10. Cardiovascular Disease andRisk Management: Standards ofMedical Care in Diabetesd2019Diabetes Care 2019;42(Suppl. 1):S103–S123 | https://doi.org/10.2337/dc19S010

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includes ADA’s current clinical practice recommendations and is intended to providethe components of diabetes care, general treatment goals and guidelines, and toolsto evaluate quality of care. Members of the ADA Professional Practice Committee, amultidisciplinary expert committee, are responsible for updating the Standards ofCare annually, or more frequently as warranted. For a detailed description of ADAstandards, statements, and reports, as well as the evidence-grading system forADA’s clinical practice recommendations, please refer to the Standards of CareIntroduction. Readers who wish to comment on the Standards of Care are invitedto 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 and Adolescents.”Atherosclerotic cardiovascular disease (ASCVD)ddefined as coronary heart disease,

cerebrovascular disease, or peripheral arterial disease presumed to be of atheroscleroticorigindis the leading causeofmorbidity andmortality for individualswithdiabetes andresults in anestimated$37.3billion in cardiovascular-related spendingper year associatedwith diabetes (1). Common conditions coexisting with type 2 diabetes (e.g., hypertensionand dyslipidemia) are clear risk factors for ASCVD, anddiabetes itself confers independentrisk. Numerous studies have shown the efficacy of controlling individual cardiovascularrisk factors in preventing or slowing ASCVD in people with diabetes. Furthermore, largebenefits are seen when multiple cardiovascular risk factors are addressed simultaneously.Under the current paradigm of aggressive risk factor modification in patients withdiabetes, there is evidence thatmeasures of 10-year coronary heart disease (CHD) riskamong U.S. adults with diabetes have improved significantly over the past decade (2)and that ASCVD morbidity and mortality have decreased (3,4).Heart failure is anothermajor cause ofmorbidity andmortality fromcardiovascular

disease. Recent studies have found that rates of incident heart failure hospitalization(adjusted for age and sex) were twofold higher in patients with diabetes comparedwith those without (5,6). People with diabetes may have heart failure with preservedejection fraction (HFpEF) or with reduced ejection fraction (HFrEF). Hypertensionis often a precursor of heart failure of either type, and ASCVD can coexist with eithertype (7), whereas prior myocardial infarction (MI) is often a major factor in HFrEF.Rates of heart failure hospitalization have been improved in recent trials includingpatients with type 2 diabetes, most of whom also had ASCVD, with sodium–

glucose cotransporter 2 (SGLT2) inhibitors (8–10).For prevention andmanagement ofbothASCVDandheart failure, cardiovascular risk

factors should be systematically assessed at least annually in all patients with diabetes.These risk factors include obesity/overweight, hypertension, dyslipidemia, smoking, a

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 inDiabetesd2019. Diabetes Care 2019;42(Suppl. 1):S103–S123

© 2018 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 42, Supplement 1, January 2019 S103

10.CARDIOVASCULA

RDISEA

SEANDRISK

MANAGEM

ENT

family history of premature coronarydisease, chronic kidney disease, andthe presence of albuminuria.Modifiableabnormal risk factors should be treatedas described in these guidelines.

The Risk CalculatorThe American College of Cardiology/American Heart Association ASCVD riskcalculator (Risk Estimator Plus) is gen-erally a useful tool to estimate 10-yearASCVD risk (http://tools.acc.org/ASCVD-Risk-Estimator-Plus). Thesecalculatorshavediabetes as a risk factor, since diabetesitself confers increased risk for ASCVD,although it should be acknowledged thatthese risk calculators do not account forthe duration of diabetes or the presenceof diabetes complications, such as albumin-uria. Although some variability in calibra-tion exists in various subgroups, includingby sex, race, and diabetes, the overall riskprediction does not differ in those withor without diabetes (11–14), validatingthe use of risk calculators in people withdiabetes. The 10-year risk of a first ASCVDevent should be assessed to better stratifyASCVD risk and help guide therapy, asdescribed below.Recently, risk scores and other cardio-

vascular 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 an-tihypertensive therapy reduces ASCVDevents, heart failure, and microvascularcomplications. Please refer to the Amer-ican Diabetes Association (ADA) positionstatement “Diabetes and Hypertension”for a detailed review of the epidemiol-ogy, diagnosis, and treatment of hyper-tension (17). The recommendationspresented here reflect ADA’s updatedstance on blood pressure.

Screening and Diagnosis

Recommendations

10.1 Blood pressure should be mea-sured at every routine clinicalvisit. Patients found to have el-evated blood pressure ($140/90 mmHg) should have bloodpressure confirmed using multi-ple readings, includingmeasure-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 by atrained individual and should follow theguidelines established for the generalpopulation: measurement in the seatedposition, with feet on the floor and armsupported at heart level, after 5 min ofrest. Cuff size should be appropriate forthe upper-arm circumference. Elevatedvalues shouldbe confirmedona separateday. Postural changes in blood pressureand pulse may be evidence of autonomicneuropathy and therefore require ad-justment of blood pressure targets. Or-thostatic blood pressure measurementsshould be checked on initial visit and asindicated.

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, potential

adverse effects of antihyper-tensive medications, and patientpreferences. C

10.4 For individuals with diabetesand hypertension at higher car-diovascular risk (existing athero-sclerotic cardiovascular diseaseor 10-year atherosclerotic car-diovascular disease risk .15%),abloodpressure targetof,130/80 mmHg may be appropriate,if it can be safely attained. C

10.5 For individuals with diabetesand hypertension at lowerrisk for cardiovascular disease(10-year atherosclerotic cardio-vasculardiseaserisk,15%), treatto a blood pressure target of,140/90 mmHg. A

10.6 In pregnant patients with dia-betes and preexisting hyper-tension who are treated withantihypertensive therapy, bloodpressure targetsof120–160/80–105 mmHg are suggested in theinterest of optimizing long-termmaternal health and minimiz-ing impaired fetal growth. E

Randomized clinical trials have demon-strated unequivocally that treatmentof hypertension to blood pressure,140/90 mmHg reduces cardiovascularevents as well as microvascular compli-cations (21–27). Therefore, patients withtype 1 or type 2 diabetes who havehypertension should, at a minimum,be treated to blood pressure targetsof ,140/90 mmHg. The benefits andrisks of intensifying antihypertensivetherapy to target blood pressures lowerthan ,140/90 mmHg (e.g., ,130/80 or,120/80mmHg) have been evaluated inlarge randomized clinical trials andmeta-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

TheAction 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 pres-sure control (target systolic blood pres-sure ,140 mmHg), intensive blood

S104 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

pressure 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 ACCORD BPresults suggest that blood pressure tar-getsmore intensive than,140/90mmHgare not likely to improve cardiovascularoutcomes among most people withtype 2 diabetes but may be reasonablefor patients who may derive the most

benefit and have been educated aboutadded treatment burden, side effects,and costs, as discussed below.

Additional studies, such as the Sys-tolic Blood Pressure Intervention Trial(SPRINT) and the Hypertension OptimalTreatment (HOT) trial, also examinedeffects of intensive versus standard con-trol (Table 10.1), though the relevanceof their results to people with diabetesis less clear. The Action in Diabetesand Vascular Disease: Preterax and

Diamicron MR Controlled Evaluation–Blood Pressure (ADVANCE BP) trial didnot explicitly test blood pressure targets(29); the achieved blood pressure in theintervention group was higher thanthat achieved in the ACCORD BP in-tensive arm and would be consistentwith a target blood pressure of ,140/90 mmHg. Notably, ACCORD BP andSPRINT measured blood pressure usingautomatedoffice bloodpressuremeasure-ment,whichyieldsvaluesthataregenerally

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 with T2Daged 40–79 years withprior evidence of CVD ormultiple cardiovascularrisk factors

Systolic blood pressuretarget: ,120 mmHg

Systolic blood pressure target:130–140 mmHg

c No benefit in primary endpoint: composite of nonfatalMI, nonfatal stroke, and CVDdeath

c Stroke risk reduced 41%with intensive control, notsustained through follow-upbeyond the period of activetreatment

c Adverse events morecommon in intensive group,particularly elevated serumcreatinine and electrolyteabnormalities

Achieved (mean) systolic/diastolic: 119.3/64.4 mmHg

Achieved (mean) systolic/diastolic: 133.5/70.5 mmHg

ADVANCEBP(29)

11,140 participantswith T2Daged 55 years and olderwithpriorevidenceofCVDor multiple cardiovascularrisk factors

Intervention: a single-pill, fixed-dose combination ofperindopril and indapamide

Control: placebo c Intervention reduced riskof primary compositeend point of majormacrovascular andmicrovascular events (9%),death from any cause (14%),and death from CVD (18%)

c 6-year observationalfollow-up found reductionin risk of death in interventiongroup attenuated but stillsignificant (174)

Achieved (mean) systolic/diastolic: 136/73 mmHg

Achieved (mean) systolic/diastolic: 141.6/75.2 mmHg

HOT (173) 18,790 participants,including 1,501 withdiabetes

Diastolic blood pressuretarget: #80 mmHg

Diastolic blood pressuretarget: #90 mmHg

c In the overall trial, there wasno cardiovascular benefitwith more intensive targets

c In the subpopulation withdiabetes, an intensivediastolic target wasassociated with asignificantly reduced risk(51%) of CVD events

SPRINT (39) 9,361 participants withoutdiabetes

Systolic blood pressuretarget: ,120 mmHg

Systolic blood pressuretarget: ,140 mmHg

c Intensive systolic bloodpressure target lowered riskof the primary compositeoutcome 25% (MI, ACS,stroke, HF, and death dueto CVD)

c Intensive target reduced riskof death 27%

c Intensive therapy increasedrisks of electrolyteabnormalities and AKI

Achieved (mean): 121.4 mmHg Achieved (mean): 136.2 mmHg

ACS, acute coronary syndrome; AKI, acute kidney injury; CVD, cardiovascular disease; HF, heart failure;MI,myocardial infarction; T2D, type 2 diabetes.Data from this table can also be found in the ADA position statement “Diabetes and Hypertension” (17).

care.diabetesjournals.org Cardiovascular Disease and Risk Management S105

lower than typical office blood pressurereadings by approximately 5–10 mmHg(30), suggesting that implementing theACCORD BP or SPRINT protocols in anoutpatient clinic might require a sys-tolic blood pressure target higher than,120 mmHg, such as ,130 mmHg.A number of post hoc analyses have

attempted to explain the apparently di-vergent results of ACCORD BP and SPRINT.Some investigators have argued that thedivergent results are not due to differ-ences between people with and withoutdiabetes 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(or intensive treatment) arm. Based onthese analyses, antihypertensive treatmentappears to be beneficial when meanbaseline blood pressure is $140/90mmHg or mean attained intensiveblood pressure is $130/80 mmHg(17,21,22,24–26). Among trials withlower baseline or attained blood pres-sure, antihypertensive treatment re-duced the risk of stroke, retinopathy,and albuminuria, but effects on otherASCVD outcomes and heart failurewere not evident. Taken together, thesemeta-analyses consistently show thattreating patients with baseline bloodpressure $140 mmHg to targets ,140mmHg is beneficial, while more inten-sive targets may offer additional (thoughprobably less robust) benefits.

Individualization of Treatment Targets

Patients and clinicians should engage ina shared decision-making process todetermine 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 and

provider judgment (35). Secondary ana-lyses of ACCORD BP and SPRINT suggestthat clinical factors can help determineindividuals more likely to benefit and lesslikely to be harmed by intensive bloodpressure control (36).

Absolute benefit from blood pressurereduction correlated with absolute base-line cardiovascular risk in SPRINT and inearlier clinical trials conducted at higherbaseline blood pressure levels (11,37).Extrapolation of these studies suggeststhat patients with diabetes may also bemore likely to benefit from intensiveblood pressure control when they havehigh absolute cardiovascular risk. There-fore, itmaybe reasonable to target bloodpressure,130/80mmHgamongpatientswith diabetes and either clinically diag-nosed cardiovascular disease (particularlystroke, which was significantly reduced inACCORDBP) or10-yearASCVD risk$15%,if it can be attained safely. This approachis consistent with guidelines from theAmerican College of Cardiology/AmericanHeart Association, which advocate ablood pressure target ,130/80 mmHgfor all patients, with or without diabe-tes (38).

Potential adverse effects of antihyper-tensive therapy (e.g., hypotension, syn-cope, 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 limi-tations, or polypharmacy may be at highrisk of adverse effects, and some patientsmay 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 such adverseeffects should have a higher blood pres-sure target. In such patients, a bloodpressure target of ,140/90 mmHg isrecommended, if it can be safely attained.

