13 - Effect of Glucose Management on Coronary Heart ... · Diabetes CHD FIGURE 13-1 The “common soil” hypothesis of diabetes and coronary heart disease (CHD). 156 III M ANAGEMENT

13 Effect of Glucose Managementon Coronary Heart Disease Risk in

Downl

Patients with DiabetesKasia J. Lipska and Silvio E. Inzucchi

CHANGING EPIDEMIOLOGY OFDIABETES AND CORONARY HEARTDISEASE, 155

EPIDEMIOLOGIC RELATIONSHIP OFGLUCOSE WITH CORONARY HEARTDISEASE, 155

TRIALS OF GLUCOSE-LOWERINGINTERVENTIONS, 157

TRIALS OF GLUCOSE-LOWERINGINTERVENTIONS IN PREDIABETESAND EARLY DIABETES, 159

oaded for Aman Shah (a.shah.1@elsevFor personal use only. N

THE “HOW” OF GLUCOSELOWERING: THE EVIDENCE FORSPECIFIC MEDICATIONS ANDMEDICATION CLASSES, 161Metformin, 162Sulfonylureas, 163Thiazolidinediones, 163Insulin, 164Incretin-Based Therapies, 165Other Agents, 165

ier.com) at Elsevier - Demonstration Account from ClinicalKeyo other uses without permission. Copyright ©2017. Elsevier Inc

RISKS ASSOCIATED WITHANTIHYPERGLYCEMICMEDICATIONS, 167Hypoglycemia, 167Other Adverse Effects of

Medications, 168

IMPLICATIONS FOR CLINICALPRACTICE, 168

REFERENCES, 169

Coronary heart disease (CHD) is the most common vascularcomplication of diabetes. Because elevated glucose definesdiabetes and because diabetes is a well-recognized risk fac-tor for CHD, strategies that lower glucose should theoreti-cally reduce the risk of CHD events in diabetes. In reality,the relationship between glucose-lowering strategies andcardiovascular outcomes is complex and suggests that theimpact of interventions on patient outcomes cannot be eas-ily predicted from the effects of interventions on surrogatemeasures (such as glucose or hemoglobin A1c, HbA1c).Indeed, CHD can precede the development of diabetes,and some have suggested that both conditions (CHD anddiabetes) have common genetic and environmental rootsand spring from a “common soil” (Fig. 13-1) (see also Chap-ters 2, 8, and 9).1 This chapter describes the epidemiologicrelationship between glucose and CHD, reviews clinical trialevidence of the effects of glucose lowering on CHD out-comes, discusses the benefits and risks of glucose loweringwith specific medications and in specific patient popula-tions, and concludes with implications for clinical practice.

CHANGING EPIDEMIOLOGY OF DIABETESAND CORONARY HEART DISEASE

The general incidence and prevalence of CHD havedeclined in the United States in the last several decades,and this decline has been accompanied by a decline inCHD-related mortality.2 These trends have been attributedto better cardiovascular risk factor control and treatmentduring and after acute coronary syndromes over time, pri-marily with the use of statin medications, blood pressuremanagement, and anti-platelet therapies. In contrast toCHD trends, the incidence and prevalence of diabetes havebeen steadily increasing over time, with the disease nowaffecting close to a third of older U.S. adults (65 years orolder) (see also Chapter 1).3,4 In addition, adults with diabe-tes are living longer.5 As a result, the burden of CHD attrib-utable to diabetes is increasing (see also Chapter 7).6 These

changes in the epidemiology of diabetes and CHD haveimportant implications. First, strategies that mitigate the riskof CHD in diabetes patients will be of growing importancebecause heart disease is increasingly a complication of dia-betes. Second, these strategies will be applied to an agingpopulation with a high comorbidity burden and at higherrisk for adverse effects of therapy.

EPIDEMIOLOGIC RELATIONSHIP OF GLUCOSEWITH CORONARY HEART DISEASE

Multiple studies have assessed the relationship between var-ious glucose parameters—fasting glucose, 2-hour glucoseduring an oral glucose tolerance test, or HbA1c levels—and the risk of CHD in populations with and without diabe-tes. Most of this work suggests a continuous relationshipbetween measures of glycemia and CHD risk.

Several studies and a metaregression analysis have shownthat in nondiabetic populations, there is a graded relation-ship between initial fasting and postprandial glucose levelsand subsequent occurrence of cardiovascular events over12 years of follow-up.7 The association is apparent even atlevels below the diabetic thresholds. However, becauseHbA1c is the preferred test for monitoring blood glucosecontrol during the chronic management of diabetes, datasummarized here will be predominantly based on this glyce-mic parameter.

In the large prospective population study of Norfolk, in theUnited Kingdom, HbA1c and cardiovascular risk factorswere assessed from 1995 to 1997, and cardiovascular diseaseevents and mortality were examined during the next 6 to8 years of follow-up.8 The relationship between HbA1cand cardiovascular disease and total mortality was continu-ous and apparent even among persons without diabetes.The risk was lowest among persons with HbA1c below 5%and increased thereafter throughout the range of nondia-betic HbA1c levels up to 6.9%. Each one percentage pointincrease in HbA1c above 5% was associated with a 20% to

155.com by Elsevier on December 21, 2017.. All rights reserved.

HypertensionDyslipidemia

HyperglycemiaHyperinsulinemia

InflammationImpaired Fibrinolysis

Endothelial DysfunctionGenetic Predisposition

Insulin ResistanceInsulin ResistanceInsulin Resistance

DiabetesDiabetes CHDCHDDiabetes CHD

FIGURE 13-1 The “common soil” hypothesis of diabetes and coronary heart disease (CHD).

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25% increase in the relative risk for CHD among men andwomen in age- and risk-factor adjusted models. Moreover,when known diabetes status and HbA1c concentration wereincluded in the same model, diabetes was no longer a signif-icant independent predictor of CHD, suggesting that theincreased risk of CHD in dysglycemic states is mediatedthrough hyperglycemia itself.

The prognostic value of HbA1c was also assessed in theAtherosclerosis Risk in Communities (ARIC) study of U.S.adults without a prior history of diabetes or cardiovasculardisease and with up to 15 years of follow-up.9 Similar tothe observations from the Norfolk study, the risk for CHDincreased with higher HbA1c values in a continuous fashionindependent of classic cardiovascular risk factors. Whencompared with study participants with HbA1c of 5% to lessthan 5.5% (the reference range), the hazard ratio (HR) forCHD was increased 23% in those with HbA1c of 5.5% to lessthan 6%, 78% for HbA1c of 6% to less than 6.5%, and 95% forHbA1c of 6.5% or higher. Although, clearly, the causal role ofglucose in the development of CHD could not be evaluatedin this epidemiologic study, the findings suggest that HbA1c,even in the nondiabetic range, can be a useful independentmarker of cardiovascular risk.

Although the association between HbA1c level and CHDmay be prognostically important in nondiabetic individuals,to understand the effect of glucose lowering on CHD risk wemust examine data in patients with diabetes. A prospectiveobservational study of type 2 diabetes patients enrolled inthe United Kingdom Prospective Diabetes Study (UKPDS)

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examined the relationship between HbA1c and cardiovas-cular complications. They found that each 1% increase inthe updated HbA1c was associated with a 14% relative riskincrease for myocardial infarction (MI; Fig. 13-2).10 A meta-analysis of 13 prospective cohort studies of HbA1c and car-diovascular disease in persons with diabetes (type 1 or 2)suggested that chronic hyperglycemia is associated withan increased risk for cardiovascular disease. The pooled rel-ative risk for cardiovascular disease associated with a 1%increase in HbA1c was 1.18. In a subgroup of six studies con-ducted in patients with type 2 diabetes, a 1% increase inHbA1c was associated with a 13% increased relative riskfor CHD.11 The inclusion criteria for the meta-analysis didnot specify pharmacologic treatment for diabetes; rather,these were observational studies involving patients on bothmedication and diet therapy. These results suggest a moder-ate increase in cardiovascular risk with increasing HbA1c indiabetic adults. However, the meta-analysis relied on smallstudies with some suggestion of heterogeneity of effects thatcould not be explored in detail.

One large analysis examined data from the U.K. GeneralPractice Research Database (GPRD) on 27,965 patients withtype 2 diabetes whose oral monotherapy was intensified tooral combination therapy, and 20,005 whose oral therapywas intensified to include insulin.12 The primary and second-ary outcomes for the two cohorts were all-cause mortalityand major cardiovascular events, respectively, over themean follow-up of 4.5 years. HbA1c in the study was basedon themean of any values recorded between the therapeutic

ation Account from ClinicalKey.com by Elsevier on December 21, 2017.. Copyright ©2017. Elsevier Inc. All rights reserved.

