9. Cardiovascular Disease and RiskManagementDiabetes Care 2017;40(Suppl. 1):S75–S87 | DOI: 10.2337/dc17-S012

For prevention and management of diabetes complications in children and adoles-cents, please refer to Section 12 “Children and Adolescents.”Atherosclerotic cardiovascular disease (ASCVD)ddefined as acute coronary syn-

dromes (ACSs), a history of myocardial infarction (MI), stable or unstable angina,coronary or other arterial revascularization, stroke, transient ischemic attack, orperipheral arterial disease presumed to be of atherosclerotic origindis the leadingcause of morbidity and mortality for individuals with diabetes and is the largestcontributor to the direct and indirect costs of diabetes. The common conditionscoexisting with type 2 diabetes (e.g., hypertension and dyslipidemia) are clear riskfactors for ASCVD, and diabetes itself confers independent risk. Numerous studieshave shown the efficacy of controlling individual cardiovascular risk factors in pre-venting or slowing ASCVD in people with diabetes. Large benefits are seen whenmultiple risk factors are addressed simultaneously. There is evidence that measuresof 10-year coronary heart disease (CHD) risk among U.S. adults with diabetes haveimproved significantly over the past decade (1) and that ASCVD morbidity andmortality have decreased (2–4).In all patients with diabetes, cardiovascular risk factors should be systematically

assessed at least annually. These risk factors include hypertension, dyslipidemia,smoking, a family history of premature coronary disease, and the presence ofalbuminuria. Abnormal risk factors should be treated as described in theseguidelines.

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 aseparate day. B

Goalsc Most patients with diabetes and hypertension should be treated to a systolic

blood pressure goal of ,140 mmHg and a diastolic blood pressure goalof ,90 mmHg. A

c Lower systolic and diastolic blood pressure targets, such as 130/80 mmHg,may be appropriate for individuals at high risk of cardiovascular disease, if theycan be achieved without undue treatment burden. C

c In pregnant patients with diabetes and chronic hypertension, blood pres-sure targets of 120–160/80–105 mmHg are suggested in the interest ofoptimizing long-term maternal health and minimizing impaired fetalgrowth. E

Treatmentc Patients with confirmed office-based blood pressure.140/90 mmHg should,

in addition to lifestyle therapy, have prompt initiation and timely titration ofpharmacologic therapy to achieve blood pressure goals. A

c Patients with confirmed office-based blood pressure.160/100mmHg should,in addition to lifestyle therapy, have prompt initiation and timely titration oftwo drugs or a single pill combination of drugs demonstrated to reduce car-diovascular events in patients with diabetes. A

Suggested citation: American Diabetes Associa-tion. Cardiovascular disease and risk manage-ment. Sec. 9. In Standards of Medical Care inDiabetesd2017. Diabetes Care 2017;40(Suppl. 1):S75–S87

© 2017 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. More infor-mation is available at http://www.diabetesjournals.org/content/license.

American Diabetes Association

Diabetes Care Volume 40, Supplement 1, January 2017 S75

9.CARDIOVASCULA

RDISEA

SEANDRISK

MANAGEM

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c Treatment for hypertension shouldinclude drug classes demonstratedto reducecardiovascular events inpa-tients with diabetes (ACE inhibitors,angiotensin receptor blockers, thia-zide-like diuretics, or dihydropyridinecalcium channel blockers). Multiple-drug therapy is generally required toachieve blood pressure targets (butnot a combination of ACE inhibitorsand angiotensin receptor blockers).A

c An ACE inhibitor or angiotensin re-ceptor blocker, at the maximumtolerated dose indicated for bloodpressure treatment, is the recom-mended first-line treatment forhypertension in patients with dia-betes and urinary albumin–to–creatinine ratio $300 mg/g creati-nine (A) or 30–299 mg/g creatinine(B). If one class is not tolerated, theother should be substituted. B

c For patients treated with an ACEinhibitor, angiotensin receptorblocker, or diuretic, serum creatinine/estimated glomerular filtration rateand serum potassium levels shouldbe monitored. B

c For patients with blood pres-sure .120/80 mmHg, lifestyle in-tervention consists of weight lossif overweight or obese; a DietaryApproaches to Stop Hypertension–style dietary pattern includingreducing sodium and increasingpotassium intake; moderation ofalcohol intake; and increased phys-ical activity. B

Hypertension, defined as a sustainedblood pressure $140/90 mmHg, is acommon comorbidity of type 1 andtype 2 diabetes. The prevalence of hy-pertension depends on type of diabetes,age, sex, BMI, and race/ethnicity. Hyper-tension is a major risk factor for bothASCVD and microvascular complica-tions. In type 1 diabetes, hypertensionis often the result of underlying diabetickidney disease, while in type 2 diabetes,it usually coexists with other cardiome-tabolic risk factors. Please refer to theAmerican Diabetes Association (ADA)position statement “Diabetes and Hy-pertension” for a detailed review (5).

Screening and DiagnosisBlood pressure should bemeasured by atrained individual and should follow theguidelines established for the general

population: measurement in the seatedposition, with feet on the floor and armsupported at heart level, after 5 min ofrest. 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 found thathomemeasurementsmay better correlatewith ASCVD risk than officemeasurements(6,7). However, most of the evidence ofbenefits of hypertension treatment inpeople with diabetes is based on officemeasurements.

Treatment GoalsEpidemiological analyses show thatblood pressure.115/75 mmHg is asso-ciated with increased cardiovascularevent rates and mortality in individualswith diabetes (8). Randomized clinicaltrials have demonstrated the benefit(reduction of CHD events, stroke, anddiabetic kidney disease) of loweringblood pressure to ,140 mmHg systolicand ,90 mmHg diastolic in individualswith diabetes (9,10). There is limitedprespecified clinical trial evidence forthe benefits of lower systolic blood pres-sure (SBP) or diastolic blood pressure(DBP) targets (11). A meta-analysis ofrandomized trials of adults with type 2diabetes comparing intensive bloodpressure targets (upper limit of 130mmHg systolic and 80 mmHg diastolic)with standard targets (upper limit of140–160 mmHg systolic and 85–100mmHg diastolic) found no significantreduction in mortality or nonfatal MI.There was a statistically significant 35%relative risk (RR) reduction in strokewith intensive targets, but the absoluterisk reduction was only 1%, and inten-sive targets were associated with an in-creased risk for adverse events such ashypotension and syncope (12).

