8. Cardiovascular Disease and RiskManagementDiabetes Care 2016;39(Suppl. 1):S60–S71 | DOI: 10.2337/dc16-S011

For prevention andmanagement of diabetes complications in children and adolescents,please refer to Section 11 “Children and Adolescents.”In all patients with diabetes, cardiovascular risk factors should be systematically as-

sessed at least annually. These risk factors include dyslipidemia, hypertension, smoking, afamily history of premature coronary disease, and the presence of albuminuria. Abnor-mal risk factors should be treated as described elsewhere in these guidelines.Atherosclerotic cardiovascular disease (ASCVD)ddefined as acute coronary

syndromes (ACSs), a history of myocardial infarction (MI), stable or unstableangina, coronary or other arterial revascularization, stroke, transient ischemicattack, or peripheral arterial disease presumed to be of atherosclerotic origindisthe leading cause of morbidity andmortality for individuals with diabetes and is thelargest contributor to the direct and indirect costs of diabetes. The common con-ditions coexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) areclear risk factors for ASCVD, and diabetes itself confers independent risk. Numerousstudies have shown the efficacy of controlling individual cardiovascular risk factorsin preventing or slowing ASCVD in people with diabetes. Large benefits are seenwhen multiple risk factors are addressed simultaneously. There is evidence thatmeasures of 10-year coronary heart disease (CHD) risk among U.S. adults withdiabetes have improved significantly over the past decade (1) and that ASCVDmorbidity and mortality have decreased (2–4).

HYPERTENSION/BLOOD PRESSURE CONTROL

Recommendations

Screening and Diagnosisc Blood pressure should be measured at every routine visit. Patients found to have

elevated blood pressure should have blood pressure confirmed on a separate day. B

Goals

Systolic Targets

c People with diabetes and hypertension should be treated to a systolic bloodpressure goal of ,140 mmHg. A

c Lower systolic targets, such as,130 mmHg, may be appropriate for certain indi-viduals with diabetes, such as younger patients, those with albuminuria, and/orthosewith hypertension and oneormore additional atherosclerotic cardiovasculardisease risk factors, if they can be achieved without undue treatment burden. C

Diastolic Targets

c Individuals with diabetes should be treated to a diastolic blood pressure goalof ,90 mmHg. A

c Lower diastolic targets, such as,80 mmHg, may be appropriate for certain indi-viduals with diabetes, such as younger patients, those with albuminuria, and/orthosewith hypertension and oneormore additional atherosclerotic cardiovasculardisease risk factors, if they can be achieved without undue treatment burden. B

Treatmentc Patients with blood pressure .120/80 mmHg should be advised on lifestyle

changes to reduce blood pressure. Bc Patients with confirmed office-based blood pressure .140/90 mmHg should,

in addition to lifestyle therapy, have prompt initiation and timely subsequenttitration of pharmacological therapy to achieve blood pressure goals. A

Suggested citation: American Diabetes Associa-tion. Cardiovascular disease and risk manage-ment. Sec. 8. In Standards of Medical Care inDiabetesd2016. Diabetes Care 2016;39(Suppl. 1):S60–S71

© 2016 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

American Diabetes Association

S60 Diabetes Care Volume 39, Supplement 1, January 2016

8.CARDIOVASCULA

RDISEA

SEANDRISKMANAGEM

ENT

c In older adults, pharmacological ther-apy to achieve treatment goals of,130/70 mmHg is not recom-mended; treating to systolic bloodpressure ,130 mmHg has not beenshownto improvecardiovascularout-comes and treating to diastolic bloodpressure,70 mmHg has been asso-ciated with higher mortality. C

c Lifestyle therapy for elevated bloodpressure consists of weight loss, ifoverweight or obese; a Dietary Ap-proaches to Stop Hypertension(DASH)-style dietary pattern includ-ing reducing sodium and increasingpotassium intake; moderation of al-cohol intake; and increased physicalactivity. B

c Pharmacological therapy for patientswith diabetes and hypertensionshould comprise a regimen that in-cludes either an ACE inhibitor or anangiotensin receptor blocker but notboth. B If one class is not tolerated,the other should be substituted. C

c Multiple-drug therapy (including athiazide diuretic and ACE inhibitor/angiotensin receptor blocker, atmaximal doses) is generally requiredto achieve blood pressure targets. B

c If ACE inhibitors, angiotensin recep-tor blockers, or diuretics are used,serum creatinine/estimated glomer-ular filtration rate and serum potas-sium levels should be monitored. E

c In pregnant patients with diabetesand chronic hypertension, bloodpressure targets of 110–129/65–79mmHg are suggested in the interestof optimizing long-term maternalhealth andminimizing impaired fetalgrowth. E

Hypertension is a commondiabetes comor-bidity that affects many patients, with theprevalence depending on type of diabetes,age, BMI, and ethnicity. Hypertension is amajor risk factor for bothASCVDandmicro-vascular complications. In type 1 diabetes,hypertension is often the result of under-lying diabetic kidney disease, while intype 2 diabetes, it usually coexists withother cardiometabolic risk factors.

Screening and DiagnosisBlood pressure measurement should bedone by a trained individual and shouldfollow the guidelines established for thegeneral population:measurement in theseated position,with feet on the floor and

arm supported at heart level, after 5 minof rest. Cuff size should be appropriate forthe upper-arm circumference. Elevatedvalues should be confirmed on a separateday. Postural changes in blood pressureand pulse may be evidence of autonomicneuropathy and therefore require adjust-ment of blood pressure targets.

Home blood pressure self-monitoringand 24-h ambulatory blood pressuremonitoring may provide evidence ofwhite-coat hypertension, masked hyper-tension, or other discrepancies betweenoffice and “true” blood pressure. Studiesin individuals without diabetes foundthat home measurements may bettercorrelate with ASCVD risk than officemeasurements (5,6). However, most ofthe evidence of benefits of hyperten-sion treatment in people with diabetesis based on office measurements.

Treatment GoalsEpidemiological analyses show thatblood pressure.115/75 mmHg is asso-ciated with increased cardiovascularevent rates and mortality in individualswith diabetes and that systolic bloodpressure (SBP) .120 mmHg predictslong-term end-stage renal disease.Randomized clinical trials have dem-onstrated the benefit (reduction ofCHD events, stroke, and diabetic kidneydisease) of lowering blood pressure to,140 mmHg systolic and ,90 mmHgdiastolic in individuals with diabetes(7). There is limited prespecified clinicaltrial evidence for the benefits of lowerSBP or diastolic blood pressure (DBP)targets (8). A meta-analysis of random-ized trials of adults with type 2 diabetescomparing intensive blood pressuretargets (upper limit of 130 mmHg systolicand 80 mmHg diastolic) with standardtargets (upper limit of 140–160 mmHgsystolic and 85–100 mmHg diastolic)found no significant reduction in mortal-ity or nonfatalMI. Therewas a statisticallysignificant 35% relative risk (RR) reduc-tion in stroke with intensive targets, butthe absolute risk reduction was only 1%,and intensive targets were associatedwith an increased risk for adverse eventssuch as hypotension and syncope (9).

ACCORD, ADVANCE, SPRINT, AND HOT

Given the epidemiological relationship be-tween lower blood pressure and betterlong-termclinical outcomes, two landmarktrials, Action to Control Cardiovascular Riskin Diabetes (ACCORD) and Action in

Diabetes and Vascular Disease: Preteraxand Diamicron MR Controlled Evalua-tion–Blood Pressure (ADVANCE-BP), ex-amined the benefit of tighter bloodpressure control in patients with type 2diabetes.

ACCORD. The ACCORD trial examinedwhether a lower SBP of ,120 mmHg inpatients with type 2 diabetes at high riskfor ASCVD provided greater cardiovascularprotection than an SBP of 130–140 mmHg(10). The study did not find a benefit inprimary end point (nonfatal MI, nonfatalstroke, and cardiovascular death) compar-ing intensive blood pressure treatment(goal ,120 mmHg, average blood pres-sure achieved 5 119/64 mmHg on 3.4medications) with standard treatment(average blood pressure achieved 5143/70 mmHg on 2.1 medications). InACCORD, there was no benefit of ag-gressive blood pressure lowering, de-spite the extra cost and efforts.

ADVANCE. In ADVANCE, the active bloodpressure intervention arm (a single-pill,fixed-dose combination of perindopriland indapamide) showed a significantreduction in the risk of the primary com-posite end point (major macrovascularor microvascular event) and significantreductions in the risk of death from anycause and of death from cardiovascularcauses (11). The baseline blood pres-sure among the study subjects was145/81 mmHg. Compared with the pla-cebo group, the patients treated with asingle-pill, fixed-dose combination ofperindopril and indapamide experiencedan average reduction of 5.6 mmHg in SBPand 2.2 mmHg in DBP. The final bloodpressure in the treated group was136/73 mmHg, not quite the intensiveor tight control achieved in ACCORD.Recently published 6-year follow-upof the ADVANCE–Post-Trial ObservationalStudy (ADVANCE-ON) reported that thereductions in the risk of death from anycause and of death from cardiovascularcauses in the intervention group wereattenuated, but remained significant (12).

SPRINT. Systolic Blood Pressure Interven-tion Trial (SPRINT) was amulticenter, ran-domized controlled trial that comparedtwo strategies for treating SBPwith eitherthe standard target of,140 mmHg or anintensive target of,120 mmHg; primaryoutcomes were MI, ACS, stroke, heartfailure, and death due to cardiovasculardisease. Of note, patients with diabetes

care.diabetesjournals.org Cardiovascular Disease and Risk Management S61

were excluded from participating in thistrial, so the results have no direct impli-cations for blood pressure managementin this population. The National Insti-tutes of Health halted this study earlybecause intensive therapy with a targetSBP of 120 mmHg demonstrated a riskreduction of cardiovascular events byalmost a third and the risk of deathby almost a quarter compared with atarget SBP of 140 mmHg (13).