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FIGURE 13-2 Epidemiologic relationship between hemoglobin A1c andcardiovascular events. (Modified from Stratton et al. BMJ 2000.10)

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switch and death or date of censor. In combined cohortanalysis, the HbA1c decile with a median value of 7.5%(interquartile range 7.5% to 7.6%) was associated with thelowest mortality and the lowest progression to large-vesseldisease among those without prior history of cardiovascularevents. Higher and lower HbA1c values were associatedwith an increased risk, and the pattern of risk was U shaped.In the oral combination therapy group, a wider range ofHbA1c values was safe with respect to mortality risk (medianHbA1c 6.9% to 8.9%), whereas this range was narrower forpatients on insulin (median HbA1c 7.5% to 8.1%). In addi-tion, the use of insulin was associated with an approximately50% higher hazard of mortality comparedwith the use of oralagents. Although no evidence supports a direct cardiotoxiceffect of insulin in type 2 diabetes, it is certainly possible thatage, comorbidities, and diabetes duration may be related tothe decision to initiate insulin as well as to the higher mor-tality risk. The findings from this study differ significantlyfrom the graded, continuous epidemiologic relationshipsbetween HbA1c and cardiovascular outcomes in individ-uals without diabetes. In nondiabetic populations, lowerHbA1c values predict better outcomes without a clearthreshold, but the data from treated patients with diabetessuggest that there may be a risk associated with achievingnear-normal glycemia.Another retrospective cohort study, this time performed in

the United States, confirmed the results of the GPRD analysis.Here, data from 71,092 patients with type 2 diabetes age60 years or older within the Kaiser Permanente Northern Cal-ifornia system were analyzed to examine the associationbetween baseline HbA1c level and subsequent nonfatalcomplications (metabolic, microvascular, and cardiovascu-lar events) and mortality.13 The authors found a similarU-shaped relationship between HbA1c level and mortality,with higher risk in those with HbA1c below 6% and 10%

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or higher in the adjusted models. In contrast, however, therelationship between HbA1c and cardiovascular eventswas continuous with increasing risk above HbA1c of 6%.Integrating all of the outcomes together, the “optimal”HbA1c range identified by this study lay somewhere in the6% to 7.9% range. As in the GPRD study, the analysis addedimportant information about optimal glycemic targets in dia-betes, suggesting that achievement of low glycemic levelsmay provide benefits (such as lower risk of CHD), but thatvery low levels of glycemia may be associated with harm(e.g., higher mortality risk). A third study, this involving alladults with type 2 diabetes drawn from the Kaiser Perma-nente Southern California system, showed a U-shaped rela-tionship between HbA1c and cardiovascular events, withHbA1c levels of 6% or lower and greater than 8% associatedwith an increased risk of cardiovascular events.14Whether ornot low HbA1c levels are a marker of sicker patients or amediator of harm remains highly debatable. Moreover,whether this phenomenon is actually directly attributableto lower than desirable glycemia or to adverse effects ofthe medications clinicians use to achieve this range is notclear. Randomized clinical trials can test the effects of inter-ventions directly on patient outcomes and may be able toprovide greater insight into the effect of glucose loweringon CHD events.

TRIALS OF GLUCOSE-LOWERINGINTERVENTIONS

The landmark trial in type 2 diabetes that investigated theeffect of intensive glucose lowering on microvascular andmacrovascular outcomes was the UKPDS. The trial wasbegun in 1977 and the results were published in 1998. In thistrial, 3867 patients with newly diagnosed type 2 diabetes(median age 54) were randomized to intensive treatmentwith sulfonylureas (chlorpropamide, glibenclamide (glybur-ide in the U.S.), or glipizide) or with insulin, versus conven-tional therapy with diet alone.15 The median HbA1c level inthe intensive group during the course of the trial was 7%, ver-sus 7.9% in the conventional arm. Three separate aggregateendpoints were studied over the 10 years of follow-up. Therisk in the intensive group was 12% lower for any diabetes-related endpoint (P¼0.03), which included both macrovas-cular and microvascular events as well as metabolic compli-cations; not significantly lower for any diabetes-related death(�10%, P¼0.34); and not significantly lower for mortality(�6%, P¼0.44), compared with patients treated with dietonly. The reduction in diabetes-related endpoints was drivenby a 25% risk reduction in microvascular events, and thereduction in MI did not reach statistical significance(�16%, P¼0.052). A subgroup of UKPDS patients who wereoverweight (>120% ideal body weight) were randomizedeither to intensive therapy with metformin (n¼342, medianHbA1c 7.4%) or conventional diet therapy (n¼411, medianHbA1c 8%).16 In this subset of patients, treatment withmetformin was associated with a 32% reduction in anydiabetes-related endpoint (P¼0.002), 42% reduction indiabetes-related death (P¼0.017), and 36% reduction inmortality (P¼0.011). In this cohort of patients treatedwith metformin, there was a significant 39% reduction inMI (P¼0.01) (Fig. 13-3). In summary, the UKPDS trialestablished that intensive glucose control reduces the riskof microvascular complications in patients with newly

tion Account from ClinicalKey.com by Elsevier on December 21, 2017.Copyright ©2017. Elsevier Inc. All rights reserved.

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BFIGURE 13-3 Results of the UKPDS trial with respect to myocardial infarction and coronary deaths. NS¼Non significant. (Modified from Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes [UKPDS 34]. UK Prospective Diabetes Study [UKPDS] Group, Lancet 352:854, 1998).

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diagnosed type 2 diabetes, but suggested that macrovascularbenefits may be confined to overweight patients treated withmetformin therapy.

After the UKPDS trial was completed, study participantsand their clinicians were advised to lower levels of blood glu-cose as much as possible, and patients returned to commu-nity or hospital-based diabetes care according to theirclinical needs without any attempts to maintain previouslyrandomized therapies. In the 10-year post-trial monitoringstudy of patients who survived to the end of the UKDPS trial,HbA1c levels were no longer different between theoriginal intensive and conventional arms (approximately8% at the end of the post-trial monitoring period).17 In thesulfonylurea-insulin group, relative risk reductions fordiabetes-related endpoints persisted, whereas significant riskreductions for MI (15%, P¼0.010) and mortality (13%,P¼0.007) emerged over time. In the metformin group, rela-tive risk reductions persisted for any diabetes-related end-point, MI (33%, P¼0.005), and mortality (27%, P¼0.002).These observations suggest a modest but sustained effect ofintensiveglucose loweringoncardiovascular events,butonlyafter many years of follow-up. Whether the effect is confinedto patientswith newly diagnosed type 2 diabetes orwhether itreflects the long period of time required to significantly affectsubsequent atherosclerotic outcomes is not entirely clear.

Even before the cardiovascular benefits of intensive glu-cose therapy emerged in the long-term follow-up of theUKPDS trial, guidelines recommended a target HbA1c levelof 7% or less in most patients. This was primarily driven bythe expectation of microvascular benefits, albeit with uncer-tainty over the effects on macrovascular events. To settle thequestions about the role of intensive glucose therapy in type2 diabetes, three randomized controlled trials were specifi-cally designed to examine the impact of targeting near-normal glycemia on cardiovascular risk. The HbA1c targetswere set low because of the continuous epidemiologic rela-tionship of glucose with cardiovascular risk, suggesting thatperhaps much lower glucose levels need to be achieved fora significant benefit to emerge. The three trials all recruited


participants with type 2 diabetes who had either a history ofor multiple risk factors for cardiovascular disease, thusensuring adequate event rates to study the effects of the inter-ventions. Participants were therefore quite distinct frompatients in the UKPDS trial—they were older, had a longerduration of diabetes, and had a greater comorbidity burden.

The Action to Control Cardiovascular Risk in Diabetes(ACCORD) trial enrolled 10,251 patients (mean age 62,median baseline HbA1c 8.1%, 35% with history of prior car-diovascular event) to intensive glucose therapy (targetingHbA1c <6%, median achieved HbA1c 6.4%) versus con-ventional therapy (targeting HbA1c 7% to 7.9%, medianachieved HbA1c 7.5%).18 This trial was stopped prematurelyafter a mean follow-up of 3.5 years because of a higher mor-tality rate in the intensive therapy group compared with thecontrol arm (HR 1.22, P¼0.04). The primary endpoint of thetrial, major cardiovascular events, was not significantlyreduced (HR 0.90, P¼0.16), although the rate of nonfatalMI was lower in the intensive therapy group (HR 0.76,P¼0.004). To date, analyses have not identified any clearexplanation for the higher mortality risk associated withthe intensive glucose-lowering strategy. In the intensive ther-apy group, a median HbA1c level of 6.4% was rapidlyachieved andmaintained, but subsequent post hoc analysesimplicated factors associated with persistently higherHbA1c, rather than low HbA1c, as likely contributors tothe increased mortality risk.19 In addition, rates of serioushypoglycemia requiring medical assistance were threefoldhigher in the intensive group than during standard therapy(10.5% versus 3.5%, P<0.001). Subsequent retrospective epi-demiologic analyses of ACCORD have suggested, however,that severe hypoglycemia may not, in fact, account for thedifference in mortality between the two study arms.20

Although hypoglycemia was associated with increased mor-tality within each randomized group, the risk of death wasactually lower in participants experiencing hypoglycemiain the intensive arm than in participants with hypoglycemiain the standard arm. Other explanations, such as the partic-ular medication combinations or undetected medication