Randomized Controlled Trials of Intensive

Versus Standard Blood Pressure Control

Given the epidemiological relationshipbetween lower blood pressure and bet-ter long-term clinical outcomes, two

landmark trials, Action to Control Cardio-vascular Risk in Diabetes (ACCORD) andAction in Diabetes and Vascular Disease:Preterax and Diamicron MR ControlledEvaluation–Blood Pressure (ADVANCE-BP), examined the benefit of tighter bloodpressure control in patients with type 2diabetes. Additional studies, such as theSystolic Blood Pressure Intervention Trial(SPRINT) and the Hypertension OptimalTreatment (HOT) trial, also examined thepotential benefits of intensive versus stan-dard control, though the relevance of theirresults to peoplewith diabetes is less clear.

ACCORD. The ACCORD trial examinedwhether an SBP of ,120 mmHg in pa-tients with type 2 diabetes at high riskfor ASCVD provided greater cardio-vascular protection than an SBP of130–140 mmHg (13). The study did notfind a benefit in the primary end point(nonfatal MI, nonfatal stroke, and car-diovascular death) comparing intensiveblood pressure treatment (intensive BP;goal ,120 mmHg, average blood pres-sure achieved 119/64 mmHg on 3.4medications) with standard treatment(standard BP; average blood pressureachieved 143/70 mmHg on 2.1 medica-tions). However, a follow-upanalysis founda strong interaction between glycemic con-trol and blood pressure control. Comparedwith the standard glycemia/standard BPcontrol group in the blood pressure trial,the intensive BP/intensive glycemia, inten-sive BP/standard glycemia, and standardBP/intensive glycemia groups all showedbenefit for reducing the risk of majorcardiovascular disease (14). Stroke wassignificantly reduced in the intensive BPtreatment groups, but the intensive BP/intensive glycemia group showed no ev-idence of incremental benefit comparedwith either single intensive intervention(14). Thus, more intensive blood pres-sure control may be reasonable in cer-tain motivated, ACCORD-like patients(40–79 years of age with prior evidenceof cardiovascular disease or multiple car-diovascular risk factors) who have beeneducated about the added treatmentburden, side effects, and costs of moreintensive blood pressure control and forpatients who prefer to lower their risk ofstroke beyond what can be achievedthrough standard care.

ADVANCE. In ADVANCE, the active bloodpressure intervention arm (a single-pill,fixed-dose combination of perindopril

S76 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

and 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 (15). 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 inSBP and 2.2 mmHg in DBP. The finalblood pressure in the treated group was136/73 mmHg, not quite the intensive ortight control achieved in ACCORD. Therecently published 6-year follow-up ofthe ADVANCE trial, the ADVANCE–Post-Trial Observational Study (ADVANCE-ON),reported that the reductions in the risk ofdeath from any cause and of death fromcardiovascular causes in the interventiongroup were attenuated but remained sig-nificant (16).

HOT. The Hypertension Optimal Treat-ment (HOT) trial included patients withand without diabetes and comparedDBP targets of #90, #85, and #80mmHg. Post hoc analyses found cardio-vascular benefit with more intensivetargets in the subpopulation with dia-betes (17). The HOT trial results, takentogether with the higher quality datafrom ACCORD and ADVANCE, supportthe current recommendation to achieveblood pressure levels ,140/90 mmHg,with lower targets in selected patients.

SPRINT. The Systolic Blood Pressure In-tervention Trial (SPRINT) was a multi-center, randomized controlled trialthat compared two strategies for treat-ing SBP with either the standard targetof ,140 mmHg or an intensive targetof ,120 mmHg; primary outcomeswere MI, ACS, stroke, heart failure,and death due to cardiovascular dis-ease. Patients assigned to the intensiveSBP target of ,120 mmHg, comparedwith a target SBP of 140 mmHg, hadreduced RR of cardiovascular eventsby almost a third and of death by almosta quarter, though risks of electrolyte ab-normalities and acute kidney injury wereincreased (18). Of note, patients with di-abetes were excluded from participatingin this trial, so the results have no directimplications for blood pressure manage-ment in patients with diabetes.

Systolic Blood Pressure

The evidence that SBP .140 mmHg isharmful is irrefutable, suggesting thatclinicians promptly initiate and ti-trate therapy to achieve and maintainSBP ,140 mmHg in most patients. Forsome patients, lower SBP targets closerto 130 mmHg are appropriate. A recentsystematic review and meta-analysisevaluating SBP lowering in adults withtype 2 diabetes showed that each10 mmHg reduction of SBP was associ-ated with significantly lower risk ofmortality, cardiovascular events, CHD,stroke, albuminuria, and retinopathy.However, when trials were stratified bymean baseline SBP $140 mmHg or,140 mmHg, blood pressure–loweringtreatment was associated with lowerrisks of stroke and albuminuria, regard-less of initial SBP (9). Therefore, indivi-duals in whom cardiovascular diseaserisk, particularly stroke, is a concernmay, as part of shared decision making,have lower systolic targets than 140mmHg. This is especially true if lowerblood pressure can be achieved withfew drugs and without side effects oftherapy. For older adults, treating toan SBP of ,130 mmHg has not beenshown to improve cardiovascular out-comes (19).