Pregnancy and Antihypertensive Medications

Since there is a lack of randomized con-trolled trials of antihypertensive therapyin pregnant women with diabetes, rec-ommendations for the management ofhypertension in pregnant women withdiabetes should be similar to those for

all pregnant women. The American Col-lege of Obstetricians and Gynecologists(ACOG) has recommended that womenwith mild to moderate gestational hyper-tension (systolic blood pressure ,160mmHg or diastolic blood pressure ,110mmHg) do not need to be treated withantihypertensive medications as there isnobenefit identified that clearly outweighspotential risks of therapy (42). A 2014 Co-chrane systematic review of antihyperten-sive therapy for mild to moderate chronichypertension that included 49 trials andover 4,700 women did not find any con-clusive evidence for or against blood pres-sure treatment to reduce the risk ofpreeclampsia for the mother or effectson perinatal outcomes such as pretermbirth, small-for-gestational-age infants,or fetal death (43). For pregnant womenwho require antihypertensive therapy,systolic blood pressure levels of 120–160 mmHg and diastolic blood pressurelevels of 80–105 mmHg are suggested tooptimizematernal health without riskingfetal harm. Lower targets (systolic bloodpressure 110–119 mmHg and diastolicblood pressure 65–79 mmHg) may con-tribute to improved long-term mater-nal health; however, they may beassociated with impaired fetal growth.Pregnant women with hypertension andevidence of end-organ damage from car-diovascular and/or renal disease may beconsidered for lower blood pressure tar-gets to avoid progression of these con-ditions during pregnancy.

During pregnancy, treatment withACE inhibitors, angiotensin receptorblockers (ARBs), and spironolactoneare contraindicated as they may causefetal damage. Antihypertensive drugsknown to be effective and safe in preg-nancy includemethyldopa, labetalol, andlong-acting nifedipine, while hydralzinemay be considered in the acute manage-ment of hypertension in pregnancy orsevere preeclampsia (42). Diuretics arenot recommended for blood pressurecontrol in pregnancy but may be usedduring late-stagepregnancy if needed forvolume control (42,44). ACOG also recom-mends that postpartum patients with ges-tational hypertension, preeclampsia, andsuperimposed preeclampsia have theirblood pressures observed for 72 h inthehospital and for7–10dayspostpartum.Long-term follow-up is recommended forthese women as they have increased life-time cardiovascular risk (45). See Section

S106 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

14“ManagementofDiabetesinPregnancy”for additional information.

Treatment Strategies

Lifestyle Intervention

Recommendations

10.7 For patients with blood pres-sure .120/80 mmHg, lifestyleintervention consists of weightloss if overweight or obese, aDietary Approaches to Stop Hy-pertension (DASH)-style dietarypattern including reducing so-dium and increasing potassiumintake, moderation of alcohol in-take, and increased physical ac-tivity. B

Lifestyle management is an importantcomponent of hypertension treatmentbecause it lowers blood pressure, en-hances the effectiveness of some anti-hypertensive medications, promotesother aspects of metabolic and vascularhealth, and generally leads to fewadverseeffects. Lifestyle therapy consists of re-ducing excess body weight through calo-ric restriction, restricting sodium intake(,2,300 mg/day), increasing consump-tion of fruits and vegetables (8–10 serv-ings per day) and low-fat dairy products(2–3 servings per day), avoiding excessivealcohol consumption (no more than2 servings per day in men and no morethan 1 serving per day in women) (46),and increasing activity levels (47).These lifestyle interventions are reason-

able 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) (47). A lifestyle ther-apy plan should be developed in collabo-ration with the patient and discussed aspart of diabetes management.

Pharmacologic Interventions

Recommendations

10.8 Patients with confirmed office-based blood pressure $140/90mmHg should, in addition tolifestyle therapy, have promptinitiation and timely titrationof pharmacologic therapy toachieve blood pressure goals. A

10.9 Patients with confirmed office-based blood pressure $160/100 mmHg should, in addition

to lifestyle therapy, haveprompt initiation and timelytitration of two drugs or asingle-pill combination of drugsdemonstrated to reduce car-diovascular events in patientswith diabetes. A

10.10 Treatment for hypertensionshould include drug classesdemonstrated to reduce car-diovascular events in patientswith diabetes (ACE inhibitors,angiotensin receptor blockers,thiazide-like diuretics, or dihy-dropyridine calcium channelblockers). A

10.11 Multiple-drug therapy is gen-erally required to achieveblood pressure targets. How-ever, combinations of ACEinhibitors and angiotensin re-ceptor blockers and combina-tions of ACE inhibitors orangiotensin receptor blockerswith direct renin inhibitorsshould not be used. A

10.12 An ACE inhibitor or angioten-sin receptor blocker, at themaximum tolerated dose in-dicated for blood pressuretreatment, is the recommen-ded first-line treatment for hy-pertension in patients withdiabetes and urinary albumin-to-creatinine ratio $300 mg/gcreatinine A or 30–299 mg/gcreatinine. B If one class is nottolerated, the other should besubstituted. B

10.13 For patients treated with anACE inhibitor, angiotensinreceptor blocker, or diuretic,serum creatinine/estimatedglomerular filtration rate andserum potassium levels shouldbe monitored at least annu-ally. B

InitialNumberofAntihypertensiveMedications.

Initial treatment for people with diabe-tesdependson theseverityofhypertension(Fig. 10.1). Those with blood pressure be-tween 140/90 mmHg and 159/99 mmHgmay begin with a single drug. For patientswith blood pressure $160/100 mmHg,initial pharmacologic treatment withtwo antihypertensive medications is rec-ommended in order to more effectivelyachieve adequate blood pressure control

(48–50). Single-pill antihypertensive com-binationsmay improvemedication adher-ence in some patients (51).

Classes of Antihypertensive Medications. Ini-tial treatment for hypertension shouldinclude any of the drug classes demon-strated to reduce cardiovascular events inpatients with diabetes: ACE inhibitors(52,53), ARBs (52,53), thiazide-like di-uretics (54), or dihydropyridine calciumchannel blockers (55). For patients withalbuminuria (urine albumin-to-creatinineratio$30 mg/g), initial treatment shouldincludeanACE inhibitor orARB in order toreduce the risk of progressive kidneydisease (17) (Fig. 10.1). In the absence ofalbuminuria, risk of progressive kidneydisease is low, and ACE inhibitors andARBs have not been found to afford su-perior cardioprotection when comparedwith thiazide-like diuretics or dihydro-pyridine calcium channel blockers (56).b-Blockers may be used for the treat-ment of prior MI, active angina, or heartfailure but have not been shown to re-ducemortality as blood pressure-loweringagents in the absence of these conditions(23,57).

Multiple-DrugTherapy.Multiple-drug ther-apy is often required to achieve bloodpressure targets (Fig. 10.1), particularlyin the setting of diabetic kidney disease.However, the use of both ACE inhibitorsand ARBs in combination, or the combi-nation of an ACE inhibitor or ARB and adirectrenin inhibitor, isnot recommendedgiven the lack of added ASCVD benefit andincreased rate of adverse eventsdnamely,hyperkalemia, syncope, and acute kidneyinjury (AKI) (58–60). Titration of and/oraddition of further blood pressure medi-cations should bemade in a timely fashionto overcome 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 antihy-pertensivemedicationswithregardtobloodpressure control but had no data on clinicaleffects (61). In two subgroup analyses of asingle subsequent randomized controlledtrial, moving at least one antihypertensivemedication to bedtime significantly re-duced cardiovascular events, but results

care.diabetesjournals.org Cardiovascular Disease and Risk Management S107

were based on a small number of events(62).

HyperkalemiaandAcuteKidney Injury.Treat-ment with ACE inhibitors or ARBs cancause AKI and hyperkalemia, while

diuretics can cause AKI and either hypo-kalemia or hyperkalemia (depending onmechanism of action) (63,64). Detectionand management of these abnormali-ties is important because AKI and hyper-kalemia each increase the risks of

cardiovascular events and death (65).Therefore, serum creatinine and potas-sium should be monitored during treat-ment with an ACE inhibitor, ARB, ordiuretic, particularly among patientswith reduced glomerular filtration who

Figure 10.1—Recommendations for the treatment of confirmedhypertension inpeoplewithdiabetes. *AnACE inhibitor (ACEi) or angiotensin receptor blocker(ARB) is suggested to treathypertension forpatientswithurinealbumin-to-creatinine ratio30–299mg/gcreatinineandstrongly recommended forpatientswithurine albumin-to-creatinine ratio$300 mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown to reduce cardiovascular events, such aschlorthalidoneand indapamide, are preferred. ***Dihydropyridine calciumchannel blocker (CCB). BP, bloodpressure. Adapted fromdeBoer et al. (17).

S108 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

are at increased risk of hyperkalemia andAKI (63,64,66).

Resistant Hypertension

Recommendation

10.14 Patients with hypertensionwho are not meeting bloodpressure targets on three clas-ses of antihypertensive medi-cations (including a diuretic)should be considered for min-eralocorticoid receptor antag-onist therapy. B

Resistant hypertension is defined asblood pressure $140/90 mmHg de-spite a therapeutic strategy that includesappropriate lifestyle management plusa diuretic and two other antihypertensivedrugs belonging to different classes atadequate doses. Prior to diagnosing re-sistant hypertension, a number of otherconditions should be excluded, includingmedication nonadherence, white coathypertension, and secondary hyperten-sion. In general, barriers to medicationadherence (such as cost and side ef-fects) should be identified and addressed(Fig. 10.1). Mineralocorticoid receptorantagonists are effective for manage-ment of resistant hypertension in pa-tients with type 2 diabetes when addedto existing treatment with an ACE inhib-itor or ARB, thiazide-like diuretic, anddihydropyridine calcium channel blocker(67). Mineralocorticoid receptor antag-onists also reduce albuminuria andhave additional cardiovascular benefits(68–71). However, adding a mineralo-corticoid receptorantagonist toa regimenincluding an ACE inhibitor or ARB mayincrease the risk for hyperkalemia, em-phasizing the importance of regular mon-itoring for serum creatinine and potassiumin these patients, and long-term outcomestudies are needed to better evaluate therole of mineralocorticoid receptor antag-onists in blood pressure management.

LIPID MANAGEMENT

Lifestyle Intervention

Recommendations

10.15 Lifestyle modification focusingon weight loss (if indicated);application of a Mediterraneandiet or Dietary Approaches toStop Hypertension (DASH) di-etary pattern; reduction of

saturated fat and trans fat;increaseofdietaryn-3fattyacids,viscous fiber, and plant stanols/sterols intake; and increasedphysical activity should berecommended to improve thelipid profile and reduce the riskof developing atheroscleroticcardiovascular disease in pa-tients 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 (72), increased physical activity,and medical nutrition therapy, allowssome patients to reduce ASCVD riskfactors. Nutrition intervention shouldbe tailored according to each patient’sage, diabetes type, pharmacologictreatment, lipid levels, and medicalconditions.

Recommendations should focus onapplication of a Mediterranean diet(73) or Dietary Approaches to Stop Hy-pertension (DASH) dietary pattern, re-ducing saturated and trans fat intakeand increasing plant stanols/sterols,n-3 fatty acids, and viscous fiber(such as in oats, legumes, and citrus)intake (74). Glycemic control may alsobeneficially modify plasma lipid levels,particularly in patients with very hightriglycerides and poor glycemic control.See Section 5 “Lifestyle Management”for additional nutrition information.

Ongoing Therapy and MonitoringWith Lipid Panel

Recommendations

10.17 In adults not taking statins orother lipid-lowering therapy,it is 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 weeks

after initiation or a change indose, and annually thereafteras it may help to monitor theresponse to therapy and in-form medication adherence. E

In adults with diabetes, it is reason-able to obtain a lipid profile (total choles-terol, LDL cholesterol, HDL cholesterol,and triglycerides) at the time of diagnosis,at the initial medical evaluation, and atleast every 5 years thereafter in patientsunder the age of 40 years. In youngerpatients with longer duration of disease(such as those with youth-onset type 1diabetes), more frequent lipid profilesmay be reasonable. A lipid panel shouldalso be obtained immediately before initiat-ing statin therapy. Once a patient is takinga statin, LDL cholesterol levels should beassessed 4–12 weeks after initiation ofstatin therapy, after any change in dose,and on an individual basis (e.g., tomonitor for medication adherence andefficacy). If LDL cholesterol levels are notresponding in spite of medication adher-ence, clinical judgment is recommendedto determine the need for and timing oflipid panels. In individual patients, thehighly variable LDL cholesterol–loweringresponse seen with statins is poorlyunderstood (75). Clinicians should at-tempt to find a dose or alternative statinthat is tolerable if side effects occur.There is evidence for benefit from evenextremely low, less than daily statindoses (76).