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interactions, have also been proposed, but no particularmedication class has been implicated thus far. In the end,the explanation for the increased mortality may never beknown, but the findings have led to a growing recognitionthat intensive glucose loweringmay be associatedwith somebenefits but also important risks.Subsequent follow-up of the participants from the

ACCORD trial, up to the originally planned 5 years, showedpersistently increased mortality rates in the intensive therapygroup (HR 1.19, P¼0.02), but still lower rates of nonfatal MI(HR 0.82, P¼0.01).21 Given these findings, strategies used inthe ACCORD study targeting an HbA1c below 6% are notrecommended for patients with advanced type 2 diabetesand established macrovascular complications or multiplerisk factors for cardiovascular events.At the same time the ACCORD study was published,

results from the Action in Diabetes and Vascular Disease:Preterax and Diamicron Modified Release Controlled Evalu-ation (ADVANCE) trial also became available.22 In this trial,11,140 patients with type 2 diabetes (mean age 66, medianbaseline HbA1c 7.2%, 32%with history of major macrovascu-lar disease) were randomized to intensive therapy (preferen-tially with the sulfonylurea gliclazide, targeting HbA1c�6.5%, with mean achieved HbA1c 6.5%) or to standardtherapy (HbA1c goal according to local guidelines, meanachieved HbA1c 7.3%). After a median follow-up of 5 years,there was a reduction in the primary outcome of the study,which was a composite of microvascular andmacrovascularevents (HR 0.90, P¼0.01), and this was almost entirelydriven by effects on intermediate markers of nephropathy.There was no significant effect with respect to major cardio-vascular events (HR 0.94, P¼0.32) in ADVANCE, but also noincrease in mortality (HR 0.93, P¼0.28) as in ACCORD.Investigators of ADVANCE specifically examined varioussubgroups at potentially increased risk of death, but nonewere identified. Overall, the trial findings suggest a modestimprovement in markers of microvascular complicationswith intensive treatment, but no significant benefit gainedwith respect to CHD endpoints.One additional trial confirmed the lack of significant ben-

efit of intensive glucose lowering on major cardiovascularevents, the Veterans Affairs Diabetes Trial (VADT). In thisstudy of 1791 U.S. military veterans with type 2 diabetes(mean age 60, median baseline HbA1c 9.4%, 40% with priorhistory of cardiovascular events), participants were random-ized to intensive glucose or standard therapy using a combi-nation of agents, with a goal of achieving an absolutereduction in HbA1c of 1.5% in the intensive versus the stan-dard arm. Median HbA1c levels achieved were 6.9% versus8.4% in the intensive and standard groups, respectively, overa median follow-up of 5.6 years. There was no significantbenefit with respect to the primary composite outcome, ofcardiovascular events (HR 0.88, P¼0.14), the individual out-come of death from any cause, nor any difference withrespect to most microvascular complications (no changesin retinopathy, new neuropathy, or doubling of creatinine,but reduction in some albuminuria-based endpoints). In thisstudy of patients with advanced type 2 diabetes, other car-diovascular risk factors were well controlled, and differ-ences in HbA1c levels between the two groups weremaintained. However, overall, the benefit of decreasingHbA1c from 8.4% to 6.9% was minimal, except in the pro-gression of albuminuria, an intermediate marker with uncer-tain implications for long-term renal risk.


Multiple meta-analyses have followed the three random-ized controlled trials described earlier to determine whetherpooling results of existing studies will illuminate our under-standing of these relationships (Fig. 13-4). Although theseanalyses sometimes included studies of different intent(not necessarily glucose-lowering per se) and with variablepatient characteristics (newly diagnosed versus advanceddiabetic patients), they consistently show a modest,although significant, reduction of approximately 15% inthe risk for nonfatal MI, but no impact on mortality or cardio-vascular death.23–28 Moreover, all of these studies show thatthe risk for severe hypoglycemia with intensive glucose ther-apy is more than doubled.

Why have these large randomized controlled trials failedto show that intensive glucose lowering improves cardiovas-cular outcomes when the epidemiologic relationshipbetween glycemia and cardiovascular events is so convinc-ing? Many of the expectations for reduction in risk may havearisen from the effects of statin medications on majoradverse cardiovascular events (MACEs) in early trials. Astrong epidemiologic association between cholesterol andCHD exists, and interventional studies show a 23% relativereduction in risk achieved for every 1 mmol/L (38 mg/dL)of cholesterol lowering. Glycemia is a much weaker risk fac-tor for CHD than cholesterol, but the assumption has beenthat some degree of risk reduction should result from glu-cose lowering. However, it is clear that the simple arithmetic(lower the level of a risk factor and cardiovascular eventswill naturally follow) does not apply in the case of glycemia.There may be a modest reduction in nonfatal MI, but overalldisappointing results with respect to mortality and the com-posite of major cardiovascular events. Several potentialexplanations can be proposed: significant adverse effectsof glucose therapy may counterbalance possible benefits,effects of glucose lowering applied in advanced diabetesmay be too late to prevent atherosclerotic events, or theimpact of glucose lowering may take a longer time to mate-rialize than the 5 to 7 years assessed in most clinical trials.Regardless of the reasons, currently available therapiestested in these studies do not appear to constitute a “magicbullet” for the increased cardiovascular morbidity ofdiabetes.

TRIALS OF GLUCOSE-LOWERINGINTERVENTIONS IN PREDIABETES AND EARLYDIABETES

Because one potential reason for the lack of benefit of inten-sive glucose lowering on cardiovascular disease is that it isapplied too late to prevent atherosclerosis, it is worthwhileto examine studies that have investigated glucose loweringbefore diabetes actually develops or very early in the diseasecourse.

One such study was the Diabetes Prevention Program thatrandomly assigned 3234 nondiabetic persons at high risk fordiabetes (with elevated body mass index and fasting andpostload glucose values) to intensive lifestyle therapy, met-formin monotherapy, or placebo.29 Lifestyle interventionand metformin both significantly reduced the incidence ofsubsequent diabetes. In follow-up studies of the trial popula-tion, the lifestyle intervention also improved cardiovascularrisk factors compared with metformin or placebo treatment,but the number of cardiovascular events was too small


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0.13 (0.79 to 1.63) 4 (�9 to 17)

0.97 (0.76 to 1.24) �3 (�14 to 7)

Heterogeneity P � 0.002; I 2 � 76.3%

FIGURE 13-4 Relative risk and risk differences estimates (per 1000 patients over 5 years of treatment), with 95% confidence intervals (CI), for the main studyoutcomes in the UKPDS, ACCORD, ADVANCE, and VADT. A, Primary composite cardiovascular outcome. B, Cardiovascular mortality. (Modified from Kelly TN, BazzanoLA, Fonseca VA, et al. Systematic review: glucose control and cardiovascular disease in type 2 diabetes, Ann Intern Med 151:394-403, 2009.)

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(n¼89 at 3 years) to allow any meaningful examination ofthe differences among groups.30 After 10 years of follow-upof the Diabetes Prevention Program, the cumulative inci-dence of diabetes was still lowest in the former lifestyle inter-vention group.31 Cardiovascular disease risk factorsimproved in all three treatment groups, but averaged over


all follow-up, systolic and diastolic blood pressure and tri-glyceride levels were lower in the lifestyle than in the othergroups (even though the use of antihypertensive medica-tions was less frequent). However, the number of clinicalevents remained too small to determine the effect of diabe-tes prevention strategies on actual cardiovascular events.


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In the Study to Prevent Non–Insulin-Dependent DiabetesMellitus (STOP-NIDDM), investigators examined the effectof postprandial glucose lowering on the incidence of diabe-tes in 1429 participants with impaired glucose tolerance, ele-vated fasting glucose, and overweight or obesity.32 As asecondary outcome, investigators specifically examinedthe effect of intervention on major cardiovascular eventsand hypertension, although the trial was not adequatelypowered to answer that question. The participants were ran-domized to receive either acarbose or placebo and were fol-lowed for a mean of 3.3 years. In the course of the trial,almost one quarter of participants discontinued participa-tion prematurely (including significantly greater numbersrandomized to acarbose). Moreover, concerns about incon-sistencies, failure to follow intention-to-treat analysis, andchanges in the trial endpoints have been raised. Neverthe-less, the trial reported an unanticipated 49% relative riskreduction (P¼0.03) in major cardiovascular events (includ-ing revascularization procedures, congestive heart failure,and peripheral vascular disease in addition to the conven-tional major cardiovascular events) associated with acar-bose therapy. This composite endpoint was primarilydriven by an incredible 91% reduction in MI (P¼0.02).Clearly, these trial findings will need to be confirmed infuture studies before acarbose therapy can be recom-mended for cardiovascular risk reduction. One such trial,the Acarbose Cardiovascular Evaluation (ACE) study, is cur-rently ongoing and testing the impact of acarbose on cardio-vascular outcomes in persons with impaired glucosetolerance and established cardiovascular disease or acutecoronary syndromes.Encouraged by the STOP-NIDDM results, investigators of