Diastolic Blood Pressure

Similarly, strong evidence from random-ized clinical trials supports DBP targetsof,90 mmHg. These targets are in har-mony with the Eighth Joint NationalCommittee (JNC 8) recommendationof a DBP threshold of ,90 mmHg forindividuals over 18 years of age with di-abetes (11). A DBP of ,80 mmHg maystill be appropriate for patients withlong life expectancy, chronic kidney dis-ease, elevated urinary albumin excretion,evidence of cardiovascular disease, oradditional risk factors such as dyslipidemia,smoking, or obesity (17). In older adults,treating to a DBP of,70 mmHg has beenassociated with a greater risk of mortality(20).

Treatment Strategies

Lifestyle Intervention

Although there are no well-controlledstudies of diet and exercise in the treat-ment of elevated blood pressure or hy-pertension in individuals with diabetes,the Dietary Approaches to Stop Hyperten-sion (DASH) study evaluated the impact ofhealthy dietary patterns in individuals

without diabetes and has shown antihy-pertensive effects similar to those of phar-macologic monotherapy.

Lifestyle therapy consists of reduc-ing excess body weight through caloricrestriction, restricting sodium intake(,2,300 mg/day), increasing consump-tion of fruits and vegetables (8–10 serv-ings per day) and low-fat dairy products(2–3 servings per day), avoiding exces-sive alcohol consumption (no more than2 servings per day in men and no morethan 1 serving per day in women) (21),and increasing activity levels (11).

These lifestyle (nonpharmacologic)strategies may also positively affect gly-cemia and lipid control and should beencouraged in those with even mildlyelevated blood pressure, although theimpact of lifestyle therapy on cardiovas-cular events has not been established.Nonpharmacologic therapy is reasonablein individuals with diabetes and mildly el-evated blood pressure (SBP .120 mmHgor DBP.80 mmHg). If the blood pressureis confirmed to be $140 mmHg systolicand/or $90 mmHg diastolic, pharma-cologic therapy should be initiatedalong with nonpharmacologic therapy(11). A lifestyle therapy plan should bedeveloped in collaboration with the pa-tient and discussed as part of diabetesmanagement.

Pharmacologic Interventions

Lowering of blood pressure with regimensbased on a variety of antihypertensiveagents, including ACE inhibitors, angioten-sin receptor blockers (ARBs), diuretics, andcalcium channel blockers has been shownto be effective in reducing cardiovascularevents (9,22).

In people with diabetes and albumin-uria, ACE inhibitors or ARBs 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 and the development of albumin-uria when compared with placebo, evenafter adjustment for differences inblood pressure, an effect that has beentermed a “blood pressure independenteffect” (23). In patients with congestiveheart failure, including subgroups withdiabetes, ARBs have been shown to re-duce major ASCVD outcomes (24–26).Among patients with type 2 diabetes,urine albumin–to–creatinine ratio (UACR)

care.diabetesjournals.org Cardiovascular Disease and Risk Management S77

$300 mg/g creatinine, and elevated se-rum creatinine concentration, an ARB sig-nificantly reduced progression of kidneydisease compared with placebo (27). Ameta-analysis confirmed that treatmentof patients with diabetic kidney diseasewith an ACE inhibitor or ARB reduces therisk of progressing to end-stage renal dis-ease, though strong evidence of benefitwas limited to participants with baselineUACR$300 mg/g creatinine (28). Smallertrials also suggest reduction in compositecardiovascular events and reduced pro-gression of advanced nephropathy(29–31).However, the superiority of ACE in-

hibitors or ARBs over other antihyper-tensive agents for prevention ofcardiovascular outcomes has not beenconsistently shown for all patients withdiabetes (22,28,32,33). In particular, a recentmeta-analysis suggests that thiazide-type diuretics or dihydropyridine calciumchannel blockers have cardiovascularbenefit similar to that of ACE inhibitorsor ARBs (22). Therefore, among patientswithout albuminuria for whom cardio-vascular disease prevention is the pri-mary goal of blood pressure control, athiazide-like diuretic or dihydropyridinecalcium channel blocker may be consid-ered instead of or in addition to an ACEinhibitor or ARB.There are no adequate head-to-head

comparisons of ACE inhibitors and ARBs,but there is clinical trial support for eachof the following statements: In patientswith type 1 diabetes with hypertensionand any degree of albuminuria, ACE in-hibitors have been shown to reduce lossof glomerular filtration rate and delaythe progression of nephropathy. Inpatients with type 2 diabetes, hyper-tension, and UACR 30–299 mg/g cre-atinine, ACE inhibitors and ARBs havebeen shown to delay the progression toUACR $300 mg/g creatinine. The use ofboth ACE inhibitors and ARBs in combina-tion is not recommended given the lack ofadded ASCVD benefit and increased rateof adverse eventsdnamely, hyperkale-mia, syncope, and acute kidney injury(34,35).

Combination Drug Therapy

The blood pressure arm of the ADVANCEtrial demonstrated that routine admin-istration of a fixed-dose combinationof the ACE inhibitor perindopril andthe thiazide-like diuretic indapamide

significantly reduced combined micro-vascular and macrovascular outcomes,as well as death from cardiovascularcauses and total mortality. The improvedoutcomes could also have been due tolower achieved blood pressure in theperindopril–indapamidearm (15). Anothertrial showed a decrease in morbidity andmortality in those receiving ACE inhibi-tor benazepril and calcium channelblocker amlodipine versus benazepriland thiazide-like diuretic hydrochloro-thiazide (36,37). If needed to achieveblood pressure targets, amlodipineand indapamide or hydrochlorothia-zide or thiazide-like diuretic chlorthalidonecan be added. If estimated glomerularfiltration rate is ,30 mL/min/1.73 m2,a loop diuretic should be prescribed.Titration of and/or addition of furtherblood pressure medications should bemade in a timely fashion to overcomeclinical inertia in achieving blood pres-sure targets.

Bedtime Dosing

Growing evidence suggests that there isan association between absence of noc-turnal blood pressure dipping and theincidence of ASCVD. A randomized con-trolled trial of 448 participants withtype 2 diabetes and hypertension dem-onstrated reduced cardiovascular eventsandmortality with median follow-up of5.4 years if at least one antihyperten-sive medication was given at bedtime(38). Consider administering one ormore antihypertensive medications atbedtime (39).