Statin Treatment

Recommendations

10.19 For patients of all ages withdiabetes and atheroscleroticcardiovascular disease or 10-year atherosclerotic cardio-vascular disease risk .20%,high-intensity statin therapyshould be added to lifestyletherapy. A

10.20 For patients with diabetes aged,40 years with additionalatherosclerotic cardiovascu-lar disease risk factors, thepatient and provider shouldconsider using moderate-intensity statin in addition tolifestyle therapy. C

10.21 For patients with diabetesaged 40–75 years A and

care.diabetesjournals.org Cardiovascular Disease and Risk Management S109

.75 years B without athero-sclerotic cardiovascular dis-ease, use moderate-intensitystatin in addition to lifestyletherapy.

10.22 In patients with diabetes whohave multiple atheroscleroticcardiovascular disease risk fac-tors, it is reasonable to con-sider high-intensity statintherapy. C

10.23 For patients who do not tol-erate the intended intensity,the maximally tolerated sta-tin dose should be used. E

10.24 For patients with diabetes andatherosclerotic cardiovasculardisease, if LDL cholesterol is$70 mg/dL on maximally tol-erated statin dose, consider add-ing additional LDL-loweringtherapy (such as ezetimibe orPCSK9 inhibitor). A Ezetimibemay be preferred due to lowercost.

10.25 Statin therapy is contraindi-cated in pregnancy. B

Initiating Statin Therapy Based on Risk

Patients with type 2 diabetes have anincreased prevalence of lipid abnormal-ities, contributing to their high risk ofASCVD. Multiple clinical trials have

demonstrated the beneficial effects ofstatin therapy on ASCVD outcomes insubjects with and without CHD (77,78).Subgroup analyses of patients with di-abetes in larger trials (79–83) and trials inpatients with diabetes (84,85) showedsignificant primary and secondary pre-vention of ASCVD events and CHD deathin patients with diabetes. Meta-analyses,including data from over 18,000 patientswithdiabetes from14randomized trialsofstatin therapy (mean follow-up 4.3 years),demonstrate a 9% proportional reductionin all-causemortality and13%reduction invascular mortality for each mmol/L (39mg/dL) reduction in LDL cholesterol (86).

Accordingly, statins are the drugs ofchoice for LDL cholesterol lowering andcardioprotection. Table 10.2 shows rec-ommended lipid-lowering strategies,and Table 10.3 shows the two statindosing intensities that are recommendedfor use in clinical practice: high-intensitystatin therapy will achieve approximatelya 50% reduction in LDL cholesterol, andmoderate-intensity statin regimensachieve 30–50% reductions in LDL cho-lesterol. Low-dose statin therapy is gen-erally not recommended in patients withdiabetes but is sometimes the only doseof statin that a patient can tolerate. Forpatientswhodonot tolerate the intendedintensityofstatin, themaximally toleratedstatin dose should be 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 the overall bene-fits of statin therapy in people with di-abetes at moderate or even low risk forASCVDareconvincing (87,88).The relativebenefit of lipid-lowering therapy has beenuniform across most subgroups tested(78,86), including subgroups that variedwith respect to age andother risk factors.

Primary Prevention (Patients Without

ASCVD)

For primary prevention, moderate-dosestatin therapy is recommended for those40 years and older (80,87,88), 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 in pa-tients with diabetes who have multipleASCVD risk factors, it is reasonable toprescribe high-intensity statin therapy(12,89). Furthermore, for patients withdiabetes whose ASCVD risk is.20%, i.e.,an ASCVD risk equivalent, the same high-intensity statin therapy is recommendedas for thosewithdocumentedASCVD(12).

The evidence is lower for patientsaged .75 years; relatively few olderpatients with diabetes have been en-rolled in primary prevention trials. How-ever, heterogeneity by age has not beenseen in the relative benefit of lipid-lowering therapy in trials that includedolder participants (78,85,86), and be-cause older age confers higher risk, theabsolute benefits are actually greater(78,90).Moderate-intensity statin therapyis recommended in patientswith diabetesthat are 75 years or older. However, therisk-benefit profile should be routinelyevaluated in this population, with down-ward titration of dose performed asneeded. See Section 12 “Older Adults” formore details on clinical considerationsfor this population.

Age < 40 Years and/or Type 1 Diabetes. Verylittle clinical trial evidence exists for

Table 10.2—Recommendations for statin and combination treatment in adultswith diabetes

Age

ASCVD or10-year ASCVDrisk .20%

Recommended statin intensity^ and combinationtreatment*

,40 years No None†Yes High

c In patients with ASCVD, if LDL cholesterol $70mg/dL despite maximally tolerated statin dose,consider adding additional LDL-lowering therapy(such as ezetimibe or PCSK9 inhibitor)#

$40 years No Moderate‡Yes High

c In patients with ASCVD, if LDL cholesterol $70mg/dL despite maximally tolerated statin dose,consider adding additional LDL-lowering therapy(such as ezetimibe or PCSK9 inhibitor)

ASCVD, atherosclerotic cardiovascular disease; PCSK9, proprotein convertase subtilisin/kexin type9. *In addition to lifestyle therapy. ^For patients who do not tolerate the intended intensity ofstatin, the maximally tolerated statin dose should be used. †Moderate-intensity statin may beconsidered based on risk-benefit profile and presence of ASCVD risk factors. ASCVD risk factorsinclude LDL cholesterol$100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidneydisease, albuminuria, and family history of premature ASCVD. ‡High-intensity statin may beconsidered based on risk-benefit profile and presence of ASCVD risk factors. #Adults aged ,40years with prevalent ASCVD were not well represented in clinical trials of non-statin–based LDLreduction. Before initiating combination lipid-lowering therapy, consider the potential forfurther ASCVD risk reduction, drug-specific adverse effects, and patient preferences.

S110 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

patients with type 2 diabetes under theage of 40 years or for patients with type1 diabetes of any age. For pediatric rec-ommendations, see Section 13 “Childrenand Adolescents.” In the Heart ProtectionStudy (lower age limit 40 years), the sub-groupof;600patientswithtype1diabeteshad a proportionately similar, although notstatistically significant, reduction in risk aspatients with type 2 diabetes (80). Eventhough the data are not definitive, similarstatin treatment approaches should beconsidered for patients with type 1 ortype2 diabetes, particularly in thepresenceof other cardiovascular risk factors. Patientsbelow the age of 40 have lower risk ofdeveloping a cardiovascular event over a10-yearhorizon; however, their lifetimeriskof developing cardiovascular disease andsuffering an MI, stroke, or cardiovasculardeath is high. For patients under the age of40 years and/or who have type 1 diabeteswith other ASCVD risk factors, we recom-mend that the patient and health careprovider discuss the relative benefits andrisks and consider the use of moderate-intensity statin therapy. Please refer to“Type 1 Diabetes Mellitus and Cardiovas-cular Disease: A Scientific Statement Fromthe American Heart Association and Amer-ican Diabetes Association” (91) for addi-tional discussion.

Secondary Prevention (Patients With

ASCVD)

Because risk is high in patients withASCVD, intensive therapy is indicatedand has been shown to be of benefit inmultiple large randomized cardiovascu-lar outcomes trials (86,90,92,93). 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, theyfound reductions in nonfatal cardiovascular

events with more intensive therapy, inpatients with and without diabetes(78,82,92).

Over the past few years, there havebeen multiple large randomized trialsinvestigating the benefits of adding non-statin agents to statin therapy, includingthose that evaluated further loweringof LDL cholesterol with ezetimibe (90,94)and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (93).Each trial found a significant benefit inthe reduction of ASCVD events that wasdirectly related to the degree of furtherLDL cholesterol lowering. These largetrials included a significant number ofparticipants with diabetes. For patientswith ASCVD who are on high-intensity(and maximally tolerated) statin therapyand have an LDL cholesterol$70 mg/dL,the addition of nonstatin LDL-loweringtherapy is recommended following aclinician-patient discussion about thenet benefit, safety, and cost (Table10.2).

Combination Therapy for LDLCholesterol Lowering

Statins and Ezetimibe

The IMProved Reduction of Outcomes:Vytorin Efficacy International Trial(IMPROVE-IT) was a randomized con-trolled trial in 18,144 patients comparingthe addition of ezetimibe to simvastatintherapy versus simvastatin alone. Indi-viduals were $50 years of age, hadexperienced a recent acute coronary syn-drome (ACS), and were treated for anaverageof6years.Overall, theadditionofezetimibe led to a 6.4% relative benefitand a 2% absolute reduction in majoradverse cardiovascular events, with thedegree of benefit being directly propor-tional to the change in LDL choles-terol, which was 70 mg/dL in the statingroup on average and 54 mg/dL in thecombination group (90). In those with

diabetes (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)and relative risk reduction of 14% (hazardratio [HR] 0.86 [95% CI 0.78–0.94]) overmoderate-intensity simvastatin (40 mg)alone (94).

Statins and PCSK9 Inhibitors

Placebo-controlled trials evaluating theaddition of the PCSK9 inhibitors evolo-cumab and alirocumab to maximallytolerated doses of statin therapy in par-ticipants whowere at high risk for ASCVDdemonstrated an average reduction inLDL cholesterol ranging from 36% to59%. These agents have been approvedas adjunctive therapy for patients withASCVD or familial hypercholesterolemiawho are receiving maximally toleratedstatin therapy but require additionallowering of LDL cholesterol (95,96).

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 with priorASCVD and an additional high-risk featurewho were receiving their maximally tol-erated statin therapy (two-thirds were onhigh-intensity statin) but who still had anLDL cholesterol$70 mg/dL or a non-HDLcholesterol $100 mg/dL (93). Patientswere randomized to receive subcutane-ous injections of evolocumab (either140 mg every 2 weeks or 420 mg everymonth based on patient preference) ver-sus placebo. Evolocumab reduced LDLcholesterol by 59% from a median of92 to 30 mg/dL in the treatment arm.

During the median follow-up of 2.2years, the composite outcome of car-diovascular death, MI, stroke, hospitali-zation for angina, or revascularizationoccurred in 11.3% vs. 9.8% of the pla-cebo and evolocumab groups, respec-tively, representing a 15% relative riskreduction (P , 0.001). The combinedendpointof cardiovascular death,MI, orstroke was reduced by 20%, from 7.4%to 5.9% (P , 0.001). Importantly, similarbenefits were seen in prespecified sub-group of patients with diabetes, com-prising 11,031 patients (40% of thetrial) (97).

Table 10.3—High-intensity and moderate-intensity statin therapy*

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

Moderate-intensity statin therapy(lowers LDL cholesterol by 30–50%)

Atorvastatin 40–80 mgRosuvastatin 20–40 mg

Atorvastatin 10–20 mgRosuvastatin 5–10 mgSimvastatin 20–40 mgPravastatin 40–80 mgLovastatin 40 mgFluvastatin XL 80 mgPitavastatin 2–4 mg

*Once-daily dosing. XL, extended release.

care.diabetesjournals.org Cardiovascular Disease and Risk Management S111

Treatment of Other LipoproteinFractions or Targets

Recommendations

10.26 For patients with fasting tri-glyceride levels $500 mg/dL(5.7mmol/L), evaluate for sec-ondary causes of hypertri-glyceridemia and considermedical therapy to reducethe risk of pancreatitis. C

10.27 In adults with moderate hy-pertriglyceridemia (fasting ornonfasting triglycerides 175–499 mg/dL), clinicians shouldaddress and treat lifestyle fac-tors (obes ity and meta-bol ic syndrome), secondaryfactors (diabetes, chronic liveror kidney disease and/or ne-phrotic syndrome, hypothy-roidism), and medications thatraise triglycerides. C

Hypertriglyceridemia should be addressedwith dietary and lifestyle changes includ-ing weight loss and abstinence fromalcohol (98). Severe hypertriglyceride-mia (fasting triglycerides$500 mg/dLand especially .1,000 mg/dL) maywarrant pharmacologic therapy (fibricacid derivatives and/or fish oil) to reducethe risk of acute pancreatitis. In addition,if 10-year ASCVD risk is $7.5%, it isreasonable to initiate moderate-intensitystatin therapy or increase statin inten-sity from moderate to high. In patientswith moderate hypertriglyceridemia,lifestyle interventions, treatment of sec-ondary factors, and avoidance of medi-cations that might raise triglycerides arerecommended.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 thanthat for statin therapy (99). In a largetrial in patients with diabetes, fenofibratefailed to reduce overall cardiovascularoutcomes (100).

Other Combination Therapy

Recommendations

10.28 Combination therapy (statin/fibrate) has not been shown toimprove atherosclerotic cardio-

vascular disease outcomes andisgenerallynotrecommended.A

10.29 Combination therapy (statin/niacin) has not been shown toprovide additional cardiovas-cular benefit above statin ther-apy alone, may increase therisk of stroke with additionalsideeffects, and isgenerallynotrecommended. A

Statin and Fibrate

Combination therapy (statin and fibrate)is associated with an increased risk forabnormal transaminase levels, myositis,and rhabdomyolysis. The risk of rhabdo-myolysis is more common with higherdoses of statins and renal insufficiencyandappears tobehigherwhenstatinsarecombined with gemfibrozil (comparedwith fenofibrate) (101).