the Nateglinide and Valsartan in Impaired Glucose Toler-ance Outcomes Research (NAVIGATOR) trial decided to testan alternative postprandial glucose-lowering approach witha short-acting insulin secretagogue, nateglinide, in additionto lifestyle modification. They randomized 9306 persons(mean age 64) with impaired glucose tolerance (baselineHbA1c 5.8%) at high risk for cardiovascular disease (24%had a prior history of cardiovascular events) to nateglinideor placebo and followed participants for amedian of 5 years.Nateglinide did not reduce the occurrence of the three co-primary outcomes—incident diabetes (HR 1.07, P¼0.05),cardiovascular outcome (death from cardiovascular causes,nonfatal MI, nonfatal stroke, or hospitalization for heart fail-ure, HR 0.94, P¼0.43), or the extended cardiovascular out-come (which in addition included unstable angina orarterial revascularization, HR 0.93, P¼0.16). The trial resultscontrast sharply with the findings of the STOP-NIDDM studyand show that targeting postprandial hyperglycemia withnateglinide in participants with impaired glucose tolerancedoes not lead to cardiovascular benefits.Another potential approach is to test whether early provi-

sion of basal insulin to normalize fasting plasma glucosemay reduce cardiovascular outcomes in persons with mildlyelevated glucose levels or early diabetes. This strategy doesnot specifically target postprandial hyperglycemia, butrather postulates that insulin, which has been demonstratedto have anti-inflammatory effects, may actually be cardiopro-tective and that it may also preserve pancreatic beta cellfunction over time. The Outcome Reduction with Initial Glar-gine Intervention (ORIGIN) trial randomized 12,537 people(mean age 64; 82% with early diabetes, 6% with new diabe-tes, and 12% with impaired fasting glucose or impaired


glucose tolerance; median baseline HbA1c 6.4%; 59% withprior cardiovascular disease) to insulin glargine or standardcare.33 The target in the insulin group was to achieve a fast-ing glucose level of 95 mg/dL or lower. After amedian 6 yearsof follow-up, HbA1c levels were 6.2% versus 6.5% in the insu-lin and standard arms, respectively. The trial found no signif-icant reduction in two co-primary outcomes, majorcardiovascular events (HR 1.02, P¼0.63) and major cardio-vascular events plus revascularization and heart failure (HR1.04, P¼0.27). However, there was an increased risk of hypo-glycemia with insulin therapy and some weight gain (+1.6 kgversus �0.5 kg in the two groups). Although diabetes inci-dence was decreased (a finding of questionable clinicalapplication), the trial findings were generally disappointing.The ORIGIN trial did not support the original hypothesis thatnormalizing glucose with early insulin therapy would lead tobetter cardiovascular outcomes.

These studies illustrate the impact of glucose loweringwith a variety of different approaches in persons with predi-abetes or early diabetes on cardiovascular outcomes. Withthe exception of the STOP-NIDDM study, which had impor-tant limitations, the studies to date have not supported thenotion that glucose lowering is beneficial for cardiovascularoutcomes at the prediabetic stage. Despite the epidemio-logic association of glucose with cardiovascular events thatextends well into the nondiabetic range, interventions target-ing glycemia have thus far failed to deliver an effective strat-egy to reduce this risk.

THE “HOW” OF GLUCOSE LOWERING: THEEVIDENCE FOR SPECIFIC MEDICATIONS ANDMEDICATION CLASSES

Perhaps one of the most important lessons in cardiovascularrisk reduction in type 2 diabetes has been the growing rec-ognition that the exact strategy used to reduce glucosemay actually matter with respect to outcomes. For severaldecades now, the thrust of clinical research has been to testapproaches that target specific degrees of glucose lowering.Less attention was previously paid to the different ways inwhich glycemia is actually improved and how that mayaffect downstream events. The early UKPDS experience,albeit based on a small subgroup (n¼342) of patients,has given metformin a preferred place in the diabetic regi-men for type 2 diabetes. In most subsequent trials (ACCORD,ADVANCE, VADT), combinations of various medications,including insulin use, had to be used to lower glucose levels,and there was no particular advantage to one strategy versusanother. However, these glucose-lowering trials were notdesigned to test the effects of specific medications onoutcomes.

Interest in the effects of specific antihyperglycemic medi-cations on outcomes was boosted by the publication of ameta-analysis by Nissen and colleagues in 2007 that showedan adverse effect of the thiazolidinedione rosiglitazone onMI risk.34 In the analysis of 42 trials that was performed, therewere 86 MI events in the rosiglitazone group compared with71 in the comparator arm (including placebo, metformin,sulfonylurea, or insulin), resulting in an increased odds ratioof 1.43 (P¼0.03). Although the methodology and the resultsof this meta-analysis have been debated, and some havenoted no increase in risk associated with rosiglitazoneuse,35,36 there is no doubt that the study provided a


TABLE 13-1 Major Randomized Controlled Trials inType 2 Diabetes

UKPDS ACCORD ADVANCE VADT

Study Participants

Mean age, yearsDiabetes duration,

yearsPrior

macrovasculardisease

53NewExcluded*

621035%

66832%

6011.540%

Duration of Study

Number of years 11 3.5 5 5.6

HbA1c Goal

Intensive therapyStandard therapy

†

{<6%7%-7.9%

�6.5%Standard

<6%8%-9%

HbA1c Achieved

Intensive therapyStandard therapy

7.0%7.9%

6.4%7.5%

6.4%7.0%

6.9%8.5%

Severe Hypoglycemia

Annual events per100 patients

Intensive therapyStandard therapyP value

0.710.20Not

reported

4.61.5<0.001

0.560.30<0.001

12.04.0<0.001

Primary Outcome}

HR (95% CI) forintensive versusstandardtherapy

0.88(0.79-0.99)

0.90(0.78-1.04)

0.90(0.82-0.98)

0.88(0.74-1.05)

All-Cause Mortality


0.94(0.80-1.10)

1.22(1.01-1.46)

0.93 (0.83-1.06)

1.07(0.81-1.42)

Cardiovascular Mortality


0.94(0.66-1.30)

1.35(1.04-1.76)

0.88 (0.74-1.04)

1.32(0.81-2.14)

HR¼Hazard ratio; CI¼confidence intervalBolded results represent HR reaching statistical significance, P<0.05.*Excluded myocardial infarction (MI) within 1 year prior, heart failure, angina, or

more than one vascular event.†Based on fasting plasma glucose (FPG) <108 mg/dL.{Based on FPG <270 mg/dL.}An aggregate endpoint of any diabetes-related endpoint (UKPDS); a composite of

nonfatal myocardial infarction, nonfatal stroke, and fatal myocardial infarction andstroke (ACCORD); combined microvascular and macrovascular disease (ADVANCE);and time to occurrence of a composite of major cardiovascular events (VADT).(Data from Ismail-Beigi F, Moghissi E, Tiktin M, et al. Individualizing glycemic targets intype 2 diabetes mellitus: Implications of recent clinical trials, Ann Intern Med 154:554–559, 2011.)

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cautionary tale for glucose lowering. Most important, thestudy suggested that even though a medication may reduceglucose levels, and thus appear to treat diabetes effectively,it may in fact increase the risk of clinical events that are thetarget of glucose lowering in the first place. After the rosigli-tazone experience, however, the U.S. Food and Drug Admin-istration (FDA) mandated that glucose-loweringmedications must have data that support their safety withrespect to cardiovascular events before they are approvedfor use in diabetes.37

Despite the intense interest in the specific effects of med-ication classes (and individual agents) that followed, there isa paucity of data to guide choice of therapy in diabetes withrespect to long-term outcomes. Indeed, a recent compara-tive effectiveness analysis of 140 trials and 26 observationalstudies of medications for type 2 diabetes concluded thatevidence on long-term clinical outcomes, including mortal-ity, cardiovascular disease, nephropathy, and neuropathy,was of low strength and insufficient.38 Evidence supportedmetformin as a first-line agent in treatment of diabetes, butthis evidence was primarily based on its efficacy to lowerHbA1c levels, safety, adverse effect profile, and cost. Weshall now review the available evidence for themajor classesof antihyperglycemic therapy. These results are summarizedin Table 13-1.

MetforminMetformin, which works primarily by reducing hepatic glu-cose production, remains the first-line agent in the treatmentof type 2 diabetes because it effectively reduces HbA1c levels,is weight-neutral, and does not lead to hypoglycemia whenused as monotherapy. It is also inexpensive, has a favorablesafety profile, and may have potential benefit with respect tocardiovascular disease, based on the UKPDS substudy.16

Despite the many advantages of metformin, data withrespect to cardiovascular risk reduction with metformin arenot entirely consistent. In addition to the UKPDS substudy,16

only one prior randomized controlled trial was conducted onthis subject. In the trial, 390 patients treated with insulin wererandomized to receive either metformin or placebo as add-ontherapy.39 The primary endpoint, an aggregate of microvascu-lar and macrovascular outcomes, did not differ between thetwo groups after 4.3 years of follow-up (HR 0.92, P¼0.33), butthere was a significant reduction in the secondary endpoint ofmacrovascular events (HR 0.60, P¼0.04). In addition, metfor-min usewas associatedwith beneficial effects on bodyweightand insulin requirements.