Other Considerations

An important caveat is that most pa-tients with diabetes and hypertensionrequire multiple-drug therapy to reachblood pressure treatment goals (21).Identifying and addressing barriers tomedication adherence (such as costand side effects) should routinely bedone. If blood pressure remains uncon-trolled despite confirmed adherenceto optimal doses of at least threeantihypertensive agents of differentclasses, one of which should be a di-uretic, clinicians should consider anevaluation for secondary causes ofhypertension.

Pregnancy and Antihypertensive

Medications

Since there is a lack of randomized con-trolled trials of antihypertensive ther-apy in pregnant women with diabetes,

recommendations for the managementof hypertension in pregnant womenwith diabetes should be similar to thosefor all pregnant women. The AmericanCollege of Obstetricians and Gynecolo-gists (ACOG) has recommended thatwomen with mild gestational hyperten-sion (SBP ,160 mmHg or DBP ,110mmHg) do not need to be treated withantihypertensivemedications as there isno benefit identified that clearly out-weighs potential risks of therapy (40).A 2014 Cochrane systematic review ofantihypertensive therapy for mild tomoderate chronic hypertension thatincluded 49 trials and over 4,700women did not find any conclusive ev-idence for or against blood pressuretreatment to reduce the risk of pre-eclampsia for the mother or effectson perinatal outcomes such as pretermbirth, small-for-gestational-age in-fants, or fetal death (41). For pregnantwomen who require antihypertensivetherapy, SBP levels of 120–160 mmHgand DBP levels of 80–105 mmHg aresuggested to optimize maternal healthwithout risking fetal harm. Lower tar-gets (SBP 110–119 mmHg and DBP 65–79 mmHg) may contribute to improvedlong-term maternal health; however,they may be associated with impairedfetal growth. Pregnant women withhypertension and evidence of end-organdamage from cardiovascular and/orrenal disease may be considered forlower blood pressure targets to avoidprogression of these conditions duringpregnancy.

During pregnancy, treatment withACE inhibitors, ARBs, and spironolac-tone are contraindicated as they maycause fetal damage. Antihypertensivedrugs known to be effective and safein pregnancy include methyldopa, labe-talol, hydralazine, carvedilol, clonidine,and long-acting nifedipine (40). Di-uretics are not recommended for bloodpressure control in pregnancy but maybe used during late-stage pregnancy ifneeded for volume control (40,42).ACOG also recommends that postpar-tum patients with gestational hyperten-sion, preeclampsia, and superimposedpreeclampsia have their blood pres-sures observed for 72 h in hospital andfor 7–10 days postpartum. Long-termfollow-up is recommended for thesewomen as they have increased lifetimecardiovascular risk (43).

S78 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

LIPID MANAGEMENT

Recommendations

c In adults not taking statins, it isreasonable to obtain a lipid profileat the time of diabetes diagnosis,at an 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 monitorthe response to therapy and informadherence. E

c Lifestyle modification focusing onweight loss (if indicated); the reduc-tion of saturated fat, trans fat, andcholesterol intake; increase of di-etaryv-3 fatty acids, viscous fiber,and plant stanols/sterols intake;and increased physical activityshould be recommended to im-prove the lipid profile in patientswith 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 diabe-tes and atherosclerotic cardiovas-cular disease, high-intensity statintherapy should be added to life-style 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 therapyhas been shown to provide addi-tional cardiovascular benefit com-pared with moderate-intensitystatin therapy alone for patients withrecent acute coronary syndromeand LDL cholesterol $50 mg/dL(1.3 mmol/L) and should be consid-ered for these patients A and alsoin patients with diabetes and his-tory of ASCVD who cannot toleratehigh-intensity statin therapy. E

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 maybe considered for men with bothtriglyceride level $204 mg/dL(2.3 mmol/L) and HDL cholesterollevel #34 mg/dL (0.9 mmol/L). B

c Combination therapy (statin/niacin)has not been shown to provide ad-ditional cardiovascular benefit abovestatin therapy alone and may in-crease the risk of stroke and is notgenerally 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.Nutrition intervention should be tai-lored according to each patient’s age,diabetes type, pharmacologic treatment,lipid levels, and medical conditions.

Recommendations should focus on re-ducing saturated fat, cholesterol, andtrans fat intake and increasing plantstanols/sterols, v-3 fatty acids, and vis-cous fiber (such as in oats, legumes, andcitrus). Glycemic control may also benefi-cially modify plasma lipid levels, particularlyin patients with very high triglycerides andpoor glycemic control.

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 have dem-onstrated the beneficial effects of phar-macologic (statin) therapy on ASCVDoutcomes in subjects with and withoutCHD (44,45). Subgroup analyses of pa-tients with diabetes in larger trials(46–50) and trials in patients with dia-betes (51,52) showed significant pri-mary and secondary prevention ofASCVD events and CHD death in patientswith diabetes. Meta-analyses, includingdata from over 18,000 patients with di-abetes from 14 randomized trials ofstatin therapy (mean follow-up4.3 years),demonstrate a 9% proportional reduc-tion in all-cause mortality and 13% re-duction in vascular mortality for eachmmol/L (39 mg/dL) reduction in LDLcholesterol (53).

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 (54,55). 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 (56), suggesting that the initiationand intensification of statin therapybe based on risk profile (Table 9.1 andTable 9.2).

The Risk Calculator. The American Collegeof Cardiology/American Heart Associa-tion ASCVD risk calculator may be a use-ful tool to estimate 10-year ASCVD risk(http://my.americanheart.org). As dia-betes itself confers increased risk forASCVD, the risk calculator has limited

care.diabetesjournals.org Cardiovascular Disease and Risk Management S79

use for assessing cardiovascular risk inindividuals with diabetes.

