10. Cardiovascular Disease andRisk Management: Standards ofMedical Care in Diabetesd2020Diabetes Care 2020;43(Suppl. 1):S111–S134 | https://doi.org/10.2337/dc20-s010

The American Diabetes Association (ADA) “Standards of Medical Care in Diabe-tes” includes theADA’s currentclinicalpractice recommendationsand is intendedtoprovide the components of diabetes care, general treatment goals and guidelines,and tools to evaluate quality of care. Members of the ADA Professional PracticeCommittee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or morefrequently aswarranted. For a detailed descriptionofADAstandards, statements,and reports, as well as the evidence-grading system for ADA’s clinical practicerecommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Careare invited to do so at professional.diabetes.org/SOC.

For prevention and management of diabetes complications in children and adoles-cents, please refer to Section 13 “Children andAdolescents” (https://doi.org/10.2337/dc20-S013).

Atherosclerotic cardiovascular disease (ASCVD)ddefined as coronary heart disease(CHD), cerebrovascular disease, or peripheral arterial disease presumed to be ofatherosclerotic origindis the leading cause of morbidity and mortality for individualswith diabetes and results in an estimated $37.3 billion in cardiovascular-related spendingper year associatedwith diabetes (1). Common conditions coexistingwith type 2 diabetes(e.g., hypertension and dyslipidemia) are clear risk factors for ASCVD, and diabetes itselfconfers independent risk. Numerous studies have shown the efficacy of controllingindividual cardiovascular risk factors in preventing or slowing ASCVD in people withdiabetes.Furthermore, largebenefitsareseenwhenmultiplecardiovascularriskfactorsareaddressed simultaneously. Under the current paradigm of aggressive risk factor mod-ification in patients with diabetes, there is evidence that measures of 10-year coronaryheart disease (CHD) risk amongU.S. adults with diabetes have improved significantly overthe past decade (2) and that ASCVD morbidity and mortality have decreased (3,4).Heart failure is another major cause of morbidity and mortality from cardiovascu-

lar disease. Recent studies have found that rates of incident heart failure hospitalization(adjustedforageandsex)weretwofoldhigherinpatientswithdiabetescomparedwiththosewithout (5,6). People with diabetesmay have heart failure with preserved ejection fraction(HFpEF) orwith reducedejection fraction (HFrEF). Hypertension is oftenaprecursor of heartfailure of either type, and ASCVD can coexist with either type (7), whereas prior myocardialinfarction (MI) is often a major factor in HFrEF. Rates of heart failure hospitalization havebeen improved in recent trials including patients with type 2 diabetes, most of whom alsohad ASCVD, with sodium–glucose cotransporter 2 (SGLT2) inhibitors (8–10).For prevention and management of both ASCVD and heart failure, cardio-

vascular risk factors should be systematically assessed at least annually in all patients

This section has received endorsement from theAmerican College of Cardiology.

Suggested citation: American Diabetes Asso-ciation. 10. Cardiovascular disease and riskmanagement: Standards of Medical Care inDiabetesd2020. Diabetes Care 2020;43(Suppl.1):S111–S134

© 2019 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 43, Supplement 1, January 2020 S111

10.CARDIOVASCULA

RDISEA

SEANDRISK

MANAGEM

ENT

with diabetes. These risk factors in-clude obesity/overweight, hyperten-sion, dyslipidemia, smoking, a familyhistory of premature coronary disease,chronic kidney disease, and the pres-ence of albuminuria. Modifiable abnor-mal risk factors should be treated asdescribed in these guidelines.

THE RISK CALCULATOR

The American College of Cardiology/American Heart Association ASCVD riskcalculator (Risk Estimator Plus) is generallya useful tool to estimate 10-year ASCVDrisk (available online at tools.acc.org/ASCVD-Risk-Estimator-Plus). The calcu-lator includes diabetes as a risk factor,since diabetes itself confers increased riskforASCVD, although it should beacknowl-edged that these risk calculators do notaccount for thedurationofdiabetesor thepresence of diabetes complications, suchas albuminuria. Although some variabilityin calibration exists in various subgroups,including by sex, race, and diabetes, theoverall risk prediction does not differ inthose with or without diabetes (11–14),validating the use of risk calculators inpeoplewithdiabetes. The10-year risk of afirst ASCVD event should be assessed tobetter stratify ASCVD risk and help guidetherapy, as described below.Recently, risk scores and other car-

diovascular biomarkers have been devel-oped for risk stratification of secondaryprevention patients (i.e., those who arealready high risk because they haveASCVD) but are not yet in widespreaduse (15,16).With newer,more expensivelipid-lowering therapies now available,use of these risk assessments may helptarget these new therapies to “higherrisk” ASCVD patients in the future.

HYPERTENSION/BLOOD PRESSURECONTROL

Hypertension, defined as a sustainedblood pressure$140/90 mmHg, is com-mon among patients with either type 1or type 2 diabetes. Hypertension is amajor risk factor for both ASCVD andmicrovascular complications. Moreover,numerous studies have shown that anti-hypertensive therapy reduces ASCVDevents, heart failure, and microvascularcomplications. Please refer to the Amer-ican Diabetes Association (ADA) positionstatement “Diabetes and Hyperten-sion” for a detailed review of the

epidemiology, diagnosis, and treatmentof hypertension (17).

Screening and Diagnosis

Recommendations

10.1 Blood pressure should be mea-sured at every routine clinicalvisit. Patients found to have el-evatedbloodpressure ($140/90mmHg) should have blood pres-sure confirmed using multiplereadings, including measure-ments on a separate day, todiagnose hypertension. B

10.2 All hypertensive patients withdiabetes should monitor theirblood pressure at home. B

Blood pressure should be measured atevery routine clinical visit by a trainedindividual and should follow theguidelines established for the general pop-ulation: measurement in the seated posi-tion, with feet on the floor and armsupported at heart level, after 5 min ofrest. Cuff size should be appropriate for theupper-arm circumference. Elevated valuesshould be confirmed on a separate day.Postural changes in blood pressure andpulse may be evidence of autonomic neu-ropathy and therefore require adjustmentofbloodpressuretargets.Orthostaticbloodpressuremeasurements shouldbecheckedon initial visit and as indicated.

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 (17). Inaddition to confirming or refuting a di-agnosis of hypertension, home bloodpressure assessment may be useful tomonitor antihypertensive treatment.Studies of individuals without diabetesfound that home measurements maybetter correlate with ASCVD risk thanoffice measurements (18,19). Moreover,home blood pressure monitoring mayimprove patient medication adherenceand thus help reduce cardiovascularrisk (20).

Treatment Goals

Recommendations

10.3 For patients with diabetes andhypertension, blood pressuretargets should be individual-ized through a shared decision-

making process that addressescardiovascular risk, potentialadverse effects of antihyper-tensive medications, and pa-tient preferences. C

10.4 For individuals with diabetesand hypertension at higher car-diovascular risk (existingathero-sclerotic cardiovascular disease[ASCVD] or 10-year ASCVD risk$15%), a bloodpressure targetof ,130/80 mmHg may be ap-propriate, if it can be safelyattained. C

10.5 For individuals with diabetesand hypertension at lower riskfor cardiovascular disease (10-year atherosclerotic cardio-vascular disease risk ,15%),treat to a blood pressure targetof ,140/90 mmHg. A

10.6 In pregnant patients with dia-betes and preexisting hyperten-sion, a blood pressure targetof#135/85 mmHg is suggestedin the interest of reducing therisk for accelerated maternalhypertension A and minimizingimpaired fetal growth. E

Randomized clinical trials have demon-strated unequivocally that treatment ofhypertension tobloodpressure,140/90mmHg reduces cardiovascular eventsas well as microvascular complications(21–27). Therefore, patients with type 1or type 2 diabetes who have hyperten-sion should, at a minimum, be treatedto blood pressure targets of ,140/90mmHg. The benefits and risks of inten-sifying antihypertensive therapy to tar-get blood pressures lower than ,140/90mmHg (e.g., ,130/80 or ,120/80mmHg) have been evaluated in largerandomized clinical trials and meta-analyses of clinical trials. Notably, thereis an absence of high-quality data avail-able to guide blood pressure targets intype 1 diabetes.

Randomized Controlled Trials of Intensive

Versus Standard Blood Pressure Control

The Action to Control Cardiovascular Riskin Diabetes Blood Pressure (ACCORD BP)trial provides the strongest direct assess-ment of the benefits and risks of intensiveblood pressure control among peoplewith type 2 diabetes (28). In ACCORDBP, compared with standard blood

S112 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

pressure control (target systolic bloodpressure ,140 mmHg), intensive bloodpressure control (target systolic bloodpressure ,120 mmHg) did not reducetotal major atherosclerotic cardiovascu-lar events but did reduce the risk ofstroke, at the expense of increased ad-verse events (Table 10.1). The ACCORDBP results suggest that blood pressuretargets more intensive than ,140/90mmHg are not likely to improve car-diovascular outcomes among mostpeople with type 2 diabetes but maybe reasonable for patients who mayderive the most benefit and havebeen educated about added treatmentburden, side effects, and costs, as dis-cussed below.Additional studies, such as the Sys-

tolic Blood Pressure Intervention Trial(SPRINT) and the HypertensionOptimalTreatment (HOT) trial, also examinedeffects of intensive versus standardcontrol (Table 10.1), though the

relevance of their results to peoplewith diabetes is less clear. The Actionin Diabetes and Vascular Disease: Pre-terax and Diamicron MR ControlledEvaluation–Blood Pressure (ADVANCEBP) trial did not explicitly test bloodpressure targets (29); the achievedblood pressure in the interventiongroup was higher than that achievedin the ACCORD BP intensive arm andwould be consistent with a targetblood pressure of ,140/ 90 mmHg.Notably, ACCORD BP and SPRINT mea-sured blood pressure using automatedoffice blood pressure measurement,which yields values that are generallylower than typical office blood pres-sure readings by approximately 5–10mmHg (30), suggesting that im-plementing the ACCORD BP or SPRINTprotocols in an outpatient clinic mightrequire a systolic blood pressure tar-get higher than ,120 mmHg, such as,130 mmHg.

A number of post hoc analyses haveattempted to explain the apparentlydivergent results of ACCORD BP andSPRINT. Some investigators have arguedthat the divergent results are not due todifferences between peoplewith andwith-out diabetes but rather are due to differ-ences in study design or to characteristicsother than diabetes (31–33). Others haveopined that the divergent results are mostreadily explained by the lack of benefit ofintensive blood pressure control on cardio-vascular mortality in ACCORD BP, whichmay be due to differential mechanismsunderlying cardiovascular disease in type2 diabetes, to chance, or both (34).

Meta-analyses of Trials

To clarify optimal blood pressure targetsin patients with diabetes, meta-analyseshave stratified clinical trials by meanbaseline blood pressure or mean bloodpressure attained in the intervention (orintensive treatment) arm. Based on these

Table 10.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies

Clinical trial Population Intensive Standard Outcomes

ACCORD BP (28) 4,733 participants withT2D aged 40–79 yearswith prior evidenceof CVD or multiplecardiovascular riskfactors

SBP target:,120 mmHg

Achieved (mean)SBP/DBP:119.3/64.4 mmHg

SBP target:130–140 mmHg

Achieved (mean)SBP/DBP:13.5/70.5 mmHg

c No benefit in primary end point: compositeof nonfatal MI, nonfatal stroke, and CVDdeath

c Stroke risk reduced 41% with intensivecontrol, not sustained through follow-upbeyond the period of active treatment

c Adverse events more common in intensivegroup, particularly elevated serumcreatinine and electrolyte abnormalities

ADVANCE BP (29) 11,140 participantswith T2D aged55 years and olderwith prior evidenceof CVD or multiplecardiovascular riskfactors

Intervention: a single-pill,fixed-dose combinationof perindopril andindapamide

Achieved (mean)SBP/DBP:136/73 mmHg

Control: placeboAchieved (mean)SBP/DBP:141.6/75.2 mmHg

c Intervention reduced risk of primarycomposite end point of majormacrovascular and microvascular events(9%), death from any cause (14%), anddeath from CVD (18%)

c 6-year observational follow-up foundreduction in risk of death in interventiongroup attenuated but still significant (174)

HOT (185) 18,790 participants,including 1,501with diabetes

DBP target:#80 mmHg

DBP target:#90 mmHg

c In the overall trial, there was nocardiovascular benefit with more intensivetargets

c In the subpopulation with diabetes, anintensive DBP target was associated witha significantly reduced risk (51%) of CVDevents

SPRINT (39) 9,361 participantswithout diabetes

SBP target:,120 mmHg

Achieved (mean):121.4 mmHg

SBP target:,140 mmHg

Achieved (mean):136.2 mmHg

c Intensive SBP target lowered risk of theprimary composite outcome 25% (MI, ACS,stroke, heart failure, and death due to CVD)

c Intensive target reduced risk of death 27%c Intensive therapy increased risks ofelectrolyte abnormalities and AKI

ACCORD BP, Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial; ACS, acute coronary syndrome; ADVANCE BP, Action in Diabetesand Vascular Disease: Preterax and Diamicron MR Controlled Evaluation–Blood Pressure trial; AKI, acute kidney injury; CVD, cardiovasculardisease; DBP, diastolic blood pressure; HOT, Hypertension Optimal Treatment trial; MI, myocardial infarction; SBP, systolic blood pressure; SPRINT,Systolic Blood Pressure Intervention Trial; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes andHypertension” (17).