HOT. The results from the ACCORD andHypertension Optimal Treatment (HOT)(14) trials support the recommendationto achieve blood pressure levels ,140/90mmHg and underscore the importantclinical difference between patients whoare able to easily achieve lower bloodpressure levels (e.g., as seen in observa-tional epidemiological studies) and pa-tients who require intensive medicalmanagement to achieve lower bloodpressure goals (e.g., the clinical trials).

Systolic Blood Pressure

There is strong evidence that SBP .140mmHg isharmful, suggesting that cliniciansshould promptly initiate and titrate ther-apy in an ongoing fashion to achieve andmaintain SBP ,140 mmHg in most pa-tients (see Section 10 “Older Adults”). Arecent systematic review and meta-anal-ysis evaluating SBP lowering in adultswithtype2diabetes showedthateach10-mmHgreduction of SBPwas associatedwith signif-icantly lower riskofmortality, cardiovascularevents, CHD, stroke, albuminuria, and reti-nopathy. However, when trials were strati-fied by mean baseline SBP$140 mmHg or,140 mmHg, blood pressure–loweringtreatmentwas associatedwith lower risksof stroke and albuminuria, regardless ofinitial SBP (15). Therefore, individuals inwhomstroke risk is a concernmay, as partof shared decision making, have lowersystolic targets such as ,130 mmHg.This is especially true if lower blood pres-sure can be achieved with few drugs andwithout side effects of therapy.

Diastolic Blood Pressure

Similarly, strong evidence from random-ized clinical trials supports DBP targetsof,90 mmHg. Prior recommendations forlowerDBP targets (,80mmHg)werebasedprimarily on a post hoc analysis of the HOTtrial (14). A DBP of,80 mmHg may still beappropriate forpatientswith long lifeexpec-tancy, those with chronic kidney disease,elevated urinary albumin excretion, and

additional ASCVD risk factors such as dysli-pidemia, smoking, or obesity (14). The2016 American Diabetes Association(ADA) Standards of Care recommendationshave been revised to reflect the higher-quality evidence that exists to support agoal of DBP ,90 mmHg, although lowertargets may be appropriate for certain in-dividuals. These targets are in harmoniza-tionwith a recent publication by the EighthJoint National Committee that recom-mended for individuals over 18 years ofage with diabetes a DBP threshold of,90 mmHg and SBP,140 mmHg (8).

Treatment Strategies

Lifestyle Modification

Although there are no well-controlledstudies of diet and exercise in the treat-ment of elevated blood pressure orhypertension in individuals with diabe-tes, the Dietary Approaches to StopHypertension (DASH) study evaluatedthe impact of healthy dietary patternsin individuals without diabetes and hasshown antihypertensive effects similar tothose of pharmacological monotherapy.

Lifestyle therapy consists of reducingexcess body weight, restricting sodiumintake (,2,300mg/day), increasing con-sumption of fruits and vegetables (8–10servings per day) and low-fat dairyproducts (2–3 servings per day), avoidingexcessive alcohol consumption (no morethan 2 servings per day in men and nomore than 1 serving per day in women)(16), and increasing activity levels (17).

These lifestyle (nonpharmacological)strategies may also positively affectglycemia and lipid control and should beencouraged in those with even mildly ele-vated blood pressure, although the impactof lifestyle therapyoncardiovascular eventshas not been established. Nonpharmaco-logical therapy is reasonable in individualswith diabetes and mildly elevated bloodpressure (SBP .120 mmHg or DBP .80mmHg). If thebloodpressure is confirmedto be $140 mmHg systolic and/or $90mmHg diastolic, pharmacological therapyshould be initiated along with nonpharma-cological therapy (17). To enable long-termadherence, lifestyle therapyshouldbeadap-ted to suit the needs of the patient anddiscussed as part of diabetes management.

Pharmacological Interventions

ACE Inhibitors. Lowering of blood pres-sure with regimens based on a variety of

antihypertensive agents, including ACE in-hibitors, angiotensin receptor blockers(ARBs), b-blockers, diuretics, and calciumchannel blockers, has been shown to beeffective in reducing cardiovascularevents. Several studies have suggestedthat ACE inhibitors may be superior todihydropyridine calcium channel blockersin reducing cardiovascular events (18–20).However, several studies have also shownno specific advantage to ACE inhibitors asan initial treatment of hypertension in thegeneral hypertensive population, whileshowing an advantage of initial therapywith low-dose thiazide diuretics on car-diovascular outcomes (17,21,22).

Angiotensin Receptor Blockers. In peoplewith diabetes, inhibitors of the renin-angiotensin system (RAS) may haveunique advantages for initial or earlytreatment of hypertension. In a trial ofindividuals at high risk for ASCVD,including a large subset with diabetes,an ACE inhibitor reduced ASCVD out-comes (23). In patients with congestiveheart failure, including subgroups withdiabetes, ARBs have been shown to re-duce major ASCVD outcomes (24–27).In patients with type 2 diabetes withsignificant diabetic kidney disease,ARBs were superior to calcium channelblockers for reducing heart failure (28).Although evidence fordistinct advantagesof RAS inhibitors on ASCVD outcomes indiabetes remains conflicting (11,22), thehigh ASCVD risks associatedwith diabetesand the high prevalence of undiagnosedASCVD may still favor recommendationsfor their use as first-line antihypertensivetherapy in people with diabetes (17).

However, the use of both ACE inhibitorsand ARBs in combination is not recom-mended given the lack of added ASCVDbenefit and increased rate of adverseeventsdnamely, hyperkalemia, syncope,and renal dysfunction (29).

Other Pharmacological Interventions

The blood pressure arm of the ADVANCEtrial demonstrated that routine adminis-tration of a fixed combination of the ACEinhibitor perindopril and the diureticindapamide significantly reduced com-bined microvascular and macrovascularoutcomes, as well as death from cardio-vascular causes and total mortality.The improved outcomes could alsohave been due to lower achieved bloodpressure in the perindopril–indapamidearm (11). Another trial showedadecrease

S62 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

inmorbidity andmortality in those receiv-ing benazepril and amlodipine versus be-nazepril and hydrochlorothiazide (HCTZ)(30). The compelling benefits of RAS in-hibitors in patients with diabetes and al-buminuria or renal insufficiency provideadditional rationale for the use of theseagents (see Section 9 “MicrovascularComplications and Foot Care”). If neededto achieve blood pressure targets, amlo-dipine, HCTZ, or chlorthalidone can beadded. If estimated glomerular filtrationrate is ,30 mL/min/1.73 m2, a loop di-uretic, rather than HCTZ or chlorthali-done, should be prescribed. Titration ofand/or addition of further blood pressuremedications should be made in a timelyfashion to overcome clinical inertia inachieving blood pressure targets.

Bedtime Dosing

Growing evidence suggests that there isan association between increase in sleep-time blood pressure and incidence ofASCVD events. A randomized controlledtrial of 448 participants with type 2 di-abetes and hypertension demonstratedreduced cardiovascular events andmor-tality withmedian follow-up of 5.4 yearsif at least one antihypertensive medica-tionwas given at bedtime (31). Consideradministering one or more antihyper-tensive medications at bedtime (32).

Other Considerations

An important caveat is that most patientswith diabetes with hypertension requiremultiple-drug therapy to reach treatmentgoals (16). Identifying and addressingbarriers to medication adherence (suchas cost and side effects) should rou-tinely be done. If blood pressure remainsuncontrolled despite confirmed adher-ence to optimal doses of at least threeantihypertensive agents of different clas-ses, one of which should be a diuretic,clinicians should consider an evaluationfor secondary causes of hypertension.

Pregnancy and Antihypertensive

Medications

In a pregnancy complicated by diabetesand chronic hypertension, target bloodpressure goals of SBP 110–129 mmHgand DBP 65–79 mmHg are reasonable,as they contribute to improved long-term maternal health. Lower bloodpressure levels may be associated withimpaired fetal growth. During preg-nancy, treatment with ACE inhibitorsand ARBs is contraindicated, as theymay cause fetal damage.Antihypertensive

drugs known to be effective and safe inpregnancy include methyldopa, labetalol,diltiazem, clonidine, and prazosin. Chronicdiuretic use during pregnancy is not rec-ommended as it has been associated withrestrictedmaternal plasma volume, whichmay reduce uteroplacental perfusion (33).

