update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in ·...

Update on Prevention ofCardiovascular Disease in AdultsWith Type 2 Diabetes Mellitus inLight of Recent Evidence: AScientific Statement From theAmerican Heart Association andthe American Diabetes AssociationDOI: 10.2337/dci15-0012

Cardiovascular disease risk factor control as primary prevention in patients withtype 2 diabetesmellitus has changed substantially in the past few years. The purposeof this scientific statement is to review the current literature and key clinical trialspertaining to blood pressure and blood glucose control, cholesterol management,aspirin therapy, and lifestyle modification. We present a synthesis of the recentliterature, new guidelines, and clinical targets, including screening for kidney andsubclinical cardiovascular disease for the contemporary management of patientswith type 2 diabetes mellitus.

Diabetes mellitus, defined by elevated glycemic markers, is a major risk factor forcardiovascular disease (CVD), which is the most common cause of death amongadults with diabetes mellitus (1), underscoring the need for aggressive CVD riskfactor management. In 1999, the American Heart Association (AHA) and the Amer-ican Diabetes Association (ADA) published a joint statement focused on CVD pre-vention in diabetes mellitus (2). In 2007, the AHA and ADA again issued a combinedset of recommendations focused on the primary prevention of CVD in diabetesmellitus (3). Since then, several new clinical trials have emerged that have changedthe clinical practice of CVD risk management in diabetes mellitus.Since the earlier scientific statement, diabetes mellitus screening and diagnosis

have changed, with the inclusion of glycated hemoglobin (A1c) of at least 6.5% in thediagnostic criteria of type 2 diabetes mellitus (4). This change in criteria has iden-tified separate subsets of newly diagnosed patients with diabetes mellitus while theoverall diabetes mellitus epidemic continues, with a 75% increase in the number ofaffected individuals with diabetes mellitus across all age-groups from 1988 to 2010(5). Fewer than half of U.S. adults meet recommended guidelines for diabetesmellitus care (6), underscoring the magnitude of the public health burden of type2 diabetes mellitus.Given the changes in the diabetes mellitus landscape over the past 5 years, the

purpose of this scientific statement is to summarize key clinical trials pertaining tolifestyle, blood glucose, blood pressure, and cholesterol management for the pri-mary prevention of CVD.We have synthesized the established clinical guidelines and

The input provided by Drs. Fox, Ershow, Nelson,and Fradkin is from their own perspective, andthe opinions expressed in this article do not re-flect the view of the National Institutes of Health,Department of Health and Human Services, orthe U.S. government. Dr. Pignone is a memberof the U.S. Preventive Services Task Force. Hiscontributions here represent his views aloneand not necessarily those of the U.S. PreventiveServices Task Force.

The American Diabetes Association and theAmerican Heart Association make every effortto avoid any actual or potential conflicts of in-terest that may arise as a result of an outsiderelationship or a personal, professional, or busi-ness interest of a member of the writing panel.Specifically, all members of the writing group arerequired to complete and submit a DisclosureQuestionnaire showing all such relationshipsthat might be perceived as real or potential con-flicts of interest.

Corresponding author: Caroline S. Fox, [email protected].

This document was approved by the AmericanDiabetes Association on 7 January 2015 andthe American Heart Association Science Advisoryand Coordinating Committee on 30 April 2015and the American Heart Association ExecutiveCommittee on 22 May 2015.

This article has been copublished in Circulation.

© 2015 by the American Diabetes Associationand the American Heart Association, Inc.

Caroline S. Fox, Co-Chair;

Sherita Hill Golden, Co-Chair;

Cheryl Anderson; George A. Bray;

Lora E. Burke; Ian H. de Boer;

Prakash Deedwania; Robert H. Eckel;

Abby G. Ershow; Judith Fradkin;

Silvio E. Inzucchi; Mikhail Kosiborod;

Robert G. Nelson; Mahesh J. Patel;

Michael Pignone; Laurie Quinn;

Philip R. Schauer; Elizabeth Selvin; and

Dorothea K. Vafiadis; on behalf of the

American Heart Association Diabetes

Committee of the Council on Lifestyle and

Cardiometabolic Health, Council on

Clinical Cardiology, Council on

Cardiovascular and Stroke Nursing,

Council on Cardiovascular Surgery and

Anesthesia, Council on Quality of Care and

Outcomes Research, and the American

Diabetes Association

Diabetes Care 1

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Diabetes Care Publish Ahead of Print, published online August 5, 2015

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clinical targets for the contemporarymanagement of patients with type 2 di-abetes mellitus to reduce CVD risk. Whenpossible, we have included the AHA/American College of Cardiology (ACC)Class of Recommendation/Level of Evi-dence grading system (Table 1) or theADA evidence grading system for clinicalpractice recommendations (Table 2) (4).Specifically, we start with the updated

diagnostic criteria for diabetes mellitus.Next, we focus on lifestyle managementin diabetes mellitus, including physical

activity and nutrition. Then, we focus onCVD risk factor management in diabetesmellitus, including weight management,aspirin use, glucose control, blood pressuremanagement, and lipid management.Next, we move to screening for renal andCVD complications of diabetes mellitus.Finally, we close with a list of selectedareas of controversy requiring furtherresearch. Throughout, we emphasizethat this document is not a comprehen-sive review of the literature but rather afocus on the major new trials that have

led to recent guideline changes in thearea of primary prevention of CVD intype 2 diabetes mellitus.

NEW DIAGNOSTIC CRITERIA FORDIABETES MELLITUS ANDPREDIABETES

In 2010, the ADA included A1c for the firsttime among the tests recommended forthe diagnosis of diabetes mellitus. Thisrecommendation has also been adoptedby the European Association for theStudy of Diabetes, the World Health

Table 1—Applying classification of recommendations and Level of Evidence

A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed inthe guidelines do not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus thata particular test or therapy is useful or effective. *Data available from clinical trials or registries about the usefulness/efficacy in differentsubpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. †Forcomparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbsshould involve direct comparisons of the treatments or strategies being evaluated.

2 Scientific Statement Diabetes Care

Organization, and other professionalgroups in the U.S. Clinical practice recom-mendations from the ADA now statethat an A1c value of $6.5% or previouscriteria for fasting glucose ($126 mg/dL)or 2-h glucose ($200 mg/dL) can beused for the diagnosis of diabetes mel-litus (Table 3) (4). In 2010, the ADA alsoadded A1c to the tests used to identifypeople with prediabetes, who are atincreased risk for type 2 diabetes mel-litus. Thus, along with fasting glucoseof 100 to 125 mg/dL or 2-h glucose of140 to 199 mg/dL, individuals with A1cin the range of 5.7% to 6.4% are

classified as having an increased riskfor diabetes mellitus (Table 3) (4).

A1c and Diabetes MellitusA major strength of using A1c for the di-agnosis of diabetes mellitus is the evi-dence linking A1c to clinical outcomes.Randomized, clinical trials have demon-strated that improvements in glycemiccontrol reduce the risk of microvascularcomplications (8–11). Evidence for currentdiagnostic cut points also includes epide-miological studies demonstrating strong,graded, cross-sectional associations forfasting glucose, 2-h glucose, and A1c with

prevalent retinopathy (11–15). In one ofthe few prospective studies of retinopa-thy, an analysis of data from a large Japa-nese population showed that individualswith an A1c of$6.5% had an elevated riskof newly developed retinopathy during 3years of follow-up compared with thosewith A1c values in the range of 5.0% to5.4% (16). Recent studies have also estab-lished robust relationships of A1c with fu-ture risk of diabetes mellitus, chronickidney disease (CKD), CVD, and all-causemortality in initially nondiabetic popula-tions (17–20). These data linking A1c toboth microvascular and macrovascularoutcomes provide further evidence tosupport the new A1c criteria.

A1c and PrediabetesEpidemiological studies have shown thatindividuals with A1c in the range of 5.7%to 6.4% have a high risk of future diabetesmellitus (20–22), supporting the use ofthis range to define prediabetes. How-ever, the A1c threshold for increased di-abetes mellitus risk is less clearly definedthan that for a diagnosis of diabetesmellitus. There is a strong risk gradientbetween 5.7% and 6.4%, with no obviousthreshold. Elevated A1c, even below thethreshold for diagnosis of diabetes melli-tus, is also associated with cardiovascularoutcomes after adjustment for traditionalcardiovascular risk factors (19,20,23,24).The evidence for an association of im-paired fasting glucose (100–125 mg/dL)with cardiovascular outcomes is less robust(25), possibly because of the higher vari-ability in fasting glucose levels comparedwith A1c (26,27). Indeed, in a recent verylarge study that pooleddata from.50 sep-arate epidemiological cohorts, greatly en-hancing the power to detect a modestassociation, fasting glucose levels in thenondiabetes range were moderately butsignificantly associatedwith risk of vasculardeath (28). The high risk of both diabetesmellitus and CVD among people with anA1c of 5.7% to 6.4% highlights the needfor cardiovascular and diabetes mellitusprevention efforts in this population.

Strengths and Limitations of Using A1c

for Diabetes Mellitus DiagnosisThere are a number of advantages ofusing A1c for diagnosing diabetes melli-tus; however, there are also some limi-tations to consider (18,20,26,29–33)that are summarized in Table 4.

Some A1c measurement methods areknown to give falsely high or low values

Table 2—ADA evidence grading system for clinical practice recommendations (4)

Level of Evidence Description

A Clear evidence from well-conducted, generalizable RCTs that areadequately powered, including the following:c Evidence from a well-conducted multicenter trialc Evidence from a meta-analysis that incorporated quality ratings intothe analysis

Compelling nonexperimental evidence (i.e., “all or none” rule developed

by the Centre for Evidence-BasedMedicine at the University of Oxford)Supportive evidence from well-conducted RCTs that are adequately

powered, including the following:

c Evidence from a well-conducted trial at one or more institutions

c Evidence from a meta-analysis that incorporated quality ratings intothe analysis

B Supportive evidence from well-conducted cohort studiesc Evidence from awell-conducted prospective, cohort study or registryc Evidence from a well-conducted meta-analysis of cohort studies

Supportive evidence from a well-conducted case-control study

C Supportive evidence from poorly controlled or uncontrolled studiesc Evidence from randomized clinical trials with one or more major orthree or more minor methodological flaws that could invalidate theresults

c Evidence from observational studies with a high potential for bias(e.g., case series with comparison with historical control subjects)

c Evidence from case series or case reports

Conflicting evidence with the weight of evidence supporting the

recommendation

E Expert consensus or clinical experience

Table 3—Diagnostic criteria for diabetes mellitus and categories of increased riskfor diabetes mellitus and prediabetes

Diabetes mellitus Prediabetes

A1c, % $6.5 5.7–6.4

Fasting glucose, mg/dL $126 100–125

2-h glucose, mg/dL $200 140–199

Random glucose in patients with classic symptoms ofdiabetes mellitus, mg/dL $200 N/A

Modified from “Standards of Medical Care in Diabetesd2015” (4). Copyright © 2015, AmericanDiabetes Association.

care.diabetesjournals.org Fox and Associates 3

in the presence of hemoglobin variants,although modern assays are mostly un-affected by common variants (29). How-ever, other nonglycemic determinantsof A1c, that is, hemoglobin characteristics(other than hemoglobinopathies), red cellturnover, and the tendency of hemoglo-bin to undergo glycation, may contributeto variability in the population (30).In summary, updated diagnostic criteria

for diabetes mellitus are well aligned withthe current evidence linking A1c to long-term complications. Because the sametests identify diabetes mellitus and predi-abetes, current guidelines represent aconvenient approach to identifying indi-viduals with either condition, so individ-uals with prediabetes can be targetedfor diabetes mellitus risk reductionand patients with diabetes mellituscan receive aggressive cardiovascularrisk prevention.

LIFESTYLE MANAGEMENT OF TYPE2 DIABETES MELLITUS

Once type 2 diabetes mellitus is diag-nosed, lifestyle management is a corner-stone of clinical care. This section reviewssome of the evidence from large clinicaltrials that focus on lifestyle managementin type 2 diabetes mellitus.

Physical ActivityThe Look AHEAD (Action for Health in Di-abetes) study, conducted from 2001 to2012, provided extensive longitudinaldata on the effect of an intensive lifestyleintervention, targeting weight reductionthrough caloric restriction and increasedphysical activity, on CVD rates (the pri-mary outcome) and CVD risk factorsamong adults with type 2 diabetes melli-tus. In this trial, 2,575 participants wererandomized to a control group and 2,570to an intervention that consisted ofa weekly goal for physical activity of50 min/week initially, increasing to$175

min/week of moderately intense activityby week 26 (34). The second componentof the physical activity interventionincluded a focus on lifestyle activity (e.g.,using the stairs instead of elevators, walk-ing instead of riding), which is equally aseffective as aerobic activity in leading toweight loss and improvement in CVD riskfactors (35). Participants were provided apedometer in the seventh week and in-structed to increase their daily steps by250 each week until they reached thegoal of $10,000 a day. One-year resultsrevealed that participants in the intensivelifestyle intervention achieved an averageof 136.7 6 110.4 min/week of physicalactivity; moreover, there was a significantassociation between the minutes of phys-ical activity and weight loss at 12 months(36).