In the ACCORD study, in patientswith type 2 diabetes who were athigh risk for ASCVD, the combinationof fenofibrate and simvastatin did notreduce the rate of fatal cardiovascularevents, nonfatal MI, or nonfatal strokeas compared with simvastatin alone.Prespecified subgroup analyses sug-gested heterogeneity in treatment ef-fects with 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) (102). Aprospective trial of a newer fibrate inthis specific population of patients isongoing (103).

Statin and Niacin

The Atherothrombosis Intervention inMetabolic Syndrome With Low HDL/High Triglycerides: Impact on GlobalHealth Outcomes (AIM-HIGH) trial ran-domized over 3,000 patients (about one-third with diabetes) with establishedASCVD, 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) andapossible

increase in ischemic stroke in those oncombination therapy (104).

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 (105). A total of 25,673 patientswith prior vascular disease were 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 therapywith astatin and niacin is not recommendedgiven the lack of efficacy onmajor ASCVDoutcomes and increased side effects.

Diabetes With Statin UseSeveral studies have reported amodestlyincreased risk of incident diabetes withstatin use (106,107), 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 car-diovascular event rate reduction withstatins far outweighed the risk of in-cident diabetes even for patients at high-est risk for diabetes (108). The absoluterisk increase was small (over 5 years offollow-up, 1.2% of participants on pla-cebo developed diabetes and 1.5% onrosuvastatin developed diabetes) (108).A meta-analysis of 13 randomized statintrialswith 91,140 participants showed anodds ratio of 1.09 for a new diagnosis ofdiabetes, so that (on average) treatmentof 255 patients with statins for 4 yearsresulted in one additional case of diabe-tes while simultaneously preventing 5.4

S112 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

vascular events among those 255 patients(107).

Lipid-Lowering Agents and CognitiveFunctionAlthough this issue has been raised,several lines of evidence point againstthis association, as detailed in a 2018European Atherosclerosis Society Con-sensus Panel statement (109). First, thereare three large randomized trials of statinversus placebo where specific cognitivetests were performed, and no differenceswere seen between statin and placebo(110–113). In addition, no change incognitive function has been reportedin studies with the addition of ezetimibe(90) or PCSK9 inhibitors (93,114) to statintherapy, including among patientstreated to very low LDL cholesterollevels. In addition, the most recent sys-tematic review of the U.S. Food andDrug Administration’s (FDA’s) postmar-keting surveillance databases, random-ized controlled trials, and cohort, case-control, and cross-sectional studies eval-uating cognition in patients receiving sta-tins found that published data do notreveal an adverse effect of statins oncognition (115). Therefore, a concernthat statinsorother lipid-loweringagentsmight cause cognitive dysfunction ordementia is not currently supported byevidence and should not deter their usein individuals with diabetes at high riskfor ASCVD (115).

ANTIPLATELET AGENTS

Recommendations

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

10.31 For patients with atheroscle-rotic cardiovascular diseaseand documented aspirin al-lergy, clopidogrel (75 mg/day)should be used. B

10.32 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

10.33 Aspirintherapy(75–162mg/day)may be considered as a

primary prevention strategyin those with diabetes whoare at increased cardiovascu-lar risk, after a discussion withthe patient on the benefitsversus increased risk ofbleeding. C

Risk ReductionAspirin has been shown to be effectivein reducing cardiovascular morbidityand mortality in high-risk patients withprevious 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 (116,117).

Previous randomized controlled trialsof aspirin specifically in patients withdiabetes failed to consistently show asignificant reduction in overall ASCVDend points, raising questions about the ef-ficacy of aspirin for primary prevention inpeople with diabetes, although some sexdifferences were suggested (118–120).

The Antithrombotic Trialists’ Collabo-ration published an individual patient–level meta-analysis (116) of the six largetrials of aspirin for primary prevention inthe general population. These trials col-lectively enrolled over 95,000 partic-ipants, including almost 4,000 withdiabetes. Overall, they found that aspirinreduced the risk of serious vascularevents by 12% (RR 0.88 [95% CI 0.82–0.94]). The largest reduction was fornonfatal MI, with little effect on CHDdeath (RR 0.95 [95% CI 0.78–1.15]) ortotal stroke.

Most recently, the ASCEND (A Study ofCardiovascular Events iN Diabetes) trialrandomized 15,480 patients with diabe-tes but no evident cardiovascular dis-ease to aspirin 100 mg daily or placebo(121). The primary efficacy end pointwas vascular death, MI, or stroke ortransient ischemic attack. The primarysafety outcomewasmajor bleeding (i.e.,intracranial hemorrhage, sight-threateningbleeding in the eye, gastrointestinal bleed-ing, or other serious bleeding). Duringa mean follow-up of 7.4 years, therewas a significant 12% reduction in theprimaryefficacyendpoint (8.5%vs. 9.6%;P 5 0.01). In contrast, major bleedingwas significantly increased from 3.2% to4.1% in the aspirin group (rate ratio 1.29;P5 0.003), withmost of the excess being

gastrointestinal bleeding and other extra-cranial bleeding. There were no significantdifferences by sex, weight, or duration ofdiabetes or other baseline factors includ-ing 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])(122) and in the elderly (ASPREE [Aspirinin Reducing Events in the Elderly]) (123),including 11% with diabetes, found nobenefit of aspirin on the primary efficacyend point and an increased risk of bleed-ing. In ARRIVE, with 12,546 patients overa period of 60 months follow-up, theprimary end point occurred in 4.29% vs.4.48% of patients in the aspirin versusplacebo groups (HR 0.96; 95% CI 0.81–1.13;P50.60).Gastrointestinal bleedingevents (characterized as mild) occurredin 0.97% of patients in the aspirin groupvs. 0.46% in the placebo group (HR 2.11;95% CI 1.36–3.28; P 5 0.0007). InASPREE, including 19,114 persons, forthe rate of cardiovascular disease (fatalCHD, MI, stroke, or hospitalization forheart failure) after a median of 4.7 yearsof follow-up, the rates per 1,000 person-years were 10.7 vs. 11.3 events in aspi-rin vs. placebo groups (HR 0.95; 95%CI 0.83–1.08). The rate of major hem-orrhage per 1,000 person-years was8.6 events vs. 6.2 events, respec-tively (HR 1.38; 95% CI 1.18–1.62;P , 0.001).

Thus, aspirin appears to have amodesteffect on ischemic vascular events, withthe absolute decrease in events depend-ing on the underlying ASCVD risk. Themain adverse effect is an increased riskof gastrointestinal bleeding. The excessrisk may be as high as 5 per 1,000 peryear in real-world settings. However, foradults with ASCVD risk .1% per year,the number of ASCVD events preventedwill be similar to the number of episodesof bleeding induced, although these com-plications do not have equal effects onlong-term health (124).

Treatment ConsiderationsIn 2010, a position statement of the ADA,the American Heart Association, and theAmerican College of Cardiology Founda-tion recommended that low-dose (75–162mg/day) aspirin for primary preventionis reasonable for adults with diabetesand no previous history of vascular dis-ease who are at increased ASCVD risk

care.diabetesjournals.org Cardiovascular Disease and Risk Management S113

and who are not at increased risk forbleeding (125). These recommendationsfor using aspirin as primary preventioninclude both men and women aged$50years with diabetes and at least oneadditional major risk factor (family his-tory of premature ASCVD, hypertension,dyslipidemia, smoking, or chronic kidneydisease/albuminuria) who are not at in-creased risk of bleeding (e.g., older age,anemia, renal disease) (126–129). Non-invasive imaging techniques such ascoronary computed tomography angiog-raphy may potentially help further tailoraspirin therapy, particularly in those atlow risk (130), but are not generallyrecommended. For patients over theage of 70 years (with or without diabe-tes), the balance appears to have greaterrisk than benefit (121,123). Thus, forprimary prevention, the use of aspirinneeds tobe carefully considered andmaygenerally not be recommended. Aspirinmay be considered in the context of highcardiovascular riskwith lowbleeding risk,but generally not in older adults. Forpatientswith documented ASCVD, use ofaspirin for secondary prevention has fargreater benefit than risk; for this indica-tion, aspirin is still recommended (116).

Aspirin Use in People <50 Years of AgeAspirin is not recommended for thoseat low 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 (131). 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 50 mg to 650 mgbut were mostly in the range of 100–325mg/day. There is little evidence tosupportany specific dose, but using the lowestpossible dose may help to reduce sideeffects (132). In the U.S., the most com-mon low-dose tablet is 81 mg. Althoughplatelets from patients with diabetes

have 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(133). “Aspirin resistance” has been de-scribed in patients with diabetes whenmeasured by a variety of ex vivo andin vitro methods (platelet aggregometry,measurement of thromboxane B2) (134),but other studies suggest no impairmentin aspirin response among patients withdiabetes (135). A recent trial suggestedthat more frequent dosing regimens ofaspirin may reduce platelet reactivity inindividuals with diabetes (136); how-ever, these observations alone are in-sufficient to empirically recommend thathigher doses of aspirin be used in thisgroup at this time. Another recent meta-analysis raised the hypothesis that low-dose aspirin efficacy is reduced in thoseweighingmore than70kg (137); however,the ASCEND trial found benefit of lowdose aspirin in those in this weight range,which would thus not validate this sug-gested hypothesis (121). It appears that75–162 mg/day is optimal.

Indications for P2Y12 ReceptorAntagonist UseA P2Y12 receptor antagonist in combi-nation with aspirin should be used for atleast 1 year in patients following an ACSand may have benefits beyond this pe-riod. Evidence supports use of eitherticagrelor or clopidogrel if no percuta-neous coronary intervention was per-formed and clopidogrel, ticagrelor, orprasugrel if a percutaneous coronaryintervention was performed (138). Inpatients with diabetes and prior MI(1–3 years before), adding ticagrelorto aspirin significantly reduces the riskof recurrent ischemic events includingcardiovascular and CHD death (139).

CARDIOVASCULAR DISEASE

Recommendations

Screening10.34 In asymptomatic patients, rou-

tine screening for coronaryarterydisease is not recommen-ded as it does not improve out-comesas longasatherosclerotic

cardiovascular disease risk fac-tors are treated. A

10.35 Consider investigations for coro-nary artery disease in the pres-ence of any of the following:atypical cardiac symptoms (e.g.,unexplained dyspnea, chest dis-comfort); signs or symptomsof associated vascular diseaseincluding carotid bruits, tran-sient ischemic attack, stroke,claudication, or peripheral ar-terial disease; or electrocar-diogram abnormalities (e.g.,Q waves). E

Treatment10.36 In patientswith knownathero-

sclerotic cardiovascular dis-ease, consider ACE inhibitor orangiotensin receptor blockertherapy to reduce the risk ofcardiovascular events. B

10.37 In patients with prior myocar-dial infarction, b-blockers shouldbe continued for at least 2years after the event. B

10.38 In patients with type 2 dia-betes with stable congestiveheart failure, metformin maybe used if estimated glomer-ular filtration rate remains.30 mL/min but should beavoided in unstable or hospi-talized patients with conges-tive heart failure. B

10.39 Among patients with type 2diabeteswhohave establishedatherosclerotic cardiovasculardisease, sodium–glucose co-transporter 2 inhibitors orglucagon-like peptide 1 recep-tor agonists with demon-strated cardiovascular diseasebenefit (Table 9.1) are recom-mended as part of the antihy-perglycemic regimen. A

10.40 Among patients with athero-sclerotic cardiovascular dis-ease at high risk of heartfailureor inwhomheart failurecoexists, sodium–glucose co-transporter 2 inhibitors arepreferred. C

Cardiac TestingCandidates for advanced or invasive car-diac testing include those with 1) typi-cal or atypical cardiac symptoms and

S114 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

2) an abnormal resting electrocardiogram(ECG). Exercise ECG testing without orwith echocardiography may be usedas the initial test. In adults with diabetes$40 years of age, measurement of cor-onary artery calcium is also reasonablefor cardiovascular risk assessment. Phar-macologic stress echocardiography ornuclear imaging should be consideredin individuals with diabetes in whomresting ECG abnormalities preclude ex-ercise stress testing (e.g., left bundlebranch block or ST-T abnormalities). Inaddition, individuals who require stresstesting and are unable to exercise shouldundergo pharmacologic stress echocar-diography or nuclear imaging.