LIPID MANAGEMENT

Recommendations

c In adults not taking statins, it isreasonable to obtain a lipid profileat the time of diabetes diagnosis, atan initial medical evaluation, andevery 5 years thereafter, or morefrequently if indicated. E

c Obtain a lipid profile at initiationof statin therapy and periodicallythereafter as it may help to mon-itor the response to therapy andinform adherence. E

c Lifestyle modification focusing onweight loss (if indicated); the reduc-tion of saturated fat, trans fat, andcholesterol intake; increase ofomega-3 fatty acids, viscous fiber,and plant stanols/sterols intake; andincreased physical activity should berecommended to improve the lipidprofile in patients with diabetes. A

c Intensify lifestyle therapy and opti-mize glycemic control for patientswith elevated triglyceride levels($150 mg/dL [1.7 mmol/L]) and/orlow HDL cholesterol (,40 mg/dL[1.0 mmol/L] for men, ,50 mg/dL[1.3 mmol/L] for women). C

c For patients with fasting triglyceridelevels $500 mg/dL (5.7 mmol/L),evaluate for secondary causes ofhypertriglyceridemia and considermedical therapy to reduce the riskof pancreatitis. C

c For patients of all ages with diabetesandatherosclerotic cardiovascular dis-ease, high-intensity statin therapyshouldbeadded to lifestyle therapy.A

c For patients with diabetes aged,40 years with additional athero-sclerotic cardiovascular disease riskfactors, consider using moderate-intensity or high-intensity statinand lifestyle therapy. C

c For patients with diabetes aged40–75 years without additionalatherosclerotic cardiovascular dis-ease risk factors, consider usingmoderate-intensity statin and life-style therapy. A

c For patients with diabetes aged40–75 years with additional ath-erosclerotic cardiovascular dis-ease risk factors, consider usinghigh-intensity statin and lifestyletherapy. B

c For patients with diabetes aged.75 years without additional ath-erosclerotic cardiovascular dis-ease risk factors, consider usingmoderate-intensity statin therapyand lifestyle therapy. B

c For patients with diabetes aged.75 years with additional athero-sclerotic cardiovascular disease riskfactors, consider using moderate-intensity or high-intensity statintherapy and lifestyle therapy. B

c In clinical practice, providers mayneed to adjust intensity of statintherapy based on individual patientresponse to medication (e.g., sideeffects, tolerability, LDL cholesterollevels). E

c The addition of ezetimibe tomoderate-intensity statin therapyhasbeenshown toprovideadditionalcardiovascular benefit comparedwith moderate-intensity statin ther-apy alone and may be consideredfor patients with a recent acute cor-onary syndromewith LDL cholesterol$50mg/dL (1.3mmol/L) or for thosepatients who cannot tolerate high-intensity statin therapy. A

c Combination therapy (statin/fibrate)has not been shown to improve ath-erosclerotic cardiovascular diseaseoutcomes and is generally not rec-ommended. A However, therapywith statin and fenofibrate may beconsidered for men with both tri-glyceride level $204 mg/dL (2.3mmol/L) and HDL cholesterollevel#34 mg/dL (0.9 mmol/L). B

c Combination therapy (statin/niacin)has not been shown to provideadditional cardiovascular benefitabove statin therapy alone andmay increase the risk of stroke andis not generally recommended. A

c Statin therapy is contraindicatedin pregnancy. B

Lifestyle InterventionLifestyle intervention, including weightloss, increased physical activity, andmedical nutrition therapy, allows somepatients to reduce ASCVD risk factors.

care.diabetesjournals.org Cardiovascular Disease and Risk Management S63

Nutrition intervention should be tailoredaccording to each patient’s age, diabe-tes type, pharmacological treatment,lipid levels, and medical conditions.Recommendations should focus on re-ducing saturated fat, cholesterol, andtrans fat intake and increasing plantstanols/sterols, omega-3 fatty acids,and viscous fiber (such as in oats, le-gumes, and citrus). Glycemic controlcan also beneficially modify plasma lipidlevels, particularly in patients with veryhigh triglycerides and poor glycemiccontrol.

Statin Treatment

Initiating Statin Therapy Based on Risk

Patients with type 2 diabetes have anincreased prevalence of lipid abnormal-ities, contributing to their high risk ofASCVD. Multiple clinical trials havedemonstrated the beneficial effects ofpharmacological (statin) therapy onASCVD outcomes in subjects with andwithout CHD (34,35). Subgroup analy-ses of patients with diabetes in largertrials (36–40) and trials in patientswith diabetes (41,42) showed signifi-cant primary and secondary preventionof ASCVD events and CHD death inpatients with diabetes. Meta-analyses,including data from over 18,000 patientswith diabetes from 14 randomized trialsof statin therapy (mean follow-up 4.3years), demonstrate a 9%proportional re-duction in all-cause mortality and 13% re-duction in vascular mortality for eachmmol/L (39 mg/dL) reduction in LDL cho-lesterol (43).As in those without diabetes, abso-

lute reductions in ASCVD outcomes(CHD death and nonfatal MI) are great-est in people with high baseline ASCVDrisk (known ASCVD and/or very high LDLcholesterol levels), but the overall ben-efits of statin therapy in people with di-abetes at moderate or even low risk forASCVD are convincing (44,45). Statinsare the drugs of choice for LDL choles-terol lowering and cardioprotection.Most trials of statins and ASCVD out-

comes tested specific doses of statinsagainst placebo or other statins ratherthan aiming for specific LDL cholesterolgoals (46). In light of this fact, the 2016ADA Standards of Care position state-ment was revised to recommend whento initiate and intensify statin therapy(high vs. moderate intensity) based onrisk profile (Table 8.1 and Table 8.2).

The Risk Calculator. The American Collegeof Cardiology/American Heart AssociationASCVD risk calculator may be a useful toolto estimate 10-year ASCVD (http://my.americanheart.org). As diabetes itselfconfers increased risk for ASCVD, therisk calculator has limited use forassessing cardiovascular risk in indi-viduals with diabetes.

Age ‡40 Years

In all patients with diabetes aged $40years, moderate-intensity statin treat-ment should be considered in additionto lifestyle therapy. Clinical trials in high-risk patients, such as those with ACS orprevious cardiovascular events (47–49),have demonstrated that more aggressivetherapy with high doses of statins led to asignificant reduction in further events.Therefore, high-dose statins are recom-mended in patients with increased car-diovascular risk (e.g., LDL cholesterol$100 mg/dL [2.6 mmol/L], high bloodpressure, smoking, albuminuria, andfamily history of premature ASCVD) orwith ASCVD.

Age >75 Years

For adults with diabetes over 75 years ofage, there are limited data regarding thebenefits and risks of statin therapy.Statin therapy should be individualizedbased on risk profile. High-intensitystatins, if well tolerated, are still appropri-ate and recommended for older adultswith ASCVD. High-intensity statin therapymay also be appropriate in adults withdiabetes.75 years of agewith additionalASCVD risk factors. However, the risk–benefit profile should be routinely evalu-ated in this population, with downwardtitration (e.g., high tomoderate intensity)performed as needed. See Section 10“Older Adults” for more details on clinicalconsiderations for this population.

Age <40 Years and/or Type 1 Diabetes

Very little clinical trial evidence existsfor patients with type 2 diabetes underthe age of 40 years or for patients withtype 1 diabetes of any age. In the HeartProtection Study (lower age limit40 years), the subgroup of ;600 patientswith type 1 diabetes had a proportionately

Table 8.1—Recommendations for statin and combination treatment in peoplewith diabetes

Age Risk factors Recommended statin intensity*

,40 years NoneASCVD risk factor(s)**ASCVD

NoneModerate or highHigh

40–75years

NoneASCVD risk factorsASCVDACS and LDL cholesterol.50 mg/dL (1.3 mmol/L)in patientswho cannot tolerate high-dose statins

ModerateHighHighModerate plus ezetimibe

.75 years NoneASCVD risk factorsASCVDACSandLDL cholesterol.50mg/dL (1.3mmol/L) inpatients who cannot tolerate high-dose statins

ModerateModerate or highHighModerate plus ezetimibe

*In addition to lifestyle therapy.**ASCVD risk factors include LDL cholesterol $100 mg/dL (2.6 mmol/L), high blood pressure,smoking, overweight and obesity, and family history of premature ASCVD.

Table 8.2—High-intensity and moderate-intensity statin therapy*

High-intensity statin therapy Moderate-intensity statin therapy

Lowers LDL cholesterol by $50%Atorvastatin 40–80 mgRosuvastatin 20–40 mg

Lowers LDL cholesterol by 30% to ,50%Atorvastatin 10–20 mgRosuvastatin 5–10 mgSimvastatin 20–40 mgPravastatin 40–80 mgLovastatin 40 mgFluvastatin XL 80 mgPitavastatin 2–4 mg

*Once-daily dosing.

S64 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

similar, although not statistically signifi-cant, reduction in risk as patients withtype 2 diabetes (37). Even though thedata are not definitive, similar statintreatment approaches should be consid-ered for patients with type 1 or type 2diabetes, particularly in the presence ofother cardiovascular risk factors. Pleaserefer to “Type 1 Diabetes Mellitus andCardiovascular Disease: A ScientificStatement From the American Heart As-sociation and American Diabetes Associ-ation” (50) for additional discussion.High-intensity statin therapy is recom-

mended for all patients with diabetes andASCVD. Treatment with a moderate doseof statin should be considered if thepatient does not have ASCVD but hasadditional ASCVD risk factors.

Ongoing Therapy and MonitoringWith Lipid PanelIn adults with diabetes, it is reasonable toobtain a lipid profile (total cholesterol,LDL cholesterol, HDL cholesterol, andtriglycerides) at the time of diagnosis,at the initial medical evaluation, and atleast every 5 years thereafter. A lipidpanel should also be obtained immedi-ately before initiating statin therapy.Once a patient is taking a statin, testingfor LDL cholesterol may be consideredon an individual basis (e.g., to monitorfor adherence and efficacy). In caseswhere patients are adherent, but theLDL cholesterol level is not responding,clinical judgment is recommended to de-termine the need for and timing of lipidpanels. In individual patients, the highlyvariable LDL cholesterol–lowering re-sponse seen with statins is poorly under-stood (51). When maximally tolerateddoses of statins fail to substantially lowerLDL cholesterol (,30% reduction fromthe patient’s baseline), there is no strongevidence that combination therapyshould be used. Clinicians should attemptto find a dose or alternative statin that istolerable, if side effects occur. There isevidence for benefit from even extremelylow, less than daily, statin doses (52).Increased frequency of LDL cholesterol

monitoring should be considered for pa-tients with new-onset ACS. A recent ran-domized controlled trial evaluated theaddition of ezetimibe to moderate-intensity statin therapy and demon-strated ASCVD risk benefit over statinmonotherapy (53). Increased frequencyof LDL cholesterol monitoring may also

be considered in adults with heterozygousfamilial hypercholesterolemia who requireadditional lowering of LDL cholesterol.