The primary results of Look AHEADwere published in 2013 (37). At 1 year,greater weight loss was observed in theintervention arm (8.6%) compared withthe usual care arm (0.7%), which was at-tenuated but still sustained by the end ofthe study (6.0% versus 3.5%). In additiontoweight loss, thepatients in the interven-tion arm had improved physical fitnessand HDL cholesterol (HDL-C) levels, hadgreater reductions inA1c andwaist circum-ference, and required less medication forglucose, blood pressure, and lipid control.However, after a median follow-up of 9.6years, the trial was stopped early becauseof futility: There were 403 CVD events inthe intervention arm compared with 418CVD events in the usual care arm (hazardratio [HR] 0.95 [95% CI 0.83–1.09]; P 50.51). The reasons for this are not clear(38) but may be the result of decreaseduse of cardioprotective drugs, particularlystatins, in the intervention group resultingfrom an improvement in risk factors withthe lifestyle intervention. At a minimum,the study informs clinicians that increasedphysical activity and improvements in diet

can safely lead to weight loss and reducedrequirement for medication to controlCVD risk factors without a concomitant in-crease in the risk of cardiovascular events.

In addition to absolute amounts of ex-ercise, the type of exercise in patientswithdiabetes mellitus might make a differ-ence. A recent randomized, controlled tri-al (RCT) of 262 sedentary patients withdiabetes mellitus randomized to the non-exercise control group or to a resistancetraining alone, an aerobic training alone,or a combined resistance and aerobictraining group showed that only the com-bined exercise was associated with lowerA1c levels (mean decline 0.34%; P5 0.03)(39). These findings highlight howexercisetype may be as important as exercisequantity in type 2 diabetes mellitus.

NutritionIn addition to physical activity, nutritionplays an important role in the treatmentof type 2 diabetes mellitus and CVD riskprevention. Published recommenda-tions for the treatment of people withdiabetes mellitus assert the continuedimportance of diet, exercise, and educa-tion as a cornerstone of optimal diabe-tes mellitus treatment (4,40–43).

Current nutrition recommendations forindividuals with type 2 diabetes mellituscenter around a dietary pattern that em-phasizes intake of fruits, vegetables, re-duced saturated fat, and low-fat dairyproducts. The recommendations also con-sist of individualizedmodification ofmacro-nutrient intake to accommodate individualneeds for the distribution of calories andcarbohydrates over the course of the day.Eating patterns such as the Dietary Ap-proaches to Stop Hypertension (DASH),Mediterranean, low-fat, or monitored car-bohydrate diet are effective for controllingglycemia and loweringCVD risk factors (44).The Prevencion con Dieta Mediterranea(PREDIMED) trial was an RCT looking at

Table 4—Strengths and limitations of using A1c for diabetes mellitus diagnosis

Strengths Limitations

Reflects chronic hyperglycemia, providing global index of glycemicexposure (tracks well over time)

Less biological (day-to-day) variability compared with single fastingor 2-h glucose (26,31,32)

Eliminates need for fasting or timed samplesUnaffected by acute illness or recent activity (e.g., physical activity) (30)Already used as a guide to adjust diabetes mellitus treatment (33)Laboratory methods are well standardized in the U.S. and some other

countries (33)More robustpredictorof complications than fastingbloodglucose (18,20)

Certain conditions interferewith the interpretationof results (18,29,33)(www.ngsp.org), including hemoglobin traits and alterations in redcell turnover (e.g., hemolytic anemia, recent transfusion, pregnancy,loss of blood)

Lack of assay standardization in many parts of the worldCost and lack of availability in resource-poor areas


Table 5—Current recommendations for CVD risk factor management in type 2 diabetes mellitus

Risk factor Relevant statement or guideline Specific recommendation and Level of Evidence

Nutrition “Nutrition Therapy Recommendations for the Managementof Adults With Diabetes” (43)

Reduction of energy intake for overweight or obese patients(ADA Level of Evidence A).

Individualizedmedical nutrition therapy for all patients withdiabetes mellitus (ADA Level of Evidence A).

Carbohydrate monitoring as an important strategy forglycemic control (ADA Level of Evidence B).

Consumption of fruits, legumes, vegetables, whole grains,and dairy products in place of other carbohydrate sources(ADA Level of Evidence B).

Mediterranean-style dietary pattern may improve glycemiccontrol and CVD risk factors (ADA Level of Evidence B).

Limit of sodium to ,2,300 mg/day, similar torecommendations for the general population (ADA Level ofEvidence B; note that the AHA differs and recommendssodium,1,500 mg/day).

Obesity “2013 AHA/ACC/TOS Guideline for the Management ofOverweight and Obesity in Adults: A Report of theAmerican College of Cardiolgy/American HeartAssociation Task Force on Practice Guidelines and TheObesity Society” (58)

Overweight and obese patients should be counseled thatlifestyle changes can produce a 3%–5% rate of weight lossthat can be sustained over time and that this can beassociated with clinically meaningful health benefits(ACC/AHA Class I; Level of Evidence A).

For patients with BMI$40 kg/m2 or BMI$35 kg/m2with anobesity-related comorbidity who want to lose weight buthave not responded to behavioral treatment with orwithout pharmacological treatment, bariatric surgery mayimprove health (ACC/AHA Class IIa; Level of Evidence A).

Blood glucose “Management of Hyperglycemia in Type 2 Diabetes: APatient-Centered Approach: Position Statement of theAmerican Diabetes Association (ADA) and the EuropeanAssociation for the Study of Diabetes (EASD)” (59)

“Standards of Medical Care in Diabetesd2015” (4)

Lower A1c to#7.0% inmost patients to reduce the incidenceof microvascular disease (ADA Level of Evidence B); this canbeachievedwith ameanplasmaglucoseof�8.3–8.9mmol/L(�150–160 mg/dL); ideally, fasting and premeal glucoseshould be maintained at,7.2 mmol/L (,130 mg/dL) andpostprandial glucose at,10 mmol/L (,180 mg/dL).

More stringent A1c targets (e.g.,,6.5%)might be considered inselected patients (with short disease duration, long lifeexpectancy, no significant CVD) if this can be achievedwithout significant hypoglycemia or other adverse effects oftreatment (ADA Level of Evidence C).

Less stringent A1c goals (e.g.,,8.0% or even slightly higher) areappropriate for patients with a history of severehypoglycemia, limited life expectancy, advancedcomplications, cognitive impairment, and extensivecomorbid conditions and those inwhom the target is difficultto attain despite intensive self-management education,repeated counseling, and effective doses ofmultiple glucose-lowering agents, including insulin (ADA Level of Evidence B).

Blood pressure “An Effective Approach to High Blood Pressure Control: AScience Advisory From the American Heart Association,the American College of Cardiology, and the Centers forDisease Control and Prevention” (60)

“2014 Evidence-Based Guideline for the Management ofHigh Blood Pressure in Adults: Report From the PanelMembers Appointed to the Eighth Joint NationalCommittee (JNC 8)” (61)


Formost individuals with diabetesmellitus, achieve a goal of,140/90 mmHg; lower targets may be appropriate forsome individuals, although the guidelines have not yetbeen formally updated to incorporate this newinformation (Expert Opinion, Grade E) (60,61).

Pharmacological therapy should include a regimen witheither an ACEI or an ARB (ADA Level of Evidence B); if oneclass is not tolerated, the other should be substituted(ADA Level of Evidence C) (4).

For patients with CKD, antihypertension treatment shouldinclude an ACEI or ARB (Expert Opinion, Grade E).

Hypertension/blood pressure control has been revised tosuggest that the systolic blood pressure goal for manypeople with diabetes mellitus and hypertension shouldbe,140 mmHg (ADA Level of Evidence A) but that lowersystolic targets (e.g., ,130 mmHg) may be appropriatefor certain individuals such as younger patients if it can beachieved without undue treatment burden (ADA Level ofEvidence C) (4).

Continued on p. 6


the effect of a Mediterranean diet on CVDoutcomes. Those patients randomized totheMediterranean diet had a 30% reducedrisk of CVD events (45). The prespecifieddiabetes mellitus subgroup demon-strated similar results, suggesting that aMediterranean diet may promote CVD riskreduction inpatientswithdiabetesmellitus.Some data suggest that eating pat-

terns with low glycemic index may beeffective in achieving glycemic control(i.e., positive effects on postprandialblood glucose and insulin) and in lower-ing triglyceride levels (46–48), whereasother studies have shown no effect oflow–glycemic index diets on triglycer-ides (49–51). The importance of the gly-cemic index needs further investigation.Given that individualswith diabetesmel-

litus commonly have elevated triglyceridesand reducedHDL-C levels, it is important tooptimize nutrition-related practices, includ-ing moderate alcohol intake, substitutinghealthy fats (e.g., monounsaturated fattyacids, polyunsaturated fatty acids) for satu-rated and trans fats, limiting added sugars,engaging in regular physical activity, andlosing excess weight. These changes canreduce triglycerides by 20% to 50% (52).

Dietary SupplementsWith regard to dietary supplements, noconsistent findings have emerged fromlarge-scale, randomized trials in individ-uals with diabetes mellitus (53,54). Inindividuals without diabetes mellitus,some studies have demonstrated an as-sociation with lower CVD risk when ahealthful diet is supplementedwith antiox-idant vitamins, B vitamins, or specific fattyacids (e.g., omega-3 fatty acids) (54–57).

However, there are no conclusive stud-ies in patients with diabetes mellitus.Whether vitamin D supplementationwill ultimately be important in pre-venting diabetes mellitus remains tobe determined.

Nutritional RecommendationsThe ADA recently issued a position state-ment on nutritional recommendationsfor adults living with diabetes mellitus(43). The stated goals of nutrition therapyfor adults with diabetes mellitus are toattain individualized glycemic, lipid, andblood pressure goals; to achieve andmaintain healthy bodyweight; to preventor delay diabetes mellitus complications;and to provide those living with diabetesmellitus tools for meal planning. Key spe-cific recommendations (43) can be foundin Table 5.

WEIGHT MANAGEMENT

The next section of this update focuseson weight management through life-style, pharmacological, and surgical ap-proaches in type 2 diabetes mellitus.

LifestyleThe primary approach to weight man-agement is lifestyle, which includes threecomponents: dietary change that is fo-cused on caloric restriction, increased en-ergy expenditure through increased dailyphysical activity and regular aerobic activ-ity 3 to 5 days/week, and behavior changesrelated to lifestyle. Numerous clinical trialshave established the efficacy of this ap-proach (64,65). In type 2 diabetesmellitus, a landmark trial is the recentLook AHEAD study. In terms of the specificintervention, the Look AHEAD trial

intensive intervention diverged fromthat of the Diabetes Prevention Program(DPP) in that there were more counselingsessions extending over a longer durationwith both individual and group treatmentin addition to the meal replacements thatwere provided (34). Meal replacementsare an approach that addresses portioncontrol and the difficulty individualshave in estimating calorie content of con-sumed foods (66,67). The dietary compo-nent of the trial included an energy goal of1,200 to 1,500 kcal/day for thoseweighing,114 kg and 1,500 to 1,800 for thoseweighing $114 kg. Additional goals in-cluded restricting fat to,30% of total cal-ories and ,10% from saturated fat. Thephysical activity component is describedin detail in the previous section.

The third component was focused onbehavior modification and included groupsessions during the first year; in subse-quent years, contact was achieved bymonthly individual sessions and by tele-phone. Of all the behavioral strategiestaught in these sessions, self-monitoringor recording one’s food intake and physi-cal activity was likely the most importantstrategy for success. There is extensiveempirical evidence on the association be-tween self-monitoring and successful out-comes in weight loss treatment (68,69).Individuals were weighed before eachsession and were provided feedback;they were also encouraged to weighthemselves more often because there isevidence that more frequent weighing isassociated with improved weight loss andmaintenance (70,71).

The final component of the lifestyleprogram was the use of a toolbox, a

Table 5—Continued

Risk factor Relevant statement or guideline Specific recommendation and Level of Evidence

Cholesterol “2013 ACC/AHA Guideline on the Treatment of BloodCholesterol to Reduce Atherosclerotic CardiovascularRisk in Adults: A Report of the American College ofCardiology/American Heart Association Task Force onPractice Guidelines” (62)


Patients with diabetes mellitus between 40 and 75 years ofage with LDL-C between 70 and 189 mg/dL should betreated with a moderate-intensity statin*† (ACC/AHAClass I; Level of Evidence A) (ADA Level of Evidence A).

Statin therapy of high intensity‡ should be given toindividuals with diabetes mellitus between 40 and 75years of age with a$7.5% estimated risk of ASCVD (ACC/AHA Class IIa; Level of Evidence B).

Among individualswithdiabetesmellituswho are,40 or.75years of age, practitioners should evaluate the benefit ofstatin treatment (ACC/AHA Class IIa; Level of Evidence C).

Evaluate and treat patients with fasting triglycerides.500 mg/dL.

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ASCVD, atherosclerotic cardiovascular disease; TOS, The ObesitySociety. *Moderate-intensity statin therapy lowers LDL-C on average by 30% to 50%. †We note that these recommendations do not replaceclinical judgment, including consideration of potential risks, benefits, drug interactions, and adverse events. ‡High-intensity statin lowers LDL-C onaverage by .50%.


strategy also used in the DPP. The pur-pose of the toolbox was to have an arrayof strategies to usewith an individual whowas not achieving adequate adherence tothe protocol or who had lost ,1% ofbaseline weight. Treatment options in-cluded the use of motivational interview-ing strategies to assist an individual in goalsetting and improved adherence to writ-ten contracts with the lifestyle counselor.Other techniques used over the subse-quent years to keep participants engagedand motivated and to promote weightloss maintenance included refreshercourses, campaigns, and incentives suchas prizes for campaign winners (72).At 4 years, participants in the intensive

lifestyle arm of Look AHEAD lost 4.7% ofinitial weight compared with 1.1% in theusual care group. Consistent with the DPPfindings, older individuals had greater ad-herence to session attendance, greaterparticipation in the intervention, andlower self-reported energy intake andlost more weight than their younger coun-terparts. However, it is important to reflecton the primary results of Look AHEAD, re-viewed above, which, despite weight lossand concomitant improvement in CVD riskfactors, did not demonstrate reduced CVDevents in the intensive lifestyle arm. Thus,further work in type 2 diabetes mellitus isneeded to elucidate the role of physicalactivity and weight loss in reducing clinicalCVD end points (37).