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analyses, antihypertensive treatment ap-pears to be beneficial when mean base-line blood pressure is$140/90mmHg ormean attained intensive blood pressureis $130/80 mmHg (17,21,22,24–26).Among trials with lower baseline orattained blood pressure, antihyperten-sive treatment reduced the risk of stroke,retinopathy, and albuminuria, but effectson other ASCVD outcomes and heartfailurewere not evident. Taken together,these meta-analyses consistently showthat treating patients with baseline bloodpressure $140 mmHg to targets ,140mmHg isbeneficial,whilemore-intensivetargets may offer additional (thoughprobably less robust) benefits.

Individualization of Treatment Targets

Patients and clinicians should engage ina shared decision-making process to de-termine individual blood pressure tar-gets (17). This approach acknowledgesthat the benefits and risks of intensiveblood pressure targets are uncertain andmay vary across patients and is consis-tent with a patient-focused approach tocare that values patient priorities andprovider judgment (35). Secondary anal-yses of ACCORD BP and SPRINT suggestthat clinical factors can help determineindividuals more likely to benefit andless likely to be harmed by intensiveblood pressure control (36).Absolute benefit from blood pres-

sure reduction correlated with absolutebaseline cardiovascular risk in SPRINTand in earlier clinical trials conductedat higher baseline blood pressure levels(11,37). Extrapolation of these studiessuggests that patients with diabetesmay also be more likely to benefitfrom intensive blood pressure controlwhen they have high absolute cardio-vascular risk. Therefore, it may be rea-sonable to target blood pressure,130/80 mmHg among patients withdiabetes and either clinically diag-nosed cardiovascular disease (particu-larly stroke, which was significantlyreduced in ACCORD BP) or 10-yearASCVD risk $15%, if it can be attainedsafely. This approach is consistent withguidelines from the American College ofCardiology/American Heart Association,which advocate a blood pressure target,130/80 mmHg for all patients, with orwithout diabetes (38).Potential adverse effects of antihyper-

tensive therapy (e.g., hypotension,

syncope, falls, acute kidney injury, andelectrolyte abnormalities) should also betaken into account (28,39–41). Patientswith older age, chronic kidney disease,and frailty have been shown to be athigher risk of adverse effects of intensiveblood pressure control (41). In addition,patients with orthostatic hypotension,substantial comorbidity, functional lim-itations, or polypharmacy may be at highrisk of adverse effects, and somepatientsmay prefer higher blood pressure targetsto enhance quality of life. Patients withlow absolute cardiovascular risk (10-yearASCVD risk ,15%) or with a history ofadverse effects of intensive blood pres-sure control or at high risk of suchadverse effects should have a higherblood pressure target. In such patients,a blood pressure target of ,140/90mmHg is recommended, if it can be safelyattained.

Pregnancy and Antihypertensive

Medications

There are few randomized controlledtrials of antihypertensive therapy in preg-nant women with diabetes. A 2014Cochrane systematic review of antihy-pertensive therapy for mild to moder-ate chronic hypertension that included49 trials and over 4,700 women did notfind any conclusive evidence for oragainst blood pressure treatment toreduce the risk of preeclampsia forthe mother or effects on perinatal out-comes such as preterm birth, small-for-gestational-age infants, or fetal death(42). The more recent Control of Hyper-tension in Pregnancy Study (CHIPS) (43)enrolled mostly women with chronichypertension. In CHIPS, targeting a di-astolic blood pressure of 85 mmHg dur-ing pregnancy was associated withreduced likelihood of developing accel-erated maternal hypertension and nodemonstrable adverse outcome for in-fants compared with targeting a higherdiastolic blood pressure. The mean sys-tolic blood pressure achieved in themore intensively treated group was133.1 6 0.5 mmHg, and the mean di-astolic blood pressure achieved in thatgroup was 85.36 0.3 mmHg. Therefore,current evidence supports controllingblood pressure to these levels, with atarget of #135/85 mmHg. A similarapproach is supported by the Interna-tional Society for the Study of Hyperten-sion in Pregnancy, which specifically

recommends use of antihypertensivetherapy to maintain systolic blood pres-sure between 110 and 140 mmHg anddiastolic blood pressure between 80 and85 mmHg (44).

During pregnancy, treatmentwithACEinhibitors, angiotensin receptor blockers(ARBs), and spironolactone are contra-indicated as they may cause fetal dam-age. Antihypertensive drugs known to beeffective and safe in pregnancy includemethyldopa, labetalol, and long-actingnifedipine, while hydralzine may be con-sidered in the acute management ofhypertension in pregnancy or severepreeclampsia (45). Diuretics are not rec-ommended for blood pressure control inpregnancy but may be used during late-stage pregnancy if needed for volumecontrol (45,46). The American College ofObstetricians and Gynecologists also rec-ommends that postpartum patients withgestational hypertension, preeclampsia,and superimposed preeclampsia havetheir blood pressures observed for72 h in the hospital and for 7–10 dayspostpartum. Long-term follow-up is rec-ommended for these women as theyhave increased lifetime cardiovascularrisk (47). See Section 14 “Managementof Diabetes in Pregnancy” (https://doi.org/10.2337/dc20-S014) for additionalinformation.

Treatment Strategies

Lifestyle Intervention

Recommendation

10.7 Forpatientswithbloodpressure.120/80 mmHg, lifestyle inter-vention consists of weight loss ifoverweight or obese, a DietaryApproaches to Stop Hyperten-sion (DASH)-style eating patternincluding reducing sodium andincreasing potassium intake,moderation of alcohol intake,and increasedphysical activity.A

Lifestyle management is an importantcomponent of hypertension treatmentbecause it lowers blood pressure, enhan-ces the effectiveness of some antihyper-tensive medications, promotes otheraspects ofmetabolic and vascular health,andgenerally leads to fewadverseeffects.Lifestyle therapy consists of reducing ex-cess body weight through caloric restric-tion, restricting sodium intake (,2,300mg/day), increasing consumption of fruits

S114 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

and vegetables (8–10 servings per day)and low-fat dairy products (2–3 servingsper day), avoiding excessive alcohol con-sumption (no more than 2 servings perday inmenandnomore than1 servingperday in women) (48), and increasing ac-tivity levels (49).These lifestyle interventions are rea-

sonable for individuals with diabetes andmildly elevated blood pressure (systolic.120 mmHg or diastolic .80 mmHg)and should be initiated along with phar-macologic therapy when hypertension isdiagnosed (Fig. 10.1) (49). A lifestyletherapy plan should be developed incollaboration with the patient and dis-cussed as part of diabetes management.

Pharmacologic Interventions

Recommendations

10.8 Patients with confirmed office-based blood pressure $140/90 mmHg should, in additionto lifestyle therapy, have promptinitiation and timely titration ofpharmacologic therapy to achieveblood pressure goals. A

10.9 Patients with confirmed office-based blood pressure $160/100 mmHg should, in additionto lifestyle therapy, have promptinitiation and timely titration oftwo drugs or a single-pill combi-nation of drugs demonstrated toreduce cardiovascular events inpatients with diabetes. A

10.10 Treatment for hypertensionshould include drug classesdemonstrated to reduce cardio-vascular events in patients withdiabetes (ACE inhibitors, angioten-sin receptor blockers, thiazide-likediuretics, or dihydropyridine cal-cium channel blockers). A

10.11 Multiple-drug therapy is gener-ally required to achieve bloodpressure targets. However, com-binations of ACE inhibitors andangiotensin receptor blockersand combinations of ACE inhib-itors or angiotensin receptorblockers with direct renin inhib-itors should not be used. A

10.12 An ACE inhibitor or angiotensinreceptor blocker, at the maxi-mum tolerated dose indicatedfor blood pressure treatment,is the recommended first-linetreatment for hypertension in

patients with diabetes and uri-nary albumin-to-creatinine ra-tio $300 mg/g creatinine A or30–299 mg/g creatinine. B Ifone class is not tolerated, theother should be substituted. B

10.13 For patients treatedwith an ACEinhibitor, angiotensin receptorblocker, or diuretic, serum cre-atinine/estimated glomerular fil-tration rate and serum potassiumlevels should be monitored atleast annually. B

Initial Number of Antihypertensive

Medications. Initial treatment for peoplewith diabetes depends on the severityof hypertension (Fig. 10.1). Those withblood pressure between 140/90 mmHgand 159/99 mmHg may begin with asingle drug. For patients with bloodpressure $160/100 mmHg, initial phar-macologic treatment with two antihy-pertensivemedications is recommendedin order to more effectively achieveadequate blood pressure control (50–52).Single-pill antihypertensive combinationsmay improve medication adherence insome patients (53).Classes of Antihypertensive Medications.

Initial treatment for hypertension shouldinclude any of the drug classes demon-strated to reduce cardiovascular eventsin patients with diabetes: ACE inhibitors(54,55), ARBs (54,55), thiazide-like di-uretics (56), or dihydropyridine calciumchannel blockers (57). For patientswith albuminuria (urine albumin-to-creatinine ratio [UACR]$30mg/g), initialtreatment should include an ACE inhib-itor or ARB in order to reduce the riskof progressive kidney disease (17) (Fig.10.1). In the absence of albuminuria,risk of progressive kidney disease islow, and ACE inhibitors and ARBs havenot been found to afford superiorcardioprotection when compared withthiazide-like diuretics or dihydropyridinecalcium channel blockers (58). b-Blockersmay be used for the treatment of priorMI, active angina, or heart failure buthavenot been shown to reducemortalityas blood pressure–lowering agents in theabsence of these conditions (23,59).Multiple-Drug Therapy. Multiple-drugtherapy is often required to achieveblood pressure targets (Fig. 10.1), par-ticularly in the setting of diabetic kidneydisease. However, the use of both ACEinhibitors and ARBs in combination, or

the combination of an ACE inhibitor orARB and a direct renin inhibitor, is notrecommended given the lack of addedASCVD benefit and increased rate ofadverse eventsdnamely, hyperkalemia,syncope, and acute kidney injury (AKI)(60–62). Titration of and/or addition offurther blood pressure medicationsshould be made in a timely fashion toovercome clinical inertia in achievingblood pressure targets.Bedtime Dosing. Growing evidence sug-gests that there is an association be-tween the absence of nocturnal bloodpressure dipping and the incidence ofASCVD. A meta-analysis of randomizedclinical trials found a small benefit ofevening versus morning dosing of anti-hypertensive medications with regard toblood pressure control but had no dataon clinical effects (63). In two subgroupanalyses of a single subsequent random-ized controlled trial, moving at least oneantihypertensive medication to bedtimesignificantly reduced cardiovascular events,but results were based on a small num-ber of events (64).Hyperkalemia and Acute Kidney Injury.

Treatment with ACE inhibitors or ARBscan cause AKI and hyperkalemia, whilediuretics can cause AKI and either hypo-kalemia or hyperkalemia (depending onmechanism of action) (65,66). Detectionand management of these abnormalitiesis important because AKI and hyperkale-mia each increase the risks of cardiovas-cular events and death (67). Therefore,serum creatinine and potassium shouldbe monitored during treatment with anACE inhibitor,ARB,ordiuretic, particularlyamong patients with reduced glomerularfiltration who are at increased risk ofhyperkalemia and AKI (65,66,68).