Combination Therapy for LDLCholesterol Lowering

Statins and Ezetimibe

The IMProved Reduction of Outcomes:Vytorin Efficacy International Trial(IMPROVE-IT) was a randomized con-trolled trial comparing the addition ofezetimibe to simvastatin therapy versussimvastatin alone. Individuals were$50 years of age who experienced anACS within the preceding 10 days andhad an LDL cholesterol level$50 mg/dL(1.3 mmol/L). In those with diabetes(27%), the combination of moderate-intensity simvastatin (40mg) and ezetimibe(10 mg) showed a significant reductionof major adverse cardiovascular eventswith an absolute risk reduction of5% (40% vs. 45%) and RR reduction of14% (RR 0.86 [95% CI 0.78–0.94]) overmoderate-intensity simvastatin (40 mg)alone (53). Therefore, for peoplemeetingIMPROVE-IT eligibility criteria who canonly tolerate a moderate-dose statin, theaddition of ezetimibe to statin therapyshould be considered.

Statins and PCSK9 Inhibitors

Placebo-controlled trials evaluating theaddition of the novel PCSK9 inhibitors,evolocumab and alirocumab, to maxi-mally tolerated doses of statin therapyin participants who were at high risk forASCVD demonstrated an average reduc-tion in LDL cholesterol ranging from 36%to 59%. These agents may thereforebe considered as adjunctive therapyfor patients with diabetes at high risk forASCVD eventswho require additional low-ering of LDL cholesterol or who requirebut are intolerant to high-intensity statintherapy (54,55). It is important to notethat the effects of this novel class of agentson ASCVD outcomes are unknown asphase 4 studies are currently under way.

Treatment of Other LipoproteinFractions or TargetsHypertriglyceridemia should be addressedwith dietary and lifestyle changes includ-ing abstinence from alcohol (56). Severehypertriglyceridemia (.1,000 mg/dL)may warrant immediate pharmacologicaltherapy (fibric acid derivatives and/or fishoil) to reduce the risk of acute pancreatitis.

Low levels of HDL cholesterol, oftenassociated with elevated triglyceride

levels, are the most prevalent patternof dyslipidemia in individuals withtype 2 diabetes. However, the evidencefor the use of drugs that target theselipid fractions is substantially less robustthan that for statin therapy (57). In alarge trial in patients with diabetes,fenofibrate failed to reduce overallcardiovascular outcomes (58).

Combination Therapy

Statin and Fibrate

Combination therapy (statin and fibrate)is associated with an increased risk forabnormal transaminase levels, myositis,and rhabdomyolysis. The risk of rhabdo-myolysis is more common with higherdoses of statins and renal insufficiencyand appears to be higher when statinsare combined with gemfibrozil (59)(compared with fenofibrate).

In the ACCORD study, in patients withtype 2 diabetes whowere at high risk forASCVD, the combination of fenofibrateand simvastatin did not reduce the rateof fatal cardiovascular events, nonfatalMI, or nonfatal stroke as compared withsimvastatin alone. Prespecified subgroupanalyses suggested heterogeneity intreatment effects with possible benefitfor men with both a triglyceride level$204 mg/dL (2.3 mmol/L) and an HDLcholesterol level #34 mg/dL (0.9mmol/L) (60).

Statin and Niacin

The Atherothrombosis Interventionin Metabolic Syndrome With LowHDL/High Triglycerides: Impact onGlobal Health Outcomes (AIM-HIGH) tri-al randomized over 3,000 patients(about one-third with diabetes) with es-tablished ASCVD, low LDL cholesterollevels (,180 mg/dL [4.7 mmol/L]), lowHDL cholesterol levels (men ,40 mg/dL[1.0 mmol/L] and women ,50 mg/dL[1.3 mmol/L]), and triglyceride levels of150–400 mg/dL (1.7–4.5 mmol/L) to sta-tin therapy plus extended-release niacinor placebo. The trial was halted early dueto lack of efficacy on the primary ASCVDoutcome (first event of the compositeof death from CHD, nonfatal MI, ische-mic stroke, hospitalization for an ACS, orsymptom-driven coronary or cerebral re-vascularization) and a possible increasein ischemic stroke in those on combina-tion therapy (61). Therefore, combina-tion therapy with a statin and niacin isnot recommended given the lack ofefficacy on major ASCVD outcomes,

care.diabetesjournals.org Cardiovascular Disease and Risk Management S65

possible increase in risk of ischemicstroke, and side effects.

Diabetes With Statin UseSeveral studies have reported an increasedrisk of incident diabetes with statin use(62,63), which may be limited to thosewith diabetes risk factors. An analysis ofone of the initial studies suggested thatalthough statins were linked to diabetesrisk, the cardiovascular event rate reduc-tion with statins far outweighed the risk ofincident diabetes even for patients at high-est risk for diabetes (64). The absolute riskincrease was small (over 5 years of follow-up, 1.2% of participants on placebo devel-oped diabetes and 1.5% on rosuvastatindeveloped diabetes) (64). A meta-analysisof 13 randomized statin trials with 91,140participants showed an odds ratio of 1.09for a new diagnosis of diabetes, so that(on average) treatment of 255 patientswith statins for 4 years resulted in oneadditional case of diabetes, while simul-taneously preventing 5.4 vascular eventsamong those 255 patients (63).

Statins and Cognitive FunctionA recent systematic review of the U.S.Food and Drug Administration’s post-marketing surveillance databases, ran-domized controlled trials, and cohort,case-control, and cross-sectional stud-ies evaluating cognition in patients re-ceiving statins found that publisheddata do not reveal an adverse effect ofstatins on cognition. Therefore, a con-cern that statins might cause cognitivedysfunction or dementia should notprohibit their use in individuals withdiabetes at high risk for ASCVD (65).

ANTIPLATELET AGENTS

Recommendations

c Consider aspirin therapy (75–162mg/day) as a primary preventionstrategy in those with type 1 ortype 2 diabeteswho are at increasedcardiovascular risk (10-year risk.10%). This includes most men orwomen with diabetes aged $50years who have at least one addi-tional major risk factor (family his-tory of premature atheroscleroticcardiovascular disease, hyperten-sion, smoking, dyslipidemia, or al-buminuria) and are not at increasedrisk of bleeding. C

c Aspirin should not be recommendedfor atherosclerotic cardiovascular

disease prevention for adults withdiabetes at low atheroscleroticcardiovascular disease risk (10-year atherosclerotic cardiovascu-lar disease risk ,5%), such as inmen or women with diabetes aged,50 years with no major additionalatherosclerotic cardiovascular dis-ease risk factors, as the potentialadverse effects from bleeding likelyoffset the potential benefits. C

c In patients with diabetes,50 yearsof age with multiple other risk fac-tors (e.g., 10-year risk 5–10%), clin-ical judgment is required. E

c Use aspirin therapy (75–162mg/day)as a secondary prevention strat-egy in those with diabetes and ahistory of atherosclerotic cardio-vascular disease. A

c For patients with atheroscleroticcardiovascular disease and docu-mented aspirin allergy, clopidog-rel (75 mg/day) should be used. B

c Dual antiplatelet therapy is reason-able for up to a year after an acutecoronary syndrome. B

Risk ReductionAspirin has been shown to be effectivein reducing cardiovascular morbidityand mortality in high-risk patients withprevious MI or stroke (secondary preven-tion). Its net benefit in primary preventionamong patients with no previous cardio-vascular events is more controversial,both for patients with diabetes and forpatients without diabetes (66,67). Previ-ous randomized controlled trials of aspi-rin specifically in patients with diabetesfailed to consistently show a significantreduction in overall ASCVD end points,raising questions about the efficacy ofaspirin for primary prevention in peoplewith diabetes, although some sex differ-ences were suggested (68–71).

The Antithrombotic Trialists’ (ATT)collaborators published an individualpatient-level meta-analysis of the sixlarge trials of aspirin for primary preven-tion in the general population. These tri-als collectively enrolled over 95,000participants, including almost 4,000with diabetes. Overall, they found thataspirin reduced the risk of serious vascularevents by 12% (RR 0.88 [95% CI 0.82–0.94]). The largest reduction was for non-fatal MI, with little effect on CHD death(RR 0.95 [95% CI 0.78–1.15]) or total

stroke. There was some evidence of a dif-ference in aspirin effect by sex: aspirinsignificantly reduced ASCVD events inmen, but not in women. Conversely, as-pirin had no effect on stroke in men butsignificantly reduced stroke in women.However, there was no heterogeneity ofeffect by sex in the risk of serious vascularevents (P 5 0.9). Sex differences inaspirin’s effects have not been observedin studies of secondary prevention (66).In the six trials examined by the ATTcollaborators, the effects of aspirin onmajor vascular events were similar forpatients with or without diabetes: RR0.88 (95% CI 0.67–1.15) and RR 0.87(95% CI 0.79–0.96), respectively. The con-fidence interval was wider for those withdiabetes because of smaller numbers.