Another study examining the role ofintensive lifestyle management on CVDrisk factors was the Italian Diabetes andExercise Study (IDES). The IDES was anRCT designed to examine the effects ofan intensive exercise intervention strat-egy on modifiable CVD risk factors in606 sedentary subjects with type 2 diabe-tes mellitus enrolled in 22 outpatient di-abetes mellitus clinics across Italy (73).The subjects were randomized by center,age, and diabetes mellitus treatment to150 min of twice-a-week supervised aer-obic and resistance training plus struc-tured exercise counseling (exercisegroup) or to structured individualizedcounseling alone (control group) for 12months. In the structured individualizedcounseling sessions, which occurred ev-ery 3 months, participants were encour-aged to meet the current physical activityrecommendations through increasing en-ergy expenditure during commuting, oc-cupational, home, and leisure time.Subjects in both groups received dietarycounseling, which included caloric intake(55% complex carbohydrates, 30% fat,and 15% protein) designed to obtain anegative balance of 500 kcal/day againstenergy expended. Compared with thecontrol group, supervised exercise pro-duced significant improvements in physi-cal fitness, A1c, systolic and diastolic bloodpressures, HDL-C and LDL cholesterol(LDL-C) levels, waist circumference, BMI,

insulin resistance, inflammation, and cor-onary heart disease (CHD) risk scores (74).

The association of smoking cessation,an important CVD prevention strategy,with weight gain deserves specific men-tion. A previously unanswered questionwas whether the weight gain of 3 kg to6 kg that occurs after smoking cessationwould be associated with an increasedcardiovascular risk in those with diabetesmellitus. A recent observational studyfound that, despite a mean weight in-crease of 3.6 kg for recent (,4 years)quitters, smoking cessation was still asso-ciated with a decreased risk of CHD (75).

Pharmacological TherapyWhen lifestyle interventions for weightloss fail to achieve the desired goals, thephysician andpatientmaywish to consideralternatives, including medications or sur-gery. In clinical trials, medications and sur-gery almost always produce more weightloss than the lifestyle/placebo interven-tions against which they are compared.In accordance with the new AHA/ACC/The Obesity Society guidelines for weightloss (58), pharmacological therapy is indi-cated for individuals with a BMI of 25 to30 kg/m2 with comorbidities or a BMI.30 kg/m2 with or without comorbidities.The new guidelines for obesity are brieflysummarized in Table 5, although they con-tain no specific recommendation for theuse of medications.

Table 6—Drugs approved by the FDA for weight loss*

Generic name, year of approval Trade name(s) Dose DEA schedule

Pancreatic lipase inhibitor approved by the FDA for long-term use ($12 months)

Orlistat, 1999 Xenical 120 mg 3 times daily before meals Not scheduledOrlistat, 2007 Alli (over the counter) 60 mg 3 times daily before meals Not scheduled

Serotinin-2C receptor agonist approved by the FDA forlong-term use (12 months)

Lorcaserin, 2012 Belviq 10 mg twice daily IV

Combination of phentermine-topiramate approved by theFDA for long-term use (12 months)

Phentermine-topiramate, 2012 Qsymia 3.75/23 mg7.5/46 mg15/92 mg

IV

Noradrenergic drugs approved for short-term use (usually,12 weeks)

Diethylpropion, 1959 Tenuate 25 mg 3 times a day IVTenuate Dospan 75 mg every morning

Phentermine, 1959 Adipex and many others 15–30 mg/day IVBenzphetamine, 1960 Didrex 25–50 mg 3 times daily IIIPhendimetrazine, 1959 Bontril 17.5–70 mg 3 times daily III

Prelu-2 105 mg daily

DEA, U.S. Drug Enforcement Administration; FDA, U.S. Food and Drug Administration. *Side effect profiles can be found in the package inserts foreach agent.


The weight loss achieved with an in-tensive lifestyle intervention usuallywanes over time. The first step in eval-uating medications for the obese pa-tient is to make sure that the patient isnot taking drugs that produce weightgain. These potentially include certainantidiabetes drugs, antidepressants, andantiepileptics (76–78). If such agents areidentified and if there are acceptable al-ternatives that are weight neutral or pro-duceweight loss, the health care providershould consider changing to the drugsthat produce weight loss (78).Several drugs are approved by the U.S.

Food and Drug Administration for treat-ment of the patient with obesity (Table 6)(76,79,80), several for short-term use(usually considered ,12 weeks) andthree, orlistat (81), lorcaserin (82), andextended-releasetopiramate/phentermine,for longer-term use (83). Bupropion/naltrexone is currently under reviewwhile a cardiovascular outcome trial isbeing conducted (84). In addition, fourpharmacological agents (phentermine,diethylpropion, benzphetamine, andphendimetrazine) are approved forshort-term use. All agents except orlistatare classified by the U.S. Drug Enforce-ment Administration as having the poten-tial for abuse and are schedule III or IVdrugs. Several guiding principles shouldbe followed when weight loss agentsare prescribed. First, the patient shouldbe familiarized with the drugs and theirpotential side effects. Second, the patientshould receive effective lifestyle sup-port for weight loss along with thepharmacological agent. Third, becauseresponse to medications is variable,patients should be re-evaluated regu-larly, and if they have not lost 5% oftheir body weight after 3 months oftreatment, a new plan should be imple-mented (85,86).Many overweight and obese patients

also have type 2 diabetes mellitus, andthere are several hypoglycemic therapiesto choose from (76), some that increaseweight and others reduce weight. Forexample, thiazolidinediones, insulin, gli-nides, and sulfonylureas produce weightgain; dipeptidyl peptidase-4 inhibitorsare weight neutral; and metformin,pramlintide, exenatide, liraglutide, andsodium–glucose cotransporter-2 inhibi-tors produce weight loss (76). Exenatideand liraglutide are both glucagon-likepeptide-1 agonists and produce modest

weight loss of 5% at doses recom-mended for the treatment of diabetesmellitus. In clinical trials, a higher doseof liraglutide is being investigated as along-term treatment for obesity (87).The sodium–glucose cotransporter-2 in-hibitors block the sodium–glucose co-transporter in the renal tubule and canproduce modest weight loss, althoughlong-term safety data are not yet avail-able (88). If all other things are equal, thehealth care provider may wish to useantidiabetes drugs that produce weightloss. However, there are many selectionfactors to consider in the choice of glucose-lowering agents for patients with diabetesmellitus, including cost.

Surgical Procedures for SevereObesity and Metabolic DiseaseBariatric surgery (i.e.,weight loss surgery) isthe most effective treatment for attainingsignificant and durable weight loss in se-verely obese patients. Because metabolicandweight-related comorbidities are oftenimproved or resolved through weight lossor neuroendocrine mechanisms, the termmetabolic surgery is rapidly replacing bari-atric surgery. In general, metabolic opera-tions alter the gastrointestinal tract byreducing stomach capacity (gastric restric-tive operations); rerouting nutrient flow,leading to some degree of malabsorption(bypass procedures); or combining bothconcepts. Metabolic procedures haveevolved since the abandoned jejunoilealbypass of the early 1950s and 1960s. Com-monly performed procedures (frequencyof use) include the Roux-en-Y gastric by-pass (49%), sleeve gastrectomy (30%), ad-justable gastric banding (19%), andbiliopancreatic diversion (2%). The devel-opment of laparoscopic approaches to allthese metabolic procedures in the mid-1990s was a major advance resulting in asignificant reduction in perioperative mor-bidity and mortality.

The indications for weight loss sur-gery have evolved since the seminal Na-tional Institutes of Health guidelinesfrom 1991, which recommended surgi-cal intervention for weight loss in patientswith aBMI$40kg/m2or aBMI$35kg/m2

with significant obesity-related comor-bidities (89). The most recent guidelinesfor bariatric surgery pertaining to pa-tients with type 2 diabetes mellituscame from the International DiabetesFederation in 2011. This group recom-mended considering surgery for obese

individuals (BMI .30 kg/m2) with type2 diabetesmellitus who had not achievedthe International Diabetes Federationtreatment targets with an optimal medi-cal regimen, especially if other cardiovas-cular risk factors were present (90). Thenew AHA/ACC/The Obesity Societyguidelines recommend that adults withBMI $35 kg/m2 and an obesity-relatedcomorbidity such as diabetes mellituswho are motivated to lose weight shouldbe considered for referral to a bariatricsurgeon (58).

Effect of Surgery on Weight Loss

The primary intent of bariatric proce-dures is a reduction of excess body fatand comorbidity improvement or reso-lution. A meta-analysis (136 studies) ofmostly short-term (,5 years) weightloss outcomes after .22,000 bariatricprocedures demonstrated an overallmean excess weight loss (defined as fol-lows: initial body weight in kilogramsminus current weight in kilograms di-vided by initial body weight in kilogramsminus ideal body weight times 100%) of61.2% (95% CI 58.1–64.4), 47.5% (95%CI 40.7–54.2) for patients who under-went gastric banding, 61.6% (95% CI56.7–66.5) for those who had gastricbypass, 68.2% (95% CI 61.5–74.8) forpatients with gastroplasty, and 70.1%(95% CI 66.3–73.9) for patients with bil-iopancreatic diversion or duodenalswitch (91).

The best long-term surgical weightloss data come from the SwedishObese Subjects (SOS) study, a prospec-tive study (.90% follow-up rate) eval-uating the long-term effects of bariatricsurgery compared with nonsurgicalweight management of severely obesepatients in a community setting (92).At 15 years, weight loss (percent oftotal body weight) was 27 6 12% forgastric bypass, 18 6 11% for vertical-banded gastroplasty, and 13 6 14%for gastric banding compared with aslight weight gain for control subjects.In contrast, long-term medical (non-surgical) weight loss rarely exceeded8% (37).

Effect of Surgery on Glycemic Control, CVD

Risk Factors, and CVD Outcomes

Observational Data. Multiple observa-tional studies demonstrate significant,sustained improvements in glycemia intype 2 diabetes mellitus among patients


with severe obesity (BMI$35 kg/m2) afterweight loss procedures. A meta-analysisinvolving 19 studies (mostly observational)and 4,070 patients reported an overalltype 2 diabetes mellitus resolution rateof 78% after bariatric surgery (93). Resolu-tion was typically defined as becomingnondiabetic with normal A1c withoutmed-ications. Most of these studies, however,were retrospective, with follow-up of only1 to 3 years on average, and varied by typeof procedure. A1c typically improved frombaseline by a minimum of 1% up to 3%after surgery, an effect rarely equaled bymedical treatment alone. In the SOS study,the remission rate for type 2 diabetesmel-litus was 72% at 2 years and 36% at 10years compared with 21% and 13%, re-spectively, for the nonsurgical control sub-jects (P,0.001) (95). Bariatric surgerywasalsomarkedly more effective than nonsur-gical treatment in the prevention of type 2diabetes mellitus, with a relative risk re-duction of 78% (96). A systematic reviewof long-term cardiovascular risk factor re-duction after bariatric surgery involved 73studies and 19,543 patients (93). At ameanfollow-up of 57.8 months, the average ex-cess weight loss for all procedures was54%, and remission/improvement was63% for hypertension, 73% for type 2 dia-betes mellitus, and 65% for hyperlipidemia.Few, mostly retrospective, studies have

evaluated the effect of metabolic surgeryon the progression of microvascular dis-ease such as retinopathy, nephropathy,and neuropathy in type 2 diabetes melli-tus. The results are far from conclusive butsuggest a potential reversal in or reduceddevelopment of nephropathy after bariat-ric surgery (97,98). Recently, 12 cohort-matched studies comparing bariatricsurgery with nonsurgical controls were re-viewed (99). Collectively, all but two ofthese studies support a lower CVD eventrate and all-cause mortality rate amongpatients who had undergone bariatric sur-gery. Of these studies, the SOS study hasthe longest outcomes follow-up (median14.7 years). CVD mortality in the surgicalgroup was lower than for control patients(adjusted HR 0.47 [95% CI 0.29–0.76]; P50.002) despite a greater prevalence ofsmoking and higher baseline weights andblood pressures in the surgical cohort (92).RCT Data. Four short-term (1–2 years)RCTs have compared bariatric surgerywith medical treatment of type 2 diabetesmellitus. Among60patientswithmild type2 diabetes mellitus and a BMI of 30 to

40 kg/m2, adjustable gastric banding pro-duced larger reductions in weight, fastingblood glucose, A1c, and diabetes mellitusmedication use compared with medicaltreatment and achieved remission (de-fined as A1c ,6.3% without medications)rates of 73% compared with only 13% formedical management (P , 0.05) (100). Alarger RCT of 150 patients with mild tomoderate obesity (BMI 27–43 kg/m2)and poorly controlled type 2 diabetesmel-litus (mean A1c 9%) (101) demonstratedbetter glycemic control (defined as A1c,6% with or without medications) afterRoux-en-Y gastric bypass (42%) or sleevegastrectomy (37%) compared with inten-sive medical therapy (12%) at 1 year (P,0.001). Both surgical procedures resultedin greater improvement in other CVD riskfactors, including triglycerides and HDL-C,compared with intensive medical therapy.Two other RCTs in patients with obesityand type 2 diabetes mellitus consisting of60 (102) and 120 (103) patients demon-strated similar results. All four RCTsshowed that surgery in the short term(1–2 years) was well tolerated, with fewmajor complications, and resulted in bothsuperior glycemic control and greater im-provements in CVD risk factors comparedwith medical treatment alone in up to 24months of follow-up. The longer-term

durability of these findings remains un-known, as well as whether improvementsin CVD risk factors will ultimately translateintoCVDevent reduction. These issues rep-resent important future areas of research.Complications of Surgery. The safety ofbariatric surgery is of primary concern inthe determination of whether the poten-tial benefits outweigh the surgical risks. Ameta-analysis of published mortality dataafter bariatric surgery reported an overall30-day postoperative mortality of 0.28%(n 5 84,931) and total mortality from 30days to 2 years of 0.35% (n 5 19,928)(104). The Longitudinal Assessment ofBariatric Surgery (LABS) study subse-quently reported a similarly low 30-daymortality rate (0.3%) among 4,776 pa-tients (105). Immediate- and long-termperioperative morbidity rates for bariatricsurgery are lower than might be expectedfor this medically comorbid population;the LABS Consortium reported a 4.3% in-cidence of major adverse events in theearly postoperativeperiod.Although thesereports are encouraging, a numberof com-plications associated with bariatric surgeryare potentially fatal and merit careful con-sideration. The most common complica-tions are summarized in Table 7 (105).