Resistant Hypertension

Recommendation

10.14 Patients with hypertension whoare not meeting blood pres-sure targets on three classesof antihypertensive medica-tions (including a diuretic)should be considered for min-eralocorticoid receptor antag-onist therapy. B

Resistant hypertension is defined asblood pressure $140/90 mmHg despitea therapeutic strategy that includes ap-propriate lifestyle management plus adiuretic and two other antihypertensive

care.diabetesjournals.org Cardiovascular Disease and Risk Management S115

drugs belonging to different classes atadequate doses. Prior to diagnosing re-sistant hypertension, a number of otherconditions should be excluded, including

medication nonadherence, white coathypertension, and secondary hyperten-sion. In general, barriers to medicationadherence (such as cost and side effects)

should be identified and addressed (Fig.10.1). Mineralocorticoid receptor antag-onists are effective for management ofresistant hypertension in patients with

Figure 10.1—Recommendations for the treatment of confirmedhypertension in peoplewith diabetes. *AnACE inhibitor (ACEi) or angiotensin receptorblocker (ARB) is suggested to treat hypertension for patients with urine albumin-to-creatinine ratio 30–299 mg/g creatinine and stronglyrecommended for patients with urine albumin-to-creatinine ratio $300 mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown toreduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine calcium channel blocker (CCB). BP, bloodpressure. Adapted from de Boer et al. (17).

S116 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

type 2 diabetes when added to existingtreatment with an ACE inhibitor or ARB,thiazide-like diuretic, and dihydropyri-dine calcium channel blocker (69).Mineralocorticoid receptor antagonistsalso reduce albuminuria and have addi-tional cardiovascular benefits (70–73).However, adding a mineralocorticoid re-ceptor antagonist to a regimen includingan ACE inhibitor or ARBmay increase therisk for hyperkalemia, emphasizing theimportance of regular monitoring forserum creatinine and potassium in thesepatients, and long-term outcome studiesare needed to better evaluate the role ofmineralocorticoid receptor antagonistsin blood pressure management.

LIPID MANAGEMENT

Lifestyle Intervention

Recommendations

10.15 Lifestyle modification focusingon weight loss (if indicated);applicationofaMediterraneanstyle or Dietary Approachesto Stop Hypertension (DASH)eating pattern; reduction ofsaturated fat and trans fat;increase of dietary n-3 fattyacids, viscous fiber, and plantstanols/sterols intake; and in-creased physical activity shouldbe recommended to improvethe lipid profile and reduce therisk of developing atheroscle-rotic cardiovascular disease inpatients with diabetes. A

10.16 Intensify lifestyle therapy andoptimize glycemic control forpatients with elevated triglyc-eride levels ($150 mg/dL [1.7mmol/L]) and/or low HDL cho-lesterol (,40 mg/dL [1.0mmol/L] for men, ,50 mg/dL[1.3 mmol/L] for women). C

Lifestyle intervention, including weightloss (74), increased physical activity, andmedical nutrition therapy, allows somepatients to reduce ASCVD risk factors.Nutrition intervention should be tailoredaccording to each patient’s age, diabetestype, pharmacologic treatment, lipidlevels, and medical conditions.Recommendations should focus on

application of a Mediterranean stylediet (75) or Dietary Approaches to StopHypertension (DASH) eating pattern, re-ducing saturated and trans fat intake and

increasing plant stanols/sterols, n-3 fattyacids, and viscous fiber (such as in oats,legumes, and citrus) intake (76). Glyce-mic control may also beneficially modifyplasma lipid levels, particularly in pa-tients with very high triglycerides andpoor glycemic control. See Section 5“Facilitating Behavior Change and Well-being to Improve Health Outcomes”(https://doi.org/10.2337/dc20-S010) for ad-ditional nutrition information.

Ongoing Therapy and MonitoringWith Lipid Panel

Recommendations

10.17 In adults not taking statins orother lipid-lowering therapy, itis reasonable to obtain a lipidprofile at the time of diabetesdiagnosis, at an initial medicalevaluation, and every 5 yearsthereafter if under the age of40 years, or more frequently ifindicated. E

10.18 Obtain a lipid profile at initia-tion of statins or other lipid-lowering therapy, 4–12 weeksafter initiation or a changein dose, and annually thereaf-ter as it may help to monitorthe response to therapy and in-form medication adherence. E

In adults with diabetes, it is reasonableto obtain a lipid profile (total cholesterol,LDL cholesterol, HDL cholesterol, and tri-glycerides) at the time of diagnosis, at theinitialmedical evaluation, andat least every5 years thereafter in patients under the ageof 40 years. In younger patientswith longerduration of disease (such as those withyouth-onset type 1 diabetes), more fre-quent lipid profiles may be reasonable. Alipid panel should also be obtained imme-diately before initiating statin therapy.Once a patient is taking a statin, LDLcholesterol levels should be assessed 4–12 weeks after initiation of statin therapy,after any change in dose, and on an in-dividual basis (e.g., to monitor for medica-tion adherence and efficacy). If LDLcholesterol levels are not responding inspite of medication adherence, clinicaljudgment is recommended to determinethe need for and timing of lipid panels. Inindividual patients, the highly variable LDLcholesterol–lowering response seen withstatins is poorly understood (77). Clini-cians should attempt to find a dose oralternative statin that is tolerable if side

effects occur. There is evidence for ben-efit from even extremely low, less thandaily statin doses (78).

STATIN TREATMENT

Primary Prevention

Recommendations

10.19 For patients with diabetes aged40–75 years without atheroscle-rotic cardiovascular disease, usemoderate-intensity statin ther-apy in addition to lifestyle ther-apy. A

10.20 For patients with diabetesaged 20–39 years with addi-tional atherosclerotic cardiovas-culardiseaserisk factors, itmaybereasonable to initiate statin ther-apy in addition to lifestyletherapy. C

10.21 In patients with diabetes athigher risk, especially thosewith multiple atheroscleroticcardiovascular disease risk fac-tors or aged 50–70 years, it isreasonable to use high-inten-sity statin therapy. B

10.22 In adults with diabetes and10-year atherosclerotic cardio-vascular disease risk of 20% orhigher, itmay be reasonable toadd ezetimibe to maximallytolerated statin therapy to re-duce LDL cholesterol levels by50% or more. C

Secondary Prevention

Recommendations

10.23 For patients of all ages withdiabetes and atheroscleroticcardiovascular disease, high-in-tensity statin therapy should beadded to lifestyle therapy. A

10.24 For patients with diabetes andatherosclerotic cardiovasculardisease considered very highrisk using specific criteria, ifLDL cholesterol is $70 mg/dLon maximally tolerated statindose, consider adding additionalLDL-lowering therapy (such asezetimibe or PCSK9 inhibitor).A Ezetimibe may be preferreddue to lower cost.

10.25 For patients who do not toler-ate the intended intensity, themaximally tolerated statin doseshould be used. E

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10.26 In adults with diabetes aged.75 years already on statintherapy, it is reasonable tocontinue statin treatment. B

10.27 In adults with diabetes aged.75years, it may be reasonable toinitiate statin therapy after dis-cussion of potential benefits andrisks. C

10.28 Statin therapy is contraindi-cated in pregnancy. B

Initiating Statin Therapy Based on Risk

Patients with type 2 diabetes have anincreasedprevalenceof lipid abnormalities,contributing to their high risk of ASCVD.Multiple clinical trials have demonstratedthe beneficial effects of statin therapy onASCVD outcomes in subjects with andwithout CHD (79,80). Subgroup analysesof patients with diabetes in larger trials(81–85) and trials in patients with diabetes(86,87) showed significant primary andsecondary prevention of ASCVD eventsand CHD death in patients with diabetes.Meta-analyses, including data from over18,000 patients with diabetes from 14 ran-domized trials of statin therapy (meanfollow-up 4.3 years), demonstrate a 9%proportional reduction in all-cause mortal-ity and 13% reduction in vascular mortalityfor each mmol/L (39 mg/dL) reduction inLDL cholesterol (88).Accordingly, statins are the drugs of

choice for LDL cholesterol lowering andcardioprotection. Table 10.2 shows thetwo statin dosing intensities that arerecommended for use in clinical practice:high-intensity statin therapy will achieveapproximately a $50% reduction in LDLcholesterol, and moderate-intensity sta-tin regimens achieve 30–49% reductionsin LDL cholesterol. Low-dose statin ther-apy is generally not recommended inpatients with diabetes but is sometimes

the only dose of statin that a patient cantolerate. For patients who do not toleratethe intended intensity of statin, themaximally tolerated statin dose shouldbe used.

As in those without diabetes, absolutereductions in ASCVD outcomes (CHDdeath and nonfatal MI) are greatest inpeople with high baseline ASCVD risk(known ASCVD and/or very high LDLcholesterol levels),but theoverallbenefitsof statin therapy in people with diabetesat moderate or even low risk for ASCVDare convincing (89,90). The relative ben-efit of lipid-lowering therapy has beenuniform across most subgroups tested(80,88), including subgroups that variedwith respect to age and other risk factors.

Primary Prevention (Patients Without

ASCVD)

For primary prevention,moderate-dose sta-tin therapy is recommended for those40 years and older (82,89,90), thoughhigh-intensity therapy may be consid-ered on an individual basis in the contextof additional ASCVD risk factors. Theevidence is strong for patients with di-abetes aged 40–75 years, an age-groupwell represented in statin trials showingbenefit. Since risk is enhanced in patientswith diabetes, as noted above, patientswho also have multiple other coronaryrisk factors have increased risk, equiva-lent to that of those with ASCVD. As such,recent guidelines recommend that inpatients with diabetes who are at higherrisk, especially those with multipleASCVD risk factors or aged 50–70 years,it is reasonable to prescribe high-intensitystatin therapy (12,91). Furthermore, forpatients with diabetes whose ASCVD riskis $20%, i.e., an ASCVD risk equivalent,the same high-intensity statin therapy isrecommended as for those with docu-mented ASCVD (12). In those individuals,

it may also be reasonable to add ezeti-mibe to maximally tolerated statin ther-apy if needed to reduce LDL cholesterollevels by 50% or more (12). The evidenceis lower for patients aged .75 years;relatively few older patients with diabe-tes have been enrolled in primary pre-vention trials. However, heterogeneityby age has not been seen in the relativebenefit of lipid-lowering therapy in tri-als that included older participants(80,87,88), and because older age con-fers higher risk, theabsolutebenefits areactually greater (80,92). Moderate-in-tensity statin therapy is recommendedin patients with diabetes who are 75years or older. However, the risk-benefitprofile should be routinely evaluated inthis population, with downward titra-tion of dose performed as needed. SeeSection 12 “Older Adults” (https://doi.org/10.2337/dc20-S012) for more de-tails on clinical considerations for thispopulation.Age <40 Years and/or Type 1 Diabetes. Verylittle clinical trial evidence exists forpatients with type 2 diabetes underthe age of 40 years or for patientswith type 1 diabetes of any age. Forpediatric recommendations, see Section13 “Children and Adolescents” (https://doi.org/10.2337/dc20-S013). In theHeart Protection Study (lower age limit40 years), the subgroup of;600 patientswith type 1 diabetes had a proportion-ately similar, although not statisticallysignificant, reduction in risk as patientswith type 2 diabetes (82). Even thoughthe data are not definitive, similar statintreatment approaches should be consid-ered for patients with type 1 or type 2diabetes, particularly in the presenceof other cardiovascular risk factors. Pa-tients below the age of 40 have lowerrisk of developing a cardiovascular eventover a 10-year horizon; however, theirlifetime risk of developing cardiovascu-lar disease and suffering an MI, stroke,or cardiovascular death is high. Forpatients who are younger than 40 yearsof age and/or have type 1 diabeteswith other ASCVD risk factors, it is rec-ommended that the patient and healthcare provider discuss the relative bene-fits and risks and consider the useof moderate-intensity statin therapy.Please refer to “Type 1 DiabetesMellitus and Cardiovascular Dis-ease: A Scientific Statement Fromthe American Heart Association and

Table 10.2—High-intensity and moderate-intensity statin therapy*

High-intensity statin therapy(lowers LDL cholesterol by $50%)

Moderate-intensity statin therapy(lowers LDL cholesterol by 30–49%)

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 1–4 mg

*Once-daily dosing. XL, extended release.