Aspirin appears to have a modest effecton ischemic vascular events with theabsolute decrease in events dependingon the underlying ASCVD risk. The mainadverse effects appear to be an increasedriskof gastrointestinal bleeding. Theexcessrisk may be as high as 1–5 per 1,000 peryear in real-world settings. In adults withASCVD risk.1% per year, the number ofASCVD events preventedwill be similar toor greater than the number of episodes ofbleeding induced, although these compli-cations do not have equal effects on long-term health (72).

Treatment ConsiderationsIn 2010, a position statement of theADA, the American Heart Association,and the American College of CardiologyFoundation recommended that low-dose(75–162 mg/day) aspirin for primaryprevention is reasonable for adultswith diabetes and no previous historyof vascular disease who are at increasedASCVD risk (10-year risk of ASCVD eventsover 10%) and who are not at increasedrisk for bleeding. This previous recom-mendation included most men over age50 years and women over age 60 yearswho also have one or more of the follow-ingmajor risk factors: smoking, hyperten-sion, dyslipidemia, family history ofpremature ASCVD, and albuminuria (73).

Sex ConsiderationsMultiple recent well-conducted studiesand meta-analyses reported a risk ofheart disease and stroke that is equiva-lent if not higher in women comparedwith men with diabetes, including amongnonelderly adults. Thus, the recommen-dations for using aspirin as primary

S66 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

prevention are now revised to includeboth men and women aged $50 yearswith diabetes and one or more majorrisk factors to reflect these more recentfindings (74–77). Sex differences in theantiplatelet effect of aspirin have beensuggested in the general population(78); however, further studies are neededto investigate the presence of such differ-ences in individuals with diabetes.

Aspirin Use in People <50 Years of AgeAspirin is not recommended for those atlow risk of ASCVD (such as men andwomen aged ,50 years with diabeteswith no other major ASCVD risk factors;10-year ASCVD risk ,5%) as the lowbenefit is likely to be outweighed bythe risks of significant bleeding. Clinicaljudgment should be used for those atintermediate risk (younger patientswith one or more risk factors or olderpatients with no risk factors; thosewith 10-year ASCVD risk of 5–10%) untilfurther research is available. Aspirin usein patients aged ,21 years is contrain-dicated due to the associated risk ofReye syndrome.

Aspirin DosingAverage daily dosages used in most clini-cal trials involving patients with diabetesranged from 50 mg to 650 mg but weremostly in the range of 100–325 mg/day.There is little evidence to support anyspecific dose, but using the lowestpossible dose may help to reduce sideeffects (79). In the U.S., the most com-mon low-dose tablet is 81 mg. Althoughplatelets from patients with diabeteshave altered function, it is unclear what,if any, effect that finding has on therequired dose of aspirin for cardiopro-tective effects in the patient with dia-betes. Many alternate pathways forplatelet activation exist that are inde-pendent of thromboxane A2 and thusnot sensitive to the effects of aspirin(80). “Aspirin resistance” appears higherin patients with diabetes when mea-sured by a variety of ex vivo and in vitromethods (platelet aggregometry, mea-surement of thromboxane B2) (78). A re-cent trial suggested that more frequentdosing regimens of aspirin may reduceplatelet reactivity in individuals with dia-betes (81); however, these observationsalone are insufficient to empirically rec-ommend that higher doses of aspirin beused in this group at this time. It appearsthat 75–162 mg/day is optimal.

Indications for P2Y12 UseA P2Y12 receptor antagonist in combi-nation with aspirin should be used for atleast 1 year in patients following an ACS.Evidence supports use of either ticagreloror clopidogrel if no percutaneous cor-onary intervention was performed andclopidogrel, ticagrelor, or prasugrel if apercutaneous coronary interventionwas performed (82).

CORONARY HEART DISEASE

Recommendations

Screeningc In asymptomatic patients, routine

screening for coronary artery dis-ease is not recommended as itdoes not improve outcomes aslong as atherosclerotic cardiovascu-lar disease risk factors are treated.A

c Consider investigations for coro-nary artery disease in the presenceof any of the following: atypical car-diac symptoms (e.g., unexplaineddyspnea, chest discomfort); signsor symptoms of associated vasculardisease including carotid bruits,transient ischemic attack, stroke,claudication, or peripheral arterialdisease; or electrocardiogram ab-normalities (e.g., Q waves). E

Treatmentc In patients with known atheroscle-

rotic cardiovascular disease, use as-pirin and statin therapy (if notcontraindicated) A and considerACE inhibitor therapy C to reducethe risk of cardiovascular events.

c In patients with prior myocardial in-farction, b-blockers should be con-tinued for at least 2 years after theevent. B

c In patients with symptomaticheart failure, thiazolidinedionetreatment should not be used. A

c In patientswith type 2 diabeteswithstable congestive heart failure, met-forminmay be used if renal functionis normal but should be avoided inunstable or hospitalized patientswith congestive heart failure. B

Cardiac TestingCandidates for advanced or invasivecardiac testing include thosewith 1) typ-ical or atypical cardiac symptoms and 2)an abnormal resting electrocardiogram(ECG). Exercise ECG testing without orwith echocardiography may be used as

the initial test. In adults with diabetes$40 years of age, measurement of cor-onary artery calcium is also reasonablefor cardiovascular risk assessment.Pharmacological stress echocardiographyor nuclear imaging should be consideredin individuals with diabetes in whom rest-ing ECG abnormalities preclude exercisestress testing (e.g., left bundle branchblock or ST-T abnormalities). In addition,individuals who require stress testing andare unable to exercise should undergopharmacological stress echocardiographyor nuclear imaging.

Screening Asymptomatic PatientsThe screening of asymptomatic patientswith highASCVD risk is not recommended(44), in part because these high-riskpatients should already be receivingintensive medical therapydan approachthat provides similar benefit as invasiverevascularization (83,84). There is alsosome evidence that silentMImay reverseover time, adding to the controversy con-cerning aggressive screening strategies(85). In prospective trials, coronary arterycalcium has been established as an inde-pendent predictor of future ASCVDevents in patients with diabetes andis superior to both the UK ProspectiveDiabetes Study (UKPDS) risk engineand the Framingham Risk Score in pre-dicting risk in this population (86–88).However, a randomized observationaltrial demonstrated no clinical benefitto routine screening of asymptomaticpatients with type 2 diabetes and normalECGs (89). Despite abnormal myocardialperfusion imaging in more than one infive patients, cardiac outcomes wereessentially equal (and very low) inscreened versus unscreened patients.Accordingly, indiscriminate screeningis not considered cost-effective. Studieshave found that a risk factor–basedapproach to the initial diagnostic eval-uation and subsequent follow-up forcoronary artery disease fails to identifywhich patients with type 2 diabetes willhave silent ischemia on screening tests(90,91). Any benefit of newer noninva-sive coronary artery disease screeningmethods, such as computed tomographyand computed tomography angiography,to identify patient subgroups for differenttreatment strategies remains unproven.Although asymptomatic patients with di-abetes with higher coronary disease bur-den have more future cardiac events

care.diabetesjournals.org Cardiovascular Disease and Risk Management S67

(86,92,93), the role of these tests beyondrisk stratification is not clear. Their routineuse leads to radiation exposure and mayresult in unnecessary invasive testing suchas coronary angiography and revasculari-zationprocedures. Theultimatebalanceofbenefit, cost, and risks of such an approachin asymptomatic patients remains contro-versial, particularly in the modern settingof aggressive ASCVD risk factor control.

Lifestyle and PharmacologicalInterventionsIntensive lifestyle intervention focusingon weight loss through decreased calo-ric intake and increased physical activityas performed in the Action for Health inDiabetes (Look AHEAD) trial may be con-sidered for improving glucose control,fitness, and some ASCVD risk factors.Patients at increased ASCVD risk shouldreceive aspirin and a statin and ACE in-hibitor or ARB therapy if the patient hashypertension, unless there are contrain-dications to a particular drug class.While clear benefit exists for ACE inhib-itor and ARB therapy in patients with ne-phropathy or hypertension, the benefitsin patients with ASCVD in the absence ofthese conditions are less clear, especiallywhen LDL cholesterol is concomitantlycontrolled (94,95). In patients with priorMI, b-blockers should be continued for atleast 2 years after the event (96).

Diabetes and Heart FailureAlmost 50% of patients with type 2 di-abetes will develop heart failure (97).Data on the effects of glucose-loweringagents on heart failure outcomes havedemonstrated that thiazolidinedioneshave a strong and consistent relationshipwith heart failure (98–100). Therefore,thiazolidinedione use should be avoidedin patientswith symptomatic heart failure.Recent studies have now examined

the relationship between dipeptidylpeptidase 4 (DPP-4) inhibitors andheart failure and have mixed results.The Saxagliptin Assessment of VascularOutcomes Recorded in Patients with Di-abetes Mellitus–Thrombolysis in Myo-cardial Infarction 53 (SAVOR-TIMI 53)study showed that patients treatedwith saxagliptin (a DPP-4 inhibitor) weremore likely to be hospitalized for heartfailure than were those given placebo(3.5% vs. 2.8%, respectively) (101). How-ever, Examination of CardiovascularOutcomeswith Alogliptin versus Standardof Care (EXAMINE) and Trial Evaluating

Cardiovascular Outcomes with Sitagliptin(TECOS), recent multicenter, randomized,double-blind, noninferiority trials, evalu-ated heart failure andmortality outcomesin patients with type 2 diabetes takingdifferent DPP-4 inhibitors, alogliptinand sitagliptin, respectively, comparedwith placebo. EXAMINE reported thatthe hospital admission rate for heart fail-ure was 3.1% for patients randomly as-signed to alogliptin compared with 2.9%for those randomly assigned to placebo(hazard ratio 1.07 [95% CI 0.79–1.46])(102). Alogliptin had no effect on thecomposite end point of cardiovasculardeath and hospital admission for heartfailure in the post hoc analysis (hazardratio 1.00 [95% CI 0.82–1.21]) (102).TECOS showed a nonsignificant differencein the rate of heart failure hospitaliza-tion for the sitagliptin group (3.1%; 1.07per 100 person-years) compared withthe placebo group (3.1%; 1.09 per 100person-years) (103).