In observational studies, metformin use (either as mono-therapy or in combination with another oral agent) hasbeen associated with reduced mortality,40–42 cardiovasculardeaths,40 and cardiovascular events.41–43 Because metfor-min is generally the preferred initial agent for diabetes treat-ment and remains contraindicated in patients withadvanced chronic kidney disease, patients who are not trea-ted with this medication in an observational study may differin important ways from those who are. These analyses eitheradjusted for potential confounders ormatched patient popu-lations for the propensity to be prescribed metformin versusanother medication (usually a sulfonylurea). However,these investigations were observational in nature, so unmea-sured factors may potentially still have contributed to the dif-ferences in outcomes.

Alongside the evidence that supports the safety and effec-tiveness of metformin, there are data that provide a less


reassuring picture. Although the UKPDS substudy showedbenefits of metformin in overweight participants, the trialalso reported an increased death rate in nonoverweightpatients who took metformin and a sulfonylurea comparedwith those who took a sulfonylurea alone (relative risk 1.60,P¼0.04).16 Combined analysis of the two UKPDS studies didnot reveal an increased risk for mortality in patients treatedwith this combination, and the increased mortality in theUKPDS substudy has not been fully explained. In a subse-quent meta-analysis of 13 randomized controlled trialsinvolving more than 13,000 type 2 diabetes patients, com-pared with other treatments, metformin therapy had no sig-nificant effect on the risk for mortality (relative risk 0.99 withwide 95% confidence intervals that could not exclude a 25%


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reduction or 31% increase in risk), cardiovascular mortality(relative risk 1.05), or rates of MI (relative risk 0.90 with 95%confidence intervals that could not exclude 26% risk reduc-tion or 9% harm).23 Similar findings were reported in a meta-analysis that specifically examined the effects of metforminwith insulin compared with insulin alone in 23 trials withover 2000 participants.44 The study found that metforminadded to insulin did not significantly change mortality risk(relative risk 1.30, with 95% confidence intervals 0.57 to2.99) or cardiovascular mortality risk (relative risk 1.70, with95% confidence intervals 0.35 to 8.30) but provided littlereassurance with regard to each of these endpoints giventhe wide confidence intervals.

entonCoronary

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SulfonylureasSulfonylureas, insulin secretagogues, are the oldest oral agentclass for treatment of hyperglycemia. Whereas sulfonylureasare effective at glucose lowering, they increase the risk ofhypoglycemia, are associated with a modest weight gain,and likely result in less durable effects on glucose controlcompared with metformin or thiazolidinediones.45

Questions about cardiovascular safety of sulfonylureasdate back to 1970 when the University Group DiabetesProgram (UGDP) trial reported an increased risk for cardio-vascular death associated with the use of tolbutamide com-pared with placebo or insulin.46 Subsequently the FDAmandated a boxed warning for all sulfonylureas. Sulfonyl-ureas inhibit the adenosine triphosphate (ATP)–dependentpotassium channels that are present within cardiomyocytesand coronary vascular endothelial cells, and it has been pos-tulated that the presence of sulfonylureas at the time of anacute coronary event prevents adequate coronary vasodila-tion and thus may result in a larger area of myocardial dam-age. However, the risk of cardiovascular death noted by theUGDP group was not supported by the subsequent UKPDSstudy, which showed no difference in cardiovascular riskbetween the use of sulfonylureas (chlorpropamide, gliben-clamide, or glipizide) or insulin therapy15 (but a benefit withthe use of metformin, as noted earlier16). The large A Diabe-tes Outcome Prevention Trial (ADOPT) study comparedmetformin, rosiglitazone, or glyburide therapy with respectto glycemic control, but again found no difference withrespect to cardiovascular events (which were not frequentand were collected as adverse events during the trial) acrossthe treatment groups after 4 years of treatment.45 Finally, theADVANCE study of intensive glucose lowering primarilyused gliclazide in its intensive glucose control arm andfound no risk associated with this strategy.22

Subsequent observational studies have, however, mostlysuggested harmwith sulfonylurea treatment, especially com-pared with metformin therapy.40,41,47,48 Whether sulfonyl-ureas are associated with adverse effects or metforminis protective remains debatable. Sulfonylureas are stillconsidered a viable option for second-line therapy in diabe-tes, primarily based on their effectiveness in loweringglucose and extensive accrued experience with the use ofthese agents.

ThiazolidinedionesThiazolidinediones, which lower glucose by activatingthe nuclear transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ), are insulin sensitizers.


They do not increase the risk of hypoglycemia and mayresult in more durable blood glucose control than sulfonyl-ureas or metformin.45 Although these agents improve manyintermediate markers of cardiovascular risk (e.g., C-reactiveprotein and markers of endothelial function), they areassociated with substantial weight gain, lower-extremityedema, heart failure, bone fractures, and possibly bladdercancer risk.

Rosiglitazone, but not pioglitazone, has actually beenassociated with an increased risk of MI,34 which led to itsrestricted use in diabetes. Therefore the two members ofthe thiazolidinediones class need to be considered sepa-rately if their individual risks and benefits are to be under-stood. It is worth noting that most analyses of the effects ofglucose-lowering therapies on clinical outcomes grouptogether medications of the same class and perform class-based comparisons. This practice is based on the assump-tion that medications in the same class have a similar modeof action and therefore will have a similar effect on clinicaloutcomes. The experience with rosiglitazone and pioglita-zone, both members of the thiazolidinedione class, suggestthat individual medications within the same class can affectclinical outcomes in different ways.

As already mentioned, the effect of rosiglitazone on car-diovascular events was analyzed in a highly publicizedmeta-analysis, which showed an increased risk of MI associ-ated with its use.34 Several other meta-analyses confirmedadverse effects associated with rosiglitazone,49,50 but notall found harm.35,36 However, observational studies compar-ing rosiglitazone with other oral diabetes medications51 orwith pioglitazone52–54 have consistently shown increasedrisk of mortality and heart failure with rosiglitazone use.The only trial specifically designed to evaluate cardiovascu-lar outcomes associated with rosiglitazone was the Rosiglita-zone Evaluated for Cardiovascular Outcomes in Oral AgentCombination Therapy for Type 2 Diabetes (RECORD)study.55 RECORD randomized 4447 diabetes patients withinadequately controlled hyperglycemia treated with metfor-min or sulfonylurea monotherapy to receive, in addition, asulfonylurea, metformin, or rosiglitazone. In the final analy-sis of the trial, there was no difference in the primary end-point (cardiovascular hospitalization or cardiovasculardeath) among the groups, but the event rate was lower thanexpected and the dropout rate in the trial was high, decreas-ing the power to detect significant differences in outcomes.Notably, the risk of heart failure was increased approxi-mately twofold with rosiglitazone.

Finally, in the Bypass Angioplasty Revascularization Inves-tigation 2 Diabetes (BARI 2D) trial, 2368 patients with type 2diabetes and obstructive coronary artery disease were facto-rially randomized to a) medical therapy with insulin provi-sion [insulin or sulfonylurea] versus insulin sensitization[metformin or rosiglitazone]); and b) randomized to medi-cal treatment versus coronary revascularization (a prioridetermined to be percutaneous coronary intervention[PCI] or coronary artery bypass grafting [CABG]), evaluatingthe effects on death and major cardiovascular events.56 Therewas no difference in the rates of death and cardiovascularevents between patients undergoing revascularization ormedical therapy, or between strategies of insulin provisionand insulin sensitization. However, in the CABG stratum, riskof major cardiovascular events was significantly lower withrevascularization and insulin sensitization (18.7%) comparedwith insulin sensitization therapy alone (32%, P¼0.002).


25

20

15

10

5

00 6 1812 24 30 36

2,488 2,373 2,2182,302 2,146 3482,530 2,413 2,2152,317 2,122 345

Time from randomization (months)

A

B

0.15

Kaplan-Meier event rate N events: 3-year estimate:

Placebo 358/2,633 14.4%Pioglitazone 301/2,605 12.3%

0.10

0.05

0.0N at risk:

0 6 1812 24

Pioglitazonevs placebo

0.841 0.722, 0.981 0.0273

HR 95% CI P value

30 36

5,238 5,102 4,8774,991 4,752 4,651 786 (256)

Time from randomization (months)

Pro

port

ion

of e

vent

s (%

)

Pioglitazone (514 events)Placebo (572 events)

HR=0·90 (95% CI 0·80–1·02)p=0·095

Numbers at riskPioglitazone

Placebo

FIGURE 13-5 PROactive study. Time to primary composite endpoint (all-causemortality, nonfatal myocardial infarction, stroke, acute coronary syndrome,revascularization, and above-knee amputation) and time to secondary endpoint(major cardiovascular events).

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Because rosiglitazone was the primary thiazolidinedioneused for insulin sensitization, there did not appear to be harmassociated with its use in the setting of this trial. However, thetrial was not designed to specifically address rosiglitazone’ssafety.