S118 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

American Diabetes Association” (93)for additional discussion.

Secondary Prevention (Patients With

ASCVD)

Because risk is high in patients withASCVD, intensive therapy is indicatedand has been shown to be of benefitin multiple large randomized cardiovas-cular outcomes trials (88,92,94,95).High-intensity statin therapy is recommendedfor all patients with diabetes and ASCVD.This recommendation is based on theCholesterol Treatment Trialists’ Collab-oration involving 26 statin trials, ofwhich 5 compared high-intensity versusmoderate-intensity statins. Together,they found reductions in nonfatal car-diovascular events with more intensivetherapy, in patients with and withoutdiabetes (80,84,94).Over the past few years, there have

been multiple large randomized trialsinvestigating the benefits of addingnonstatin agents to statin therapy, in-cluding those that evaluated furtherlowering of LDL cholesterol with eze-timibe (92,96) and proprotein conver-tase subtilisin/kexin type 9 (PCSK9)inhibitors (95). Each trial found a sig-nificant benefit in the reduction ofASCVD events that was directly relatedto the degree of further LDL cholesterollowering. These large trials included asignificant number of participants withdiabetes. For very high-risk patientswith ASCVD who are on high-intensity(and maximally tolerated) statintherapy and have an LDL chole-sterol $70 mg/dL, the addition ofnonstatin LDL-lowering therapy canbe considered following a clinician-patient discussion about the net ben-efit, safety, and cost. Definition of veryhigh-risk patients with ASCVD includesthe use of specific criteria (majorASCVD events and high-risk condi-tions); refer to the 2018 American Col-lege of Cardiology/American HeartAssociation multisociety guideline onthe management of blood cholesterolfor further details regarding this def-inition of risk (12).Please see 2018 AHA/ACC/AACVPR/

AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Manage-ment of Blood Cholesterol: ExecutiveSummary: A Report of the AmericanCollege of Cardiology/American HeartAssociation Task Force on Clinical Practice

Guidelines (12) for recommendations forprimary and secondary prevention and forstatinandcombinationtreatmentinadultswith diabetes (97).

Combination Therapy for LDLCholesterol Lowering

Statins and Ezetimibe

The IMProved Reduction of Outcomes:Vytorin Efficacy International Trial(IMPROVE-IT) was a randomized controlledtrial in 18,144 patients comparing theaddition of ezetimibe to simvastatintherapy versus simvastatin alone. Indi-viduals were $50 years of age, hadexperienced a recent acute coronarysyndrome (ACS), and were treated foran average of 6 years. Overall, the ad-dition of ezetimibe led to a 6.4% relativebenefit and a 2% absolute reduction inmajor adverse cardiovascular events,with the degree of benefit being directlyproportional to the change in LDL cho-lesterol, whichwas 70mg/dL in the statingroup on average and 54 mg/dL in thecombination group (92). In those withdiabetes (27% of participants), the com-bination of moderate-intensity simvas-tatin (40 mg) and ezetimibe (10 mg)showed a significant reduction of majoradverse cardiovascular events with anabsolute risk reduction of 5% (40% vs.45% cumulative incidence at 7 years) anda relative risk reduction of 14% (hazardratio [HR] 0.86 [95% CI 0.78–0.94]) overmoderate-intensity simvastatin (40 mg)alone (96).

Statins and PCSK9 Inhibitors

Placebo-controlled trials evaluating theaddition of the PCSK9 inhibitors evolo-cumab and alirocumab to maximallytolerated doses of statin therapy inparticipants who were at high risk forASCVD demonstrated an average reduc-tion in LDL cholesterol ranging from36% to 59%. These agents have beenapproved as adjunctive therapy forpatients with ASCVD or familial hyper-cholesterolemia who are receiving max-imally tolerated statin therapy butrequire additional lowering of LDL cho-lesterol (98,99).

The effects of PCSK9 inhibition onASCVD outcomes was investigated inthe Further Cardiovascular OutcomesResearch With PCSK9 Inhibition in Sub-jects With Elevated Risk (FOURIER)trial, which enrolled 27,564 patients withprior ASCVD and an additional high-risk

feature who were receiving their maxi-mally tolerated statin therapy (two-thirds were on high-intensity statin)butwhostillhadLDLcholesterol$70mg/dLor non-HDL cholesterol $100 mg/dL (95).Patients were randomized to receive sub-cutaneous injections of evolocumab (either140 mg every 2 weeks or 420 mg everymonth based on patient preference)versus placebo. Evolocumab reducedLDL cholesterol by 59% from a me-dian of 92 to 30mg/dL in the treatmentarm.

During the median follow-up of 2.2years, the composite outcome of cardio-vascular death, MI, stroke, hospitaliza-tion for angina, or revascularizationoccurred in 11.3%vs. 9.8%of the placeboand evolocumab groups, respectively,representing a 15% relative risk reduc-tion (P , 0.001). The combined endpoint of cardiovascular death, MI, orstroke was reduced by 20%, from7.4% to 5.9% (P , 0.001). Importantly,similar benefits were seen in a prespe-cified subgroup of patients with diabe-tes, comprising 11,031 patients (40% ofthe trial) (100).

Treatment of Other LipoproteinFractions or Targets

Recommendations

10.29 For patients with fasting tri-glyceride levels $500 mg/dL,evaluate for secondary causesofhypertriglyceridemiaandcon-sider medical therapy to reducethe risk of pancreatitis. C

10.30 In adultswithmoderate hyper-triglyceridemia (fastingornon-fasting triglycerides 175–499mg/dL), clinicians should ad-dress and treat lifestyle factors(obesity and metabolic syn-drome), secondary factors(diabetes, chronic liver or kid-ney disease and/or nephroticsyndrome, hypothyroidism),and medications that raise tri-glycerides. C

10.31 In patients with atheroscleroticcardiovascular disease or othercardiovascular risk factors on astatin with controlled LDL cho-lesterol but elevated trigly-cerides (135–499 mg/dL), theaddition of icosapent ethyl canbe considered to reduce cardio-vascular risk. A

care.diabetesjournals.org Cardiovascular Disease and Risk Management S119

Hypertriglyceridemia should be ad-dressed with dietary and lifestylechanges including weight loss and ab-stinence from alcohol (101). Severehypertriglyceridemia (fasting triglycer-ides$500 mg/dL and especially.1,000mg/dL)maywarrantpharmacologic ther-apy (fibric acid derivatives and/or fishoil) to reduce the risk of acute pancre-atitis. Moderate- or high-intensity statintherapy should also be used as indicatedto reduce risk of cardiovascular events(see STATIN TREATMENT). In patients withmoderate hypertriglyceridemia, lifestyleinterventions, treatment of secondaryfactors, and avoidance of medicationsthat might raise triglycerides are recom-mended.The Reduction of Cardiovascular

Events with Icosapent Ethyl–InterventionTrial (REDUCE-IT) enrolled 8,179 adultsreceiving statin therapy with mod-erately elevated triglycerides (135–499 mg/dL, median baseline of 216mg/dL) who had either established car-diovascular disease (secondary preven-tion cohort) or diabetes plus at least oneother cardiovascular risk factor (primaryprevention cohort). Patients were ran-domized to icosapent ethyl 4 g/day (2 gtwice daily with food) versus placebo.The trial met its primary end point,demonstrating a 25% relative risk reduc-tion (P,0.001) for theprimary endpointcomposite of cardiovascular death, non-fatal myocardial infarction, nonfatalstroke, coronary revascularization, orunstable angina. The composite of car-diovascular death, nonfatal myocardialinfarction, or nonfatal stroke was re-duced by 26% (P , 0.001). Additionalischemic end points were significantlylower in the icosapent ethyl group than inthe placebo group, including cardiovas-cular death, which was reduced by 20%(P 5 0.03). The proportions of patientsexperiencing adverse events and seriousadverse events were similar between theactive and placebo treatment groups. Itshould be noted that data are lackingwith other n-3 fatty acids, and results ofthe REDUCE-IT trial should not be ex-trapolated to other products (102).Low levels of HDL cholesterol, often

associated with elevated triglyceride lev-els, are the most prevalent pattern ofdyslipidemia in individuals with type 2diabetes. However, the evidence for theuse of drugs that target these lipid frac-tions is substantially less robust than

that for statin therapy (103). In a largetrial in patients with diabetes, fenofi-brate failed to reduce overall cardiovas-cular outcomes (104).

Other Combination Therapy

Recommendations

10.32 Statin plusfibrate combinationtherapy has not been shown toimprove atherosclerotic car-diovascular disease outcomesand is generally not recom-mended. A

10.33 Statin plus niacin combinationtherapy has not been shown toprovide additional cardiovas-cular benefit above statin ther-apy alone, may increase therisk of stroke with additionalside effects, and is generallynot recommended. A

Statin and Fibrate Combination Therapy

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 (com-pared with fenofibrate) (105).

In the ACCORD study, in patientswith type 2 diabetes who were at highrisk for ASCVD, the combination of fe-nofibrate and simvastatin did not reducethe rate of fatal cardiovascular events,nonfatal MI, or nonfatal stroke as com-pared with simvastatin alone. Prespeci-fied subgroup analyses suggestedheterogeneity in treatment effectswith possible benefit for men withboth a triglyceride level $204 mg/dL(2.3 mmol/L) and an HDL cholesterollevel #34 mg/dL (0.9 mmol/L) (106).A prospective trial of a newer fibratein this specific population of patients isongoing (107).

Statin and Niacin Combination Therapy

The Atherothrombosis Intervention inMetabolic Syndrome With Low HDL/High Triglycerides: Impact on GlobalHealth Outcomes (AIM-HIGH) trial ran-domized over 3,000 patients (aboutone-thirdwithdiabetes)withestablishedASCVD, low LDL cholesterol levels(,180 mg/dL [4.7 mmol/L]), low HDLcholesterol 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) tostatin therapy plus extended-release ni-acin or placebo. The trial was halted earlydue to lack of efficacy on the primaryASCVD outcome (first event of the com-posite of death from CHD, nonfatal MI,ischemic stroke, hospitalization for anACS, or symptom-driven coronary orcerebral revascularization) andapossibleincrease in ischemic stroke in those oncombination therapy (108).

The much larger Heart ProtectionStudy 2–Treatment of HDL to Reducethe Incidence of Vascular Events (HPS2-THRIVE) trial also failed to show a benefitof adding niacin to background statintherapy (109). A total of 25,673 patientswith prior vascular diseasewere random-ized to receive 2 g of extended-releaseniacin and 40 mg of laropiprant (anantagonist of the prostaglandin D2 re-ceptor DP1 that has been shown toimprove adherence to niacin therapy)versus a matching placebo daily andfollowed for a median follow-up periodof 3.9 years. There was no significantdifference in the rate of coronary death,MI, stroke, or coronary revascularizationwith the addition of niacin–laropiprantversus placebo (13.2% vs. 13.7%; rateratio 0.96; P5 0.29). Niacin–laropiprantwas associated with an increased inci-dence of new-onset diabetes (absoluteexcess, 1.3 percentage points; P, 0.001)and disturbances in diabetes controlamong those with diabetes. In addition,there was an increase in serious adverseevents associated with the gastrointes-tinal system, musculoskeletal system,skin, and, unexpectedly, infection andbleeding.

Therefore, combination therapy witha statin and niacin is not recommendedgiven the lack of efficacy on majorASCVD outcomes and increased sideeffects.

Diabetes Risk With Statin UseSeveral studies have reported amodestlyincreased risk of incident diabetes withstatin use (110,111), which may be lim-ited to those with diabetes risk factors.An analysis of one of the initial studiessuggested that although statin use wasassociated with diabetes risk, the cardio-vascular event rate reduction with sta-tins far outweighed the risk of incidentdiabetes even for patients at highestrisk for diabetes (112). The absolute

S120 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

risk increase was small (over 5 years offollow-up, 1.2% of participants on placebodeveloped diabetes and 1.5% on rosuvas-tatin developed diabetes) (112). A meta-analysis of 13 randomized statin trials with91,140participants showedanoddsratioof1.09 for anewdiagnosisofdiabetes, so that(onaverage) treatmentof255patientswithstatins for 4 years resulted inoneadditionalcase of diabetes while simultaneously pre-venting 5.4 vascular events among those255 patients (111).

