 diabetes.Diabetes Care 2004; 27: 1910–1914.

90. Toft-Nielsen MB, Madsbad S, Holst JJ. Continuous subcutaneous infusionof glucagon-like peptide 1 lowers plasma glucose and reduces appetitein type 2 diabetic patients. Diabetes Care 1999; 22: 1137–1143.

91. Meier JJ, Gallwitz B, Salmen S et al. Normalization of glucose concen-trations and deceleration of gastric emptying after solid meals duringintravenous glucagon-like peptide 1 in patients with type 2 diabetes.J Clin Endocrinol Metab 2003; 88: 2719–2725.

92. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normal-ization of fasting hyperglycaemia by exogenous glucagon-like peptide1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients.Diabetologia 1993; 36: 741–744.

93. Nauck MA, Weber I, Bach I et al. Normalization of fasting glycaemia byintravenous GLP-1 ([7–36 amide] or [7-37]) in type 2 diabetic patients.Diabet Med 1998; 15: 937–945.

94. Rachman J, Barrow BA, Levy JC, Turner RC. Near-normalisation of diurnalglucose concentrations by continuous administration of glucagon-likepeptide-1 (GLP-1) in subjects with NIDDM. Diabetologia 1997; 40:205–211.

95. Willms B, Idowu K, Holst JJ, Creutzfeldt W, Nauck MA. Overnight GLP-1normalizes fasting but not daytime plasma glucose levels in NIDDMpatients. Exp Clin Endocrinol Diabetes 1998; 106: 103–107.

96. Deane AM, Chapman MJ, Fraser RJ et al. Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the criticallyill: relationship to glycemia. Crit Care Med 2010; 38: 1261–1269.

97. Meneilly GS, Greig N, Tildesley H, Habener JF, Egan JM, Elahi D. Effects of3 months of continuous subcutaneous administration of glucagon-likepeptide 1 in elderly patients with type 2 diabetes. Diabetes Care 2003;26: 2835–2841.

98. Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course ofglucagon-like peptide 1 on glycaemic control, insulin sensitivity, andbeta-cell function in type 2 diabetes: a parallel-group study. Lancet2002; 359: 824–830.

99. Schmoelzer I, Kettler-Schmutt E, Pressl H, Sourij I, Wascher TC. DiabeticAngiopathy Research Group. Efficacy and safety of continuous,intravenous glucagon-like-peptide 1 (GLP-1) in comparison to insulininfusion for normalisation of hyperglycaemia in patients with type 2diabetes (Abstract). Diabetologia 2007; 50(Suppl. 1): S351.

100. Sokos GG, Bolukoglu H, German J et al. Effect of glucagon-like peptide-1(GLP-1) on glycemic control and left ventricular function in patientsundergoing coronary artery bypass grafting. Am J Cardiol 2007; 100:824–829.

101. Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M.Cardioprotective and vasodilatory actions of glucagon-like peptide1 receptor are mediated through both glucagon-like peptide 1receptor-dependent and -independent pathways. Circulation 2008; 117:2340–2350.

102. Mussig K, Oncu A, Lindauer P et al. Effects of intravenous glucagon-likepeptide-1 on glucose control and hemodynamics after coronary arterybypass surgery in patients with type 2 diabetes. Am J Cardiol 2008; 102:646–647.

103. Nauck MA, Walberg J, Vethacke A et al. Blood glucose control in healthysubject and patients receiving intravenous glucose infusion or totalparenteral nutrition using glucagon-like peptide 1. Regul Pept 2004;118: 89–97.

104. Deane AM, Chapman MJ, Fraser RJ, Burgstad CM, Besanko LK, Horowitz M.The effect of exogenous glucagon-like peptide-1 on the glycaemicresponse to small intestinal nutrient in the critically ill: a randomiseddouble-blind placebo-controlled cross over study. Crit Care 2009; 13:R67.

105. Yoo BK, Triller DM, Yoo DJ. Exenatide: a new option for the treatment oftype 2 diabetes. Ann Pharmacother 2006; 40: 1777–1784.

106. Fehse F, Trautmann M, Holst JJ et al. Exenatide augments first- andsecond-phase insulin secretion in response to intravenous glucosein subjects with type 2 diabetes. J Clin Endocrinol Metab 2005; 90:5991–5997.

107. Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterol-ogy 2007; 132: 2131–2157.

108. Neumiller JJ. Differential chemistry (structure), mechanism of action, andpharmacology of GLP-1 receptor agonists and DPP-4 inhibitors. J AmPharm Assoc (2003) 2009; 49(Suppl. 1): S16–S29.


glp 1 e seus análogos em terapia intesnsiva

Health & Medicine