Age 40–75 Years

In low-risk patients with diabetes aged40–75 years, moderate-intensity statintreatment should be considered in addi-tion to lifestyle therapy. Clinical trials inhigh-risk patients with increased cardio-vascular risk (e.g., LDL cholesterol$100mg/dL [2.6 mmol/L], high blood pres-sure, smoking, albuminuria, and familyhistory of premature ASCVD) and withASCVD (57–59) have demonstrated thatmore aggressive therapy with highdoses of statins led to a significant re-duction in cardiovascular events. High-intensity statins are recommended in allsuch patients.

Age >75 Years

For adults with diabetes .75 years ofage, there are limited data regardingthe benefits and risks of statin therapy.Statin therapy should be individualized

based on risk profile. High-intensity sta-tins, if well tolerated, are still appropri-ate and recommended for older adultswith ASCVD. High-intensity statin ther-apy may also be appropriate in adultswith diabetes.75 years of age with ad-ditional ASCVD risk factors. However,the risk–benefit profile should be rou-tinely evaluated in this population,with downward titration (e.g., high tomoderate intensity) performed asneeded. See Section 11 “Older Adults”for more details on clinical consider-ations 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 limit 40years), the subgroup of ;600 patientswith type 1 diabetes had a proportion-ately similar, although not statistically

significant, reduction in risk as patientswith type 2 diabetes (47). Even thoughthe data 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” (60) for additional discussion.

High-intensity statin therapy is rec-ommended for all patients with diabe-tes and ASCVD. Treatment with amoderate dose of statin should be con-sidered if the patient does not haveASCVD but has additional ASCVD riskfactors.

Ongoing Therapy and MonitoringWith Lipid PanelIn adults with diabetes, it is reasonableto obtain a lipid profile (total choles-terol, LDL cholesterol, HDL cholesterol,and triglycerides) at the time of diagno-sis, at the initial medical evaluation, andat least 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 todetermine the need for and timing oflipid panels. In individual patients, thehighly variable LDL cholesterol–loweringresponse seen with statins is poorly un-derstood (61). Whenmaximally tolerateddoses of statins fail to substantially lowerLDL cholesterol (,30% reduction fromthe patient’s baseline), there is no strongevidence that combination therapy shouldbe used. Clinicians should attempt tofind a dose or alternative statin that is tol-erable, if side effects occur. There is evi-dence for benefit from even extremelylow, less than daily, statin doses (62).

Increased frequency of LDL choles-terol monitoring should be consideredfor patients with new-onset ACS. In-creased frequency of LDL cholesterolmonitoring may also be considered inadults with heterozygous familial hyper-cholesterolemia who require additionallowering of LDL cholesterol.

Table 9.1—Recommendations for statin and combination treatment in peoplewith diabetes

Age Risk factorsRecommendedstatin intensity*

,40 years None None

ASCVD risk factor(s)** Moderate or high

ASCVD High

40–75 years None Moderate

ASCVD risk factors High

ASCVD High

ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L)or in patients with a history of ASCVD whocannot tolerate high-dose statins

Moderate plusezetimibe

.75 years None Moderate

ASCVD risk factors Moderate or high

ASCVD High

ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L)or in patients with a history of ASCVD whocannot tolerate high-dose statins

Moderate plusezetimibe

*In addition to lifestyle therapy. **ASCVD risk factors include LDL cholesterol $100 mg/dL(2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and familyhistory of premature ASCVD.

Table 9.2—High-intensity and moderate-intensity statin therapy*

High-intensity statin therapy Moderate-intensity statin therapy(lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30% to ,50%)

Atorvastatin 40–80 mg Atorvastatin 10–20 mg

Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg

Simvastatin 20–40 mg

Pravastatin 40–80 mg

Lovastatin 40 mg

Fluvastatin XL 80 mg

Pitavastatin 2–4 mg

*Once-daily dosing. XL, extended release.

S80 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

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 of eze-timibe to simvastatin therapy versussimvastatin alone. Individuals were $50years of age, had experienced an ACSwithin the preceding 10 days, and hadan LDL cholesterol level $50 mg/dL(1.3 mmol/L). In those with diabetes(27%), the combination of moderate-intensity simvastatin (40mg) andezetimibe(10 mg) showed a significant reduction ofmajor adverse cardiovascular events withan absolute risk reduction of 5% (40% vs.45%) and RR reduction of 14% (RR 0.86[95% CI 0.78–0.94]) overmoderate-intensitysimvastatin (40mg) alone (63). Therefore,for people meeting IMPROVE-IT eligibil-ity criteria, ezetimibe should be addedto moderate-intensity statin therapy.Though not explicitly studied, these re-sults may also suggest that the additionof ezetimibe should be considered forany patient with diabetes and history ofASCVD who cannot tolerate high-intensitystatin therapy.

Statins and PCSK9 Inhibitors

Placebo-controlled trials evaluatingthe addition of the PCSK9 inhibitorsevolocumab 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 therefore beconsidered as adjunctive therapy forpatients with diabetes at high risk forASCVD events who require additionallowering of LDL cholesterol or who re-quire but are intolerant to high-intensitystatin therapy (64,65). It is important tonote that the effects of this novel classof agents on ASCVD outcomes are un-known as phase 4 studies are currentlyunder way.

Treatment of Other LipoproteinFractions or TargetsHypertriglyceridemia should be ad-dressed with dietary and lifestylechanges including abstinence from alco-hol (66). Severe hypertriglyceridemia(.1,000 mg/dL) may warrant pharma-cologic therapy (fibric acid derivativesand/or fish oil) to reduce the risk ofacute pancreatitis.

Low levels of HDL cholesterol, oftenassociated with elevated triglyceridelevels, 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 (67). In alarge trial in patients with diabetes, fe-nofibrate failed to reduce overall cardio-vascular outcomes (68).