EMPA-REG OUTCOME StudyThe BI 10773 (Empagliflozin) Cardio-vascular Outcome Event Trial inType 2 Diabetes Mellitus Patients(EMPA-REG OUTCOME) was a random-ized, double-blind, placebo-controlledtrial that assessed the effect ofempagliflozin, a sodium–glucose co-transporter 2 inhibitor on cardiovascularoutcomes (stroke, MI, amputation, orcoronary, carotid, or peripheral arteryobstruction) in patients with type 2diabetes at high risk for cardiovasculardisease. Study participants had a meanage of 63 years, 57% had diabetes formore than 10 years, and 70% had a his-tory of either stroke or MI. EMPA-REGOUTCOME showed that the therapy re-duced the aggregate outcome of MI,stroke, and cardiovascular death by14% (absolute rate 10.5% vs. 12.1% inthe placebo group), due to a 38% reduc-tion in cardiovascular death (absolute rate3.7% vs. 5.9%) (104). Empagliflozin is thefirst of the recently approved diabetestreatments associated with a lower riskof cardiovascular disease.Whether empa-gliflozin or other sodium–glucose cotrans-porter 2 inhibitors will have a similareffect in lower-risk patients with diabetesremains unknown.

MetforminA systematic review of 34,000 patientsshowed that metformin is as safe as

other glucose-lowering treatments inpatients with diabetes and congestiveheart failure, even in thosewith reducedleft ventricular ejection fraction or con-comitant chronic kidney disease; however,metformin should be avoided in hospi-talized patients (105).

References1. Ali MK, Bullard KM, Saaddine JB, Cowie CC,Imperatore G, Gregg EW. Achievement of goalsin U.S. diabetes care, 1999-2010. N Engl J Med2013;368:1613–16242. Buse JB, Ginsberg HN, Bakris GL, et al.; Amer-ican Heart Association; American Diabetes As-sociation. Primary prevention of cardiovasculardiseases in people with diabetes mellitus: a sci-entific statement from the American Heart As-sociation and the American Diabetes Association.Diabetes Care 2007;30:162–1723. Gaede P, Lund-Andersen H, Parving H-H,Pedersen O. Effect of a multifactorial interven-tion on mortality in type 2 diabetes. N Engl JMed 2008;358:580–5914. Centers for Disease Control and Prevention,National Center for Health Statistics, Division ofHealth Care Statistics. Crude and age-adjustedhospital discharge rates for major cardiovascu-lar disease as first-listed diagnosis per 1,000 di-abetic population, United States, 1988–2006[Internet]. Available from http://www.cdc.gov/diabetes/statistics/cvdhosp/cvd/fig3.htm.Accessed 27 August 20155. Bobrie G, Genes N, Vaur L, et al. Is “isolatedhome” hypertension as opposed to “isolatedoffice” hypertension a sign of greater cardiovas-cular risk? Arch Intern Med 2001;161:2205–22116. Sega R, Facchetti R, Bombelli M, et al. Prog-nostic value of ambulatory and home bloodpressures compared with office blood pressurein the general population: follow-up resultsfrom the Pressioni Arteriose Monitorate eLoro Associazioni (PAMELA) study. Circulation2005;111:1777–17837. Arguedas JA, Leiva V, Wright JM. Blood pres-sure targets for hypertension in people with di-abetes mellitus. Cochrane Database Syst Rev2013;10:CD0082778. James PA, Oparil S, Carter BL, et al. 2014evidence-based guideline for the managementof high blood pressure in adults: report from thepanel members appointed to the Eighth JointNational Committee (JNC 8). JAMA 2014;311:507–5209. McBrien K, Rabi DM, Campbell N, et al. In-tensive and standard blood pressure targets inpatients with type 2 diabetes mellitus: system-atic review and meta-analysis. Arch Intern Med2012;172:1296–130310. Cushman WC, Evans GW, Byington RP,et al.; ACCORD Study Group. Effects of intensiveblood-pressure control in type 2 diabetes melli-tus. N Engl J Med 2010;362:1575–158511. Patel A, MacMahon S, Chalmers J, et al.;ADVANCE Collaborative Group. Effects of a fixedcombination of perindopril and indapamide onmacrovascular and microvascular outcomes inpatients with type 2 diabetes mellitus (theADVANCE trial): a randomised controlled trial.Lancet 2007;370:829–840

S68 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

12. Zoungas S, Chalmers J, Neal B, et al.;ADVANCE-ON Collaborative Group. Follow-upof blood-pressure lowering and glucose controlin type 2 diabetes. N Engl J Med 2014;371:1392–140613. SPRINT Research Group. A randomized trialof intensive versus standard blood-pressurecontrol. N Engl J Med. 9 November 2015 [Epubahead of print]. DOI: 10.1056/NEJMoa151193914. Cruickshank JM. Hypertension OptimalTreatment (HOT) trial. Lancet 1998;352:573–57415. Emdin CA, Rahimi K, Neal B, Callender T,Perkovic V, Patel A. Blood pressure lowering intype 2 diabetes: a systematic review and meta-analysis. JAMA 2015;313:603–61516. Sacks FM, Svetkey LP, Vollmer WM, et al.;DASH-Sodium Collaborative Research Group. Ef-fects onbloodpressureof reduceddietary sodiumand the Dietary Approaches to Stop Hypertension(DASH) diet. N Engl J Med 2001;344:3–1017. Chobanian AV, Bakris GL, Black HR, et al.;National Heart, Lung, and Blood Institute JointNational Committee on Prevention, Detection,Evaluation, and Treatment of High Blood Pres-sure; National High Blood Pressure EducationProgram Coordinating Committee. The SeventhReport of the Joint National Committee on Pre-vention, Detection, Evaluation, and Treatmentof High Blood Pressure: the JNC 7 report. JAMA2003;289:2560–257218. Tatti P, Pahor M, Byington RP, et al. Out-come results of the Fosinopril Versus Amlodi-pine Cardiovascular Events Randomized Trial(FACET) in patients with hypertension andNIDDM. Diabetes Care 1998;21:597–60319. Estacio RO, Jeffers BW, Hiatt WR,Biggerstaff SL, Gifford N, Schrier RW. The effectof nisoldipine as compared with enalapril on car-diovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. N Engl JMed 1998;338:645–65220. Schrier RW, Estacio RO, Mehler PS, HiattWR. Appropriate blood pressure control in hy-pertensive and normotensive type 2 diabetesmellitus: a summary of the ABCD trial. Nat ClinPract Nephrol 2007;3:428–43821. ALLHAT Officers and Coordinators for theALLHAT Collaborative Research Group. Majoroutcomes in high-risk hypertensive patientsrandomized to angiotensin-converting enzymeinhibitor or calcium channel blocker vs diuretic:the Antihypertensive and Lipid-Lowering Treat-ment to Prevent Heart Attack Trial (ALLHAT).JAMA 2002;288:2981–299722. Psaty BM, Smith NL, Siscovick DS, et al.Health outcomes associated with antihyperten-sive therapies used as first-line agents. A sys-tematic review and meta-analysis. JAMA 1997;277:739–74523. Heart Outcomes Prevention EvaluationStudy Investigators. Effects of ramipril on car-diovascular andmicrovascular outcomes in peo-ple with diabetes mellitus: results of the HOPEstudy and MICRO-HOPE substudy. Lancet 2000;355:253–25924. Granger CB, McMurray JJV, Yusuf S, et al.;CHARM Investigators and Committees. Effectsof candesartan in patients with chronic heartfailure and reduced left-ventricular systolicfunction intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial.Lancet 2003;362:772–776