Given the weight of the evidence, in 2011 the FDA placedrestrictions on prescription and use of rosiglitazone-containing medications through a Risk Evaluation and Miti-gation Strategy (REMS).57 The use of rosiglitazone was lim-ited to patients already successfully treated with thismedication, or patients whose blood glucose levels couldnot be controlled with other antihyperglycemia medicinesand who did not wish to use pioglitazone instead. In June2013, the FDA reviewed readjudicated data from theRECORD trial and concluded that the trial had not foundan elevated risk of MI or death associated with rosiglitazone.Therefore in November 2013 the FDA lifted its earlier restric-tions on rosiglitazone use. Given the highly publicizeddebates over the safety of rosiglitazone, it is unclear if thismedication will ever become widely used again in patientswith type 2 diabetes.

In contrast to rosiglitazone, data with pioglitazone appearto be more reassuring with respect to cardiovascular out-comes.48,52–54,58 The largest completed trial investigatingeffects of pioglitazone on cardiovascular outcomes wasthe Prospective Pioglitazone Clinical Trial in MacrovascularEvents (PROactive) study, in which 5238 patients with type 2diabetes and established macrovascular disease receivedpioglitazone or placebo, added to their baseline diabetestherapy.59 After an average follow up of 2.9 years, therewas a 10% relative risk reduction in the primary endpoint(including all-cause mortality, nonfatal MI, stroke, acute cor-onary syndrome, revascularization, and above-knee amputa-tion), but this did not reach statistical significance(P¼0.095) (Fig. 13-5). The secondary, and more conven-tional, outcome of major cardiovascular events was signifi-cantly decreased with pioglitazone (HR 0.84, P¼0.03).Concerns have been raised about the late definition of thesecondary endpoint after the trial was under way, the largenumber of secondary endpoints (more than eight), and theincreased risk of heart failure in the intervention group (16%versus 11.5%), which may have, over time, negativelyaffected study results.

In summary, the cardiovascular benefits of thiazolidine-diones are not entirely clear. The association of rosiglitazonewith MI, heart failure, and mortality is concerning, and mostguidelines recommend against the use of rosiglitazone forthose reasons. The potential benefits of pioglitazone in thePROactive study must be weighed against the increased riskof heart failure and fractures.

InsulinAs type 2 diabetes progresses, beta cell function declinesand the effectiveness of oral agents for glucose controldiminishes. However, endogenous insulin secretion is notentirely lost in type 2 diabetes, and strategies for insulinuse can be less complex than those used in the treatmentof type 1 diabetes. The main side effects of insulin use areweight gain and hypoglycemia. Given that insulin has beenused in clinical practice for decades and is a naturally occur-ring peptide hormone, fewer concerns have been previouslyraised about its cardiovascular safety. However, insulin mayobviously induce hypoglycemia, whichmay in turn promote


adrenergic discharges and arrhythmia, promotes fluid reten-tion, and may result in hypokalemia (especially whenadministered intravenously) as a result of potassium shiftsfrom the extracellular to intracellular space. Recent con-cerns about the cardiovascular safety of insulin use in type2 diabetes have been raised.60 These concerns are primarilybased on observational studies that show an increased riskof mortality, cardiovascular mortality, and cardiovascularevents in diabetes patients treated with insulin comparedwith other agents.12,61–63 In one such recent analysis, dataon over 84,000 patients with type 2 diabetes in the GPRDwere used to determine the risk of the primary outcome (firstmajor adverse cardiac event, first cancer, or mortality) asso-ciated with five different glucose-lowering regimens (metfor-min monotherapy, sulfonylurea monotherapy, insulinmonotherapy, metformin plus sulfonylurea, and insulin plusmetformin).63 When compared with all other regimens, insu-lin monotherapy was associated with an increased risk of theprimary outcome and all-cause mortality. The observationalnature of the study does not permit conclusions about thecausal nature of these associations; the risk of harms maybemediated by insulin itself or by the clinical characteristicsof patients who require and are prescribed insulin. Indeed,there were important differences in baseline characteristics


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among treatment groups; despite adjustment for a variety ofvariables, residual confounding remains an importantlimitation.Although few trials have specifically focused on the effec-

tiveness and safety of insulin for prevention of cardiovascu-lar events, several trials have tested the use of insulin duringand after an acute MI for secondary prevention of cardiovas-cular disease and mortality. The first Diabetes Mellitus, Insu-lin Glucose Infusion in Acute Myocardial Infarction(DIGAMI) study showed significant reduction in mortality(absolute reduction of 11%) associated with the use ofinsulin-glucose infusion during admission and subcutane-ous insulin after hospitalization for glycemic control com-pared with standard therapy in diabetic patients.64

Because it was unclear whether the mortality benefit wasthe result of inpatient or outpatient glycemic control inDIGAMI, the DIGAMI-2 study tested three different strategies,including combinations of insulin-based inpatient and out-patient glycemic control regimens.65 However, the studystruggled with patient recruitment and did not achieve differ-ences in glycemic control among the three groups. Therewere no differences in mortality among the three groups.However, in the post hoc analysis of the DIGAMI-2 trial, insu-lin treatment was actually associated with an increased riskfor nonfatal cardiovascular events, but not mortality.66

The previously described ORIGIN trial provided morereassuring evidence on the use of insulin glargine in adultswith prediabetes or early diabetes but did not suggest cardio-vascular benefits.33 The use of insulin in this trial was asso-ciated with a very modest reduction in already low HbA1clevels (6.3% versus 6.0% in the standard versus insulin group,respectively) at the end of 2 years, no significant reduction inthe cardiovascular endpoints, but increase in weight gainand hypoglycemic events. Moreover, there was no effectof glargine on the incidence of various cancers, a concernraised because of insulin’s role in cell growth, differentia-tion, and proliferation and because of epidemiologic studiespointing to the increased risk of cancer associated with itsuse.67,68

s

Incretin-Based TherapiesMedications that work through the incretin system havebeen relatively recently introduced into the type 2 diabetespharmacopeia. These agents either mimic or increase thecirculating concentrations of endogenous glucagon-likepeptide 1 (GLP-1), thereby stimulating pancreatic insulinsecretion in a glucose-dependent fashion, suppressing pan-creatic glucagon output, slowing gastric emptying, anddecreasing appetite. The main advantage of the injectableGLP-1 agonists is weight loss, which is modest in mostpatients but can be significant in some. A limiting side effectis nausea and vomiting, particularly early in the course oftreatment. Concerns regarding an increased risk of pancrea-titis remain unresolved. The oral dipeptidyl peptidase 4(DPP-4) inhibitors work predominately through effects onthe endocrine pancreas and appear to be weight neutral.Typically, neither of the incretin-based classes causes hypo-glycemia as monotherapy.Give the recent introduction of these agents to the market

and limited long-term experience, results of trials evaluatingcardiovascular outcomes are only beginning to be reported,and many are still under way (Table 13-2). GLP-1 analoguesare effective in improving glycemic control and reduce


several cardiovascular risk factors. Based on animal studies,GLP-1–based therapy may mitigate ischemia-induced car-diac injury,69 but more data will be needed to assess long-term cardiovascular outcomes in humans.70

More information is currently available on the cardiovas-cular effects of DPP-4 inhibitors, and so far they appear toneither increase nor decrease cardiovascular events.71,72

These effects are disappointing, given that several industry-sponsored pooled cardiovascular analyses of DPP-4 inhibi-tors described risk ratios well below 1 for cardiovascularevents,73–75 raising hopes for a class of agents that couldactually reduce cardiovascular risk. However, two largerandomized controlled trials showed that saxagliptin andalogliptin had an overall neutral effect on major cardiovas-cular events. In the Saxagliptin Assessment of VascularOutcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53)trial, 16,492 patients with type 2 diabetes who had risk factorsor a history of cardiovascular events were assigned toreceive saxagliptin or placebo in addition to their existingdiabetes medication therapy.71 After a median of 2.1 years,there was no difference in the primary endpoint (MI, ische-mic stroke, or cardiovascular death) between the twogroups (HR 1.0, 95% CI 0.89-1.12). However, more patientsin the saxagliptin group reported hypoglycemic events(15.3% versus 11.7%, P<0.001), and, somewhat unexpect-edly, more patients on saxagliptin were hospitalized forheart failure (3.5% versus 2.8%, P¼0.007). The findings ofincreased heart failure risk are concerning and warrant addi-tional investigation. In the Examination of CardiovascularOutcomes with Alogliptin Versus Standard of Care (EXAM-INE) trial, 5380 patients with type 2 diabetes who had hadan acute coronary event in the preceding 15 to 90 days wererandomly assigned to receive either alogliptin or placebo inaddition to an existing antihyperglycemic regimen.72 Similarto the findings of the SAVOR trial, there was no difference inthe primary endpoint (MI, stroke, or cardiovascular death)between the two groups (HR 0.96, upper boundary of theone-sided CI 1.16). Heart failure hospitalization was not aprespecified endpoint in EXAMINE, but when it was exam-ined in a post hoc fashion (including those events thatoccurred after a primary endpoint), there were numerically,but not statistically, more events in the alogliptin group (106versus 89, HR 1.19, P¼0.22).76 Three other DPP-4 inhibitorcardiovascular trials are currently ongoing (TECOS [saxa-gliptin], CAROLINA [linagliptin] and CARMELINA (linaglip-tin)). Several others involving GLP-1 receptor agonists(LEADER [liraglutide], EXSCEL [exenatide once weekly exe-natide], ELIXA (lixisenatide), SUSTAIN 6 [semaglutide]) willprovide additional data needed to assess cardiovasculareffects of these therapies.69

In summary, incretin-based therapies reduce HbA1clevels, do not lead to hypoglycemia (at least, as monother-apy), and are not associated with weight gain or MI, stroke,or cardiovascular death. Therefore they appear to be attrac-tive agents for the management of type 2 diabetes. On theother hand, they are very expensive, they may increasethe risk of heart failure in the case of saxagliptin, and theirother long-term risks and benefits are not yet known.