Combination Therapy

Statin and Fibrate

Combination therapy (statin and fi-brate) is associated with an increasedrisk for abnormal transaminase levels,myositis, and rhabdomyolysis. The riskof rhabdomyolysis is more commonwith higher doses of statins and renalinsufficiency and appears to be higherwhen statins are combined with gemfi-brozil (compared with fenofibrate) (69).

In the ACCORD study, in patients withtype 2 diabetes who were 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 sub-group analyses suggested heterogeneityin treatment effects with possible ben-efit for men with both a triglyceridelevel $204 mg/dL (2.3 mmol/L) andan HDL cholesterol level #34 mg/dL(0.9 mmol/L) (70).

Statin and Niacin

The Atherothrombosis Intervention inMetabolic Syndrome With Low HDL/HighTriglycerides: Impact on Global HealthOutcomes (AIM-HIGH) trial randomizedover 3,000 patients (about one-thirdwith diabetes) with established ASCVD,low LDL cholesterol levels (,180 mg/dL[4.7 mmol/L]), low HDL cholesterol lev-els (men ,40 mg/dL [1.0 mmol/L] andwomen ,50 mg/dL [1.3 mmol/L]), andtriglyceride levels of 150–400 mg/dL(1.7–4.5 mmol/L) to statin therapyplus extended-release niacin or pla-cebo. The trial was halted early due tolack of efficacy on the primary ASCVDoutcome (first event of the compositeof death from CHD, nonfatal MI, ische-mic stroke, hospitalization for an ACS,or symptom-driven coronary or cere-bral revascularization) and a possibleincrease in ischemic stroke in those oncombination therapy (71). Therefore,combination therapy with a statin and

niacin is not recommended given thelack of efficacy on major ASCVD out-comes, possible increase in risk of ische-mic stroke, and side effects.

Diabetes With Statin UseSeveral studies have reported an in-creased risk of incident diabetes withstatin use (72,73), which may be limitedto those with diabetes risk factors.An analysis of one of the initial studiessuggested that although statins werelinked to diabetes risk, the cardiovascu-lar event rate reduction with statins faroutweighed the risk of incident diabeteseven for patients at highest risk for di-abetes (74). The absolute risk increasewas small (over 5 years of follow-up,1.2% of participants on placebo devel-oped diabetes and 1.5% on rosuvastatindeveloped diabetes) (74). Ameta-analysisof 13 randomized statin trials with91,140 participants showed an odds ratioof 1.09 for a new diagnosis of diabetes, sothat (onaverage) treatmentof255patientswith statins for 4 years resulted in oneadditional case of diabetes while simulta-neously preventing 5.4 vascular eventsamong those 255 patients (73).

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 concernthat statins might cause cognitive dys-function or dementia should not detertheir use in individuals with diabetes athigh risk for ASCVD (75).

ANTIPLATELET AGENTS

Recommendations

c Useaspirin 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, clopidogrel(75 mg/day) should be used. B

c Dual antiplatelet therapy is reason-able for up to a year after an acutecoronary syndrome and may havebenefits beyond this period. B

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c Consider aspirin therapy (75–162mg/day) as a primary preventionstrategy in those with type 1 ortype 2 diabetes who are at in-creased cardiovascular risk. Thisincludes most men and womenwith diabetes aged $50 yearswho have at least one additionalmajor risk factor (family historyof premature atherosclerotic car-diovascular disease, hypertension,dyslipidemia, smoking, or albu-minuria) and are not at increasedrisk of bleeding. C

c Aspirin should not be recommendedfor atherosclerotic cardiovasculardisease prevention for adults withdiabetes at low atherosclerotic car-diovascular disease risk, such asin men or women with diabetesaged,50 years with no othermajoratherosclerotic cardiovascular dis-ease risk factors, as the potential ad-verse effects from bleeding likelyoffset the potential benefits. C

c When considering aspirin therapyin patients with diabetes ,50years of age with multiple otheratherosclerotic cardiovascular dis-ease risk factors, clinical judgmentis required. E

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 bothfor patients with diabetes and for patientswithout diabetes (76,77). Previous ran-domized controlled trials of aspirin specif-ically in patients with diabetes failed toconsistently show a significant reductionin overall ASCVD end points, raising ques-tions about the efficacy of aspirin for pri-mary prevention in people with diabetes,although some sex differences were sug-gested (78–80).The Antithrombotic Trialists’ (ATT)

collaborators published an individualpatient-level meta-analysis of the sixlarge trials of aspirin for primary pre-vention in the general population. Thesetrials collectively enrolled over 95,000participants, including almost 4,000with diabetes. Overall, they found thataspirin reduced the risk of serious

vascular events by 12% (RR 0.88 [95%CI 0.82–0.94]). The largest reductionwas for nonfatal MI, with little effecton CHD death (RR 0.95 [95% CI 0.78–1.15]) or total stroke. There was someevidence of a difference in aspirin effectby sex: aspirin significantly reducedASCVD events in men but not in women.Conversely, aspirin had no effect onstroke in men but significantly reducedstroke in women. However, there wasno heterogeneity of effect by sex in therisk of serious vascular events (P 5 0.9).

Sex differences in aspirin’s effectshave not been observed in studies ofsecondary prevention (76). In the six tri-als examined by the ATT collaborators,the effects of aspirin on major vascularevents were similar for patients with orwithout diabetes: RR 0.88 (95% CI 0.67–1.15) and RR 0.87 (95% CI 0.79–0.96),respectively. The confidence intervalwas wider for those with diabetes be-cause of smaller numbers.

Aspirin appears to have a modest ef-fect on ischemic vascular events, withthe absolute decrease in events depend-ing on the underlying ASCVD risk. Themain adverse effects appear to be anincreased risk of gastrointestinal bleed-ing. The excess risk may be as high as1–5 per 1,000 per year in real-worldsettings. In adults with ASCVD risk .1%per year, the number of ASCVDevents pre-ventedwill be similar to or greater than thenumber of episodes of bleeding induced,although these complications do not haveequal effects on long-term health (81).