Screening Asymptomatic PatientsThe screening of asymptomatic patientswith high ASCVD risk is not recommended(140), in part because these high-riskpatients should already be receiving in-tensive medical therapydan approachthat provides similar benefit as invasiverevascularization (141,142). There is alsosome evidence that silent ischemia mayreverse over time, adding to the contro-versy concerning aggressive screeningstrategies (143). In prospective studies,coronary artery calcium has been estab-lished as an independent predictor offuture ASCVD events in patients withdiabetes and is consistently superiorto both the UK Prospective DiabetesStudy (UKPDS) risk engine and the Fra-mingham Risk Score in predicting risk inthis population (144–146). However, arandomized observational trial demon-strated no clinical benefit to routinescreening of asymptomatic patientswith type 2 diabetes and normal ECGs(147). Despite abnormal myocardial per-fusion imaging in more than one in fivepatients, cardiac outcomes were essen-tially equal (and very low) in screenedversus unscreened patients. Accord-ingly, indiscriminate screening is notconsidered cost-effective. Studies havefound that a risk factor–based approachto the initial diagnostic evaluation andsubsequent follow-up for coronaryarterydisease fails to identify which patientswith type 2 diabetes will have silentischemia on screening tests (148,149).Any benefit of newer noninvasive cor-

onary artery disease screening methods,such as computed tomography cal-cium scoring and computed tomographyangiography, to identify patient subgroups

for different treatment strategies remainsunproven in asymptomatic patients withdiabetes, though research is ongoing.Although asymptomatic patients withdiabeteswith higher coronary disease bur-den have more future cardiac events(144,150,151), the role of these testsbeyond risk stratification is not clear.

While coronary artery screening meth-ods, such as calcium scoring, may im-prove cardiovascular risk assessment inpeople with type 2 diabetes (152), theirroutine use leads to radiation exposureand may result in unnecessary invasivetesting such as coronary angiographyand revascularization procedures. Theultimatebalance ofbenefit, cost, and risksof such an approach in asymptomaticpatients remains controversial, particu-larly in the modern setting of aggressiveASCVD risk factor control.

Lifestyle and PharmacologicInterventionsIntensive lifestyle intervention focusingon weight loss through decreased calo-ric intake and increased physical activ-ity as performed in the Action for Healthin Diabetes (Look AHEAD) trial may beconsidered for improving glucose control,fitness, and some ASCVD risk factors(153). Patients at increased ASCVD riskshould receive aspirin and a statin andACE inhibitor or ARB therapy if thepatient has hypertension, unless thereare contraindications to a particular drugclass. While clear benefit exists for ACEinhibitor or ARB therapy in patients withdiabetic kidney disease or hypertension,the benefits in patients with ASCVD inthe absence of these conditions are lessclear, especially when LDL cholesterolis concomitantly controlled (154,155).In patients with prior MI, active angina,orHFrEF,b-blockers should beused (156).

Antihyperglycemic Therapies andCardiovascular OutcomesIn 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 cardiovascularrisk (157). Previously approved diabetesmedications were not subject to theguidance. Recently published cardiovas-cular outcomes trials have provided ad-ditional data on cardiovascular outcomesin patients with type 2 diabetes withcardiovascular disease or at high risk for

cardiovascular disease (see Table 10.4).Cardiovascular outcomes trials of dipep-tidyl peptidase 4 (DPP-4) inhibitors haveall, so far, not shown cardiovascularbenefits relative to placebo. However,results from other new agents haveprovided a mix of results.

The BI 10773 (Empagliflozin) Cardio-vascular Outcome Event Trial in Type 2Diabetes Mellitus Patients (EMPA-REGOUTCOME) trial was a randomized,double-blind trial that assessed the effectof empagliflozin, an SGLT2 inhibitor, ver-sus placebo on cardiovascular outcomesin 7,020 patients with type 2 diabetesand existing cardiovascular disease. Studyparticipants had a mean age of 63 years,57%haddiabetes formore than10 years,and 99% had established cardiovasculardisease. EMPA-REG OUTCOME showedthat over a median follow-up of 3.1years, treatment reduced the compositeoutcome of MI, stroke, and cardiovascu-lar death by 14% (absolute rate 10.5% vs.12.1% in the placebo group, HR in theempagliflozin group 0.86; 95% CI 0.74–0.99; P 5 0.04 for superiority) and car-diovascular death by 38% (absolute rate3.7% vs. 5.9%, HR 0.62; 95% CI 0.49–0.77; P , 0.001) (8). The FDA added anindication for empagliflozin to reducethe risk of major adverse cardiovascu-lar death in adults with type 2 diabetesand cardiovascular disease.

A second large cardiovascular out-comes trial program of an SGLT2 inhib-itor, canagliflozin, has been reported (9).The Canagliflozin Cardiovascular Assess-ment Study (CANVAS) integrated datafrom two trials, including the CANVAStrial that started in 2009 beforethe approval of canagliflozin and theCANVAS-Renal (CANVAS-R) trial thatstarted in 2014 after the approval of cana-gliflozin. Combining both these trials,10,142 participants with type 2 diabetes(two-thirds with established CVD) wererandomized to canagliflozin or placeboand were followed for an average 3.6years. The mean age of patients was63 years and 66% had a history of car-diovascular disease. The combined anal-ysis of the two trials found thatcanagliflozin significantly reduced thecomposite outcome of cardiovasculardeath, MI, or stroke versus placebo (oc-curring in 26.9 vs. 31.5 participants per1,000 patient-years; HR 0.86 [95% CI0.75–0.97]; P, 0.001 for noninferiority;P 5 0.02 for superiority). The specific

care.diabetesjournals.org Cardiovascular Disease and Risk Management S115

estimates for canagliflozin versus placeboon the primary composite cardiovascularoutcome were HR 0.88 (0.75–1.03) forthe CANVAS trial and 0.82 (0.66–1.01) forCANVAS-R, with no heterogeneity foundbetween trials. In the combined analysis,there was not a statistically significantdifference in cardiovascular death (HR0.87 [95% CI 0.72–1.06]). The initialCANVAS trial was partially unblindedprior to completion because of theneed to file interim cardiovascular out-comes data for regulatory approval ofthe drug (158). Of note, there was anincreased risk of lower-limb amputationwith canaglifozin (6.3 vs. 3.4 participantsper 1,000 patient-years; HR 1.97 [95% CI1.41–2.75]) (9).The Liraglutide Effect and Action in

Diabetes: Evaluation of CardiovascularOutcome Results (LEADER) trial was arandomized, double-blind trial that as-sessedtheeffectof liraglutide, aglucagon-like peptide 1 (GLP-1) receptor agonist,versus placebo on cardiovascular out-comes in 9,340 patients with type 2 di-abetes at high risk for cardiovasculardisease or with cardiovascular disease.Study participants had a mean age of64 years and amean duration of diabetesof nearly 13 years. Over 80% of studyparticipants had established cardiovas-cular disease. After a median follow-upof 3.8 years, LEADER showed that theprimary compositeoutcome (MI, stroke,or cardiovascular death) occurred infewer participants in the treatmentgroup (13.0%) when compared withthe placebo group (14.9%) (HR 0.87;95% CI 0.78–0.97; P , 0.001 for non-inferiority; P 5 0.01 for superiority).Deaths from cardiovascular causeswere significantly reduced in the liraglu-tide group (4.7%) compared with theplacebo group (6.0%) (HR 0.78; 95% CI0.66–0.93; P 5 0.007) (159). The FDAapproved the use of liraglutide to re-duce the risk of major adverse cardiovas-cular events, including heart attack, stroke,and cardiovascular death, in adultswith type 2 diabetes and establishedcardiovascular disease.Results from a moderate-sized trial of

another GLP-1 receptor agonist, sema-glutide, were consistent with the LEADERtrial (160). Semaglutide is a once-weeklyGLP-1 receptor agonist approved bythe FDA for the treatment of type 2 diabe-tes. The Trial to Evaluate Cardiovascularand Other Long-term Outcomes With

Semaglutide in Subjects With Type 2Diabetes (SUSTAIN-6) was the initial ran-domized trial powered to test noninfer-iority of semaglutide for the purpose ofinitial regulatory approval. In this study,3,297 patients with type 2 diabetes wererandomized to receive once-weekly sem-aglutide (0.5mgor 1.0mg) 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 semaglutidegroup vs. 146 patients (8.9%) in theplacebo group (HR 0.74 [95% CI 0.58–0.95]; P , 0.001). More patients dis-continued treatment in the semaglutidegroup because of adverse events, mainlygastrointestinal.

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 (161).A total of 6,068 patients with type 2diabetes with a recent hospitalizationfor MI or unstable angina within theprevious 180 days were randomized toreceive lixisenatide or placebo in addi-tion to standard care and were followedfor a median of approximately 2.1 years.The primary outcome of cardiovasculardeath, MI, stroke, or hospitalization forunstable angina occurred in 406 patients(13.4%) in the lixisenatide group vs.399 (13.2%) in the placebo group (HR1.2 [95% CI 0.89–1.17]), which demon-strated the noninferiority of lixisenatideto placebo (P, 0.001) but did not showsuperiority (P 5 0.81).

The Exenatide Study of CardiovascularEvent Lowering (EXSCEL) trial also re-ported results with the once-weeklyGLP-1 receptor agonist extended-releaseexenatide and found that major adversecardiovascular events were numericallylower with use of extended-releaseexenatide compared with placebo,although this difference was not sta-tistically significant (162).A total of14,752patients with type 2 diabetes (of whom10,782 [73.1%] had previous cardiovas-cular disease) were randomized to re-ceive extended-release exenatide 2 mgor placebo and followed for a median of3.2 years. The primary end point ofcardiovascular death, MI, or stroke oc-curred in839patients (11.4%;3.7eventsper 100 person-years) in the exenatidegroup and in 905 patients (12.2%; 4.0

events per 100 person-years) in theplacebo group (HR 0.91 [95% CI 0.83–1.00]; P , 0.001 for noninferiority) butwasnot superior to placebowith respectto the primary end point (P 5 0.06 forsuperiority). However, all-cause mortal-ity was lower in the exenatide group (HR0.86 [95% CI 0.77–0.97]. The incidenceof acute pancreatitis, pancreatic cancer,medullary thyroid carcinoma, and seri-ous adverse events did not differ sig-nificantly between the two groups.

The Harmony Outcomes trial random-ized 9,463 patients with type 2 diabetesand cardiovascular disease to once-weekly subcutaneous albiglutide ormatching placebo, in addition to theirstandard care. Over a median durationof 1.6 years, the GLP-1 receptor agonistreduced the risk of cardiovascular death,MI, or stroke to an incidence rate of 4.6events per 100 person-years in the albi-glutide group vs. 5.9 events in the pla-cebo group (HR ratio 0.78, P5 0.0006 forsuperiority) (163). This agent is not cur-rently available for clinical use.

In summary, there are now severallarge randomized controlled trials report-ing statistically significant reductions incardiovascular events for two of the FDA-approved SGLT2 inhibitors (empagliflozinand canagliflozin) and three FDA-approvedGLP-1 receptor agonists (liraglutide, albiglu-tide [although that agent was removedfrom the market for business reasons],and semaglutide [lower risk of cardiovas-cular events in a moderate-sized clinicaltrial but one not powered as a cardiovas-cular outcomes trial]). In these trials, themajority, if not all, patients in the trial hadASCVD. The empagliflozin and liraglutidetrials further demonstrated significantreductions in cardiovascular death. Once-weekly exenatide did not have statisticallysignificant reductions in major adversecardiovascular events or cardiovascularmortality but did have a significant re-duction in all-cause mortality. In con-trast, other GLP-1 receptor agonists havenot shown similar reductions in cardio-vascular events (Table 10.4). Additionallarge randomized trials of other agentsin these classes are ongoing.