Other AgentsAcarbose is an alpha-glucosidase inhibitor that delays gutcarbohydrate absorption. Acarbose is infrequently used in


TABLE 13-2 Summary of Cardiovascular Effects Associated with Various Classes of Glucose-Lowering Agents

AGENT MECHANISM OF ACTION

EXPECTEDHBA1C

REDUCTION ADVERSE EFFECTS CARDIOVASCULAR EFFECTS

Sulfonylureas

Glyburide (akaglibenclamide)

GlipizideGlimepirideGliclazideTolbutamideChlorpropamide

Bind to sulfonylurea receptors onpancreatic islet cells, closingKATP channels, stimulatinginsulin release. Relatively longduration of action.

Approximately1%-2%

HypoglycemiaWeight gain

Hypoglycemia may precipitate ischemia,arrhythmia.

Cardiac KATP channel closure may impairischemic preconditioning.

Observational studies suggest worse CVDoutcomes compared with metformin.

Glinides

RepaglinideNateglinide

Bind to sulfonylurea receptors onpancreatic islet cells, closingKATP channels, stimulatinginsulin release. Relatively shortduration of action.

Approximately1%-2%

HypoglycemiaWeight gain

Hypoglycemia may precipitate ischemia,arrhythmia.

Cardiac KATP channel closure may impairischemic preconditioning.

Few CVD outcome studies exist.

Biguanide

Metformin Activates AMP-kinase and reduceshepatic glucose production.

Approximately1%-2%

Diarrhea, nauseaLactic acidosisDecreases B12 levels

May improve CVD outcomes (UKPDS 34).Favorable CVD outcomes in most

observational studies.Should not be used in patients with acute or

unstable HF because of lactic acidosis risk.

α-Glucosidase Inhibitors

VogliboseAcarboseMiglitol

Slow gut carbohydrate absorption. Approximately0.5%-1.0%

Gas, bloating May reduce MI risk (STOP-NIDDM).

Thiazolidinediones

PioglitazoneRosiglitazone

Activate the nuclear receptorPPAR-γ, increasing peripheralinsulin sensitivity. Also reducehepatic glucose production.

Approximately1%-1.5%

Weight gainEdema, HFFractures? Bladder cancer

(pioglitazone)

Contraindicated in NYHA Class III or IV HF(because of fluid retention); notrecommended in Class II HF.

Pioglitazone may reduce MI, stroke risk(PROactive) but increases HF risk.

Rosiglitazone may increase MI risk.

GLP-1 ReceptorAgonists

ExenatideLiraglutideAlbiglutide

Increase glucose-dependentinsulin secretion, decreaseglucagon secretion, and delaygastric emptying.

Approximately1%-1.5%

Approximately0.6%-0.8%

Nausea, vomiting—

Long-term outcomes not known.

DPP-4 Inhibitors

SitagliptinSaxagliptinLinagliptinVildagliptinAlogliptin

Inhibit degradation ofendogenous GLP-1 (and GIP-1),thereby enhancing incretin levels.

Alogliptin and saxagliptin have a neutraleffect on cardiovascular outcomes, butsaxagliptin may increase risk of HF.

Amylin Analogue

Pramlintide Decreases glucagon secretion anddelays gastric emptying.


Nausea, vomiting Long-term outcomes not known.

Insulins

Glargine, detemir,degludec

NPHRegularLispro, aspart, glulisinePremixed

Increase insulin supply. Theoreticallylimitless

HypoglycemiaWeight gainEdema (at high doses)

Few randomized controlled trials showneutral effects on cardiovascularoutcomes, but observational studiessuggest increased risk of cardiovascularevents and mortality compared with oralantihyperglycemic agents.

SGLT-2 Inhibitors

CanagliflozinDapagliflozinEmpagliflozin

Blocks reabsorption of filteredglucose load in the proximaltubule, leading to glucosuria


Genital mycotic infectionsUrinary tract infectionsReversible decrease in GFRHemodynamic side effectsIncrease in LDL-cholesterol

Reduction in systolic blood pressureWeight lossNo long-term data on CV outcomes

AMP ¼ Adenosine monophosphate; CVD ¼ Cardiovascular disease; GFR ¼ glomerular filtration rate; GIP-1 ¼ Gastric inhibitory polypeptide-1; GLP-1 ¼ Glucagon-like peptide-1;HF ¼ Heart failure; KATP¼adenosine triphosphate (ATP) sensitive potassium channel; NYHA¼New York Heart Association; SGLT-2 ¼ sodium-glucose co-transporter 2.Data from Inzucchi and McGuire.

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Downloaded for Aman Shah ([email protected]) at Elsevier - Demonstration Account from ClinicalKey.com by Elsevier on December 21, 2017.For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved.

14

Placebo

Hazard ratio, 1.00 (95% CI, 0.89–1.12)P � 0.001 for noninferiorityP � 0.99 for superiority

Saxagliptin

Pat

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s w

ith e

ndpo

int (

%) 12

8

6

4

2

10

00 180 540360 720 900

DaysA

24

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Hazard ratio, 0.96 (upper boundaryof the one-sided repeated CI, 1.16)

Alogliptin

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inci

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endp

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the United States because of gastrointestinal side effects. Posthoc analyses of the STOP-NIDDM trial showed a reduction incardiovascular endpoints, but, as mentioned earlier, therewere problems with the trial design and conduct.32 Anotheragent, colesevelam, a bile acid sequestrant, is typically usedto lower low-density lipoprotein (LDL) levels, but also mod-estly reduces glucose. The dopamine agonist bromocriptinereduces glucose levels, but very modestly, and is available inthe United States only for antihyperglycemic therapy. A 52-week trial evaluated the short-term overall and cardiovascu-lar safety of bromocriptine in type 2 diabetes.77 The fre-quency of serious adverse events was comparablebetween treatment arms, but fewer patients experienced car-diovascular events in the bromocriptine compared with theplacebo group (HR 0.60, 95% CI 0.35-0.96). Future studieswill need to confirm whether bromocriptine is indeed asso-ciated with cardiovascular risk reduction in the long-term.Newer agents, such as the SGLT-2 inhibitors, that lower

glucose by inhibiting a renal cotransporter and therebydecrease glucose reabsorption in the kidney, have beenrecently approved by the FDA, but studies are under wayto determine their long-term safety and efficacy.78,79 Short-term studies suggest that these agents lower HbA1c by0.5% to 1%, do not lead to hypoglycemia (in monotherapy),and lower blood pressure and weight, but are associatedwith mycotic genital infections and adverse events relatedto osmotic diuresis.80–85 Other glucose-loweringmedicationsthat stimulate glucose-dependent insulin secretion are beingtested for their efficacy and safety, as well.86 It will take sometime to understand the cardiovascular impact of these neweragents on patients with type 2 diabetes.

0 6 1812 24 30MonthsB

FIGURE 13-6 Summary of results from A, SAVOR and B, EXAMINE trials, in whichsaxagliptin and alogliptin were compared against placebo with respect to majorcardiovascular outcomes (myocardial infarction, stroke, or cardiovascular death).71

(Modified from NEJM.)

tients

with

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RISKS ASSOCIATED WITHANTIHYPERGLYCEMIC MEDICATIONS

If efforts to reduce glucose levels were not associated withany risk, there might be less hesitation to normalize themin diabetic patients. In reality, the benefits of glucose lower-ing must be weighed against the burden of treatment andknown, as well as potential, risks of therapy. Because dataon the impact of various anti-hyperglycemic agents onlong-term clinical outcomes are limited, clinical decisionsabout the type and intensity of glucose lowering must bemade with some uncertainty in mind (Fig. 13-6). We willnow review data on the known risks associated with antihy-perglycemic agents. This information is critical to informeddecision making and should be discussed with patients asstrategies for treatment are considered.