Treatment ConsiderationsIn 2010, a position statement of theADA, the American Heart Association,and the American College of Cardiol-ogy Foundation recommended thatlow-dose (75–162 mg/day) aspirin forprimary prevention is reasonable foradults with diabetes and no previoushistory of vascular disease who are atincreased ASCVD risk and who are notat increased risk for bleeding (82). Thisprevious statement included sex-specificrecommendations for use of aspirin ther-apy as primary prevention persons withdiabetes. However, since that time,multiple recent well-conducted studiesand meta-analyses have reported a riskof heart disease and stroke that isequivalent if not higher in women com-paredwithmenwith diabetes, includingamong nonelderly adults. Thus, current

recommendations for using aspirin asprimary prevention include both menand women aged$50 years with diabe-tes and at least one additional majorrisk factor (family history of prematureASCVD, hypertension, dyslipidemia,smoking, or chronic kidney disease/albuminuria) who are not at increasedrisk of bleeding (83–86). While risk calcu-lators such as those from the AmericanCollege of Cardiology/American Heart As-sociation (http://my.americanheart.org)may be a useful tool to estimate 10-yearASCVD risk, diabetes itself confers in-creased risk for ASCVD. As a result, suchrisk calculators have limited utility in help-ing to assess the potential benefits of as-pirin therapy in individuals with diabetes.Noninvasive imaging techniques such ascoronary computed tomography angiog-raphy may potentially help further tailoraspirin therapy, particularly in those atlow risk (87), but are not generally recom-mended. Sex differences in the antiplate-let effect of aspirin have been suggestedin the general population (88); however,further studies are needed to investigatethe presence of such differences in indi-viduals 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)as the low benefit is likely to be out-weighed by the risks of bleeding. Clinicaljudgment should be used for those atintermediate risk (younger patientswith one or more risk factors or olderpatients with no risk factors) until fur-ther research is available. Patients’ will-ingness to undergo long-term aspirintherapy should also be considered(89). Aspirin use in patients aged ,21years is generally contraindicated dueto the associated risk of Reye syndrome.

Aspirin DosingAverage daily dosages used in mostclinical trials involving patients with di-abetes ranged from 50 mg to 650 mgbut were mostly in the range of 100–325 mg/day. There is little evidence tosupport any specific dose, but using thelowest possible dose may help to re-duce side effects (90). In the U.S., themost common low-dose tablet is 81 mg.Although platelets from patients withdiabetes have altered function, it is

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unclear what, if any, effect that findinghas on the required dose of aspirin forcardioprotective effects in the patientwith diabetes. Many alternate pathwaysfor platelet activation exist that are in-dependent of thromboxane A2 and thusnot sensitive to the effects of aspirin(91). “Aspirin resistance” has been de-scribed in patients with diabetes whenmeasured by a variety of ex vivo andin vitro methods (platelet aggregometry,measurement of thromboxane B2) (88),but other studies suggest no impairmentin aspirin response among patients withdiabetes (92). A recent trial suggestedthat more frequent dosing regimens ofaspirin may reduce platelet reactivity inindividuals with diabetes (93); however,these observations alone are insuffi-cient to empirically recommend thathigher doses of aspirin be used in thisgroup at this time. It appears that 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 ACSand may have benefits beyond thisperiod. Evidence supports use of eitherticagrelor or clopidogrel if no percuta-neous coronary intervention was per-formed and clopidogrel, ticagrelor, orprasugrel if a percutaneous coronaryintervention was performed (94). In pa-tients with diabetes and prior MI (1–3years before), adding ticagrelor to as-pirin significantly reduces the risk ofrecurrent ischemic events including car-diovascular and coronary heart diseasedeath (95). More studies are needed toinvestigate the longer-term benefits ofthese therapies after ACS among pa-tients with diabetes.

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: atypicalcardiac symptoms (e.g., unexplaineddyspnea, chest discomfort); signs

or symptoms of associated vasculardisease including carotidbruits, tran-sient ischemic attack, stroke, claudi-cation, or peripheral arterial disease;or electrocardiogram abnormalities(e.g., Q waves). E

Treatmentc In patients with known atheroscle-

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

c In patients with prior myocardialinfarction, b-blockers should becontinued for at least 2 years afterthe event. B

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

c In patients with type 2 diabeteswith stable congestive heart failure,metforminmay be used if estimatedglomerular filtration remains .30mL/minbut should be avoided in un-stable or hospitalized patients withcongestive heart failure. B

Cardiac TestingCandidates for advanced or invasive car-diac testing include those with 1) typicalor atypical cardiac symptoms and 2) anabnormal resting electrocardiogram(ECG). Exercise ECG testing without orwith echocardiography may be used asthe initial test. In adults with diabetes$40 years of age, measurement of cor-onary artery calcium is also reason-able for cardiovascular risk assessment.Pharmacologic stress echocardiographyor nuclear imaging should be consideredin individuals with diabetes in whomresting ECG abnormalities preclude ex-ercise stress testing (e.g., left bundlebranch block or ST-T abnormalities). Inaddition, individuals who require stresstesting and are unable to exerciseshould undergo pharmacologic stressechocardiography or nuclear imaging.