25. McMurray JJV, Ostergren J, Swedberg K,et al.; CHARM Investigators and Committees.Effects of candesartan in patients with chronicheart failure and reduced left-ventricular systolicfunction taking angiotensin-converting-enzyme in-hibitors: the CHARM-Added trial. Lancet 2003;362:767–77126. Pfeffer MA, Swedberg K, Granger CB, et al.;CHARM Investigators and Committees. Effectsof candesartan on mortality and morbidity inpatients with chronic heart failure: theCHARM-Overall programme. Lancet 2003;362:759–76627. Lindholm LH, Ibsen H, Dahlof B, et al.; LIFEStudy Group. Cardiovascular morbidity andmortality in patients with diabetes in the Losar-tan Intervention For Endpoint reduction in hy-pertension study (LIFE): a randomised trialagainst atenolol. Lancet 2002;359:1004–101028. Berl T, Hunsicker LG, Lewis JB, et al.; Irbe-sartan Diabetic Nephropathy Trial. Collabora-tive Study Group. Cardiovascular outcomes inthe Irbesartan Diabetic Nephropathy Trial of pa-tients with type 2 diabetes and overt nephrop-athy. Ann Intern Med 2003;138:542–54929. Yusuf S, Teo KK, Pogue J, et al.; ONTARGETInvestigators. Telmisartan, ramipril, or both inpatients at high risk for vascular events. N Engl JMed 2008;358:1547–155930. Jamerson K, Weber MA, Bakris GL, et al.;ACCOMPLISH Trial Investigators. Benazeprilplus amlodipine or hydrochlorothiazide for hy-pertension in high-risk patients. N Engl J Med2008;359:2417–242831. Hermida RC, Ayala DE, Mojon A, FernandezJR. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk in hy-pertensivepatientswith type 2 diabetes. DiabetesCare 2011;34:1270–127632. Zhao P, Xu P, Wan C, Wang Z. Evening ver-sus morning dosing regimen drug therapy forhypertension. Cochrane Database Syst Rev2011;10:CD00418433. Sibai BM. Treatment of hypertension inpregnant women. N Engl J Med 1996;335:257–26534. Baigent C, Keech A, Kearney PM, et al.; Cho-lesterol Treatment Trialists’ (CTT) Collaborators.Efficacy and safety of cholesterol-loweringtreatment: prospective meta-analysis of datafrom 90,056 participants in 14 randomised trialsof statins. Lancet 2005;366:1267–127835. Mihaylova B, Emberson J, Blackwell L, et al.;Cholesterol Treatment Trialists’ (CTT) Collabo-rators. The effects of lowering LDL cholesterolwith statin therapy in people at low risk of vas-cular disease: meta-analysis of individual datafrom 27 randomised trials. Lancet 2012;380:581–59036. Pyorala K, Pedersen TR, Kjekshus J,Faergeman O, Olsson AG, Thorgeirsson G. Cho-lesterol lowering with simvastatin improvesprognosis of diabetic patients with coronaryheart disease. A subgroup analysis of the Scan-dinavian Simvastatin Survival Study (4S). Diabe-tes Care 1997;20:614–62037. Collins R, Armitage J, Parish S, Sleigh P, PetoR; Heart Protection Study Collaborative Group.MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people withdiabetes: a randomised placebo-controlled trial.Lancet 2003;361:2005–2016

38. Goldberg RB, Mellies MJ, Sacks FM, et al.;The CARE Investigators. Cardiovascular eventsand their reduction with pravastatin in diabeticand glucose-intolerant myocardial infarction sur-vivors with average cholesterol levels: subgroupanalyses in the Cholesterol And Recurrent Events(CARE) trial. Circulation 1998;98:2513–251939. Shepherd J, Barter P, Carmena R, et al. Effectof lowering LDL cholesterol substantially belowcurrently recommended levels in patients withcoronary heart disease and diabetes: the Treatingto New Targets (TNT) study. Diabetes Care 2006;29:1220–122640. Sever PS, Poulter NR, Dahlof B, et al.Reduction in cardiovascular events with ator-vastatin in 2,532 patients with type 2 diabe-tes: Anglo-Scandinavian Cardiac OutcomesTrial–lipid-lowering arm (ASCOT-LLA). DiabetesCare 2005;28:1151–115741. Knopp RH, d’Emden M, Smilde JG, PocockSJ. Efficacy and safety of atorvastatin in the pre-vention of cardiovascular end points in subjectswith type 2 diabetes: the Atorvastatin Study forPrevention of Coronary Heart Disease End-points in non-insulin-dependent diabetes melli-tus (ASPEN). Diabetes Care 2006;29:1478–148542. Colhoun HM, Betteridge DJ, Durrington PN,et al.; CARDS Investigators. Primary preventionof cardiovascular disease with atorvastatin intype 2 diabetes in the Collaborative Atorvasta-tin Diabetes Study (CARDS): multicentre rando-mised placebo-controlled trial. Lancet 2004;364:685–69643. Kearney PM, Blackwell L, Collins R, et al.;Cholesterol Treatment Trialists’ (CTT) Collabo-rators. Efficacy of cholesterol-lowering therapyin 18,686 people with diabetes in 14 rando-mised trials of statins: a meta-analysis. Lancet2008;371:117–12544. Taylor F, Huffman MD, Macedo AF, et al.Statins for the primary prevention of cardiovas-cular disease. Cochrane Database Syst Rev2013;1:CD00481645. Carter AA, Gomes T, Camacho X, JuurlinkDN, Shah BR, Mamdani MM. Risk of incidentdiabetes among patients treated with statins:population based study. BMJ 2013;346:f261046. Hayward RA, Hofer TP, Vijan S. Narrativereview: lack of evidence for recommendedlow-density lipoprotein treatment targets: asolvable problem. Ann Intern Med 2006;145:520–53047. Cannon CP, Braunwald E, McCabe CH, et al.;Pravastatin or Atorvastatin Evaluation and In-fection Therapy-Thrombolysis in Myocardial In-farction 22 Investigators. Intensive versusmoderate lipid lowering with statins after acutecoronary syndromes. N Engl J Med 2004;350:1495–150448. de Lemos JA, Blazing MA, Wiviott SD, et al.Early intensive vs a delayed conservative sim-vastatin strategy in patients with acute coro-nary syndromes: phase Z of the A to Z trial.JAMA 2004;292:1307–131649. Nissen SE, Tuzcu EM, Schoenhagen P, et al.;REVERSAL Investigators. Effect of intensivecompared with moderate lipid-lowering ther-apy on progression of coronary atherosclerosis:a randomized controlled trial. JAMA 2004;291:1071–108050. de Ferranti SD, de Boer IH, Fonseca V, et al.Type 1 diabetes mellitus and cardiovascular

care.diabetesjournals.org Cardiovascular Disease and Risk Management S69

disease: a scientific statement from the Ameri-can Heart Association and American DiabetesAssociation. Circulation 2014;130:1110–113051. Chasman DI, Posada D, Subrahmanyan L,Cook NR, Stanton VP Jr, Ridker PM. Pharmaco-genetic study of statin therapy and cholesterolreduction. JAMA 2004;291:2821–282752. Meek C,Wierzbicki AS, Jewkes C, et al. Dailyand intermittent rosuvastatin 5 mg therapy instatin intolerant patients: an observationalstudy. Curr Med Res Opin 2012;28:371–37853. Cannon CP, BlazingMA, Giugliano RP, et al.;IMPROVE-IT Investigators. Ezetimibe added tostatin therapy after acute coronary syndromes.N Engl J Med 2015;372:2387–239754. Moriarty PM, Jacobson TA, Bruckert E, et al.Efficacy and safety of alirocumab, a monoclonalantibody to PCSK9, in statin-intolerant patients:design and rationale of ODYSSEY ALTERNATIVE, arandomized phase 3 trial. J Clin Lipidol 2014;8:554–56155. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety andefficacy of anti-PCSK9 antibodies: a meta-analysisof 25 randomized, controlled trials. BMC Med2015;13:12356. Berglund L, Brunzell JD, Goldberg AC, et al.;Endocrine Society. Evaluation and treatment ofhypertriglyceridemia: an Endocrine Society clin-ical practice guideline. J Clin Endocrinol Metab2012;97:2969–298957. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target: asystematic review. JAMA 2007;298:786–79858. Keech A, Simes RJ, Barter P, et al.; FIELDStudy Investigators. Effects of long-term fenofi-brate therapy on cardiovascular events in 9795people with type 2 diabetes mellitus (the FIELDstudy): randomised controlled trial. Lancet2005;366:1849–186159. Jones PH, Davidson MH. Reporting rate ofrhabdomyolysis with fenofibrate 1 statin ver-sus gemfibrozil1 any statin. Am J Cardiol 2005;95:120–12260. Ginsberg HN, Elam MB, Lovato LC, et al.;ACCORD Study Group. Effects of combinationlipid therapy in type 2 diabetes mellitus. NEngl J Med 2010;362:1563–157461. BodenWE, Probstfield JL, Anderson T, et al.;AIM-HIGH Investigators. Niacin in patients withlow HDL cholesterol levels receiving intensivestatin therapy. N Engl J Med 2011;365:2255–226762. Rajpathak SN, Kumbhani DJ, Crandall J,Barzilai N, Alderman M, Ridker PM. Statin ther-apy and risk of developing type 2 diabetes: ameta-analysis. Diabetes Care 2009;32:1924–192963. Sattar N, Preiss D, Murray HM, et al. Statinsand risk of incident diabetes: a collaborativemeta-analysis of randomised statin trials. Lan-cet 2010;375:735–74264. Ridker PM, Pradhan A,MacFadyen JG, LibbyP, Glynn RJ. Cardiovascular benefits and diabe-tes risks of statin therapy in primary prevention:an analysis from the JUPITER trial. Lancet 2012;380:565–57165. Richardson K, Schoen M, French B, et al.Statins and cognitive function: a systematic re-view. Ann Intern Med 2013;159:688–69766. Baigent C, Blackwell L, Collins R, et al.; An-tithrombotic Trialists’ (ATT) Collaboration. Aspi-rin in the primary and secondary prevention of