Of note, these studies examined thedrugs in combination with metformin(Table 10.4) in the great majority ofpatients for whom metformin was notcontraindicated or was tolerated. Forpatients with type 2 diabetes who haveASCVD, on lifestyle and metformin

S116 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

Table

10.4—Cardiova

scularoutcomestrials

ofava

ilable

antihyp

erg

lyce

mic

medicationsco

mpletedaftertheissu

ance

oftheFD

A2008guidelines

DPP

-4inhibitors

GLP-1

receptoragonists

SGLT2inhibitors

SAVOR-TIM

I53

(168)

(n5

16,492)

EXAMINE(175

)(n

55,380)

TECOS(171)

(n5

14,671)

ELIXA(161)

(n5

6,068)

LEADER

(159)

(n5

9,340)

SUSTAIN-6

(160)*

(n5

3,297)

EXSCEL

(162

)(n

514,752)

EMPA

-REG

OUTC

OME(8)

(n5

7,020)

CANVAS(9)

(n5

4,330)

CANVAS-R(9)

(n5

5,812)

Interven

tion

Saxagliptin/

placebo

Alogliptin/

placebo

Sitagliptin/

placebo

Lixisenatide/

placebo

Liraglutide/placebo

Semaglutide/placebo

Exen

atideQW/

placebo

Empagliflozin/

placebo

Canagliflozin/placebo

Maininclusion

criteria

Type2diabetes

andhistory

ofor

multiple

risk

factors

forCVD

Type2diabetes

andACSwithin

15–90

days

before

randomization

Type2diabetes

andpreexisting

CVD

Type2

diabetes

and

history

ofACS

(,180days)

Type2diabetes

andpreexistingCVD,

kidney

disease,orHFat

$50

yearsofageor

cardiovascularrisk

at$60

yearsofage

Type2diabetes

and

preexistingCVD,HF,

or

CKD

at$50

yearsofage

or

cardiovascularrisk

at$60

yearsofage

Type2diabetes

withorwithout

preexistingCVD

Type2diabetes

andpreexisting

CVD

Type2diabetes

andpreexistingCVD

at$30

yearsofageor.2cardiovascular

risk

factors

at$50

yearsofage

A1C

inclusioncriteria

(%)

$6.5

6.5–11.0

6.5–8.0

5.5–11.0

$7.0

$7.0

6.5–10.0

7.0–10.0

7.0–10.5

Age

(years)††

65.1

61.0

65.4

60.3

64.3

64.6

6263.1

63.3

Diabetes

duration

(years)††

10.3

7.1

11.6

9.3

12.8

13.9

1257%

.10

13.5

Med

ianfollow-up

(years)

2.1

1.5

3.0

2.1

3.8

2.1

3.2

3.1

5.7

2.1

Statin

use

(%)

7891

8093

7273

7477

75

Metform

inuse

(%)

7066

8266

7673

7774

77

PriorCVD/CHF(%

)78/13

100/28

74/18

100/22

81/18

60/24

73.1/16.2

99/10

65.6/14.4

MeanbaselineA1C

(%)

8.0

8.0

7.2

7.7

8.7

8.7

8.0

8.1

8.2

Meandifference

inA1C

between

groupsat

endof

treatm

ent(%

)20.3^

20.3^

20.3^

20.3^

20.4^

20.7or–1.0^†

20.53

^20.3^‡

20.58

^

Year

started/

reported

2010/2013

2009/2013

2008/2015

2010/2015

2010/2016

2013/2016

2010/2017

2010/2015

2009/2017

Prim

aryoutcome§

3-pointMACE

3-pointMACE

4-pointMACE

4-pointMACE

3-pointMACE

3-pointMACE

3-pointMACE

3-pointMACE

3-pointMACE

Progressionto

albuminuria**

1.00

(0.89–1.12)

0.96

(95%

UL#1.16)

0.98

(0.89–1.08)

1.02

(0.89–1.17)

0.87

(0.78–0.97)

0.74

(0.58–0.95)

0.91

(0.83–1.00)

0.86

(0.74–

0.99)

0.86

(0.75–0.97)§

0.73

(0.47–

0.77)

Keysecondary

outcome§

Expanded

MACE

4-pointMACE

3-pointMACE

Expanded

MACE

Expanded

MACE

Expanded

MACE

Individual

componen

tsof

MACE(see

below)

4-pointMACE

All-cause

and

cardiovascular

mortality(see

below)

40%

reductionin

composite

eGFR,

renal

replacemen

t,renal

death

1.02

(0.94–1.11)

0.95

(95%

UL

#1.14)

0.99

(0.89–1.10)

1.00

(0.90–1.11)

0.88

(0.81–0.96)

0.74

(0.62–0.89)

0.89

(0.78–

1.01)

0.60

(0.47–

0.77)

Cardiovascular

death§

1.03

(0.87–1.22)

0.85

(0.66–1.10)

1.03

(0.89–1.19)

0.98

(0.78–1.22)

0.78

(0.66–0.93)

0.98

(0.65–1.48)

0.88

(0.76–1.02)

0.62

(0.49–

0.77

)0.96

(0.77–1.18)¶

0.87

(0.72–1.06)#

MI§

0.95

(0.80–1.12)

1.08

(0.88–1.33)

0.95

(0.81–1.11)

1.03

(0.87–1.22)

0.86

(0.73–1.00)

0.74

(0.51–1.08)

0.97

(0.85–1.10)

0.87

(0.70–

1.09)

0.85

(0.65–1.11)

0.85

(0.61–

1.19)

Stroke§

1.11

(0.88–1.39)

0.91

(0.55–1.50)

0.97

(0.79–1.19)

1.12

(0.79–1.58)

0.86

(0.71–1.06)

0.61

(0.38–0.99)

0.85

(0.70–1.03)

1.18

(0.89–

1.56)

0.97

(0.70–1.35)

0.82

(0.57–

1.18)

HFhospitalization§

1.27

(1.07–1.51)

1.19

(0.90–1.58)

1.00

(0.83–1.20)

0.96

(0.75–1.23)

0.87

(0.73–1.05)

1.11

(0.77–1.61)

0.94

(0.78–1.13)

0.65

(0.50–

0.85)

0.77

(0.55–1.08)

0.56

(0.38–

0.83)

Con

tinu

edon

p.S118

care.diabetesjournals.org Cardiovascular Disease and Risk Management S117

therapy, it is recommended to incor-porate an agent with strong evidencefor cardiovascular risk reduction, espe-cially those with proven reduction of car-diovascular death, after consideration ofdrug-specific patient factors (Table 9.1).See Fig. 9.1 for additional recommenda-tions on antihyperglycemic treatment inadults with type 2 diabetes.

Antihyperglycemic Therapies and Heart

Failure

As many as 50% of patients with type 2diabetesmaydevelop heart failure (164).Data on the effects of glucose-loweringagents on heart failure outcomes havedemonstrated that thiazolidinedioneshave a strong and consistent relation-ship with increased risk of heart failure(165–167). Therefore, thiazolidinedioneuse should be avoided in patients withsymptomatic heart failure.

Recent studies have also examined therelationship between DPP-4 inhibitorsand heart failure and have had mixedresults. The Saxagliptin Assessment ofVascular Outcomes Recorded in Patientswith Diabetes Mellitus2Thrombolysis inMyocardial Infarction 53 (SAVOR-TIMI53) study showed that patients treatedwith saxagliptin (a DPP-4 inhibitor) weremore likely to be hospitalized for heartfailure than those given placebo (3.5%vs. 2.8%, respectively) (168). Two otherrecent multicenter, randomized, double-blind, noninferiority trials, Examinationof Cardiovascular Outcomes with Aloglip-tin versus Standard of Care (EXAMINE)and Trial Evaluating Cardiovascular Out-comes with Sitagliptin (TECOS), did notshow associations between DPP-4 inhib-itor use and heart failure. The FDA re-ported that the hospital admission rate forheart failure in EXAMINE was 3.9% forpatients randomly assigned to alogliptincompared with 3.3% for those randomlyassigned to placebo (169). Alogliptin hadno effect on the composite end point ofcardiovascular death and hospital admis-sion for heart failure in the post hocanalysis (HR 1.0 [95% CI 0.82–1.21])(170). TECOS showed no difference inthe rate of heart failure hospitalizationfor the sitagliptin group (3.1%; 1.07 per100 person-years) compared with theplacebo group (3.1%; 1.09 per 100 person-years) (171).

In four cardiovascular outcome trialsof GLP-1 receptor agonists, no evidencefor an increased risk of heart failure was

Table

10.4—Continued

DPP

-4inhibitors

GLP-1

receptoragonists

SGLT2inhibitors

SAVOR-TIM

I53

(168)

(n5

16,492)

EXAMINE(175

)(n

55,380)

TECOS(171)

(n5

14,671)

ELIXA(161)

(n5

6,068)

LEADER

(159)

(n5

9,340)

SUSTAIN-6

(160)*

(n5

3,297)

EXSCEL

(162

)(n

514,752)

EMPA

-REG

OUTC

OME(8)

(n5

7,020)

CANVAS(9)

(n5

4,330)

CANVAS-R(9)

(n5

5,812)

Unstable

angina

hospitalization§

1.19

(0.89–1.60)

0.90

(0.60–1.37)

0.90

(0.70–1.16)

1.11

(0.47–2.62)

0.98

(0.76–1.26)

0.82

(0.47–1.44)

1.05

(0.94–1.18)

0.99

(0.74–

1.34

)d

All-cause

mortality§

1.11

(0.96–1.27)

0.88

(0.71–1.09)

1.01

(0.90–1.14)

0.94

(0.78–1.13)

0.85

(0.74–0.97)

1.05

(0.74–1.50)

0.86

(0.77–0.97)

0.68

(0.57–

0.82)

0.87

(0.74–1.01

)‡‡

0.90

(0.76–1.07)##

Worsen

ing

nep

hropathy§|

1.08

(0.88–1.32)

dd

d0.78

(0.67–0.92)

0.64

(0.46–0.88)

d0.61

(0.53–

0.70)

0.60

(0.47–

0.77)

d,notassessed

/rep

orted

;ACS,

acute

coronarysyndrome;

CHF,

congestiveheart

failu

re;CKD,chronic

kidney

disease;CVD,cardiovasculardisease;DPP-4,

dipep

tidyl

peptidase4;

eGFR

,estimated

glomerularfiltrationrate;GLP-1,glucago

n-likepep

tide1;

HF,

heart

failure;MACE,

majorad

versecardiaceven

t;MI,myocardialinfarction;SG

LT2,

sodium–glucose

cotran

sporter

2;UL,

upper

limit.

Datafrom

thistable

was

adap

tedfrom

Cefaluet

al.(176

)in

theJanuary20

18issueofDiabetes

Care.*P

owered

torule

outahazardratioof1.8;

superiority

hypothesisnotprespecified

.**Onthe

basisofprespecified

outcomes,therenal

outcomes

arenotview

edas

statistically

sign

ificant.††Age

was

reported

asmea

nsin

alltrialsexcep

tEX

AMINE,

whichreportedmedians;

diabetes

durationwas

repo

rted

asmeans

inallbutfour

trials,withSAVOR-TIM

I58,EXAMINE,

andEXSCEL

repo

rtingmedians

andEM

PA-REG

OUTCOMErepo

rtingas

percentage

ofpopu

lation

withdiabetes

duration

.10

years.†A1Cchan

geof0.66%

with0.5

mgan

d1.05%

with1mgdose

ofsemaglutide.‡AlC

chan

geof0.30in

EMPA-REG

OUTC

OMEisbased

onpooledresultsforboth

doses(i.e.,0.24%

for

10mgan

d0.36%

for25mgofem

paglifl

ozin).§O

utcomes

reportedas

hazardratio(95%

CI).||Worsen

ingnep

hropathyisdefi

ned

asthenew

onsetofurinealbumin-to-creatinineratio

.300mg/gcrea

tinineoradoublin

goftheserum

crea

tininelevelan

dan

estimated

glomerularfiltrationrate

of,45mL/min/1.73m

2,thenee

dforcontinuousrenal-rep

lacemen

ttherap

y,ordea

thfrom

renal

disea

sein

EMPA-REG

OUTC

OME,

LEADER

,an

dSU

STAIN-6

andas

doublin

gofcreatininelevel,initiationofdialysis,

renal

tran

splantation,orcreatinine.6.0

mg/dL

(530mmol/L)

inSA

VOR-TIM

I53.Worsen

ingnep

hropathywas

aprespecifiedexploratory

adjudicatedoutcomein

SAVOR-TIM

I53,LEADER

,an

dSU

STAIN-6

butnotin

EMPA-REG

OUTC

OME.

¶Truncateddataset(prespecified

intrea

tinghierarchyas

theprincipaldata

setforanalysisforsuperiorityof

all-cause

mortalityandcardiovascular

deathin

theCANVASProgram).^Significant

difference

inA1C

betw

eengrou

ps(P

,0.05).#N

ontrun

cateddata

set.‡‡Trun

catedintegrated

data

set(refersto

pooled

data

from

CANVASafter20

Novem

ber2012

plus

CANVAS-R;prespecified

intreating

hierarchyas

theprincipaldata

setforanalysisforsuperiorityof

all-cause

mortalityandcardiovascular

deathin

theCANVASProgram).##Non

trun

catedintegrated

data

(refersto

pooled

data

from

CANVAS,

includ

ingbefore

20Novem

ber2012

plus

CANVAS-R).

S118 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

found and the agents had a neutral effecton hospitalization for heart failure (159–162).A benefit on the incidence of heart

failure has been observed with the useof some SGLT2 inhibitors. In EMPA-REG OUTCOME, the addition of empa-gliflozin to standard care led toa significant35% reduction in hospitalization forheart failure compared with placebo(8). Although the majority of patientsin the study did not have heart failureat baseline, this benefit was consistentin patients with and without a priorhistory of heart failure (172). Similarly,in CANVAS, there was a 33% reduction inhospitalization for heart failure withcanagliflozin versus placebo (9). Al-though heart failure hospitalizationswere prospectively adjudicated in bothtrials, the type(s) of heart failure eventsprevented were not characterized. Thesepreliminary findings, which strongly sug-gest heart failure–related benefits ofSGLT2 inhibitors (particularly the preven-tion of heart failure), are being followedup with new outcomes trials in patientswith established heart failure, bothwith and without diabetes, to deter-mine their efficacy in treatment of heartfailure.