Lipid-Lowering Agents and CognitiveFunctionAlthough concerns regarding a potentialadverse impact of lipid-lowering agents oncognitive function have been raised, sev-eral lines of evidence point against thisassociation, as detailed in a 2018 EuropeanAtherosclerosis Society Consensus Panelstatement (113). First, there are three largerandomized trials of statin versus placebowhere specific cognitive tests were per-formed, and no differences were seenbetween statin and placebo (114–117).In addition, no change in cognitive functionhas been reported in studies with theaddition of ezetimibe (92) or PCSK9 inhib-itors (95,118) to statin therapy, includingamong patients treated to very low LDLcholesterol levels. In addition, the mostrecent systematic reviewof theU.S. Foodand Drug Administration’s (FDA’s) post-marketing surveillance databases, ran-domized controlled trials, and cohort,case-control, and cross-sectional studiesevaluating cognition in patients receivingstatins found that published data do notreveal an adverse effect of statins oncognition (119). Therefore, a concernthat statinsorother lipid-loweringagentsmight cause cognitive dysfunction ordementia is not currently supportedby evidence and should not deter theiruse in individuals with diabetes at highrisk for ASCVD (119).

ANTIPLATELET AGENTS

Recommendations

10.34 Use aspirin therapy (75–162mg/day) as a secondary pre-vention strategy in those withdiabetes and a history of ath-erosclerotic cardiovasculardisease. A

10.35 For patients with atheroscle-rotic cardiovascular disease anddocumented aspirin allergy,

clopidogrel (75mg/day) shouldbe used. B

10.36 Dual antiplatelet therapy (withlow-dose aspirin and a P2Y12inhibitor) is reasonable for ayear after an acute coronarysyndrome A and may havebenefits beyond this period. B

10.37 Aspirin therapy (75–162 mg/day)may be considered as a pri-mary prevention strategy inthose with diabetes who areat increased cardiovascularrisk, after a comprehensive dis-cussion with the patient on thebenefits versus the comparableincreased risk of bleeding. A

Risk ReductionAspirin has been shown to be effective inreducing cardiovascular morbidity andmortality in high-risk patients with pre-vious MI or stroke (secondary preven-tion) and is strongly recommended. Inprimary prevention, however, amongpatients with no previous cardiovascularevents, its net benefit is more contro-versial (120,121).

Previous randomized controlled trialsof aspirin specifically in patients withdiabetes failed to consistently show asignificant reduction in overall ASCVDend points, raising questions about theefficacy of aspirin for primary preven-tion in people with diabetes, althoughsome sex differences were suggested(122–124).

The Antithrombotic Trialists’ Collabo-ration published an individual patient–level meta-analysis (120) of the six largetrials of aspirin for primary preventionin the general population. These trialscollectively enrolled over 95,000 partic-ipants, including almost 4,000 with di-abetes. Overall, they found that aspirinreduced the risk of serious vascularevents by 12% (relative risk 0.88 [95%CI 0.82–0.94]). The largest reduction wasfor nonfatal MI, with little effect on CHDdeath (relative risk 0.95 [95% CI 0.78–1.15]) or total stroke.

Most recently, the ASCEND (A Study ofCardiovascular Events iN Diabetes) trialrandomized 15,480 patients with diabe-tes but no evident cardiovascular diseaseto aspirin 100 mg daily or placebo (125).The primary efficacy end point was vas-cular death, MI, or stroke or transientischemic attack. The primary safety

outcome was major bleeding (i.e., in-tracranial hemorrhage, sight-threateningbleeding in theeye, gastrointestinal bleed-ing, or other serious bleeding). During amean follow-up of 7.4 years, there was asignificant 12% reduction in the primaryefficacy end point (8.5% vs. 9.6%; P 50.01). In contrast, major bleeding wassignificantly increased from 3.2% to4.1% in the aspirin group (rate ratio1.29; P5 0.003), with most of the excessbeing gastrointestinal bleeding and otherextracranial bleeding. There were no sig-nificant differences by sex, weight, orduration of diabetes or other baselinefactors including ASCVD risk score.

Two other large randomized trials ofaspirin for primary prevention, in pa-tients without diabetes (ARRIVE [Aspirinto Reduce Risk of Initial Vascular Events])(126) and in the elderly (ASPREE [Aspirinin Reducing Events in the Elderly]) (127),which included 11%with diabetes, foundnobenefit of aspirinon theprimaryefficacyendpoint and an increased risk of bleeding.In ARRIVE, with 12,546 patients over a pe-riod of 60 months follow-up, the primaryend point occurred in 4.29% vs. 4.48% ofpatients in the aspirin versus placebogroups (HR 0.96; 95% CI 0.81–1.13; P 50.60). Gastrointestinal bleeding events(characterized as mild) occurred in 0.97%of patients in the aspirin group vs. 0.46% inthe placebo group (HR 2.11; 95% CI 1.36–3.28; P 5 0.0007). In ASPREE, including19,114 persons, for the rate of cardiovas-cular disease (fatal CHD, MI, stroke, orhospitalization for heart failure) after amedian of 4.7 years of follow-up, the ratesper 1,000 person-years were 10.7 vs. 11.3events in aspirin vs. placebo groups (HR0.95; 95% CI 0.83–1.08). The rate of majorhemorrhage per 1,000 person-years was8.6 events vs. 6.2 events, respectively (HR1.38; 95% CI 1.18–1.62; P , 0.001).

Thus, aspirin appears to have amodesteffect on ischemic vascular events, with

the absolute decrease in events depend-

ing on the underlying ASCVD risk. The

main adverse effect is an increased risk

of gastrointestinal bleeding. The excess

risk may be as high as 5 per 1,000 per

year in real-world settings. However, for

adultswith ASCVD risk.1%per year, the

number of ASCVD events prevented will

be similar to the number of episodes

ofbleeding induced, although thesecom-

plications do not have equal effects on

long-term health (128).

care.diabetesjournals.org Cardiovascular Disease and Risk Management S121

Recommendations for using aspirin asprimary prevention include both menand women aged $50 years with di-abetes and at least one additional majorrisk factor (family history of prematureASCVD, hypertension, dyslipidemia, smok-ing, or chronic kidney disease/albuminuria)who are not at increased risk of bleeding(e.g., older age, anemia, renal disease)(129–132).Noninvasiveimagingtechniquessuch as coronary calcium scoring maypotentially help further tailor aspirin ther-apy, particularly in those at low risk (133)(134). For patients over the age of 70 years(with or without diabetes), the balanceappears to have greater risk than benefit(125,127).Thus, forprimaryprevention, theuse of aspirin needs to be carefully con-sidered and may generally not be recom-mended. Aspirin may be considered in thecontext of high cardiovascular risk with lowbleeding risk, but generally not in olderadults. Aspirin therapy for primary preven-tion may be considered in the context ofshared decision-making, which carefullyweighs the cardiovascular benefits withthe fairly comparable increase in risk ofbleeding. For patients with documentedASCVD, use of aspirin for secondary pre-ventionhas far greaterbenefit than risk; forthis indication, aspirin is still recommended(120).

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 patients withone ormore risk factors or older patientswithno risk factors)until further researchis available. Patients’ willingness to un-dergo long-term aspirin therapy shouldalso be considered (135). Aspirin use inpatients aged ,21 years is generallycontraindicated due to the associatedrisk of Reye syndrome.

Aspirin DosingAverage daily dosages used in mostclinical trials involving patients with di-abetes ranged from 50mg to 650mg butweremostly in the range of 100–325mg/day. There is little evidence to supportany specific dose, but using the lowestpossible dose may help to reduce sideeffects (136). In the U.S., the most com-mon low-dose tablet is 81 mg. Although

platelets from patients with diabeteshave altered function, it is unclearwhat, if any, effect that finding has onthe required dose of aspirin for cardio-protective effects in the patient withdiabetes. Many alternate pathways forplatelet activation exist that are inde-pendent of thromboxane A2 and thus arenot sensitive to the effects of aspirin(137). “Aspirin resistance” has been de-scribed in patients with diabetes whenmeasured by a variety of ex vivo and invitro methods (platelet aggregometry,measurement of thromboxane B2)(138), but other studies suggest no im-pairment in aspirin response among pa-tients with diabetes (139). A recent trialsuggested that more frequent dosingregimens of aspirin may reduce plateletreactivity in individuals with diabetes(140); however, these observationsalone are insufficient to empirically rec-ommend that higher doses of aspirinbeused in this groupat this time.Anotherrecent meta-analysis raised the hypoth-esis that low-dose aspirin efficacy isreduced in those weighing more than70 kg (141); however, the ASCEND trialfound benefit of low-dose aspirin inthose in this weight range, which wouldthus not validate this suggested hypoth-esis (125). It appears that 75–162mg/dayis optimal.

Indications for P2Y12 ReceptorAntagonist UseA P2Y12 receptor antagonist in com-bination with aspirin is reasonable forat least 1 year in patients following anACS andmay have benefits beyond thisperiod. Evidence supports use of eitherticagrelor or clopidogrel if no percu-taneous coronary intervention wasperformed and clopidogrel, ticagrelor,or prasugrel if a percutaneous coro-nary intervention was performed(142). In patients with diabetes andprior MI (1–3 years before), addingticagrelor to aspirin significantly re-duces the risk of recurrent ischemicevents including cardiovascular andCHD death (143).

CARDIOVASCULAR DISEASE

Screening

Recommendations

10.38 In asymptomatic patients, rou-tinescreeningforcoronaryarterydisease is not recommended as it

does not improve outcomes aslong as atherosclerotic cardio-vascular disease risk factors aretreated. A

10.39 Consider investigations for cor-onary arterydisease in thepres-ence of any of the following:atypical cardiac symptoms (e.g.,unexplained dyspnea, chest dis-comfort); signs or symptoms ofassociated vascular disease in-cluding carotid bruits, transientischemic attack, stroke, claudi-cation, or peripheral arterialdisease; or electrocardiogramabnormalities (e.g., Q waves). E

Treatment

Recommendations

10.40 Inpatientswith knownathero-sclerotic cardiovascular dis-ease, consider ACE inhibitoror angiotensin receptor blockertherapy to reduce the risk ofcardiovascular events. B

10.41 In patients with priormyocardialinfarction, b-blockers shouldbecontinued forat least2yearsafter the event. B

10.42 In patients with type 2 diabe-tes with stable heart failure,metformin may be continuedfor glucose lowering if esti-mated glomerular filtrationrate remains .30 mL/minbut should be avoided inunstable or hospitalized pa-tients with heart failure. B

10.43 Among patients with type 2diabeteswhohaveestablishedatherosclerotic cardiovasculardisease or established kidneydisease, a sodium–glucose co-transporter 2 inhibitor or glu-cagon-like peptide 1 receptoragonist with demonstratedcardiovascular disease benefit(Table 10.3B and Table 10.3C)is recommended as part of theglucose-lowering regimen. A

10.43a In patients with type 2 diabe-tes and established atheroscle-rotic cardiovascular disease,multiple atherosclerotic cardio-vascular disease risk factors,or diabetic kidney disease, asodium–glucose cotransporter2 inhibitor with demonstrated

S122 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

cardiovascular benefit is rec-ommended to reduce the riskof major adverse cardiovascu-lar events and heart failurehospitalization. A

10.43b In patients with type 2 diabe-tesandestablishedatheroscle-rotic cardiovascular diseaseor multiple risk factors foratherosclerotic cardiovasculardisease, a glucagon-like pep-tide 1 receptor agonist withdemonstrated cardiovascularbenefit is recommended toreduce the risk of major ad-verse cardiovascular events. A

10.43c In patients with type 2 diabe-tes and established heartfailure, a sodium–glucose co-transporter 2 inhibitor may beconsidered to reduce risk ofheart failure hospitalization. C

CARDIAC TESTING

Candidates 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 coro-nary artery calcium is also reasonable forcardiovascular risk assessment. Pharma-cologic stress echocardiography or nu-clear imaging should be considered inindividualswithdiabetes inwhomrestingECG abnormalities preclude exercisestress testing (e.g., left bundle branchblock or ST-T abnormalities). In addition,individualswhorequire stress testingandare unable to exercise should undergopharmacologic stress echocardiographyor nuclear imaging.