Bariatric surgery can reverse or im-prove many obesity-related disease

Table 7—Complications of bariatric surgery

Complications Frequency, %, and outcomes

Sepsis from anastomotic leak (105) 1–2

Hemorrhage (105) 1–4

Cardiopulmonary events (105) . . .

Thromboembolic disease (105) 0.34

Late complications for AGB Surgical revision required in asmany as 20 within 5 years

Band slippage 15Leakage 2–5Erosion 1–2

Late complications of bypass proceduresAnastomotic strictures 1–5Marginal ulcers 1–5Bowel obstructions 1–2

Micronutrient and macronutrient deficiencies fromRYGB 2–3 years after surgery (105)

Iron deficiency 45–52Vitamin B12 deficiency 8–37Calcium deficiency 10Vitamin D deficiency 51

Fat-soluble vitamin deficiencies (A, D, E, K) and proteincalorie malnutrition from BPD and DS procedures 1–5

AGB, adjustable gastric banding; BPD, biliopancreatic diversion; DS, duodenal switch; RYGB,Roux-en-Y gastric bypass.


processes, including type 2 diabetes mel-litus. There is now evidence supportingdecreases in short- and medium-termCVD, although these data are derivedfrom observational studies only. Benefitsshould be weighed against short- andlong-term complications, which are bestmanaged by a long-termmultidisciplinaryeffort. Bariatric surgery may be particu-larly suitable for patients with type 2 di-abetes mellitus and severe obesity (BMI$35 kg/m2) because these patients maybenefit fromobesity comorbidity improve-ment and significantly improved glycemiccontrol compared with medical therapyalone. Taken together, thesedatahighlighthow bariatric surgery can result in weightloss, A1c improvement, and CVD risk factorimprovement. The durability of thesemet-abolic improvements, particularly from theRCT literature, over time remains to be de-termined and represents an important fu-ture area of research.

ASPIRIN THERAPY

Whether to use aspirin for the primaryprevention of CVD events in patientswith diabetes mellitus remains controver-sial. Aspirin reduces CVDevents in patientswith known CVD (secondary prevention)(106). In the general primary preventionpopulation, aspirin is effective in prevent-ing nonfatal myocardial infarction (MI) inmen (106); forwomen, the evidence is lessclear, but aspirin appears to reduce therisk of stroke (107).Trials examining the effect of aspirin for

primary prevention in patients with diabe-tes mellitus are summarized: six trials(108–113) were conducted in the generalpopulation that also includedpatientswithdiabetes mellitus, and three other trials(114–116) specifically examined patientswith diabetes mellitus. Trials ranged from3 to 10 years in duration and have ex-amined a wide range of aspirin doses. Par-ticipants were mainly late middle-agedadults; three trials (108,109,112) includedonly men. The range of underlying CVDrisk varied widely across trials. Participantsin the Japanese Primary Prevention of Ath-erosclerosis With Aspirin for Diabetes(JPAD) trial were at very low risk (0.25%annual CHD risk), whereas earlier trials hadcontrol group CHD risks exceeding 2%/year.Through 2012, seven meta-analyses

have synthesized data on the effects ofaspirin for patients with diabetes mellitus(106,117–122). The available analyses dif-fer somewhat in the trials they included.

Overall, the seven analyses suggest atbest a modest effect of aspirin, with sta-tistically nonsignificant risk reductions of�10% each for the key individual out-comes of stroke and MI. When analysesexamined total CVD events (MI andstroke together), CIs were narrower andsometimes statistically significant.

Some analyses found evidence forsex-related differences in outcomes(117,121,122), with larger reductions inCHD events for men and larger reductionsin stroke for women. Zhang et al. (117)found that for trials with .50% women,the risk of MI was 1.10 and the risk ofstroke 0.67 with aspirin use comparedwith nonuse. Conversely, trials with$50% men had a relative risk for CHDevents of 0.71 and a relative risk for strokeof 1.05 with aspirin use compared withnonuse (117). Risk of bleeding appearedto be increased$2-fold but was not statis-tically significant in any meta-analysis.

Taken as awhole, these results suggest amodest (�9%) relative reduction in risk forCVD events and $2-fold relative risk ofbleeding, mainly from the gastrointestinalsystem. The net effect of aspirin thereforedepends on the baseline risks of CVDevents and (gastrointestinal) bleeding.Modeling using data from studies of gen-eral middle-aged adults suggests that aspi-rin is highlybeneficialwhen the10-year riskof CVD events is .10% and the baselinerisk of gastrointestinal bleeding is not in-creased (124,125). It is likely that such abenefit also accrues to patients with diabe-tesmellitus, but furthermodelingwork andbetter data on sex-specific effects of aspirinare needed. A separate meta-analysis ofboth primary and secondary prevention tri-als did not find a difference in the efficacyof aspirin in diabetes mellitus according todose (119). Specific recommendationsbased on current clinical guidelines for as-pirin administration in adults with diabetesmellitus and no preexisting CVD are sum-marized (120).

Recommendations

1. Low-dose aspirin (75–162 mg/day) isreasonable among those with a 10-year CVD risk of at least 10% andwith-out an increased risk of bleeding (ACC/AHA Class IIa; Level of Evidence B)(ADA Level of Evidence C).

2. Low-dose aspirin is reasonable inadults with diabetes mellitus at inter-mediate risk (10-yearCVD risk, 5–10%)(ACC/AHA Class IIb; Level of EvidenceC) (ADA Level of Evidence E).

A1C TARGETS IN TYPE 2 DIABETESMELLITUS

Observational DataType 2 diabetes mellitus is associatedwith a 2- to 4-fold increased risk of CVD,with event rates correlating with the de-greeofhyperglycemia (126,127). In a largemultiethnic cohort, every 1-mmol/L (18-mg/dL) increase in fasting plasma glucosepredicted a 17% increase in the risk offuture cardiovascular events or death(128). After adjustment for other CVDrisk factors, an increase of 1% in A1c wasassociated with an increased risk of 18%in CVD events (129), 19% in MI (129),and 12% to 14% in all-cause mortality(130,131). However, the correlation be-tween hyperglycemia and microvasculardisease is much stronger than that formacrovascular disease, with a 37% in-crease in the risk of retinopathy or renalfailure associated with a similar 1% in-crease in A1c (132).

Randomized, Clinical Trials Lookingat A1c Level and Incident CVDDespite the strong link between hypergly-cemia and CVD risk, the evidence that in-tensive glycemic control reduces this riskis limited compared with the well-provenrisk reduction inmicrovascular and neuro-pathic complications (8,133). For example,the Diabetes Control and ComplicationsTrial (DCCT) (made up of individuals withtype 1 diabetes mellitus) and the UK Pro-spective Diabetes Study (UKPDS) foundhighly significant reductions, rangingfrom 25% to 70%, in various measures ofmicrovascular and neuropathic complica-tions from more intensive control of gly-cemia in type 1 and type 2 diabetesmellitus, respectively (8,133). However,neither study could demonstrate signifi-cant CVD risk reduction during the periodof randomized intervention. In the DCCT,the number of CVD cases was fewer in theintensive group (mean achieved hemoglo-bin A1c �7%) compared with standardcontrol (�9%) after amean treatment du-ration of 6.5 years, but the numbers ofevents were small and not significantlydifferent (8). Significant reductions inCVD events emerged nearly 10 years afterthe study ended despite subsequent sim-ilar mean A1c levels (�8%) in both groupsduring follow-up of the DCCT cohort (theEpidemiology of Diabetes Interventionsand Complications [EDIC] study). Partici-pants previously randomized to the inten-sive arm experienced a 42% reduction


(P 5 0.02) in CVD outcomes and a 57%reduction (P 5 0.02) in nonfatal MI,stroke, orCVDdeath comparedwith thosein the standard arm (134). TheUKPDS ran-domized participants newly diagnosedwith type 2 diabetes mellitus to intensive(with sulfonylureas or insulin) comparedwith conventional therapy. The overall A1cachieved was 0.9% lower in the intensivegroup (7.0% versus 7.9%). The studyfound a nonsignificant trend (16% risk re-duction; P 5 0.052) toward reduced MIwith the more intensive strategy after10 years (133). As in the DCCT/EDIC, thisapproximate risk (15%; P 5 0.01) reduc-tion in MI became significant only after10 years of observational follow-up oftheUKPDS population, despite the conver-gence of mean A1c soon after the random-ized component of the study ended (135).Three large trials in type2diabetesmel-

litus were designed to address continuinguncertainty (136) about the effects ofeven more intensive glycemic control onCVD outcomes and reported results in2008: theAction to Control CardiovascularRisk in Diabetes (ACCORD) study (137),the Action in Diabetes and Vascular Dis-ease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE)trial (138), and the Veterans Affairs Diabe-tes Trial (VADT) (139). All three studiedmiddle-aged or older (mean age 60–68years) participants with established type2 diabetes mellitus (mean duration 8–11years) and either known CVD or multiplemajor CVD risk factors. They comparedthe effects of two levels of glycemic con-trol (median A1c 6.4–6.9% in the intensivearms comparedwith 7.0–8.4% in the stan-dard arms) on macrovascular outcomes.None of the trials could demonstrate anysignificant reduction in the primary com-bined cardiovascular end points. ACCORDwas stopped early as a result of increasedmortality in the intensive group. The studyresults and post hoc analyses have beencomprehensively reviewed and analyzedin a scientific statement of the ACC Foun-dation and AHA/position statement of theADA (140). The increased mortality in theACCORD intensive arm compared withthe standard arm (1.41%/year versus1.14%/year; HR 1.22 [95% CI 1.01–1.46])was predominantly cardiovascular in na-ture and occurred in all prespecified sub-groups. Exploratory analyses were unableto link the increaseddeaths toweight gain,hypoglycemia, rapid loweringofA1c, or useof any specific drug or drug combination.

Although hypoglycemia was more fre-quent in the intensive arm, the associationof severe hypoglycemiawithmortalitywasstronger in the standard control arm (141).Within the intensive arm, participantswiththe highest A1c levels during the trial actu-ally had thehighest risk formortality. Thus,increased mortality in ACCORD was asso-ciated with individuals who were assignedto the intensive glycemic control groupbutultimately failed to achieve intensive gly-cemic control (142).

There was no difference in overall orCVD mortality between the intensive andstandard glycemic control arms inADVANCE, although the median A1c levelachieved in intensively treated patientswas similar (6.4%) to those in ACCORD.However, compared with ACCORD sub-jects, ADVANCE participants at entryhad a shorter duration of diabetesmellitus, a lower A1c, and less use of in-sulin; glucose was lowered less rapidly inADVANCE; and there was less hypoglyce-mia. In ADVANCE, intensive glycemic con-trol significantly reduced the primaryoutcome, a combination ofmicrovascularevents (nephropathy and retinopathy)and major adverse CVD events (MI,stroke, and CVD death). However, thiswas attributable solely to a significant re-duction in the microvascular outcome,primarily the development of macroalbu-minuria, with no reduction in the macro-vascular outcome (138).

VADT randomized participants withpoorly controlled type 2 diabetes mellitus(median A1c at entry 9.4%) to a strategy ofintensive glycemic control (achieved A1c6.9%) or standard glycemic control(achieved A1c 8.4%). After 5.6 years, therewas no significant difference in the cumu-lative primary outcome, a composite ofCVD events. A post hoc analysis foundthat VADT participants with a durationof diabetes mellitus of ,15 years had amortality benefit in the intensive arm,whereas those with a duration of .20years had higher mortality with themore intensive strategy (143).

A meta-analysis of trials of intensiveglycemic control suggests that glucoselowering may have a modest but statis-tically significant reduction in majorCVD outcomes, primarily nonfatal MI,but no significant effect on mortality(144–147). However, any such benefitof glucose lowering on CVD in type 2 dia-betes mellitus is slight compared with thetreatment of other CVD risk factors.