References1. American Diabetes Association. Economiccosts of diabetes in the U.S. in 2017. DiabetesCare 2018;41:917–9282. Ali MK, Bullard KM, Saaddine JB, Cowie CC,Imperatore G, Gregg EW. Achievement of goalsin U.S. diabetes care, 1999–2010. N Engl J Med2013;368:1613–16243. Buse JB, Ginsberg HN, Bakris GL, et al.; Amer-ican Heart Association; American Diabetes As-sociation. Primary prevention of cardiovasculardiseases in people with diabetes mellitus: a sci-entific statement from the American Heart As-sociationand theAmericanDiabetesAssociation.Diabetes Care 2007;30:162–1724. Gaede P, Lund-Andersen H, Parving H-H,Pedersen O. Effect of a multifactorial interven-tion onmortality in type 2 diabetes. N Engl JMed2008;358:580–5915. Cavender MA, Steg PG, Smith SC Jr, et al.;REACHRegistry Investigators. Impact of diabetesmellitus on hospitalization for heart failure,cardiovascular events, and death: outcomes at4 years from the Reduction of Atherothrombosisfor Continued Health (REACH) registry. Circula-tion 2015;132:923–9316. McAllister DA, Read S, Kerssens J, et al. In-cidence of hospitalisation for heart failure andcase-fatality among 3.25 million people withand without diabetes. Circulation. 27 June2018 [Epub ahead of print]. DOI: 10.1161/CIRCULATIONAHA.118.0349867. Lam CSP, Voors AA, de Boer RA, Solomon SD,van Veldhuisen DJ. Heart failure with preserved

ejection fraction: frommechanisms to therapies.Eur Heart J 2018;39:2780–27928. ZinmanB,Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin,cardiovascular outcomes, and mortality intype 2 diabetes. N Engl J Med 2015;373:2117–21289. Neal B, Perkovic V, Mahaffey KW, et al.;CANVAS Program Collaborative Group. Cana-gliflozin and cardiovascular and renal events intype 2 diabetes. N Engl J Med 2017;377:644–65710. Fitchett D, Butler J, van de Borne P, et al.;EMPA-REG OUTCOME� trial investigators. Ef-fects of empagliflozin on risk for cardiovasculardeath and heart failure hospitalization acrossthe spectrum of heart failure risk in the EMPA-REG OUTCOME� trial. Eur Heart J 2018;39:363–37011. Blood Pressure Lowering Treatment Tria-lists’ Collaboration. Blood pressure-loweringtreatment based on cardiovascular risk: a meta-analysis of individual patientdata. Lancet 2014;384:591–59812. Grundy SM, Stone NJ, Bailey AL, et al. 2018AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the manage-ment of blood cholesterol: a report of theAmerican College of Cardiology/American HeartAssociation Task Force on Clinical PracticeGuidelines. J Am Coll Cardiol. November2018 [Epub ahead of print]. DOI: 10.1016/j.jacc.2018.11.00313. MuntnerP, ColantonioLD,CushmanM,et al.Validation of the atherosclerotic cardiovasculardisease PooledCohort risk equations. JAMA 2014;311:1406–141514. DeFilippisAP, YoungR,McEvoy JW,et al. Riskscore overestimation: the impact of individualcardiovascular risk factors and preventive ther-apies on the performance of the American HeartAssociation-American College of Cardiology-Atherosclerotic Cardiovascular Disease risk scorein amodernmulti-ethnic cohort. Eur Heart J 2017;38:598–60815. Bohula EA, Morrow DA, Giugliano RP, et al.Atherothrombotic risk stratification and ezetimibefor secondary prevention. J Am Coll Cardiol 2017;69:911–92116. Bohula EA, Bonaca MP, Braunwald E, et al.atherothrombotic risk stratification and the ef-ficacy and safety of vorapaxar in patients withstable ischemic heart disease and previousmyocardial infarction. Circulation 2016;134:304–31317. de Boer IH, Bangalore S, Benetos A, et al.Diabetes and hypertension: a position statementby the American Diabetes Association. DiabetesCare 2017;40:1273–128418. Bobrie G, Genes N, Vaur L, et al. Is “isolatedhome” hypertension as opposed to “isolatedoffice” hypertension a sign of greater cardiovas-cular risk? Arch InternMed2001;161:2205–221119. Sega R, Facchetti R, Bombelli M, et al.Prognostic value of ambulatory and home bloodpressures compared with office blood pressurein the general population: follow-up resultsfrom the Pressioni Arteriose Monitorate e LoroAssociazioni (PAMELA) study. Circulation 2005;111:1777–178320. Omboni S, Gazzola T, Carabelli G, Parati G.Clinical usefulness and cost effectiveness ofhome blood pressure telemonitoring: meta-

analysis of randomized controlled studies. J Hy-pertens 2013;31:455–467; discussion 467–46821. Emdin CA, Rahimi K, Neal B, Callender T,Perkovic V, Patel A. Blood pressure lowering intype 2 diabetes: a systematic review and meta-analysis. JAMA 2015;313:603–61522. Arguedas JA, Leiva V, Wright JM. Bloodpressure targets for hypertension in peoplewith diabetes mellitus. Cochrane DatabaseSyst Rev 2013;10:CD00827723. Ettehad D, Emdin CA, Kiran A, et al. Bloodpressure lowering for prevention of cardiovas-cular disease and death: a systematic review andmeta-analysis. Lancet 2016;387:957–96724. Brunstrom M, Carlberg B. Effect of antihy-pertensive treatment at different blood pressurelevels in patients with diabetes mellitus: system-atic review and meta-analyses. BMJ 2016;352:i71725. Bangalore S, Kumar S, Lobach I, Messerli FH.Blood pressure targets in subjects with type 2diabetes mellitus/impaired fasting glucose:observations from traditional and Bayesianrandom-effects meta-analyses of randomizedtrials. Circulation 2011;123:2799–281026. Thomopoulos C, Parati G, Zanchetti A. Ef-fects of blood-pressure-lowering treatment onoutcome incidence in hypertension: 10 - shouldblood pressure management differ in hyperten-sivepatientswith andwithout diabetesmellitus?Overview and meta-analyses of randomizedtrials. J Hypertens 2017;35:922–94427. Xie X, Atkins E, Lv J, et al. Effects of intensiveblood pressure lowering on cardiovascular andrenal outcomes: updated systematic review andmeta-analysis. Lancet 2016;387:435–44328. CushmanWC, Evans GW, Byington RP, et al.;ACCORDStudy Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus.N Engl J Med 2010;362:1575–158529. Patel A, MacMahon S, Chalmers J, et al.;ADVANCE Collaborative Group. Effects of a fixedcombination of perindopril and indapamide onmacrovascular and microvascular outcomes inpatients with type 2 diabetes mellitus (theADVANCE trial): a randomised controlled trial.Lancet 2007;370:829–84030. BakrisGL. The implicationsof bloodpressuremeasurement methods on treatment targets forblood pressure. Circulation 2016;134:904–90531. Margolis KL, O’Connor PJ, Morgan TM, et al.Outcomes of combined cardiovascular risk factormanagement strategies in type 2 diabetes: theACCORD randomized trial. Diabetes Care 2014;37:1721–172832. Buckley LF, Dixon DL, Wohlford GF IV,WijesingheDS, BakerWL, VanTassell BW. Intensiveversus standard blood pressure control in SPRINT-eligible participants of ACCORD-BP [published cor-rection appears in Diabetes Care 2018;41:2048].Diabetes Care 2017;40:1733–173833. Brouwer TF, Vehmeijer JT, KalkmanDN, et al.Intensive blood pressure lowering in patientswith and patients without type 2 diabetes:a pooled analysis from two randomized trials.Diabetes Care 2018;41:1142–114834. Lamprea-Montealegre JA, de Boer IH. Re-evaluating the evidence for blood pressure tar-gets in type 2 Diabetes. Diabetes Care 2018;41:1132–113335. de Boer IH, Bakris G, Cannon CP. individu-alizing blood pressure targets for people with

care.diabetesjournals.org Cardiovascular Disease and Risk Management S119

diabetes and hypertension: comparing the ADAand the ACC/AHA recommendations. JAMA 2018;319:1319–132036. Basu S, Sussman JB, Rigdon J, Steimle L,Denton BT, Hayward RA. Benefit and harm ofintensive blood pressure treatment: derivationand validation of risk models using data fromthe SPRINT and ACCORD trials. PLoS Med 2017;14:e100241037. Phillips RA, Xu J, Peterson LE, Arnold RM,Diamond JA, Schussheim AE. Impact of cardio-vascular risk on the relative benefit and harm ofintensive treatment of hypertension. J Am CollCardiol 2018;71:1601–161038. Whelton PK, Carey RM, Aronow WS, et al.2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the preven-tion, detection, evaluation, and management ofhigh blood pressure in adults: a report of theAmerican College of Cardiology/American HeartAssociation Task Force onClinical PracticeGuide-lines. J Am Coll Cardiol 2018;71:e127–e24839. Wright JT Jr, Williamson JD, Whelton PK,et al.; SPRINTResearchGroup.A randomized trialof intensive versus standard blood-pressure con-trol. N Engl J Med 2015;373:2103–211640. Beddhu S, Greene T, Boucher R, et al. In-tensive systolic blood pressure control and in-cident chronic kidney disease in people with andwithout diabetes mellitus: secondary analyses oftwo randomised controlled trials. Lancet DiabetesEndocrinol 2018;6:555–56341. Sink KM, Evans GW, Shorr RI, et al. Syncope,hypotension, and falls in the treatment of hy-pertension: results from the randomized clinicalSystolic Blood Pressure Intervention Trial. J AmGeriatr Soc 2018;66:679–68642. American College of Obstetricians and Gy-necologists’ Task Force on Hypertension in Preg-nancy. Hypertension in pregnancy. Report of theAmerican College of Obstetricians and Gynecolo-gists’ Task Force on Hypertension in Pregnancy.Obstet Gynecol 2013;122:1122–113143. Abalos E, Duley L, Steyn DW. Antihyperten-sive drug therapy for mild to moderate hyper-tension during pregnancy. Cochrane DatabaseSyst Rev 2014;2:CD00225244. Al-Balas M, Bozzo P, Einarson A. Use ofdiuretics during pregnancy. Can Fam Physician2009;55:44–4545. Irgens HU, Reisaeter L, Irgens LM, Lie RT.Long term mortality of mothers and fathersafter pre-eclampsia: population based cohortstudy. BMJ 2001;323:1213–121746. Sacks FM, Svetkey LP, Vollmer WM, et al.;DASH-Sodium Collaborative Research Group.Effects on blood pressure of reduced dietarysodium and the Dietary Approaches to StopHypertension (DASH) diet. N Engl J Med 2001;344:3–1047. James PA, Oparil S, Carter BL, et al. 2014evidence-basedguideline for themanagementofhigh blood pressure in adults: report from thepanel members appointed to the Eighth JointNational Committee (JNC 8). JAMA 2014;311:507–52048. Bakris GL, Weir MR; Study of Hypertensionand the Efficacy of Lotrel in Diabetes (SHIELD)Investigators. Achieving goal blood pressure inpatientswith type 2 diabetes: conventional versusfixed-dose combination approaches. J Clin Hyper-tens (Greenwich) 2003;5:202–209

49. FeldmanRD,ZouGY,VandervoortMK,WongCJ, Nelson SAE, Feagan BG. A simplified approachto the treatment of uncomplicated hypertension:a cluster randomized, controlled trial. Hyperten-sion 2009;53:646–65350. Webster R, Salam A, de Silva HA, Selak V,StepienS, Rajapakse S, et al. Fixed low-dose triplecombination antihypertensive medication vsusual care for blood pressure control in patientswithmild tomoderate hypertension in Sri Lanka:a randomized clinical trial. JAMA 2018;320:566–57951. Bangalore S, Kamalakkannan G, Parkar S,Messerli FH. Fixed-dose combinations improvemedication compliance: a meta-analysis. Am JMed 2007;120:713–71952. Catala-Lopez F, Macıas Saint-Gerons D,Gonzalez-Bermejo D, et al. Cardiovascular andrenal outcomes of renin-angiotensin systemblockade in adult patients with diabetes mellitus:a systematic review with network meta-analyses.PLoS Med 2016;13:e100197153. Palmer SC, Mavridis D, Navarese E, et al.Comparative efficacy and safety of blood pressure-loweringagents in adultswithdiabetesandkidneydisease: a network meta-analysis. Lancet 2015;385:2047–205654. Barzilay JI, Davis BR, Bettencourt J, et al.;ALLHAT Collaborative Research Group. Cardio-vascular outcomes using doxazosin vs. chlor-thalidone for the treatment of hypertension inolder adults with and without glucose disorders:a report from the ALLHAT study. J Clin Hypertens(Greenwich) 2004;6:116–12555. Weber MA, Bakris GL, Jamerson K, et al.;ACCOMPLISH Investigators. Cardiovasculareventsduring differing hypertension therapies in pa-tients with diabetes. J Am Coll Cardiol 2010;56:77–8556. Bangalore S, Fakheri R, Toklu B, Messerli FH.Diabetes mellitus as a compelling indication foruse of renin angiotensin system blockers: sys-tematic review andmeta-analysis of randomizedtrials. BMJ 2016;352:i43857. Carlberg B, Samuelsson O, Lindholm LH.Atenolol in hypertension: is it a wise choice?Lancet 2004;364:1684–168958. Yusuf S, Teo KK, Pogue J, et al.; ONTARGETInvestigators. Telmisartan, ramipril, or both inpatients at high risk for vascular events. N Engl JMed 2008;358:1547–155959. Fried LF, Emanuele N, Zhang JH, et al.; VANEPHRON-D Investigators. Combined angio-tensin inhibition for the treatment of diabeticnephropathy. N Engl JMed 2013;369:1892–190360. Makani H, Bangalore S, Desouza KA, Shah A,Messerli FH. Efficacy and safety of dual blockadeof the renin-angiotensin system: meta-analysisof randomised trials. BMJ 2013;346:f36061. Zhao P, Xu P,Wan C,Wang Z. Evening versusmorning dosing regimen drug therapy for hy-pertension. Cochrane Database Syst Rev 2011;10:CD00418462. Hermida RC, Ayala DE, Mojon A, FernandezJR. Influence of time of day of blood pressure-lowering treatment on cardiovascular risk inhypertensive patients with type 2 diabetes. Di-abetes Care 2011;34:1270–127663. Nilsson E, Gasparini A, Arnlov J, et al. In-cidence and determinants of hyperkalemia andhypokalemia in a large healthcare system. Int JCardiol 2017;245:277–284