SCREENING ASYMPTOMATICPATIENTS

The screening of asymptomatic patientswith high ASCVD risk is not recommen-ded (144), in part because these high-riskpatients should already be receiving in-tensive medical therapydan approachthat provides similar benefit as invasiverevascularization (145,146). There is alsosome evidence that silent ischemia mayreverse over time, adding to the contro-versy concerning aggressive screeningstrategies (147). In prospective studies,coronary artery calcium has been

established as an independent predictorof future ASCVD events in patients withdiabetes and is consistently superior toboth theUKProspectiveDiabetes Study(UKPDS) risk engine and the Framing-ham Risk Score in predicting risk in thispopulation (148–150). However, a ran-domized observational trial demon-strated no clinical benefit to routinescreening of asymptomatic patientswith type 2 diabetes and normalECGs (151). Despite abnormal myo-cardial perfusion imaging in more thanone in five patients, cardiac outcomeswere essentially equal (and very low) inscreened versus unscreened patients.Accordingly, indiscriminate screening isnot considered cost-effective. Studieshave found that a risk factor–basedapproach to the initial diagnostic evalu-ation and subsequent follow-up for cor-onary artery disease fails to identifywhich patients with type 2 diabeteswill have silent ischemia on screeningtests (152,153).

Any benefit of newer noninvasive cor-onary artery disease screening methods,such as computed tomography calciumscoring and computed tomography an-giography, to identify patient subgroupsfor different treatment strategies re-mains unproven in asymptomatic pa-tients with diabetes, though researchis ongoing. Although asymptomatic pa-tientswith diabeteswith higher coronarydisease burden havemore future cardiacevents (148,154,155), the role of thesetests beyond risk stratification is notclear.

While coronary artery screeningmethods, such as calcium scoring,may improve cardiovascular risk assess-ment in people with type 2 diabetes(156), their routine use leads to radia-tion exposure and may result in unnec-essary invasive testing such as coronaryangiography and revascularization pro-cedures. The ultimate balance of ben-efit, cost, and risks of such an approachin asymptomatic patients remains con-troversial, particularly in the modernsetting of aggressive ASCVD risk factorcontrol.

LIFESTYLE AND PHARMACOLOGICINTERVENTIONS

Intensive lifestyle intervention focusingon weight loss through decreased caloricintake and increased physical activity asperformed in the Action for Health in

Diabetes (Look AHEAD) trial may be con-sidered for improving glucose control, fit-ness, and some ASCVD risk factors (157).Patients at increased ASCVD risk shouldreceivestatin,ACE inhibitor,orARBtherapyif the patient has hypertension, andpossibly aspirin, unless there are contra-indications to a particular drug class.While clear benefit exists for ACE inhib-itor or ARB therapy in patients withdiabetic kidney disease or hypertension,thebenefits inpatientswithASCVD in theabsence of these conditions are lessclear, especially when LDL cholesterolis concomitantly controlled (158,159).In patients with prior MI, active angina,or HFrEF, b-blockers should be used(160).

GLUCOSE-LOWERING THERAPIESAND CARDIOVASCULAROUTCOMES

In 2008, the FDA issued a guidance forindustry to perform cardiovascular out-comes trials for all new medications forthe treatment for type 2 diabetes amidconcerns of increased cardiovascular risk(161). Previously approved diabetes med-ications were not subject to the guidance.Recently published cardiovascular out-comes trials have provided additionaldata on cardiovascular outcomes in pa-tients with type 2 diabetes with car-diovascular disease or at high risk forcardiovascular disease (see Table 10.3A,Table 10.3B, and Table 10.3C). Cardio-vascular outcomes trials of dipeptidylpeptidase 4 (DPP-4) inhibitors have all,so far, not shown cardiovascular bene-fits relative to placebo. However, resultsfrom other new agents have provided amix of results.

SGLT2 Inhibitor TrialsThe BI 10773 (Empagliflozin) Cardiovas-cular Outcome Event Trial in Type 2 Di-abetes Mellitus Patients (EMPA-REGOUTCOME) trial was a randomized, dou-ble-blind trial that assessed the effectof empagliflozin, an SGLT2 inhibitor,versus placebo on cardiovascular out-comes in 7,020 patients with type 2diabetes and existing cardiovascular dis-ease. Study participants had a mean ageof 63 years, 57% had diabetes for morethan 10 years, and 99% had establishedcardiovascular disease. EMPA-REG OUT-COME showed that over a median fol-low-up of 3.1 years, treatment reducedthe composite outcome of MI, stroke,

care.diabetesjournals.org Cardiovascular Disease and Risk Management S123

and cardiovascular death by 14% (abso-lute rate 10.5% vs. 12.1% in the placebogroup, HR in the empagliflozin group0.86; 95% CI 0.74–0.99; P 5 0.04 forsuperiority) and cardiovascular death by38% (absolute rate 3.7% vs. 5.9%, HR0.62; 95% CI 0.49–0.77; P , 0.001) (8).The FDA added an indication for empa-gliflozin to reduce the risk of majoradverse cardiovascular death in adultswith type 2 diabetes and cardiovasculardisease.Two large outcomes trials of the SGLT2

inhibitor canagliflozin that separately

assessed 1) the cardiovascular effects oftreatment in patients at high risk formajor adverse cardiovascular events,and2) the impact of canagliflozin therapyon cardiorenal outcomes in patients withdiabetes-related chronic kidney diseasehave been conducted (162). First, theCanagliflozin Cardiovascular AssessmentStudy (CANVAS) Program integrateddatafrom two trials. The CANVAS trial thatstarted in 2009 was partially unblindedprior to completion because of theneed to file interim cardiovascular out-comesdata for regulatory approval of the

drug (163). Thereafter, the postapprovalCANVAS-Renal (CANVAS-R) trial wasstarted in 2014. Combining both of thesetrials, 10,142 participants with type 2diabetes were randomized to canagliflo-zin or placebo and were followed for anaverage 3.6 years. The mean age ofpatients was 63 years, and 66% had ahistory of cardiovascular disease. Thecombined analysis of the two trials foundthat canagliflozin significantly reducedthe composite outcome of cardiovascu-lar death, MI, or stroke versus placebo(occurring in 26.9 vs. 31.5 participants

Table 10.3A—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA2008 guidelines: DPP-4 inhibitors

SAVOR-TIMI 53 (181) EXAMINE (186) TECOS (183) CARMELINA (184,187)(n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,979)

Intervention Saxagliptin/placebo Alogliptin/placebo Sitagliptin/placebo Linagliptin/placebo

Main inclusion criteria Type 2 diabetes andhistoryof ormultiple risk factorsfor CVD

Type 2 diabetes and ACSwithin 15–90 days beforerandomization

Type 2 diabetesand preexistingCVD

Type 2 diabetes and high CV andrenal risk

A1C inclusion criteria (%) $6.5 6.5–11.0 6.5–8.0 6.5–10.0

Age (years)†† 65.1 61.0 65.4 65.8

Race (% white) 75.2 72.7 67.9 80.2

Sex (% male) 66.9 67.9 70.7 62.9

Diabetes duration (years)†† 10.3 7.1 11.6 14.7

Median follow-up (years) 2.1 1.5 3.0 2.2

Statin use (%) 78 91 80 71.8

Metformin use (%) 70 66 82 54.8

Prior CVD/CHF (%) 78/13 100/28 74/18 57/26.8

Mean baseline A1C (%) 8.0 8.0 7.2 7.9

Mean difference in A1Cbetween groups at end oftreatment (%)

20.3 20.3 20.3 20.36

Year started/reported 2010/2013 2009/2013 2008/2015 2013/2018

Primary outcome§ 3-point MACE 3-point MACE 4-point MACE 3-point MACE1.00 (0.89–1.12) 0.96 (95% UL #1.16) 0.98 (0.89–1.08) 1.02 (0.89–1.17)

Key secondary outcome§ Expanded MACE1.02 (0.94–1.11)

4-point MACE0.95 (95% UL #1.14)

3-point MACE0.99 (0.89–1.10)

Kidney composite (ESRD,sustained $40% decrease ineGFR, or renal death)

1.04 (0.89–1.22)

Cardiovascular death§ 1.03 (0.87–1.22) 0.85 (0.66–1.10) 1.03 (0.89–1.19) 0.96 (0.81–1.14)

MI§ 0.95 (0.80–1.12) 1.08 (0.88–1.33) 0.95 (0.81–1.11) 1.12 (0.90–1.40)

Stroke§ 1.11 (0.88–1.39) 0.91 (0.55–1.50) 0.97 (0.79–1.19) 0.91 (0.67–1.23)

HF hospitalization§ 1.27 (1.07–1.51) 1.19 (0.90–1.58) 1.00 (0.83–1.20) 0.90 (0.74–1.08)

Unstable anginahospitalization§

1.19 (0.89–1.60) 0.90 (0.60–1.37) 0.90 (0.70–1.16) 0.87 (0.57–1.31)

All-cause mortality§ 1.11 (0.96–1.27) 0.88 (0.71–1.09) 1.01 (0.90–1.14) 0.98 (0.84–1.13)

Worsening nephropathy§|| 1.08 (0.88–1.32) d d Kidney composite (see above)

d, not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; DPP-4,dipeptidyl peptidase 4; eGFR, estimated glomerularfiltration rate; ESRD, end-stage renal disease;GLP-1, glucagon-like peptide 1;HF, heart failure;MACE, major adverse cardiac event; MI, myocardial infarction; UL, upper limit. Data from this table was adapted from Cefalu et al. (188) inthe January 2018 issue of Diabetes Care. ††Age was reported as means in all trials except EXAMINE, which reported medians; diabetesduration was reported as means in all trials except SAVOR-TIMI 53 and EXAMINE, which reported medians. §Outcomes reported ashazard ratio (95% CI). ||Worsening nephropathy is defined as as doubling of creatinine level, initiation of dialysis, renal transplantation, orcreatinine .6.0 mg/dL (530 mmol/L) in SAVOR-TIMI 53. Worsening nephropathy was a prespecified exploratory adjudicated outcome inSAVOR-TIMI 53.^Significant difference in A1C between groups (P , 0.05).

S124 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020

Table 10.3B—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuanceof the FDA 2008 guidelines: GLP-1 receptor agonists

ELIXA (170) LEADER (165) SUSTAIN-6 (166)* EXSCEL (171)Harmony

Outcomes (168) REWIND (169)(n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,463) (n 5 9,901)

Intervention Lixisenatide/placebo

Liraglutide/placebo

Semaglutide/placebo

Exenatide QW/placebo

Albiglutide/placebo

Dulaglutide/placebo

Main inclusioncriteria

Type 2 diabetesand history ofACS (,180 days)

Type 2 diabetesand preexistingCVD, CKD, or HFat $50 years ofage or CV risk at$60 years ofage

Type 2 diabetes andpreexisting CVD,HF, or CKD at$50 years of ageor CV risk at $60years of age

Type 2 diabeteswith or withoutpreexisting CVD

Type 2 diabeteswith preexistingCVD

Type 2 diabetesand priorASCVD eventor risk factorsfor ASCVD

A1C inclusioncriteria (%)

5.5–11.0 $7.0 $7.0 6.5–10.0 $7.0 #9.5

Age (years)†† 60.3 64.3 64.6 62 64.1 66.2

Race (% white) 75.2 77.5 83.0 75.8 84.8 75.7

Sex (% male) 69.3 64.3 60.7 62 69.4 53.7

Diabetes duration(years)††

9.3 12.8 13.9 12 13.8 10.5

Median follow-up(years)

2.1 3.8 2.1 3.2 1.6 5.4

Statin use (%) 93 72 73 74 84.0 66

Metformin use (%) 66 76 73 77 73.6 81

Prior CVD/CHF (%) 100/22 81/18 60/24 73.1/16.2 100/20.2 32/9

Mean baselineA1C (%)

7.7 8.7 8.7 8.0 8.7 7.4

Mean difference inA1C betweengroups at end oftreatment (%)