The Outcome ReductionWith an InitialGlargine Intervention (ORIGIN) trial stud-ied glucose lowering earlier in the courseof type 2 diabetes mellitus. This study as-sessed CVD outcomes from the provisionof sufficient basal insulin to normalizefasting plasma glucose levels in people$50 years of age with impaired fastingglucose, impaired glucose tolerance, orearly type 2 diabetes mellitus and otherCVD risk factors. Early use of basal in-sulin achieved normal fasting plasmaglucose levels in the trial but had noeffect on CVD outcomes compared withguideline-suggested glycemic control(148).

Recommendations for A1c Targetsfor CVD Event ReductionRecommendations for individualization oftherapeutic targets have drawn from con-siderations of the time required formicro-vascular risk reduction to alter rates ofclinically significant vision loss or kidneydysfunction, comparison of the mortalityfindings in ACCORD and ADVANCE, sub-group analyses of VADT, and other posthoc analyses. These analyses suggestthat the potential risks of intensive glyce-mic control may outweigh its benefits incertain individuals such as those with along duration of diabetes mellitus, aknown history of severe hypoglycemia,advanced atherosc leros i s , and alimited life span because of advancedage, frailty, or comorbid conditions(59,149). Current recommendations forglucose-lowering and A1c targets can befound in Table 5.

Glucose-Lowering Agent Selectionfor CVD Risk ReductionMetformin is widely accepted as the first-choice agent for glycemic lowering be-cause it does not cause weight gain orhypoglycemia and may improve CVD out-comes (59). The first evidence for a CVDbenefit of metformin came from a smallUKPDS substudy involving 753 overweightpatients,which found a relative risk reduc-tion of 39% in MI in the group assigned tometformin versus conventional therapy(10). Meta-analyses also found evidenceof reduced CVDwithmetformin therapy(150,151). Another small study foundan adjusted HR of 0.54 (P 5 0.026)for a composite CVD outcome in pa-tients with type 2 diabetes mellitusand coronary artery disease (CAD) whoreceived metformin compared withglipizide (152).


Beyond metformin, there are limiteddata on the comparative effectiveness ofthe many other effective antihyperglyce-mic drugs; most studies are of short dura-tion and focus on glycemic lowering andside effects rather than CVD outcomes.Two exceptions deserve mention. Whenadded to baseline antihyperglycemic ther-apy regimens in the Prospective Pioglita-zone Clinical Trial inMacrovascular Events(PROactive), pioglitazone had no apparentbenefit on the primary end point, whichwas a broad cardiovascular compositethat include peripheral vascular events(153). However, a secondary outcome(MI, stroke, and cardiovascular mortality)was modestly reduced by 16% (HR 0.84[95% CI 0.72–0.98]; P 5 0.027), althoughan increase in heart failure has been ob-served (154). Another thiazolidinedione,rosiglitazone, has been shown to haveno such effect (155). Indeed, there is lin-gering controversy as to whether rosigli-tazonemay actually increase the risk ofMI(156,157), and this has clouded the issueconcerning the potential benefits of this in-sulin-sensitizer drug class in atherosclerosis.Finally, in a diabetes mellitus preventiontrial, Study To Prevent Non-insulin-Dependent Diabetes Mellitus (STOP-NIDDM), the a-glucosidase inhibitoracarbose was associated with a 49% rela-tive reduction in cardiovascular events(HR 0.51 [95% CI 0.28–0.95]; P 5 0.03)in patients with impaired glucose toler-ance (158). An acarbose trial (AcarboseCardiovascular Evaluation [ACE]) is cur-rently being conducted in China to deter-mine whether this apparent benefit canbe replicated in patients with already es-tablished type 2 diabetes mellitus.

New Glucose-Lowering Medicationsand CVD RiskU.S. Food and Drug Administration guid-ance now requests evidence that newglucose-lowering therapies are not asso-ciated with an increase in cardiovascularrisk in patients with type 2 diabetes mel-litus (159) (www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf). As a result, several large trials arecurrently under way to test the cardio-vascular safety and efficacy of newerantihyperglycemic therapies, includingincretin-based drugs (glucagon-likepeptide-1 receptor agonists, dipeptidylpeptidase-4 inhibitors) and the sodium–

glucose cotransporter-2 inhibitors. Two

publications on the cardiovascular safetyof dipeptidyl peptidase-4 inhibitors arethe result of this U.S. Food and DrugAdministration mandate. SaxagliptinAssessment of Vascular Outcomes Re-corded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53(SAVOR-TIMI 53) randomized 16,492 pa-tients. At a median follow-up of 2.1 years,rates of ischemic events were similar withsaxagliptin and placebo, but hospitalizationfor heart failure was significantly higherwith saxagliptin (3.5% versus 2.8%; HR1.27; P5 0.007) (160). Examination of Car-diovascular Outcomes With Alogliptin Ver-sus Standard of Care in Patients With Type2 Diabetes Mellitus and Acute CoronarySyndrome (EXAMINE) randomized 5,380patients with a mean duration of follow-up of 18 months (161). As in SAVOR-TIMI 53, the rates of CVD events weresimilar in the treatment and placeboarms. Of note, both studies were designedto demonstrate noninferiority of the studydrugs and enrolled patients with estab-lished CHD to achieve adequate event rateswitha relatively short durationof follow-up.

The Glycemia Reduction Approaches inDiabetes: A Comparative EffectivenessStudy (GRADE) (162) will compare glyce-mic lowering of four commonly used clas-ses of diabetes mellitus medications(sulfonylureas, dipeptidyl peptidase-4 in-hibitors, glucagon-like peptide-1 receptoragonists, and insulin) in combinationwithmetformin in 5,000 subjects with an an-ticipated observation period of 4 to 7years. The four drugs will also be com-pared with respect to durability, selectedmicrovascular complications, CVD riskfactors, adverse effects, tolerability, qual-ity of life, and cost-effectiveness. To date,there are no convincing data to suggestthat any single type of antihyperglycemictherapy in type 2 diabetes mellitus has aCVD advantage over another other thanperhaps metformin (159). Therefore, inchoosing among available therapies, pro-viders should consider not only efficacy inglycemic control but also safety, adverseeffects such as weight gain and hypogly-cemia, and outcomes thatmattermost topatients, including cost and quality of life.

HYPOGLYCEMIA AS A CVD RISKFACTOR IN TYPE 2 DIABETESMELLITUS

Incidence of HypoglycemiaHypoglycemia is the most common ad-verse effect of insulin therapy and a major

factor limiting glucose control in many pa-tients with type 2 diabetesmellitus, partic-ularly those with long-standing disease(163). Severe hypoglycemia is defined asan event requiring external assistance forrecovery, whereasmilder episodesmay beself-treated. The incidence of hypoglyce-mia increases with the duration of insulintherapy. Prospective, population-baseddata indicate that the overall incidence ofhypoglycemia in insulin-treated type 2 di-abetes mellitus is approximately one-thirdof that in type 1 diabetes mellitus (164).The UK Hypoglycemia Study Group foundthat patients with type 1 diabetes mellituswith an insulin therapy duration ,5 or.15 years had 110 and 320 episodes ofsevere hypoglycemia per 100 patient-years, respectively (165). Patients withtype 2 diabetes mellitus treated with in-sulin for ,2 or .5 years had incidencesof 10 and 70 episodes per 100 patient-years, respectively (165). However, the oc-currence of hypoglycemia unawarenesslimits the determination of the true inci-dence of this self-reported condition. Al-though most commonly associated withinsulin therapy, hypoglycemia is also aside effect of insulin secretagogs such assulfonylurea and glinides.

Mechanisms of Hypoglycemiaand CVDAlthough the lower range of normal post-prandial glucose is �70 mg/dL, as glucoseapproaches this level, endogenous insulinsecretion stops. When glucose falls below70 mg/dL, counterregulatory hormonesare released, and autonomic neural activa-tion occurs. These may produce symptomssuch as tremor, diaphoresis, tachycardia,anxiety, hunger, and headache. Inmost cir-cumstances, these warning symptomsprompt patients to ingest glucose or othercarbohydrates to protect against neurogly-copenia, which may alter behavior and im-pair cognition, judgment, and performanceof physical tasks. Patients with repeatedepisodes of hypoglycemia are at increasedrisk of deficient counterregulation and lossof self-awareness of hypoglycemia, puttingthem at increased risk for seizures, coma,or even death (166,167).

There are several mechanisms bywhich hypoglycemia might promote ad-verse cardiovascular outcomes in high-risk individuals (168,169). Hemodynamicchanges after autonomic activation in-duced by hypoglycemia include increasesin heart rate, systolic blood pressure,


myocardial contractility, and cardiac out-put. These effects may exacerbate ische-mia in individuals with occlusive CAD.Small studies have shown that hypoglyce-mia induces ischemic and other ECGchanges, and arrhythmias have beenreported during severe episodes (170).Hypoglycemia has also been associatedwith prolongation of the QT interval. Aninteraction of hypoglycemia-induced ab-normalities of cardiac repolarization withautonomic neuropathy, a complication oflong-standing diabetesmellitus, may con-tribute to arrhythmias and the risk of sud-den death in individuals with diabetesmellitus. Finally, hypoglycemia has addi-tionally been reported to have deleteri-ous effects on endothelial function,platelet reactivity, and coagulation whileincreasing inflammatory mediators andblood viscosity and lowering potassiumlevels (171,172).

Hypoglycemia and CVD EventsClinical trials in patients with type 2 diabe-tes mellitus with or at high risk of CVDhave raised concern about the risks of hy-poglycemia in this population (140). To-gether, ACCORD (137), ADVANCE (138),and VADT (139) randomized nearly24,000 patients to intensive versus stan-dard control with follow-up periods from3.4 to 5.6 years. Although the A1c goals forintensive and standard therapy differedamong the trials, rates of severe hypogly-cemia were substantially higher with in-tensive compared with standard therapyin all three trials: 16.2% versus 5.1% inACCORD, 2.7% versus 1.5% in ADVANCE,and 21.2% versus 9.7% in VADT. Shorterduration of diabetesmellitus, younger ageof participants, and less use of insulinlikely contributed to the lower rates ofhypoglycemia in ADVANCE.In ACCORD, rates of severe hypogly-

cemia and death were increased with in-tensive treatment; however, secondaryanalyses did not establish hypoglycemiaas the cause of the increased mortalityin the intensive group (141,173). InADVANCE and VADT, intensive glucosecontrol was not associated with excessmortality. In both ADVANCE and ACCORD,severe hypoglycemia was a risk factorfor mortality, but annual mortalityamong patients who reported severe hy-poglycemia was actually higher in thegroup receiving standard treatment thanin the group receiving intensive treatment(141,174). In addition, more frequent

hypoglycemia (,70 mg/dL) identified byself-monitoring of blood glucose was asso-ciated with a small but statistically signifi-cant reduction in mortality in the intensivebut not the standard group (175). InADVANCE, severe hypoglycemia was as-sociated not only with an increased riskof cardiovascular events and death butalso with a wide range of other adverseoutcomes, including major microvascu-lar events, death resulting from anycause, and nonvascular outcomes suchas respiratory, digestive, and skin con-ditions (174). Although secondary anal-yses could not exclude the possibilitythat severe hypoglycemia had a directcausal link with death, the investigatorshave concluded that hypoglycemiawas likely serving as a marker of inher-ent vulnerability to adverse clinicaloutcomes.

Two studies of intensive glycemic con-trol earlier in the course of type 2 diabetesmellitus were also associated with an in-creased risk of hypoglycemia comparedwith standard therapy, although the abso-lute rates were low. In ORIGIN (148), theincidence of a first episode of severe hypo-glycemia was 1.00 per 100 person-years inthe insulin-glargine group and 0.31 per 100person-years in the standard care group,the majority of whom used no insulin(P , 0.001), with no difference in CVDevents between the groups. The UKPDS(133) had a severe hypoglycemia rate of1.8%/year in the intensive control versus0.7%/year in the standard control group,with amodest andnearly significant reduc-tion in CVD event rate (P 5 0.052) in theintensive group. Thus, early in the courseof type 2 diabetes mellitus, glycemic con-trol therapies that increased the risk ofhypoglycemia do not appear to be associ-ated with an increased risk of cardiovascu-lar events.

In summary, hypoglycemia is a seriousand common complication of diabetesmellitus management and is associatedwith CVD events and mortality. Althoughcausality is unproven, avoidance of hypo-glycemia is a key goal of diabetes mellitusmanagement. Patients treated with insu-lin or insulin secretagogs should be que-ried regularly about the occurrence ofhypoglycemia, and therapy should beadjusted to mitigate its risk. Whetherthe use of drugs in type 2 diabetes melli-tus associated with lower hypoglycemiarisk improves clinical outcomes remainscontroversial.