HypoglycemiaThe pursuit of strict glucose control is frequently hamperedby concerns over hypoglycemia. Hypoglycemia requiringthird-party assistance is common in the course of type 2 dia-betes therapy and occurs with a frequency of approximately35 episodes per 100 patient-years among insulin-treatedpatients.87 Hypoglycemia occurring during treatment hasbeen associated with several adverse events, includingincreased mortality,88,89 higher risk of dementia,90 falls,91 fall-related fractures,92 cardiovascular events,89,93,94 and poorhealth-related quality of life.95,96

In particular, the relationship between hypoglycemia andsubsequent cardiac events warrants attention. There are a


number of plausible mechanisms by which acute hypogly-cemia may trigger ischemia, arrhythmia, and cardiovascularevents (Fig. 13-7). Hypoglycemia increases the levels ofcounterregulatory hormones, such as epinephrine and nor-epinephrine, which may induce increased cardiac rate and/or contractility, heightening myocardial oxygen consump-tion, while also precipitating vasoconstriction and plateletaggregation. Acute hypoglycemia in the presence of hypoka-lemia prolongs cardiac repolarization, increases the QTinterval, favoring a proarrhythmic state. One study of type1 and type 2 diabetic patients who presented to the hospitalwith severe hypoglycemia documented frequent hypokale-mia, QT prolongation, and severe hypertension during thehypoglycemic events.97 Although animal studies have veri-fied the effect of hypoglycemia on myocardial ischemicinjury,98 the data in humans are less clear, and debates con-tinue on whether hypoglycemia is a mediator or merely amarker of such adverse outcomes—that is, does the propen-sity toward hypoglycemia simply identify sicker individualswho have lost the ability to counterregulate?

Clinical trial data consistently show that assignment to anintensive glucose control strategy is associated with a two-fold to threefold higher risk of hypoglycemia compared withstandard care.15,18,22,99,100 In trial settings, hypoglycemiarequiring third-party assistance occurred with a frequency


Hypoglycemia

Myocardial ischemiaArrhythmia

Hemodynamic changes

Increased heart rateIncreased systolic blood pressureIncreased cardiac output

ECG changes

QT prolongationIncreased QT dispersion

Inflammation and coagulation

Endothelial dysfunctionPlatelet aggregation/activationThrombosis

Sympathoadrenal activation:catecholamine, glucagon release

Hypokalemia

Increase in endothelin, CRP,vascular endothelial growth factor

FIGURE 13-7 Proposed mechanisms linking hypoglycemia with cardiovascular events. CRP¼C-reactive protein; EKG¼Electrocardiogram.

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of 0.6 to 12 events annually per 100 patients in the intensivetherapy group and 0.2 to 4 events in the standard therapygroup—much less frequently than in the community setting.Although the relationship between intensive therapy andhypoglycemia appears clear, the relationship betweenachieved level of glycemic control and hypoglycemia is morecomplex. In the Diabetes Control and Complications Trial(DCCT) of type 1 diabetes patients, an inverse relationshipbetween HbA1c level and serious hypoglycemia was noted,with thenumber of events logically increasingwithdecreasingHbA1c.100 In contrast, however, detailed post hoc analyses ofACCORD participants with type 2 diabetes showed thatpatients with poorer glycemic control had a higher risk ofhypoglycemia, irrespective of treatment assignment.101 In fact,a greater drop in HbA1c level during the first 4 months of thetrial was not associated with increased hypoglycemia risk.Rather, patients who started out with higher baseline HbA1clevels and were unable to reduce their blood glucose levelsappeared to be at the highest risk for this complication. More-over, participants with persistently elevated HbA1c levelsabove 7% after initiation of the intensive strategy had a highermortality risk than those achieving lower glycemic levels(<7%).19What is actuallymediating thehigher riskof hypogly-cemia and mortality in this setting is unclear, but the findingssuggest that aggressive attempts to intensify treatment inpatients who remain hyperglycemic may confer a very highrisk for subsequent hypoglycemia.

Other apparent risk factors for hypoglycemia, aside fromintensive glucose lowering, include treatment with insulinor sulfonylurea medications,102 older age,101 lower healthliteracy level,103 longer duration of diabetes,101 renal impair-ment,102 polypharmacy,104baselinecognitive impairment,105

and recent admission to the hospital within 30 days.104

Other Adverse Effects of MedicationsIntensive glucose control usually requires polypharmacy toachieve HbA1c targets, and adverse effects of medicationsrequire careful consideration. Even in patients who do not


choose tight glycemic targets, multiple medications to lowerglucose are often required with increasing duration of thedisease, as beta cell function declines.

The relative importance of various adverse effects of med-ications may vary from patient to patient. Weight gain is typ-ically associated with the use of insulin, sulfonylureas, andthiazolidinediones. Heart failure, edema, and fractures areassociated with the use of thiazolidinediones. Gastrointesti-nal side effects complicate treatment with metformin, acar-bose, and some of the incretin-based therapies. In general,drug reactions increase in frequency with the use of multiplemedications. Addition of another medication to lower glu-cose may also pose a financial burden and significantlyincrease time and effort required to manage diabetes(including, potentially, capillary blood glucose monitoring).

IMPLICATIONS FOR CLINICAL PRACTICE

What is the effect of glucose management on CHD events inpatients with type 2 diabetes? Based on the available data,intensive glucose lowering appears, at best, to modestlydecrease the risk of CHD by approximately 15% when com-pared with standard glucose strategies. Assuming a 10-yearrisk of CHD of 17.4% (control arm of UKPDS), the numberneeded to treat (NNT) ranges on the order of 41 to 46 over10 years to prevent one CHD event.106 What about type ofantihyperglycemic therapy? Our understanding of the impli-cations of the specific type of therapy on these outcomes isonly beginning to emerge. Best cardiovascular outcomesappear to be associated with the use of metformin, but thesedata are based only on a small subgroup of UKPDS patientsand observational data. Sulfonylureas compared with met-formin appear to be associated with inferior results, andthe impact of thiazolidinediones remains somewhat unclear(with a suggestion of better outcomes for CHD with pioglita-zone, but an increase in heart failure). The effect of newerincretin-based therapies on cardiovascular outcomesappears neutral so far.


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Who is the patient, andwhat are his or her goals for care? Tohelp patients make the best decisions about their care, clini-cians must consider the clinical characteristics of a patientand thecontext inwhichheorshe lives todeterminehowthesevarious factors may influence the relationship between treat-ment and outcomes. Data to guide this type of individualizedtreatment are lacking, and future research is critically neededto provide better information to guide personalized decisions.Basedonexistingdata, patientswithhigh levelsof comorbiditymay derive less cardiovascular benefit from intensive glucosecontrol,107andmostguidelinessuggesthigherglycemic targetsfor older patients with longer duration of diabetes, establishedcardiovascular disease, and high risk of hypoglycemia. Natu-rally, these patients are at higher underlying risk of CHD, butthey appear to benefit less from tight glycemic control. In con-trast, thebenefitsof aggressive lipidandbloodpressurecontrolappear to be greatest based on high underlying CHD risk,although the relative benefits will clearly depend also on com-peting mortality risk and current medications.107

As already suggested, central to the decision makingabout treatment are patient’s preferences and goals for care.Patient-centered care needs to begin by eliciting these pref-erences and goals, because understanding them is indis-pensable for providing care that is responsive to andrespectful of patients’ needs. A shared decision-making pro-cess stresses a partnership between the patient’s values andpreferences and the physician’s knowledge of clinical evi-dence and judgment. Decisions are highly individualized,based on available evidence, and uncertainty must beacknowledged when it exists. As an example, more intensiveglycemic control in a patient already struggling with a com-plex regimen may lead to an overburdened patient who isunable to cope with his or her disease. Indeed, somewhatparadoxically, pushing forward with intensive antihypergly-cemic therapy may decrease adherence to other moreevidence-based therapies. In such a circumstance, it maybe reasonable to liberalize glycemic targets to some degree.On the other hand, a patient whose most important goal isprevention of diabetes complications may choose to takeon the additional burden of insulin therapy or multiple med-ications to control blood glucose levels with high intensity.How to prioritize glucose lowering within the patient’s

overall diabetes care plan is also critically important. Clearly,statin therapy, smoking cessation, aspirin for appropriatepatients, and blood pressure control are the central pillarsof cardiovascular risk reduction. On a population level,based on UKPDS data, fewer persons would need to be trea-ted with tight blood pressure control (NNT 23) than intensiveglucose control (NNT 46) to prevent one MI event.108 Simi-larly, lipid therapy for primary prevention (NNT 34 or 35)and secondary prevention (NNT 13 or 14) appears to bemore effective for cardiovascular events than intensive glu-cose control.109 However, for individual patients, the opti-mal strategy is still unknown. It is also unclear whetherpatients will do better if each problem is addressed sequen-tially or if they are addressed simultaneously, and how thisvaries based on degree of out-of-range risk factor levels.Despite decades of study, we remain largely ignorant of the

benefits and risks of antihyperglycemic therapy as it relates tocardiovascular disease risk. Research in the coming decadeneeds to provide us with better information so that patientscan make decisions about glucose targets and antihypergly-cemic strategies that optimize their outcomes.


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http://fda.gov/Drugs/DrugSafety/ucm2555005.htm

http://dx.doi.org/10.1016/j.ahj.2013.05.007

http://clinicaltrials.gov/show/NCT01131676

http://clinicaltrials.gov/ct2/show/NCT01874366

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