20.3 20.4 20.7 or – 1.0† 20.53 20.52 20.61

Year started/reported

2010/2015 2010/2016 2013/2016 2010/2017 2015/2018 2011/2019

Primary outcome§ 4-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE 3-point MACE1.02 (0.89–1.17) 0.87 (0.78–0.97) 0.74 (0.58–0.95) 0.91 (0.83–1.00) 0.78 (0.68–0.90) 0.88 (0.79–0.99)

Key secondaryoutcome§

Expanded MACE(0.90–1.11)

Expanded MACE0.88 (0.81–0.96)

Expanded MACE0.74 (0.62–0.89)

Individualcomponents ofMACE (seebelow)

Expanded MACE(with urgentrevascularizationfor unstableangina)

Compositemicrovascularoutcome(eye or renaloutcome)

0.78 (0.69–0.90) 0.87 (0.79–0.95)CV death or HFhospitalization

0.85 (0.70–1.04)Individualcomponents ofMACE (see below)

Cardiovasculardeath§

0.98 (0.78–1.22) 0.78 (0.66–0.93) 0.98 (0.65–1.48) 0.88 (0.76–1.02) 0.93 (0.73–1.19) 0.91 (0.78–1.06)

MI§ 1.03 (0.87–1.22) 0.86 (0.73–1.00) 0.74 (0.51–1.08) 0.97 (0.85–1.10) 0.75 (0.61–0.90) 0.96 (0.79–1.15)

Stroke§ 1.12 (0.79–1.58) 0.86 (0.71–1.06) 0.61 (0.38–0.99) 0.85 (0.70–1.03) 0.86 (0.66–1.14) 0.76 (0.61–0.95)

HFhospitalization§

0.96 (0.75–1.23) 0.87 (0.73–1.05) 1.11 (0.77–1.61) 0.94 (0.78–1.13) d 0.93 (0.77–1.12)

Unstable anginahospitalization§

1.11 (0.47–2.62) 0.98 (0.76–1.26) 0.82 (0.47–1.44) 1.05 (0.94–1.18) d 1.14 (0.84–1.54)

Continued on p. S126

care.diabetesjournals.org Cardiovascular Disease and Risk Management S125

per 1,000 patient-years; HR 0.86 [95% CI0.75–0.97]). The specific estimates forcanagliflozin versus placebo on theprimary composite cardiovascular out-come were HR 0.88 (0.75–1.03) forthe CANVAS trial and 0.82 (0.66–1.01)for CANVAS-R, with no heterogeneityfound between trials. Of note, therewas an increased risk of lower-limb am-putation with canagliflozin (6.3 vs. 3.4participants per 1,000 patient-years; HR1.97 [95% CI 1.41–2.75]) (9). Second, theCanagliflozin and Renal Events in Dia-betes with Established NephropathyClinical Evaluation (CREDENCE) trial ran-domized 4,401 patients with type 2diabetes and chronic diabetes-relatedkidney disease (UACR .300 mg/g andestimated glomerular filtration rate 30to,90mL/min/1.73 m2) to canagliflozin100 mg daily or placebo (162). The pri-mary outcome was a composite of end-stage kidney disease (ESKD), doubling ofserum creatinine, or death from renal orcardiovascular causes. The trial was stop-ped early due to conclusive evidence ofefficacy identified during a prespecifiedinterim analysis with no unexpectedsafety signals. The risk of the primarycomposite outcome was 30% lower withcanagliflozin treatment when comparedwith placebo (HR 0.70 [95% CI 0.59–0.82]). Moreover, it reduced the prespe-cifiedendpoint of ESKDaloneby 32% (HR0.68 [95% CI 0.54–0.86]). Canagliflozinwas additionally found to have a lowerrisk of the composite of cardiovasculardeath, myocardial infarction, or stroke(HR 0.80 [95% CI 0.67–0.95]), as well aslower risk of hospitalizations for heart

failure (HR 0.61 [95% CI 0.47–0.80]), andof the composite of cardiovascular deathor hospitalization for heart failure (HR0.69 [95% CI 0.57–0.83]). In terms ofsafety, no significant increase in lower-limb amputations, fractures, acute kidneyinjury, or hyperkalemia was noted forcanagliflozin relative to placebo in CRE-DENCE. An increased risk for diabeticketoacidosis was noted, however, with2.2 and 0.2 events per 1,000patient-yearsnoted in the canagliflozin and placebogroups, respectively (HR 10.80 [95% CI1.39–83.65]) (162).

The Dapagliflozin Effect on Cardiovascu-lar Events–Thrombosis in Myocardial In-farction 58 (DECLARE-TIMI 58) trial wasanother randomized,double-blind trial thatassessed the effects of dapagliflozin versusplacebo on cardiovascular and renal out-comes in 17,160 patients with type 2 di-abetes and established ASCVD or multiplerisk factors for atherosclerotic cardiovascu-lar disease (164). Study participants had amean age of 64 years, with;40% of studyparticipants having established ASCVD atbaselineda characteristic of this trial thatdiffers fromother largecardiovascular trialswhere amajority of participants had estab-lished cardiovascular disease. DECLARE-TIMI 58 met the prespecified criteria fornoninferiority to placebo with respect toMACE but did not show a lower rate ofMACE when compared with placebo (8.8%in the dapagliflozin group and 9.4% in theplacebo group; HR 0.93; 95% CI 0.84–1.03;P 5 0.17). A lower rate of cardiovasculardeath or hospitalization for heart failurewas noted (4.9% vs. 5.8%; HR 0.83; 95% CI0.73–0.95; P 5 0.005), which reflected a

lowerrateofhospitalizationforheartfailure(HR 0.73; 95% CI 0.61–0.88). No differencewas seen in cardiovascular death betweengroups.

GLP-1 Receptor Agonist TrialsThe Liraglutide Effect and Action in Di-abetes: Evaluation of CardiovascularOutcome Results (LEADER) trial was arandomized, double-blind trial thatassessed the effect of liraglutide, aglucagon-like peptide 1 (GLP-1) receptoragonist, versus placebo on cardiovascularoutcomes in 9,340 patients with type 2diabetes at high risk for cardiovasculardisease or with cardiovascular disease.Study participants had a mean age of64 years and a mean duration of diabetesof nearly 13 years. Over 80% of studyparticipants had established cardiovascu-lardisease.Afteramedianfollow-upof3.8years, LEADER showed that the primarycomposite outcome (MI, stroke, or car-diovascular death) occurred in fewerparticipants in the treatment group(13.0%) when compared with the pla-cebo group (14.9%) (HR 0.87; 95% CI0.78–0.97; P, 0.001 for noninferiority;P 5 0.01 for superiority). Deaths fromcardiovascular causes were significantlyreduced in the liraglutide group (4.7%)compared with the placebo group(6.0%) (HR 0.78; 95% CI 0.66–0.93;P 5 0.007) (165). The FDA approvedtheuseof liraglutide to reduce the risk ofmajor adverse cardiovascular events,including heart attack, stroke, and car-diovascular death, in adults with type 2diabetes and established cardiovascu-lar disease.

Table 10.3B—Continued

ELIXA (170) LEADER (165) SUSTAIN-6 (166)* EXSCEL (171)Harmony

Outcomes (168) REWIND (169)(n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 9,463) (n 5 9,901)

All-causemortality§

0.94 (0.78–1.13) 0.85 (0.74–0.97) 1.05 (0.74–1.50) 0.86 (0.77–0.97) 0.95 (0.79–1.16) 0.90 (0.80–1.01)

Worseningnephropathy§||

d 0.78 (0.67–0.92) 0.64 (0.46–0.88) d d 0.85 (0.77–0.93)

d, not assessed/reported; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; CKD, chronickidney disease; CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiac event;MI, myocardial infarction. Data from this table was adapted from Cefalu et al. (188) in the January 2018 issue of Diabetes Care. *Powered to rule outa hazard ratio of 1.8; superiority hypothesis not prespecified. ††Agewas reported as means in all trials; diabetes duration was reported as means in alltrials except EXSCEL, which reported medians. †A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide. §Outcomes reported ashazard ratio (95%CI). ||Worsening nephropathy is defined as the newonset of urine albumin-to-creatinine ratio.300mg/g creatinine or a doubling ofthe serum creatinine level and an estimated glomerular filtration rate of,45mL/min/1.73m2, the need for continuous renal replacement therapy, ordeath from renal disease in LEADER and SUSTAIN-6 and as newmacroalbuminuria, a sustained decline in estimated glomerular filtration rate of 30%ormore frombaseline, or chronic renal replacement therapy in REWIND.Worsening nephropathywas a prespecified exploratory adjudicated outcome inLEADER, SUSTAIN-6, and REWIND.^Significant difference in A1C between groups (P , 0.05).

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Table 10.3C—Cardiovascular outcomes trials of available antihyperglycemic medications completed after the issuanceof the FDA 2008 guidelines: SGLT2 inhibitors

EMPA-REGOUTCOME (8)

CANVAS (9)DECLARE-TIMI 58 (164)

(n 5 7,020) (n 5 4,330) (n 5 5,812) (n 5 17,160)

Intervention Empagliflozin/placebo

Canagliflozin/placebo

Dapagliflozin/placebo

Main inclusion criteria Type 2 diabetesandpreexistingCVD

Type 2 diabetesand preexistingCVD at $30years of ageor .2 CV riskfactors at $50years of age

Type 2 diabetes andestablished ASCVD ormultiple risk factorsfor ASCVD

A1C inclusion criteria (%) 7.0–10.0 7.0–10.5 $6.5

Age (years)†† 63.1 63.3 64.0

Race (% white) 72.4 78.3 79.6

Sex (% male) 71.5 64.2 62.6

Diabetes duration (years)†† 57% .10 13.5 11.0

Median follow-up (years) 3.1 5.7 2.1 4.2

Statin use (%) 77 75 75 (statin or ezetimibe use)

Metformin use (%) 74 77 82

Prior CVD/CHF (%) 99/10 65.6/14.4 40/10

Mean baseline A1C (%) 8.1 8.2 8.3

Mean difference in A1C betweengroups at end of treatment (%)

20.3‡ 20.58 20.43

Year started/reported 2010/2015 2009/2017 2013/2018

Primary outcome§ 3-point MACE 3-point MACE Progression toalbuminuria**0.73 (0.47–0.77)

3-point MACE 0.93 (0.84–1.03)0.86 (0.74–0.99) 0.86 (0.75–0.97)§

CV death or HF hospitalization0.83 (0.73–0.95)

Key secondary outcome§ 4-point MACE All-cause and CVmortality (seebelow)

40% reduction incompositeeGFR, renalreplacement,renal death 0.60(0.47–0.77)

Death from any cause0.93 (0.82–1.04)Renal composite ($40%

decrease in eGFR rate to,60 mL/min/1.73m2, newESRD,ordeath fromrenalorCV causes

0.76 (0.67–0.87)

Cardiovascular death§ 0.62 (0.49–0.77) 0.96 (0.77–1.18)¶ 0.98 (0.82–1.17)0.87 (0.72–1.06)#

MI§ 0.87 (0.70–1.09) 0.85 (0.65–1.11) 0.85 (0.61–1.19) 0.89 (0.77–1.01)

Stroke§ 1.18 (0.89–1.56) 0.97 (0.70–1.35) 0.82 (0.57–1.18) 1.01 (0.84–1.21)

HF hospitalization§ 0.65 (0.50–0.85) 0.77 (0.55–1.08) 0.56 (0.38–0.83) 0.73 (0.61–0.88)

Unstable angina hospitalization§ 0.99 (0.74–1.34) d d

All-cause mortality§ 0.68 (0.57–0.82) 0.87 (0.74–1.01)‡‡ 0.93 (0.82–1.04)0.90 (0.76–1.07)##

Worsening nephropathy§|| 0.61 (0.53–0.70) 0.60 (0.47–0.77) 0.53 (0.43–0.66)

d, not assessed/reported; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate;ESRD, end-stage renal disease;HF, heart failure;MACE,major adverse cardiacevent;MI,myocardial infarction; SGLT2, sodium–glucosecotransporter 2.Data from this tablewas adapted fromCefalu et al. (188) in the January 2018 issue ofDiabetes Care. **On the basis of prespecified outcomes, the renaloutcomesarenot viewedas statistically significant.††Agewas reportedasmeans inall trials; diabetesdurationwas reportedasmeans in all trials exceptEMPA-REGOUTCOME, which reported as percentage of population with diabetes duration.10 years, and DECLARE-TIMI 58, which reportedmedian.‡AlC change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for 10 mg and 0.36% for 25 mg of empagliflozin).§Outcomes reportedashazard ratio (95%CI). ||Worseningnephropathy is definedas the newonsetof urine albumin-to-creatinine ratio.300mg/gcreatinine or a doubling of the serum creatinine level and an estimated glomerular filtration rate of,45mL/min/1.73 m2, the need for continuousrenal replacement therapy, or death from renal disease in EMPA-REG OUTCOME and as $40% decrease in estimated glomerular filtration rateto,60mL/min/1.73m2, ESRD, or death from renal cause in DECLARE-TIMI 58.Worsening nephropathywas a prespecified exploratory adjudicatedoutcome in DECLARE-TIMI 58 but not in EMPA-REG OUTCOME. ¶Truncated data set (prespecified in treating hierarchy as the principal data setfor analysis for superiority of all-cause mortality and cardiovascular death in the CANVAS Program). Significant difference in A1C between groups(P, 0.05). #Nontruncated data set. ‡‡Truncated integrated data set (refers to pooled data from CANVAS after 20 November 2012 plus CANVAS-R;prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and cardiovascular death in theCANVAS Program). ##Nontruncated integrated data (refers to pooled data from CANVAS, including before 20 November 2012 plus CANVAS-R).