BLOOD PRESSURE LOWERING INTYPE 2 DIABETES MELLITUS

Increased blood pressure is a major con-tributor to higher risk of CVD events in di-abetesmellitus. A vastmajority (70%–80%)of patients with type 2 diabetesmellitushave hypertension. The presence of hy-pertension in patients with type 2 diabe-tes mellitus increases the risk of MI,stroke, and all-cause mortality. Addition-ally, the coexistence of both conditionsincreases the risk of developing heartfailure, nephropathy, and other microvas-cular events (176). Epidemiological obser-vations from landmark studies such as theMultiple Risk Factor Intervention Trial(MRFIT), UKPDS, and others have demon-strated that there is a progressive increasein the risk of macrovascular and microvas-cular events with increasing levels of sys-tolic blood pressure, starting as low as115 mmHg (176–178). In addition, someof the earlier interventional RCTs (UKPDSand Hypertension Optimal Treatment[HOT]) have demonstrated the benefit ofaggressive blood pressure reduction inlowering the risk of both macrovascularand microvascular events (113,177,178).It is important to recognize, however,that in both studies the achieved systolicblood pressure in the aggressive interven-tion arm was 144 mmHg (113,178), andolder studiesdidnot address themore con-temporary questions of usual comparedwith intensive blood pressure lowering onCVD risk.

Data From Recent RCTs on IntensiveBlood Pressure Lowering in Type 2Diabetes MellitusSeveral recent RCTs have specifically ex-amined the role of an intensive bloodpressure–lowering strategy to achievesystolic blood pressure ,130 mmHg (inpatients with diabetes mellitus and hy-pertension) on various outcomes, includ-ing CVD mortality, nonfatal MI, fatal andnonfatal stroke, all-cause mortality, andvarious microvascular events, includingnephropathy (179,180). These studiesdid not find any substantive benefit ofintensive blood pressure control (systolicblood pressure,130 mmHg) in reducingthe risk of coronary events defined as fa-tal or nonfatal MI. The ACCORD studyrandomized 4,733 patients with type 2diabetes mellitus to either intensive bloodpressure lowering (defined as systolicbloodpressure,120mmHg)or usual ther-apy (systolic blood pressure,140 mmHg)


(179); the primary study outcome was acomposite end point of nonfatal MI, non-fatal stroke, or CVD death. After 12months, systolic blood pressure was 119mmHg in the intensive blood pressure–lowering arm compared with 133 mmHgin the usual care arm. However, therewas no difference in the primary end point(HR 0.88 [95% CI 0.73–1.06]; P 5 0.20);similar results were observed for death re-sulting from all causes. The only significantfinding was observed for stroke, a prespe-cified secondary end point, for which theHR was 0.59 (95% CI 0.39–0.89; P5 0.01).Similarly, the ADVANCE trial tested the ef-fect of a fixed combination of perindopriland indapamide (180); 11,140 patientswith type 2 diabetes mellitus were ran-domized to the fixed combination com-pared with placebo. After 4.3 years offollow-up, patients in the interventionarm had lower blood pressure (systolicblood pressure 5.6 mmHg). Overall, theresult of the combined primary endpoint (composite of macrovascular andmicrovascular outcomes) was signifi-cant (HR 0.91 [95% CI 0.83–1.00]; P 50.04). However, when stratified by mac-rovascular or microvascular outcomes,neither was significant (macrovascular:HR 0.92 [95% CI 0.81–1.04]; P 5 0.16;microvascular: HR 0.91 [95% CI 0.80–1.04]; P 5 0.16).These findings are further corroborated

by the results of a meta-analysis of 37,736patients from 13 trials that similarly failedto identify benefit of an intensive bloodpressure–lowering strategy over standardbloodpressure–control strategy onmacro-vascular and microvascular (cardiac, renal,and retinal) events (181) in patients withtype 2 diabetes mellitus or impaired fast-ing glucose. However, an association withstroke reduction in the intensive versususual group was noted (17% reduction inrisk).There are additional safety concerns for

intensive blood pressure lowering in type 2diabetesmellitus.Mostpatientswith type2diabetes mellitus and hypertension requiremultiple pharmacological agents to obtainadequate blood pressure control. ACCORDand the Ongoing Telmisartan Alone and inCombination With Ramipril Global End-point Trial (ONTARGET) demonstratedthat the use of multiple antihypertensivedrugs was associated with an increased in-cidenceof serious adverse effects, includinghypotension, syncope, andworsening re-nal function (179,182). Specifically, the

ACCORD blood pressure trial found thatserious adverse events occurred in 3.3%of the intensive blood pressure–loweringarmcomparedwith 1.3% in the usual carearm (179).

The Seventh Joint National Committeeguidelines recommend that, in patientswith type 2 diabetes mellitus and hyper-tension, the target blood pressure shouldbe ,130/80 mmHg (and even lower to120/75 mmHg in those with renal impair-ment) (177). The updated report from thepanel members appointed to the EighthJoint National Committee now recom-mends that target blood pressure be,140/90mmHg (61). However, on the ba-sis of newer evidence from RCTs that ex-plicitly tested the benefit of usual versusmore intensive blood pressure lowering, itis difficult to define a universal targetblood pressure goal for all patients withtype 2 diabetes mellitus and hypertension(183). Given the appearance of heteroge-neity of the effects of intensive blood pres-sure lowering on coronary compared withcerebral events, the effects may also varyon the basis of the presence or absence ofcomorbid conditions in a given individualand the subsequent risk of events (183). Inpatients at higher risk of strokewhodonothave preexisting CHD, it may be beneficialto reduce systolic bloodpressure to targetslower than recommended for the generaldiabetes mellitus population, if this can beaccomplished safely (181,183,184). Wenote that the ADA recommends bloodpressure targets of,130/80mmHg in cer-tain individuals if these targets can beachieved safely (4). Overall, RCTs areneeded to prospectively examine anddemonstrate appropriate target bloodpressure levels that can be achieved safelyand are beneficial in such patients. Takentogether, data from recent trials do notsuggest that intensive lowering of bloodpressure in type 2 diabetesmellitus shouldbe implemented as a universal recommen-dation. Further studies are necessary toidentify the at-risk populations and theirappropriate targets.

Current clinical recommendations forblood pressure targets in diabetes mel-litus can be found in Table 5, along withthe new recommendations from thepanel members appointed to the EighthJoint National Committee and the ADA(4,60,61). Currently, most individualswith diabetes mellitus are recom-mended to achieve a blood pressuregoal of ,140/90 mmHg.

CHOLESTEROL ANDLIPOPROTEINS AND CVD RISK INTYPE 2 DIABETES MELLITUS

Lipoprotein Abnormalities in Type 2Diabetes MellitusIn patients with type 2 diabetes mellitus,triglycerides are often elevated, HDL-C isoften decreased, and LDL-C may be ele-vated, borderline, or normal. LDL particlesare small and dense. Thus, the LDL-C con-centration may be misleading becausethere will be more LDL particles for anycholesterol concentration. Additionally,these small, dense LDL particles may bemore atherogenic than would be sus-pected by their concentration alone be-cause in vitro and cell culture studiessuggest that they may be more readilyoxidized and glycated (185). Nevertheless,the relationship between LDL particle sizeand CVD is confounded by many otherCVD risk factors. Thus, targeting changesin LDL size to reduce CVD risk is not in-dicated (186). Moreover, although anelevated LDL-C level generally is not rec-ognized as the major lipid abnormality inpatients with type 2 diabetes mellitus,clinical trials amply demonstrate that sta-tin treatmentwill reduce the risk formajorcoronary events (187).

LDL-C Lowering in Type 2 DiabetesMellitusLDL-C is identified as the primary target oflipid-lowering therapy. The focus on LDL-Cis supported by results of controlled, clin-ical trials that have shown that LDL-C low-ering with statins will reduce the risk ofmajor CVD events in patientswith orwith-out diabetes mellitus. In addition, datafrom 18,686 individuals with diabetesmellitus (1,466 with type 1 and 17,220with type 2) during a mean follow-up of4.3 years demonstrated a 21% propor-tional reduction in major vascular eventsper 1-mmol/L (39-mg/dL) reduction inLDL-C in people with diabetes mellitus(relative risk 0.79 [99% CI 0.72–0.86];P, 0.0001) and a 9% proportional reduc-tion in all-cause mortality per 1-mmol/Lreduction in LDL-C (relative risk 0.91[99% CI 0.82–1.01]; P5 0.02) (187). Theseoutcomes were similar to those achievedin patients without diabetes mellitus. Itis also important to recognize that the re-sults of statin interventions in patientswith diabetes mellitus have demon-strated that the observed benefits wereindependent of baseline LDL-C and otherlipid values.


Triglyceride Lowering in Type 2Diabetes MellitusTriglyceride-rich lipoproteins, especiallyVLDL, are often elevated in patients withdiabetes mellitus, appear to be athero-genic, and represent a secondary targetof lipid-lowering therapy. According tothe National Cholesterol Education Pro-gram Adult Treatment Panel III, this goalis non–HDL-C (40). Although the ADA rec-ognizes serum triglycerides as a surrogatefor atherogenic triglyceride-rich lipopro-teins and suggests a target of,150 mg/dL(4), the 2013 ACC/AHA guidelines on thetreatment of cholesterol to reduce ath-erosclerotic cardiovascular risk in adultsprovide no evidence-based recommen-dations for the evaluation or treatmentof hypertriglyceridemia to reduce of CVDrisk (62). However, consistent with theNational Cholesterol Education ProgramAdult Treatment Panel III guidelines, thepanel continued to endorse the evalua-tion and treatment of patients with fast-ing triglycerides.500 mg/dL to preventmore severe hypertriglyceridemia andpancreatitis (62).Clinical trials conducted to date do not

support triglyceride reduction in the pres-ence or absence of diabetes mellitus as ameans to reduce CVD risk. Unfortunately,such trials have suffered from inadequateexperimental design and are few in num-ber, and theoverallfindings arehypothesisgenerating at best. The most selective ofthe triglyceride-reducing drugs are the fi-brates. Four major fibrate trials in whichpatients with CHD or diabetes mellitushave been included have been completed.The Veterans Affairs High-Density Lipopro-tein Intervention Trial (VA-HIT) was carriedout inmenwith known CVD and low levelsof HDL-C (,40 mg/dL), and gemfibrozilwas the fibrate chosen. VA-HIT was theonly fibrate study to demonstrate a signif-icant benefit of a fibrate on CVD, an effectmostly demonstrated in the 25% of pa-tientswith diabetesmellitus (188). The Be-zafibrate Infarction Prevention (BIP) had aminority of patientswith diabetesmellitus,and as in VA-HIT, no patients were on sta-tins (189), whereas the Fenofibrate Inter-vention and Event Lowering in Diabetes(FIELD) trial was conducted exclusively inpatients with diabetes mellitus with a sta-tin drop-in rate of 23% in the placebogroup and 14% in the fenofibrate group(190). In the Action to Control Cardiovas-cular Risk in Diabetes Lipid Trial (ACCORD-LIPID), all patients had diabetes mellitus

and were on simvastatin (191). Despitethe lack of benefit of a fibrate in patientswith diabetes mellitus in BIP, FIELD, andACCORD-LIPID, post hoc analyses of allthree trials suggested that those patientswith hypertriglyceridemia with (FIELD,ACCORD-LIPID) orwithout (BIP) low levelsof HDL-C appeared to benefit. At best, weare left with post hoc analyses that couldpotentially help guide the design of theoptimal trial to follow, that is, in hyper-triglyceridemic patients with diabetesmellitus with or without statin therapy.We note that ADA clinical practice guide-lines indicate that “combination therapy(statin/fibrate and statin/niacin) has notbeen shown to provide additional cardio-vascular benefit above statin therapyalone and is not generally recommended”(Level of Evidence A) (4).

HDL Raising in Type 2 DiabetesMellitusCurrently, HDL-C is not a target for therapyaccording to the ACC/AHA cholesteroltreatment guidelines (62). However, theADA considers levels of HDL-C.40 mg/dLin men and .50 mg/dL in women desir-able (4). Atherothrombosis Interventionin Metabolic Syndrome With Low HDL/High Triglycerides: Impact on GlobalHealth Outcomes (AIM-HIGH), a trial ofniacin in statin-treated patients withknown CVD, included 34% of patientswith diabetes mellitus (192). A total of3,414 patients were randomly assignedto receive niacin or placebo. The trialwas stopped after a mean follow-up pe-riod of 3 years because of a lack of effi-cacy. At 2 years, niacin increased themedian HDL-C from 35 to 42 mg/dL, low-ered triglycerides from 164 to 122mg/dL,and lowered LDL-C from 74 to 62 mg/dL;however, the primary end point of CVDevents or hospitalization for unstable an-gina was no different in the niacin versusthe placebo group. Moreover, outcomesin patients with diabetes mellitus ap-peared to be similar to those in patientswithout diabetes mellitus. Another HDL-C–raising trial, which used the cholesterolester transfer protein inhibitor dalcetra-pib, was carried out in 15,871 patientswho had experienced a recent acute cor-onary syndrome, and 25% had diabetesmellitus (193). The primary end pointwas a composite of death resulting fromCHD, nonfatal MI, ischemic stroke, unsta-ble angina, or cardiac arrest with resusci-tation. On dalcetrapib, HDL-C increased

from a baseline of 42 mg/dL by 31% to40% and by 4% to 11% in the placebogroup without LDL-C lowering in eithergroup. As in AIM-HIGH, this trial wasterminated for futility with no evidenceof CVD risk reduction in the entire co-hort, including patients with diabetesmellitus.