Screening Asymptomatic PatientsThe screening of asymptomatic pa-tients with high ASCVD risk is not rec-ommended (96), in part because thesehigh-risk patients should already be re-ceiving intensive medical therapydanapproach that provides similar benefitas invasive revascularization (97,98).There is also some evidence that silent

MI may reverse over time, adding tothe controversy concerning aggressivescreening strategies (99). In prospectivetrials, coronary artery calcium has beenestablished as an independent predictorof future ASCVD events in patients withdiabetes and is superior to both the UKProspective Diabetes Study (UKPDS) riskengine and the Framingham Risk Scorein predicting risk in this population(100–102). However, a randomized ob-servational trial demonstrated no clini-cal benefit to routine screening ofasymptomatic patients with type 2 dia-betes and normal ECGs (103). Despiteabnormal myocardial perfusion imagingin more than one in five patients, cardiacoutcomes were essentially equal (andvery low) in screened versus unscreenedpatients. Accordingly, indiscriminatescreening is not considered cost-effective.Studies have found that a risk factor–based approach to the initial diagnosticevaluation and subsequent follow-up forcoronary artery disease fails to identifywhich patients with type 2 diabetes willhave silent ischemia on screening tests(104,105). 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 withdiabetes with higher coronary diseaseburden have more future cardiac events(100,106,107), the role of these tests be-yond risk stratification is not clear. Theirroutine use leads to radiation exposureand may result in unnecessary invasivetesting such as coronary angiographyand revascularization procedures. The ul-timate balance of benefit, cost, and risksof such an approach in asymptomatic pa-tients remains controversial, particularlyin the modern setting of aggressiveASCVD risk factor control.

Lifestyle and PharmacologicInterventionsIntensive 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(108). Patients at increased ASCVD riskshould receive aspirin and a statin andACE inhibitor or ARB therapy if the

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patient has hypertension, unless thereare contraindications to a particulardrug class. While clear benefit existsfor ACE inhibitor and ARB therapy in pa-tients with nephropathy or hyperten-sion, the benefits in patients withASCVD in the absence of these condi-tions are less clear, especially whenLDL cholesterol is concomitantly con-trolled (109,110). In patients with priorMI, b-blockers should be continued forat least 2 years after the event (111).

Diabetes and Heart FailureAs many as 50% of patients with type 2diabetes may develop heart failure (112).Data on the effects of glucose-loweringagents on heart failure outcomes havedemonstrated that thiazolidinedioneshave a strong and consistent relation-ship with heart failure (113–115). There-fore, thiazolidinedione use should beavoided in patients with symptomaticheart failure.Recent studies have also examined

the relationship between dipeptidylpeptidase 4 (DPP-4) inhibitors and heartfailure and have had mixed results. TheSaxagliptin Assessment of Vascular Out-comes Recorded in Patients with DiabetesMellitus–Thrombolysis in Myocardial In-farction 53 (SAVOR-TIMI 53) study showedthat patients treated with saxagliptin(a DPP-4 inhibitor) were more likely tobe hospitalized for heart failure thanwere those given placebo (3.5% vs. 2.8%,respectively) (116). Two other recentmulticenter, randomized, double-blind,noninferiority trials, Examination of Car-diovascular Outcomes with Alogliptinversus Standard of Care (EXAMINE) andTrial Evaluating Cardiovascular Out-comes with Sitagliptin (TECOS), did notshow associations between DPP-4 inhib-itor use and heart failure. EXAMINE re-ported that the hospital admission ratefor heart failure was 3.1% for patientsrandomly assigned to alogliptin com-pared with 2.9% for those randomly as-signed to placebo (hazard ratio 1.07[95% CI 0.79–1.46]) (117). Alogliptin hadno effect on the composite end point ofcardiovascular death and hospital admis-sion for heart failure in the post hoc anal-ysis (hazard ratio 1.00 [95% CI 0.82–1.21])(117). TECOS showed a nonsignificant dif-ference in the rate of heart failure hospi-talization for the sitagliptin group (3.1%;1.07 per 100 person-years) compared

with the placebo group (3.1%; 1.09 per100 person-years) (118).

Antihyperglycemic Therapies andCardiovascular OutcomesRecently published cardiovascular out-come trials have provided additionaldata on cardiovascular outcomes inpatients with type 2 diabetes with car-diovascular disease or at high risk forcardiovascular disease. The BI 10773(Empagliflozin) Cardiovascular OutcomeEvent Trial in Type 2 Diabetes MellitusPatients (EMPA-REG OUTCOME) was arandomized, double-blind trial thatassessed the effect of empagliflozin, asodium–glucose cotransporter 2 (SGLT2)inhibitor, versus placebo and standardcare on cardiovascular outcomes in pa-tients with type 2 diabetes and existingcardiovascular disease. Study partici-pants had a mean age of 63 years, 57%had diabetes for more than 10 years, and99% had established cardiovascular dis-ease. EMPA-REG OUTCOME showed thatover a median follow-up of 3.1 years,treatment reduced the composite out-come of MI, stroke, and cardiovasculardeath by 14% (absolute rate 10.5% vs.12.1% in the placebo group) and cardio-vascular death by 38% (absolute rate3.7% vs. 5.9%) (119). The FDA recentlyadded a new indication for empagliflozin,to reduce the risk of cardiovascular deathin adults with type 2 diabetes and cardio-vascular disease. Whether other SGLT2inhibitors will have the same effect inhigh-risk patients andwhether empagliflo-zin or other SGLT2 inhibitors will have asimilar effect in lower-risk patients withdiabetes remains unknown.

The Liraglutide Effect and Action in Di-abetes: Evaluation of Cardiovascular Out-come ResultsdA Long Term Evaluation(LEADER) trial was a randomized, double-blind trial that assessed the effect ofliraglutide, a glucagon-like peptide 1 recep-tor agonist, versus placebo and standardcareoncardiovascularoutcomes inpatientswith type 2 diabetes at high risk for cardio-vascular disease or with cardiovascular dis-ease. Study participants had a mean age of64years andameandurationofdiabetesofnearly 13 years. Over 80% of study partici-pants had established cardiovascular dis-ease inclusive of a prior MI, prior strokeor transient ischemic attack, prior revascu-larization procedure, or $50% stenosis ofcoronary, carotid, or lower-extremity ar-teries. LEADER showed that the composite

primary outcome (MI, stroke, or cardiovas-cular death) occurred in fewer participantsin the treatment group (13.0%) when com-pared with the placebo group (14.9%) aftera median follow-up of 3.8 years (120).Whether other glucagon-like peptide 1 re-ceptor agonists will have the same effectin high-risk patients or if this drug classwill have similar effects in lower-risk pa-tients with diabetes remains unknown.

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