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Results from a moderate-sized trial ofanother GLP-1 receptor agonist, sema-glutide,were consistentwith the LEADERtrial (166). Semaglutide is a once-weeklyGLP-1 receptor agonist approved by theFDA for the treatment of type 2 diabetes.The Trial to Evaluate Cardiovascular andOther Long-term Outcomes With Sem-aglutide in Subjects With Type 2 Diabe-tes (SUSTAIN-6) was the initial randomizedtrial powered to test noninferiority ofsemaglutide for the purpose of initialregulatory approval. In this study, 3,297patients with type 2 diabetes were ran-domized to receive once-weekly semaglu-tide (0.5 mg or 1.0 mg) or placebo for2 years. The primary outcome (the firstoccurrence of cardiovascular death, non-fatal MI, or nonfatal stroke) occurred in108 patients (6.6%) in the semaglutidegroupvs.146patients (8.9%) intheplacebogroup (HR 0.74; 95% CI 0.58–0.95; P ,0.001). More patients discontinued treat-ment in the semaglutide group because ofadverse events, mainly gastrointestinal.The cardiovascular effects of the oral for-mulation of semaglutide compared withplacebo have been assessed in PeptideInnovation for Early Diabetes Treatment(PIONEER) 6, a preapproval trial designedto rule out anunacceptable increase in incardiovascular risk. In this trial of 3,183patients with type 2 diabetes and highcardiovascular risk followed for a me-dian of 15.9 months, oral semaglutidewas noninferior to placebo for the pri-mary composite outcome of cardiovas-culardeath,nonfatalmyocardial infarction,or nonfatal stroke (HR 0.79; 95% CI 0.57–1.11; P , 0.001 for noninferiority) (167).The cardiovascular effects of this formu-lation of semaglutidewill be further testedin a large, longer-term outcomes trial.The Harmony Outcomes trial random-

ized 9,463 patients with type 2 diabetesand cardiovascular disease to once-weekly subcutaneousalbiglutideormatch-ing placebo, in addition to their standardcare. Over a median duration of 1.6 years,theGLP-1receptoragonist reducedtheriskof cardiovascular death,MI, or stroke to anincidence rate of 4.6 events per 100 per-son-years in the albiglutide group vs. 5.9events in the placebo group (HR ratio 0.78,P 5 0.0006 for superiority) (168). Thisagent is not currently available for clinicaluse.The Researching Cardiovascular Events

With a Weekly Incretin in Diabetes (RE-WIND) trial was a randomized, double-

blind, placebo-controlled trial that as-sessed the effect of the once-weeklyGLP-1 receptor agonist dulaglutide ver-sus placebo onMACE in;9,990 patientswith type 2 diabetes at risk for cardio-vascular events or with a history ofcardiovascular disease (169). Study par-ticipantshadameanageof66years andamean duration of diabetes of;10 years.Approximately 32% of participants hadprior history of atherosclerotic cardio-vascular events at baseline. After a me-dian follow-up of 5.4 years, the primarycomposite outcome of nonfatal myocar-dial infarction, nonfatal stroke, or deathfrom cardiovascular causes occurredin 12.0% and 13.4% of participants inthe dulaglutide and placebo treatmentgroups, respectively (HR 0.88; 95% CI0.79–0.99; P 5 0.026). These findingsequated to incidence rates of 2.4 and 2.7events per 100 person-years, respec-tively. The results were consistent acrossthe subgroups of patients with and with-out prior history of CV events. All-causemortality did not differ between groups(P 5 0.067).

The Evaluation of Lixisenatide in AcuteCoronary Syndrome (ELIXA) trial studiedthe once-daily GLP-1 receptor agonistlixisenatide on cardiovascular outcomesin patients with type 2 diabetes who hadhad a recent acute coronary event (170).A total of 6,068 patients with type 2diabetes with a recent hospitalization forMIorunstableanginawithin theprevious180 days were randomized to receivelixisenatide or placebo in addition tostandard care and were followed for amedian of ;2.1 years. The primary out-come of cardiovascular death, MI, stroke,or hospitalization for unstable anginaoccurred in 406 patients (13.4%) in thelixisenatide group vs. 399 (13.2%) in theplacebo group (HR 1.2 [95% CI 0.89–1.17]), which demonstrated the noninfer-iorityof lixisenatidetoplacebo(P,0.001)but did not show superiority (P 5 0.81).

The Exenatide Study of Cardiovascu-lar Event Lowering (EXSCEL) trial alsoreported results with the once-weeklyGLP-1 receptor agonist extended-releaseexenatide and found that major adversecardiovascular events were numeri-cally lower with use of extended-releaseexenatide compared with placebo, al-though this difference was not statisti-cally significant (171). A total of 14,752patients with type 2 diabetes (of whom10,782 [73.1%] had previous cardiovascular

disease) were randomized to receive ex-tended-release exenatide 2 mg or pla-cebo and followed for a median of 3.2years. The primary end point of cardio-vascular death,MI, or stroke occurred in839 patients (11.4%; 3.7 events per100 person-years) in the exenatidegroup and in 905 patients (12.2%; 4.0events per 100 person-years) in theplacebo group (HR 0.91; 95% CI 0.83–1.00; P , 0.001 for noninferiority) butwas not superior to placebo with re-spect totheprimaryendpoint (P50.06forsuperiority). However, all-cause mortalitywas lower in the exenatide group (HR 0.86[95%CI 0.77–0.97]). The incidenceof acutepancreatitis, pancreatic cancer, medullarythyroid carcinoma, and serious adverseevents did not differ significantly betweenthe two groups.

In summary, there are now numerouslarge randomized controlled trials re-porting statistically significant reductionsin cardiovascular events for three of theFDA-approved SGLT2 inhibitors (empa-gliflozin, canagliflozin, and dapagliflozin)and four FDA-approved GLP-1 receptoragonists (liraglutide, albiglutide [al-though that agent was removed fromthe market for business reasons], sem-aglutide [lower risk of cardiovascularevents in a moderate-sized clinical trialbut one not powered as a cardiovascu-lar outcomes trial], and dulaglutide).Meta-analyses of the trials reportedto date suggest that GLP-1 receptoragonists andSGLT2 inhibitors reduceriskof atherosclerotic major adverse cardio-vascular events to a comparable degreein patients with type 2 diabetes andestablished ASCVD (172). SGLT2 inhib-itors also appear to reduce risk of heartfailure hospitalization and progressionof kidney disease in patients with es-tablished ASCVD, multiple risk factorsfor ASCVD, or diabetic kidney disease(173). In patients with type 2 diabetesand established ASCVD, multiple ASCVDrisk factors, or diabetic kidney disease,an SGLT2 inhibitor with demonstratedcardiovascular benefit is recommendedto reduce the risk of major adversecardiovascular events and heart failurehospitalization. In patients with type 2diabetes and established ASCVD or mul-tiple risk factors for ASCVD, a glucagon-like peptide 1 receptor agonist withdemonstrated cardiovascular benefit isrecommended to reduce the risk of ma-jor adverse cardiovascular events. For

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many patients, use of either an SGLT2inhibitor or a GLP-1 receptor agonist toreduce cardiovascular risk is appropri-ate. It is unknown whether use of bothclasses of drugs will provide an additivecardiovascular outcomes benefit.

Glucose-Lowering Therapies andHeart FailureAs many as 50% of patients with type 2diabetes may develop heart failure (174).Data on the effects of glucose-loweringagents on heart failure outcomes havedemonstrated that thiazolidinedioneshave a strong and consistent relationshipwith increased risk of heart failure(175–177). Therefore, thiazolidinedioneuse should be avoided in patients withsymptomatic heart failure. Restrictions touse of metformin in patients with med-ically treated heart failure were removedby the FDA in 2006 (178). In fact, obser-vational studies of patients with type 2diabetes and heart failure suggest thatmetformin users have better outcomesthan patients treated with other antihy-perglycemic agents (179).Metforminmaybe used for the management of hyper-glycemia in patients with stable heartfailure as long as kidney function remainswithin the recommended range for use(180).Recent studies examining the relation-

ship between DPP-4 inhibitors and heartfailure have had mixed results. The Sax-agliptinAssessmentofVascularOutcomesRecorded in Patients with Diabetes Mel-litus – Thrombolysis in Myocardial Infarc-tion 53 (SAVOR-TIMI 53) study showedthat patients treated with the DPP-4 in-hibitor saxagliptin were more likely to behospitalized for heart failure than thosegivenplacebo(3.5%vs.2.8%,respectively)(181). However, three other cardiovascu-lar outcomes trials, Examination of Car-diovascular Outcomes with Alogliptinversus Standard of Care (EXAMINE)(182), Trial EvaluatingCardiovascularOut-comes with Sitagliptin (TECOS) (183), andthe Cardiovascular and Renal Microvas-cular Outcome Study With Linagliptin(CARMELINA) (184) did not find a signif-icant increase in risk of heart failurehospitalization with DPP-4 inhibitor usecomparedwith placebo. No increased riskof heart failure hospitalization has beenidentified in the cardiovascular outcomestrials of the GLP-1 receptor agonistslixisenatide, liraglutide, semaglutide,exenatide QW, albiglutide, or dulaglutide

compared with placebo (Table 10.3B)(165,166,169–171).

Reduced incidence of heart failure hasbeen observed with the use of SGLT2inhibitors (162,164). In EMPA-REG OUT-COME, the addition of empagliflozin tostandard care led to a significant 35%reduction in hospitalization for heartfailure compared with placebo (8). Al-though the majority of patients in thestudy did not have heart failure at base-line, this benefit was consistent in pa-tients with andwithout a history of heartfailure (10). Similarly, in CANVAS andDECLARE-TIMI 58, there were 33% and27% reductions in hospitalization forheart failure, respectively, with SGLT2inhibitor use versus placebo (9,164).Additional data from the CREDENCE trialwith canagliflozin showed a 39% reduc-tion in hospitalization for heart failure,and 31% reduction in the composite ofcardiovascular death or hospitalizationfor heart failure, in a diabetic kidney dis-ease population with albuminuria (UACRof .300 to 5,000 mg/g) (162). Thesecombined findings from four large out-comes trials of three different SGLT2 in-hibitors are highly consistent and clearlyindicate robustbenefitsof SGLT2 inhibitorsin the prevention of heart failure hospital-izations. They also suggest, but do notprove, that SGLT2 inhibitors may be ben-eficial in patients with established heartfailure. This hypothesis is being specificallyevaluated in several large outcomes trialsin patients with established heart failure,both with and without diabetes, to de-termine the efficacy of SGLT2 inhibitors inthe treatmentofheart failurewith reducedand preserved ejection fraction.

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S134 Cardiovascular Disease and Risk Management Diabetes Care Volume 43, Supplement 1, January 2020