Recommendations for LipidManagement in Type 2 DiabetesMellitusIn adult patients with diabetes mellitus,lipid levels should be measured at leastannually for compliance with recom-mended treatment. Lifestylemodificationdeserves primary emphasis in all patientswith diabetesmellitus with a focus on thereduction of saturated and trans fat in-take, weight loss (if indicated), and in-creases in dietary fiber and physicalactivity. These lifestyle changes, espe-cially weight reduction, have been shownto improve most components of the lipidprofile in patients with diabetes mellitus(194). In patients with diabetes mellituswho are .40 years of age without overtCVD, the new ACC/AHA cholesterolguidelines indicate that there is strongevidence that moderate-intensity statintherapy should be initiated or contin-ued for adults 40 to 75 years of age orhigh-intensity statin should be startedif the individual calculated risk is high.This and additional guidelines for statintherapy are summarized in Table 5.Briefly, between 40 and 75 years ofage, all patients with diabetes mellitusand LDL-C levels between 70 and 189mg/dL should be treated with a statin.The ADA 2015 practice guidelinesare now concordant with the AHAguidelines (4).

Presently, the data do not support arecommendation that patients with di-abetes mellitus on a statin with fastingplasma triglycerides .200 mg/dL havereduced CVD risk with the addition of afibrate.

SCREENING FOR RENAL ANDCARDIOVASCULARCOMPLICATIONS

This section provides the evidence basefor screening for CVD and renal compli-cations in type 2 diabetes mellitus.

Kidney Disease in Diabetes MellitusIn type 2 diabetes mellitus, CKD is com-mon and is associated with adversehealth outcomes. Although CKD in most


patients with diabetes mellitus is attribut-able to diabetes mellitus, other causes ofCKD should be considered when the clini-cal presentation is atypical because theprognosis and treatment of these diseasesmay differ from those of diabetic kidneydisease (DKD) (195). Clinical manifesta-tions of DKD include elevated urine albu-min excretion (albuminuria) and impairedglomerularfiltration rate (GFR) (4,195,196).Among adults with diabetes mellitus in theU.S., the prevalence of DKD is �34.5%:16.8% with albuminuria (ratio of urinealbumin to creatinine $30 mg/g),10.8% with impaired GFR (estimatedGFR ,60 mL z min21 z 1.73 m22), and6.9% with both albuminuria and impairedGFR (197). Among people with or withoutdiabetes mellitus, albuminuria and im-paired GFR are independently and addi-tively associated with increased risks ofend-stage renaldisease, acutekidney injury,cardiovascular events, and death (198).Recent evidence suggests that the pres-ence of DKD identifies a subset of peo-ple with type 2 diabetes mellitus whoare at markedly increased mortalityrisk (199).Although RCTs of screening versus not

screening have not been conducted (200),the ADA and National Kidney Foundationrecommend yearly DKD screening for allpatients with type 2 diabetes mellitus, be-ginning at diabetes mellitus diagnosis, onthe basis of the considerations above(4,195). This recommendation includesmeasurement of both urine albumin ex-cretion, most conveniently measured asthe ratio of albumin to creatinine in asingle-voided urine sample, and GFR, cal-culated from serum creatinine concentra-tion with a validated formula. The stagingof DKD according to the Kidney Disease:Improving Global Outcomes (KDIGO) clin-ical practice guideline links severity ofDKD with risks of adverse outcomes, in-cluding CVD (196).Goals of care for patients with DKD in-

clude preventing progression to end-stage renal disease and reducing the risksof cardiovascular events and death. Ran-domized, clinical trials provide compellingevidence that peoplewith type 2 diabetesmellitus and substantially elevated urinealbumin excretion (i.e.,$300mg/g creat-inine) or impaired GFR (estimated GFR,60 mL z min21 z 1.73 m22) should betreated with an inhibitor of the renin-angiotensin system. In this population,renin-angiotensin system inhibitors

reduce the risks of progression to end-stage renal disease, CVD events, and death(195,200–202). A head-to-head compari-son of an angiotensin-converting enzymeinhibitor and an angiotensin receptorblocker in type 2 diabetes mellitus with el-evated urine albumin excretion suggestedthat the effects on CKD progression wereclinically equivalent (203),whereas a recentmeta-analysis reported that evidence forcardiovascular benefit was strongestfor angiotensin-converting enzyme inhibi-tors (204). A combination of angiotensin-convertingenzymeinhibitorsandangiotensinreceptor blockers is not recommendedbecause it increases the risk of impairedkidney function and hyperkalemia com-pared with either agent alone (205–207).

Renin-angiotensin system inhibitors arealso appropriate first-line antihypertensiveagents for patients with milder DKD (urinealbumin excretion $30 mg/g and ,300mg/g creatinine with normal estimatedGFR) or without evidence of DKD, but clin-ical trials conducted among such patientshave not demonstrated improvements inhard renal or cardiovascular outcomes. Onthebasis of the strong relationship of bloodpressure with kidney disease progression,the presence of DKD may also be a factorfavoring control of blood pressure to lowtarget levels (e.g., 130/80 mmHg) in selectpatients. However, as reviewed earlier, theACCORD trial did not demonstrate that alower blood pressure target significantlyimproved renalor cardiovascularoutcomesoverall (179).

The presence of DKD may modify thesafety or efficacy of commondiabetesmel-litus therapies. In particular, with DKD, thetoxicity of some medications may be in-creased by impaired drug clearance andthe presence of more frequent and severecomorbidities. For example, in theACCORDtrial, the risk of severe hypoglycemia asso-ciated with intensive glucose control wasincreased among participants with greaterurine albumin excretion or higher serumcreatinine concentration measured atbaseline (173). Patients with DKD mayalso have reduced longevity, so they maynot reap the long-term benefits of tightglucose control. As a result, in individu-alized plans for glycemic control, the pres-ence ofmore advancedDKDmay favor lessaggressive intervention (205). Additionalstudies are required to define the impactofDKDonothercommondiabetesmellitus–related interventions.

Subclinical CAD Assessment

Identification of asymptomatic CAD mayallow the opportunity for more aggressivelifestyle or pharmacological interventionsto prevent clinical events or, when diseaseis advanced, the pursuit of revasculariza-tion. Because CAD may present in a silentfashion and symptomatic disease is associ-ated with worse clinical outcomes in dia-betes mellitus, the detection of diseasebefore acute coronary syndrome eventsmay improve morbidity and mortality.However, because there is a paucity ofdata suggesting any specific benefits of in-vasive interventions over medical therapyalone, CAD screening in the asymptomaticpatient with diabetes mellitus remainshighly controversial (209,210). Althoughit is important to individualize clinical de-cision making, widespread screening forsilent CAD in diabetes mellitus cannot berecommended at this time (209).

A variety of CAD screening tests (211–229) are available (Table 8). These includethe simple, inexpensive, and noninvasiveresting ECG, which may detect evidenceof prior myocardial injury or ischemia.Several prior studies have demonstratedthat baseline ECG abnormalities are com-mon in asymptomatic patients with dia-betes mellitus and no history of CAD. Inthe UKPDS, one in six patients with newlydiagnosed type 2 diabetes mellitus hadevidence of silent MI on the baseline sur-face ECG (211). In older studies, the prev-alence of ECG abnormalities in patientswith diabetes mellitus and no knownCAD was even higher, approaching 20%(212). Although the sensitivity and speci-ficity of ECG abnormalities in patientswith diabetes mellitus have been ques-tioned (230) and their additive discrimi-nating value on top of known CAD riskfactors is marginal, data from UKPDS in-dicate that an abnormal ECG is an inde-pendent risk factor for all-cause mortalityand fatal MI in patients with diabetesmellitus (211). Given the wide availabilityand low cost of ECGs, the high prevalenceof abnormal ECG findings in patients withtype 2 diabetes mellitus, and their associ-ation with morbid outcomes, the use ofECGs in the risk stratification of patientswith type 2 diabetesmellitus appears rea-sonable (213). Further testing of patientswith diabetes mellitus and abnormal ECGfindings for inducible ischemia is currentlyendorsed by the professional societies(210). Whether such a strategy improvespatient outcomes remains unknown. This


Table 8—Screening tests for asymptomatic CAD in patients with diabetes mellitus

Test Description Key results Inclusion in a recent AHA guideline?

ECG Resting electric activity through thecardiac cycle

In the UKPDS study, one in six patientswith newly diagnosed type 2 diabetesmellitus had evidence of silent MI onthe baseline surface ECG (211).

Prevalence of ECG abnormalities inpatients with diabetes mellitus and noknown CAD was even higher in olderstudies, approaching 20% (212).

UKPDS data indicate that an abnormalECG is an independent risk factor forall-cause mortality and fatal MI inpatients with diabetes mellitus (211).

Specific ECG abnormalities associatedwith increased risk of CVD events incohort studies include pathologicalQ waves, LVH (particularly ifaccompanied by repolarizationabnormalities), QRS prolongation,ST-segment depressions, andpathological T-wave inversions (213).

Abnormal ECG findings have beendemonstrated to predict inducibleischemia (214).

Class IIa: A resting ECG is reasonable forcardiovascular risk assessment inasymptomatic adults withhypertension or diabetes mellitus(Level of Evidence C) (213).

ABI Ratio of systolic blood pressure at theankle and arm.Used as an indicatorof underlying peripheral arterialdisease

A systematic review of ABI as a predictorof future CVD events demonstratedhigh specificity (�93%) but very lowsensitivity (16%) (215), thus limiting itsutility as a screening test for CAD.

Class IIa: Measurement of ABI isreasonable for cardiovascular riskassessment in asymptomatic adults atintermediate risk (Level of Evidence B)(213).

Stress MPI Radioactive tracer (e.g., thallium-201,Tc99m sestamibi, or Tc99m

tetrofosmin) uptake within themyocardium is assessed beforeand after stress with scintigraphy.Option for pharmacological stress(dipyridamole, adenosine, orregadenoson) in those not able toexercise

MiSAD (216):c A total of 925 asymptomatic patientswith type 2 diabetes mellitus under-went an ECG stress testing, which, ifpositive or equivocal, led to stressthallium MPI.

c Silent CAD prevalence 12.5% forabnormal exercise ECG and 6.4% forboth abnormal ECG and MPI.

c Abnormal scintigraphy predictedcardiac events at 5 years (HR 5.5[95% CI 2.4–12.3]; P , 0.001).

DIAD (217,219):

c In total, 1,123 patients with type 2diabetesmellitus were enrolled frommultiple centers (mean duration ofdiabetes mellitus, 8.5 years); 522patients were randomized to aden-osine sestamibi SPECT MPI, and 561served as the control group andwererandomized to follow-up alone.

c Silent ischemia prevalence5 21.5%.c At 5 years of follow-up, there was nodifference in the primary end point,nonfatal MI and cardiac death, be-tween the screened and unscreenedcohorts (overall annual rate 0.6%; 15versus 17 events; HR 0.88 [95% CI0.44–1.80]; P 5 0.73).

c No differences in any secondary endpoints (unstable angina, heart fail-ure, stroke, coronary revascularization).

Class IIb: Stress MPI may be consideredfor advanced cardiovascular riskassessment in asymptomatic adultswith diabetes mellitus orasymptomatic adults with a strongfamily history of CHD or when previousrisk assessment testing suggests a highrisk of CHD (e.g., a CAC score of$400)(Level of Evidence C) (213).

Class III: No benefit. Stress MPI is notindicated for cardiovascular riskassessment in low- or intermediate-risk asymptomatic adults (Level ofEvidence C) (213).

Continued on p. 18


test is not currently recommended bythe ADA or the U.S. Preventive ServicesTask Force during the initial or follow-up evaluation of patients with diabetesmellitus because data are lacking thatadding an ECG improves risk stratifica-tion, although the AHA states that it isreasonable to obtain a resting ECG inasymptomatic adults with diabetesmel-litus (Table 8).Other screening tests include ECG exer-

cise tolerance testing, exercise (or pharma-cological) myocardial perfusion imaging(nuclear scintigraphy), and exercise (orpharmacological) stress echocardiography.The ankle-brachial index and coronaryartery calcium (CAC) scoring by electron-beam computed tomography (CT) areused to detect evidence of atherosclerosis,although these methods cannot assess foractive or inducible ischemia. Emergingtechniques include CT angiography, car-diacmagnetic resonance imaging, and car-diac positron emission tomography, butnone have had widespread application in

asymptomatic patients. Table 8 provides asummary overview of several additionalscreening tests, along with guidelinerecommendations from the AHA orADA.

Of these, CAC, a marker of intracoro-nary atherosclerosis, can be measuredwith CT. Patients are typically stratifiedby Agatston units, yielding CAC scores of,100 (low risk), 100 to 400 (moderaterisk), and .400 (high risk). Extensivedata indicate a linear relationship be-tween CAC and clinical CHD eventsamong individuals with and without di-abetes mellitus (220–224).

However, patients with diabetes mel-litus have a greater prevalence and ex-tent of coronary calcification than thosewithout diabetes mellitus. In fact, sev-eral studies suggest that majority ofasymptomatic patients with type 2 dia-betes mellitus have coronary calcifica-tion, and nearly 20% have markedlyelevated CAC (225–228). Furthermore,the prognostic significance of elevated

CAC in predicting adverse events ap-pears to be greater in patients with di-abetes mellitus than in those withoutdiabetes mellitus (229).

Several studies show that abnormalCAC is correlated with demonstrablemyocardial ischemia and predicts fu-ture CVD events. Anand et al. (232)measured CAC in 520 asymptomaticpatients with type 2 diabetes mellitus;moderate to large perfusion defectswere seen in 31.5% of patients withCAC .100. The entire cohort wasthen followed up for a mean of 2.2years, during which time 20 major ad-verse cardiovascular events occurred,with myocardial perfusion imaging re-sults available in 18 of these individu-als, 16 of whom had abnormal studies.In Cox models, CAC and extent ofmyocardial ischemia by myocardialperfusion imaging were the only inde-pendent predictors of adverse out-comes. The authors suggested that a2-staged approach of first identifying

Table 8—Continued

Test Description Key results Inclusion in a recent AHA guideline?