vascular disease: collaborative meta-analysis ofindividual participant data from randomised tri-als. Lancet 2009;373:1849–186067. Perk J, De Backer G, Gohlke H, et al.; Euro-pean Association for Cardiovascular Prevention& Rehabilitation (EACPR); ESC Committee forPractice Guidelines (CPG). European Guidelineson cardiovascular disease prevention in clinicalpractice (version 2012). The Fifth Joint TaskForce of the European Society of Cardiologyand Other Societies on Cardiovascular DiseasePrevention in Clinical Practice (constituted byrepresentatives of nine societies and by invitedexperts). Eur Heart J 2012;33:1635–170168. Ogawa H, Nakayama M, Morimoto T, et al.;Japanese Primary Prevention of AtherosclerosisWith Aspirin for Diabetes (JPAD) Trial Investiga-tors. Low-dose aspirin for primary prevention ofatherosclerotic events in patients with type 2diabetes: a randomized controlled trial. JAMA2008;300:2134–214169. Belch J, MacCuish A, Campbell I, Cobbe S,Taylor R, Prescott R, et al. The Prevention ofProgression of Arterial Disease and Diabetes(POPADAD) trial: factorial randomised placebocontrolled trial of aspirin and antioxidants inpatients with diabetes and asymptomatic pe-ripheral arterial disease. BMJ 2008;337:a184070. Zhang C, Sun A, Zhang P, et al. Aspirin forprimary prevention of cardiovascular events inpatients with diabetes: a meta-analysis. Diabe-tes Res Clin Pract 2010;87:211–21871. De Berardis G, Sacco M, Strippoli GF, et al.Aspirin for primary prevention of cardiovascularevents in people with diabetes: meta-analysis ofrandomised controlled trials. BMJ 2009;339:b453172. Pignone M, Earnshaw S, Tice JA, PletcherMJ. Aspirin, statins, or both drugs for the pri-mary prevention of coronary heart diseaseevents in men: a cost-utility analysis. Ann InternMed 2006;144:326–33673. Pignone M, Alberts MJ, Colwell JA, et al.;American Diabetes Association; American HeartAssociation; American College of CardiologyFoundation. Aspirin for primary prevention ofcardiovascular events in people with diabetes:a position statement of the American DiabetesAssociation, a scientific statement of the Ameri-can Heart Association, and an expert consensusdocument of the American College of CardiologyFoundation. Diabetes Care 2010;33:1395–140274. Huxley RR, Peters SAE, Mishra GD,Woodward M. Risk of all-cause mortality andvascular events in women versus men withtype 1 diabetes: a systematic review andmeta-analysis. Lancet Diabetes Endocrinol2015;3:198–20675. Peters SA, Huxley RR, Woodward M. Diabe-tes as risk factor for incident coronary heartdisease in women compared with men: a sys-tematic review and meta-analysis of 64 cohortsincluding 858,507 individuals and 28,203 coro-nary events. Diabetologia 2014;57:1542–155176. Kalyani RR, Lazo M, Ouyang P, et al. Sexdifferences in diabetes and risk of incident coro-nary artery disease in healthy young and middle-aged adults. Diabetes Care 2014;37:830–83877. Peters SA, Huxley RR, Woodward M. Diabe-tes as a risk factor for stroke in women com-pared with men: a systematic review andmeta-analysis of 64 cohorts, including 775,385

individuals and 12,539 strokes. Lancet 2014;383:1973–198078. Larsen SB, Grove EL, Neergaard-Petersen S,Wurtz M, Hvas AM, Kristensen SD. Determi-nants of reduced antiplatelet effect of aspirinin patients with stable coronary artery disease.PLoS One 2015;10:e012676779. Campbell CL, Smyth S, Montalescot G,Steinhubl SR. Aspirin dose for the preventionof cardiovascular disease: a systematic review.JAMA 2007;297:2018–202480. Davı G, Patrono C. Platelet activation andatherothrombosis. N Engl J Med 2007;357:2482–249481. Bethel MA, Harrison P, Sourij H, et al. Ran-domized controlled trial comparing impact onplatelet reactivity of twice-daily with once-dailyaspirin in people with type 2 diabetes. DiabetMed. 4 June 2015 [Epub ahead of print]. DOI:10.1111/dme.1282882. Vandvik PO, Lincoff AM, Gore JM, et al.;American College of Chest Physicians. Primaryand secondary prevention of cardiovasculardisease: Antithrombotic Therapy and Preven-tion of Thrombosis, 9th ed: American Collegeof Chest Physicians Evidence-Based ClinicalPractice Guidelines. Chest 2012;141(Suppl.):e637S–e668S83. Boden WE, O’Rourke RA, Teo KK, et al.;COURAGE Trial Research Group. Optimal medi-cal therapy with or without PCI for stable coro-nary disease. N Engl J Med 2007;356:1503–151684. BARI 2D Study Group. A randomized trial oftherapies for type 2 diabetes and coronary ar-tery disease. N Engl J Med 2009;360:2503–251585. Wackers FJT, Chyun DA, Young LH, et al.;Detection of Ischemia in Asymptomatic Dia-betics (DIAD) Investigators. Resolution ofasymptomatic myocardial ischemia in patientswith type 2 diabetes in the Detection of Ische-mia in Asymptomatic Diabetics (DIAD) study.Diabetes Care 2007;30:2892–289886. Elkeles RS, Godsland IF, Feher MD, et al.;PREDICT Study Group. Coronary calcium mea-surement improves prediction of cardiovascularevents in asymptomatic patients with type 2 di-abetes: the PREDICT study. Eur Heart J 2008;29:2244–225187. Raggi P, Shaw LJ, Berman DS, Callister TQ.Prognostic value of coronary artery calciumscreening in subjects with andwithout diabetes.J Am Coll Cardiol 2004;43:1663–166988. Anand DV, Lim E, Hopkins D, et al. Risk strat-ification in uncomplicated type 2 diabetes: pro-spective evaluation of the combined use ofcoronary artery calcium imaging and selectivemyocardial perfusion scintigraphy. Eur Heart J2006;27:713–72189. Young LH, Wackers FJT, Chyun DA, et al.;DIAD Investigators. Cardiac outcomes afterscreening for asymptomatic coronary artery dis-ease in patients with type 2 diabetes: the DIADstudy: a randomized controlled trial. JAMA2009;301:1547–155590. Wackers FJT, Young LH, Inzucchi SE, et al.;Detection of Ischemia in Asymptomatic Dia-betics Investigators. Detection of silent myo-cardial ischemia in asymptomatic diabeticsubjects: the DIAD study. Diabetes Care 2004;27:1954–196191. Scognamiglio R, Negut C, Ramondo A,Tiengo A, Avogaro A. Detection of coronary

S70 Cardiovascular Disease and Risk Management Diabetes Care Volume 39, Supplement 1, January 2016

artery disease in asymptomatic patients withtype 2 diabetes mellitus. J Am Coll Cardiol2006;47:65–7192. Hadamitzky M, Hein F, Meyer T, et al. Prog-nostic value of coronary computed tomographicangiography in diabetic patients without knowncoronary artery disease. Diabetes Care 2010;33:1358–136393. Choi E-K, Chun EJ, Choi S-I, et al. Assessmentof subclinical coronary atherosclerosis in asymp-tomatic patients with type 2 diabetes mellituswith single photon emission computed tomogra-phy and coronary computed tomography angiog-raphy. Am J Cardiol 2009;104:890–89694. Braunwald E, Domanski MJ, Fowler SE,et al.; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronaryartery disease. N Engl J Med 2004;351:2058–206895. Telmisartan Randomised AssessmeNtStudy in ACE iNtolerant subjects with cardiovas-cular Disease (TRANSCEND) Investigators. Ef-fects of the angiotensin-receptor blockertelmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting

enzyme inhibitors: a randomised controlled trial.Lancet 2008;372:1174–118396. Kezerashvili A, Marzo K, De Leon J. Betablocker use after acute myocardial infarctionin the patient with normal systolic function:when is it “ok” to discontinue? Curr CardiolRev 2012;8:77–8497. Kannel WB, Hjortland M, Castelli WP. Roleof diabetes in congestive heart failure: the Fra-mingham study. Am J Cardiol 1974;34:29–3498. Dormandy JA, Charbonnel B, Eckland DJA,et al.; PROactive Investigators. Secondary pre-vention of macrovascular events in patientswith type 2 diabetes in the PROactive Study(PROspective pioglitAzone Clinical Trial In mac-roVascular Events): a randomised controlled trial.Lancet 2005;366:1279–128999. Singh S, Loke YK, Furberg CD. Long-term riskof cardiovascular events with rosiglitazone: ameta-analysis. JAMA 2007;298:1189–1195100. Lincoff AM, Wolski K, Nicholls SJ, NissenSE. Pioglitazone and risk of cardiovascularevents in patients with type 2 diabetes mellitus:a meta-analysis of randomized trials. JAMA2007;298:1180–1188

101. Scirica BM, Bhatt DL, Braunwald E, et al.;SAVOR-TIMI 53 Steering Committee and Inves-tigators. Saxagliptin and cardiovascular out-comes in patients with type 2 diabetesmellitus. N Engl J Med 2013;369:1317–1326102. Zannad F, Cannon CP, CushmanWC, et al.;EXAMINE Investigators. Heart failure and mor-tality outcomes in patients with type 2 diabetestaking alogliptin versus placebo in EXAMINE: amulticentre, randomised, double-blind trial.Lancet 2015;385:2067–2076103. Green JB, Bethel MA, Armstrong PW,et al.; TECOS Study Group. Effect of sitagliptinon cardiovascular outcomes in type 2 diabetes.N Engl J Med 2015;373:232–242104. ZinmanB,Wanner C, Lachin JM, et al.; EMPA-REGOUTCOME Investigators. Empagliflozin, cardio-vascularoutcomes, andmortality in type2diabetes.N Engl J Med. 17 September 2015 [Epub ahead ofprint]. DOI: 10.1056/NEJMoa1504720105. Eurich DT,Weir DL,Majumdar SR, et al. Com-parative safety and effectiveness of metformin inpatients with diabetes mellitus and heart failure:systematic review of observational studies involv-ing 34,000 patients. Circ Heart Fail 2013;6:395–402

care.diabetesjournals.org Cardiovascular Disease and Risk Management S71