DYNAMIT trial (218):c Prospective, randomized, double-blind, multicenter study conductedin France.

c In total, 631 patients were random-ized to either CAD screening witheither a stress ETT or dipyridamoleSPECT MPI versus follow-up only(without screening).

c Study was stopped prematurely; nodifference in cardiac outcomes wasseen between screened and un-screened groups (HR 1.00 [95% CI0.59–1.71]).

CAC scoring Quantitative assessment of calciumdeposited within the coronaryarteries (as a marker ofatherosclerosis) via EBCT ormultidetector CT, stratified byAgatston units, yielding CAC scoresof ,100 (low risk), 100–400(moderate risk), and .400 (highrisk)

Linear relationship between CAC andclinical CHD events among individualswith and without diabetes mellitus(220–225).

Patients with diabetes mellitus havea greater prevalence and extent of CACthan those without diabetes mellitus(225–228).

Prognostic significance of elevated CAC inpredicting adverse events is greater inpatients with diabetes mellitus than inthose without diabetes mellitus (229).

No dedicated randomized trials havesuggested that the detection ofsubclinical CAD by CAC leads toimprovement in clinical events. Thisrepresents an important area of futureresearch.

In asymptomatic adults with diabetesmellitus $40 years of age,measurement of CAC is reasonable forcardiovascular risk assessment (Levelof Evidence B) (213).

ABI, ankle-brachial index; EBCT, electron-beam computed tomography; ETT, exercise tolerance testing; LVH, left ventricular hypertrophy; MPI,myocardial perfusion imaging; SPECT, single-photon emission computed tomography.


the highest-risk patients by CT andthen proceeding to screen those indi-viduals with the highest CAC scores withstress scintigraphy would be a more effi-cient approach than initial myocardialperfusion imaging alone. Importantly,however, the design of this study doesnot allow an assessment of the ability ofthis screening paradigm to reduce futurecoronary events.The rates of death and MI rise incre-

mentally with higher CAC score amongpatients with diabetes mellitus, as dem-onstrated in several prospective studies(223,232). As importantly, the absenceof coronary calcium portends a remark-ably favorable prognosis despite the pres-ence of diabetes mellitus, with 0% ofpatients experiencing adverse cardiacevents during �5 years of follow-up(229). Furthermore, CAC not only is anindependent predictor of adverse cardio-vascular events but also is superior toboth the UKPDS risk engine and the Fra-mingham Risk Score in this patient popu-lation (229,232). For these reasons,current ACC/AHA guidelines considerCAC reasonable for cardiovascular risk as-sessment in asymptomatic patients withdiabetes mellitus who are $40 years ofage (Table 8) (213).There are currently no convincing data

to suggest that performing CACmotivatespatients to better adhere to lifestyle mod-ifications or medical therapy for CVD pre-vention. Limited data suggest that CACinfluences physicians’ management ofCAD risk factors (233). Although an ex-ploratory subgroup analysis from a sin-gle randomized, clinical trial suggeststhat statin therapy in asymptomatic pa-tients with CAC.400 may improve out-comes (234), no dedicated, prospectivestudies have been performed to suggestthat the detection of subclinical CAD byCAC leads to improvement in clinicalevents.In addition to CAC, there is a large pub-

lished experience in screening patientswith diabetes mellitus for subclinicalCAD with nuclear scintigraphy, and theresults of key studies are summarized inTable 8. The Milan Study on Atheroscle-rosis andDiabetes (MiSAD) could not pro-vide an overall estimate of myocardialperfusion defects in asymptomatic pa-tients with diabetes mellitus becauseonly 112 actually had stress-induced is-chemic ECG changes qualifying them toproceed tomyocardial perfusion imaging.

The Detection of Ischemia in Asymptom-atic Diabetics (DIAD) study is the onlyprospective, randomized, controlled in-vestigation to rigorously assess the clini-cal value of screening asymptomaticpatients with diabetes mellitus for CAD(219). DIAD was able to demonstratethat such a screening strategy is not likelyto improve actual clinical outcomes. Thisconclusion is likely due in part to the verylow overall cardiac event rate in DIAD,which may reflect widespread use ofmodern CVD risk reduction strategies.The neutral results of the DIAD study ap-peared to be buttressed by those of theDo You Need to Assess Myocardial Ische-mia in Type 2 Diabetes (DYNAMIT) trial(Table 8), although the latter study wasdiscontinued prematurely because of re-cruitment difficulties and a lower-than-expected event rate. Taken together,however, the findings from these random-ized trials do not support the routine use ofnuclear imaging in patients with type 2 di-abetes mellitus for subclinical disease CADscreening.

Other ModalitiesA number of other noninvasive or semi-invasive tests are currently under study,including coronary CT angiography(CCTA), cardiac magnetic resonanceimaging, and cardiac positron emissiontomography. Although more elaborate,as with other more traditional tests,these tests appear to demonstrate dis-ease and even to predict CHD eventsacross a population of patients. TheFACTOR 64 trial randomized 900 pa-tients without symptomatic CAD witheither type 1 or type 2 diabetes mellitustoCCTA followedbyCCTA-directed therapyversus control (standard guideline-baseddiabetes mellitus management) (235).Over a mean of 4 years of follow-up, therewas no difference in the primary outcomeof fatal or nonfatal coronary disease (6.2%in the CCTA group versus 7.6% in the con-trol group; P 5 0.38). These findings sup-port the concept that CCTA should not beused for CAD screening in asymptomaticpatients with diabetes mellitus. Thus,even with more sensitive modalities, thelack of benefit remains consistent.

SELECTED AREAS OFCONTROVERSY AND FUTURERESEARCH

Several important key areas of contro-versy require further research. Below,

we highlight areas that we consider im-portant in advancing CVD prevention intype 2 diabetes mellitus over the nextfew years:

1. Antihyperglycemic therapy: The spe-cific role of antihyperglycemic ther-apy (in terms of both intensity andspecific drug strategy) in reducingcardiovascular events in type 2 diabe-tes mellitus remains poorly under-stood. Whether any specific drugclass will ever emerge as presenting aclear advantage in this regard isunknown.

2. Bariatric surgery: Bariatric surgery iscurrently an effective treatment forweight loss. It is critical to under-stand the durability of the remissionof diabetes mellitus and other CVDrisk factors in longer-term follow-upin the setting of rigorously designedRCTs.

3. Hypoglycemia: Hypoglycemia is a fre-quent complication of blood glucoselowering in type 2 diabetes mellitus.However, because hypoglycemia isdifficult to identify comprehensively,its true prevalence is likely markedlyunderestimated. Future studies arenecessary to more fully characterizethe burden of hypoglycemia and itsattendant risks, particularly on thecardiovascular system.

4. Blood pressure lowering: Recentblood pressure trials of tight com-pared with usual blood pressuretargets have failed to identify a car-diovascular benefit. However, pre-specified secondary analyses haveidentified a possible protective sig-nal for stroke (179). Further work inhigh-risk stroke populations is neces-sary to validate these findings and todetermine whether a lower bloodpressure target is beneficial in thissubpopulation of patients with dia-betes mellitus.

5. Cholesterol lowering: Most lipidguidelines indicate efficacy with sta-tin treatment in patients with type 2diabetes mellitus. However, the de-finitive trial of triglyceride loweringamong patients with type 2 diabetesmellitus and elevated triglycerides,with or without low HDL-C, with astatin background remains to beconducted. Further research is nec-essary to determine whether triglyc-eride lowering in this subpopulation


can reduce CVD events in patientswith type 2 diabetes mellitus. Further-more, the current cholesterol-loweringguidelines focus on individuals be-tween 40 and 75 years of age. Furtherresearch is necessary to best elucidatetreatment recommendations on thosefalling outside this age range.

6. Imaging for subclinical CVD assess-ment: Although the prevalence ofCAD in patients with diabetes melli-tus is substantial and associatedwith increased morbidity and mor-tality, to date, it has been difficult todemonstrate that detecting diseasein its preclinical or subclinical statewill actually reduce event rates orimprove overall patient outcomes,especially in an era when aggressiveCVD risk factor reduction is widely en-dorsed for this population. Futurelarge, randomized trials are neededto determine whether screening forsubclinical CAD, particularly with

newer modalities that may have im-proved detection of functional CADor biomarkers such as high-sensitivitytroponin, can reduce CVD event ratesin patients with diabetes mellitus.Such studies would need to be ade-quately powered to assess the poten-tial of additive impact of screeningresults and subsequent interventionson actual patient outcomes.

SUMMARY

After reaching a peak in the 1960s,mortality rates from CAD have beendeclining steadily in the U.S. Improve-ments in CVD risk factors such as low-ering smoking prevalence and totalcholesterol and blood pressure levelshave been major drivers for these im-provements in CVD outcomes (236).Although these improvements also oc-curred in patients with type 2 diabetesmellitus, the incremental CVD risks as-sociated with type 2 diabetes mellitus

persist (237). As a result, considerablework remains to be done to enhanceour understanding of how to more ef-fectively prevent CVD in patients withtype 2 diabetes mellitus. The purposeof this scientific statement was to up-date the state of the science with re-spect to CVD risk factor control andrenal and subclinical CAD screening.We have also summarized the current rel-evant CVD prevention guidelines as theypertain to type 2 diabetesmellitus. Finally,we have highlighted key areas of contro-versy that require further study to allowus tomake greater strides in lowering clin-ical CVD in this high-risk patient popula-tion. As a scientific community, our goal isbetter primary prevention of CVD in allpatients with diabetes mellitus.

Acknowledgments. The authors thank BlairUnderwood for her expertise in informationmanagement and referencing assistance.

Writing group disclosures

Writinggroupmember Employment

Researchgrant

Otherresearchsupport

Speakers’bureau/honoraria

Expertwitness

Ownershipinterest

Consultant/advisory board Other

Caroline S.Fox

NHLBI None None None None None None None

Sherita HillGolden

Johns HopkinsUniversity

NIH† None None None None None None

CherylAnderson

University ofCalifornia atSan Diego

None None None None None None None

George A.Bray

PenningtonBiomedicalResearchCenter

NIH† None Takeda* None None Novo-Nordisk*;Herbalife*; Medifast*

NIH†

Lora E.Burke

University ofPittsburgh

NIH† None None None None None NHLBI†

Ian H. deBoer

University ofWashington

Abbvie†;Medtronic*

None None None None Bayer*; Amgen* None

PrakashDeedwania

UCSF FresnoProgram


Robert H.Eckel

University ofColorado

Janssen† None None None None Janssen*; Regeneron†;Sanofi†

Janssen*

Abby G.Ershow

NIH Office ofDietary

Supplements

None None None None Johnson &Johnson†

None None

JudithFradkin

NIH/NIDDK None None None None None None NIH/NIDDK†

Silvio E.Inzucchi

Yale UniversitySchool ofMedicine

Takeda† None None Pfizer*;Takeda*

None Boehringer Ingelheim†;AstraZeneca*; Merck*;

Novo Nordisk*;Regeneron*; Janssen*

None

Continued on p. 21

Disclosures


Writing group disclosures—Continued

Writinggroupmember Employment

Researchgrant



Expertwitness

Ownershipinterest

Consultant/advisory board Other

MikhailKosiborod

Mid AmericaHeart Institute

Gilead†;Genentech†;

Sanofi Aventis†;Eisai†;

AstraZeneca†

Gilead† None None None AstraZeneca†; Eli Lilly*;Regeneron*; Roche*;

Gilead*; Amgen†; Takeda*;Edwards Lifesciences*;

Glytec*; GSK*;ZS Pharma†

None

Robert G.Nelson

NationalInstitutes of

Health


Mahesh J.Patel

MerckResearch

Laboratories

None None None None None None MerckResearch

Laboratories†

MichaelPignone

University ofNorth Carolina


LaurieQuinn

University ofIllinois atChicago


Philip R.Schauer

ClevelandClinic

STAMPEDE Trial†;ARMMS Trial†

None None None SE QualityHealthcareConsulting†;SurgiQuest*

Ethicon*; Nestle*;Intuitive*

None

ElizabethSelvin

Johns HopkinsBloombergSchool of

Public Health

NIH/NIDDK† None None None None None None

Dorothea K.Vafiadis

AmericanHeart

Association


This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest asreported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is consideredto be “significant” if (a) the person receives $10,000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) theperson owns 5% or more of the voting stock or share of the entity, or owns $10,000 or more of the fair market value of the entity. A relationship isconsidered to be “modest” if it is less than “significant” under the preceding definition. *Modest. †Significant.

Reviewer disclosures

Reviewer Employment Research grant



Expertwitness

Ownershipinterest

Consultant/advisoryboard Other

WilliamBorden

George WashingtonUniversity


DeborahChyun

New York University None None None None None None None

LeighPerrault

University of Colorado None None None None None None None

Salim S.Virani

VAMedical Center, BaylorCollege of Medicine

Department ofVeteransAffairs*; AmericanHeart Association*;American Diabetes

Association*

None None None None None None

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on theDisclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) theperson receives $10,000 or more during any 12-month period, or 5% or more of the person’s gross income; or (b) the person owns 5% or more of thevoting stock or share of the entity, or owns $10,000 or more of the fair market value of the entity. A relationship is considered to be “modest” if it isless than “significant” under the preceding definition. *Significant.


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