64. Bandak G, Sang Y, Gasparini A, et al. Hyper-kalemia after initiating renin-angiotensin systemblockade: the Stockholm Creatinine Measure-ments (SCREAM) project. J AmHeart Assoc 2017;6:e00542865. Hughes-Austin JM, Rifkin DE, Beben T, et al.The relation of serum potassium concentrationwith cardiovascular events and mortality incommunity-living individuals. Clin J Am SocNephrol 2017;12:245–25266. James MT, Grams ME, Woodward M, et al.;CKD Prognosis Consortium. A meta-analysis ofthe association of estimated GFR, albumin-uria, diabetes mellitus, and hypertension withacute kidney injury. Am J Kidney Dis 2015;66:602–61267. Iliescu R, Lohmeier TE, Tudorancea I, Laffin L,BakrisGL. Renal denervation for the treatment ofresistant hypertension: review and clinical per-spective. Am J Physiol Renal Physiol 2015;309:F583–F59468. Bakris GL, Agarwal R, Chan JC, et al.;Mineralocorticoid Receptor Antagonist Tolera-bility Study–Diabetic Nephropathy (ARTS-DN)Study Group. Effect of finerenone on albumin-uria in patients with diabetic nephropathy:a randomized clinical trial. JAMA 2015;314:884–89469. Williams B, MacDonald TM, Morant S,et al.; British Hypertension Society’s PATHWAYStudies Group. Spironolactone versus placebo,bisoprolol, and doxazosin to determine theoptimal treatment for drug-resistant hyper-tension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015;386:2059–206870. Filippatos G, Anker SD, Bohm M, et al.A randomized controlled study of finerenonevs. eplerenone in patients with worseningchronic heart failure and diabetes mellitusand/or chronic kidney disease. Eur Heart J 2016;37:2105–211471. Bomback AS, Klemmer PJ.Mineralocorticoidreceptor blockade in chronic kidney disease.Blood Purif 2012;33:119–12472. Jensen MD, Ryan DH, Apovian CM, et al.;American College of Cardiology/American HeartAssociation Task Force on Practice Guidelines;Obesity Society. 2013 AHA/ACC/TOS guidelinefor the management of overweight and obesityin adults: a report of the American Collegeof Cardiology/American Heart Association TaskForce on Practice Guidelines and The ObesitySociety. J Am Coll Cardiol 2014;129(25 Suppl. 2):S102–S13873. Estruch R, Ros E, Salas-Salvado J, et al.;PREDIMED Study Investigators. Primary preven-tion of cardiovascular disease with a Mediter-raneandiet supplementedwith extra-virgin oliveoil or nuts. N Engl J Med 2018;378:e3474. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reducecardiovascular risk: a report of the AmericanCollege of Cardiology/American Heart AssociationTask Force on Practice Guidelines. Circulation2013;129:S76–S9975. ChasmanDI,PosadaD,SubrahmanyanL,CookNR, Stanton VP Jr, Ridker PM. Pharmacogeneticstudy of statin therapy and cholesterol reduction.JAMA 2004;291:2821–282776. Meek C, Wierzbicki AS, Jewkes C, et al. Dailyand intermittent rosuvastatin 5 mg therapy in

S120 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

statin intolerant patients: an observationalstudy. Curr Med Res Opin 2012;28:371–37877. Mihaylova B, Emberson J, Blackwell L, et al.;Cholesterol Treatment Trialists’ (CTT) Collabo-rators. The effects of lowering LDL cholesterolwith statin therapy in people at low risk ofvascular disease: meta-analysis of individualdata from 27 randomised trials. Lancet 2012;380:581–59078. Baigent C, Keech A, Kearney PM, et al.;Cholesterol Treatment Trialists’ (CTT) Collabo-rators. Efficacy and safety of cholesterol-loweringtreatment:prospectivemeta-analysisofdata from90,056 participants in 14 randomised trials ofstatins. Lancet 2005;366:1267–127879. Pyorala K, Pedersen TR, Kjekshus J,Faergeman O, Olsson AG, Thorgeirsson G. Cho-lesterol lowering with simvastatin improvesprognosis of diabetic patients with coronaryheart disease. A subgroup analysis of the Scan-dinavian Simvastatin Survival Study (4S). Diabe-tes Care 1997;20:614–62080. Collins R, Armitage J, Parish S, Sleigh P, PetoR; Heart Protection Study Collaborative Group.MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people withdiabetes: a randomised placebo-controlled trial.Lancet 2003;361:2005–201681. Goldberg RB, Mellies MJ, Sacks FM, et al.;The Care Investigators. Cardiovascular eventsand their reduction with pravastatin in diabeticand glucose-intolerant myocardial infarctionsurvivors with average cholesterol levels: sub-group analyses in the Cholesterol andRecurrentEvents (CARE) trial. Circulation 1998;98:2513–251982. Shepherd J, Barter P, Carmena R, et al. Effectof lowering LDL cholesterol substantially belowcurrently recommended levels in patients withcoronary heart disease and diabetes: the Treat-ing to New Targets (TNT) study. Diabetes Care2006;29:1220–122683. Sever PS, Poulter NR, Dahlof B, et al. Re-duction in cardiovascular events with atorvas-tatin in 2,532 patients with type 2 diabetes:Anglo-Scandinavian Cardiac Outcomes Trial–lipid-lowering arm (ASCOT-LLA). Diabetes Care2005;28:1151–115784. Knopp RH, d’EmdenM, Smilde JG, Pocock SJ.Efficacy and safety of atorvastatin in the pre-vention of cardiovascular end points in subjectswith type 2 diabetes: the Atorvastatin Study forPrevention of Coronary Heart Disease Endpointsin Non-Insulin-Dependent Diabetes Mellitus(ASPEN). Diabetes Care 2006;29:1478–148585. Colhoun HM, Betteridge DJ, Durrington PN,et al.; CARDS investigators. Primary preventionof cardiovascular disease with atorvastatin intype 2 diabetes in the Collaborative AtorvastatinDiabetes Study (CARDS): multicentre rando-mised placebo-controlled trial. Lancet 2004;364:685–69686. Kearney PM, Blackwell L, Collins R, et al.;Cholesterol Treatment Trialists’ (CTT) Collabo-rators. Efficacy of cholesterol-lowering therapyin 18,686 people with diabetes in 14 randomisedtrials of statins: a meta-analysis. Lancet 2008;371:117–12587. Taylor F, Huffman MD, Macedo AF, et al.Statins for the primary prevention of cardiovas-cular disease. Cochrane Database Syst Rev 2013;1:CD004816

88. Carter AA,GomesT, CamachoX, JuurlinkDN,ShahBR,MamdaniMM.Risk of incident diabetesamong patients treated with statins: populationbased study [published correction appears in BMJ2013;347:f4356]. BMJ 2013;346:f261089. Baigent C, Blackwell L, Emberson J, et al.;Cholesterol Treatment Trialists’ (CTT) Collabora-tion. Efficacy and safety of more intensive low-ering of LDL cholesterol: a meta-analysis of datafrom 170,000 participants in 26 randomisedtrials. Lancet 2010;376:1670–168190. Cannon CP, Blazing MA, Giugliano RP, et al.;IMPROVE-IT Investigators. Ezetimibe added tostatin therapy after acute coronary syndromes.N Engl J Med 2015;372:2387–239791. de Ferranti SD, de Boer IH, Fonseca V, et al.Type 1 diabetes mellitus and cardiovasculardisease: a scientific statement fromtheAmericanHeart Association and American Diabetes Asso-ciation. Circulation 2014;130:1110–113092. Cannon CP, Braunwald E, McCabe CH, et al.;Pravastatin or Atorvastatin Evaluation and In-fection Therapy-Thrombolysis in Myocardial In-farction 22 Investigators. Intensive versusmoderate lipid lowering with statins after acutecoronary syndromes. N Engl J Med 2004;350:1495–150493. Sabatine MS, Giugliano RP, Keech AC, et al.;FOURIER Steering Committee and Investigators.Evolocumab and clinical outcomes in patientswith cardiovascular disease. N Engl J Med 2017;376:1713–172294. Giugliano RP, Cannon CP, Blazing MA, et al.;IMPROVE-IT (Improved Reduction of Outcomes:Vytorin Efficacy International Trial) Investigators.Benefit of adding ezetimibe to statin therapyon cardiovascular outcomes and safety in patientswith versus without diabetes mellitus: resultsfrom IMPROVE-IT (Improved Reduction of Out-comes: Vytorin Efficacy International Trial). Circu-lation 2018;137:1571–158295. Moriarty PM, Jacobson TA, Bruckert E, et al.Efficacy and safety of alirocumab, a monoclonalantibody to PCSK9, in statin-intolerant patients:design and rationale ofODYSSEYALTERNATIVE, arandomized phase 3 trial. J Clin Lipidol 2014;8:554–56196. Zhang X-L, Zhu Q-Q, Zhu L, et al. Safety andefficacy of anti-PCSK9 antibodies: a meta-analysisof 25 randomized, controlled trials. BMC Med2015;13:12397. Sabatine MS, Leiter LA, Wiviott SD, et al.Cardiovascular safety and efficacy of the PCSK9inhibitor evolocumab in patients with and with-out diabetes and the effect of evolocumab onglycaemia and risk of new-onset diabetes: a pre-specified analysis of the FOURIER randomised con-trolled trial. Lancet Diabetes Endocrinol 2017;5:941–95098. Berglund L, Brunzell JD, Goldberg AC, et al.;Endocrine Society. Evaluation and treatment ofhypertriglyceridemia: an Endocrine Society clin-ical practice guideline. J Clin Endocrinol Metab2012;97:2969–298999. Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as a therapeutic target:a systematic review. JAMA 2007;298:786–798100. Keech A, Simes RJ, Barter P, et al.; FIELDstudy investigators. Effects of long-term feno-fibrate therapy on cardiovascular events in9795 people with type 2 diabetes mellitus

(the FIELD study): randomised controlled trial.Lancet 2005;366:1849–1861101. Jones PH, Davidson MH. Reporting rate ofrhabdomyolysis with fenofibrate1 statin versusgemfibrozil 1 any statin. Am J Cardiol 2005;95:120–122102. Ginsberg HN, Elam MB, Lovato LC, et al.;ACCORD Study Group. Effects of combinationlipid therapy in type 2 diabetes mellitus. N Engl JMed 2010;362:1563–1574103. Kowa Research Institute, Inc. Pemafibrateto Reduce Cardiovascular OutcoMes by Reduc-ing Triglycerides IN patiENts With diabeTes(PROMINENT) In: ClinicalTrials.gov [Internet].Bethesda, MD, National Library of Medicine.Available fromhttps://clinicaltrials.gov/ct2/show/NCT03071692. NLM Identifier: NCT03071692.Accessed 8 October 2018104. BodenWE, Probstfield JL, Anderson T, et al.;AIM-HIGH Investigators. Niacin in patients withlow HDL cholesterol levels receiving intensivestatin therapy. N Engl J Med 2011;365:2255–2267105. Landray MJ, Haynes R, Hopewell JC, et al.;HPS2-THRIVE Collaborative Group. Effects ofextended-release niacin with laropiprant inhigh-risk patients. N Engl J Med 2014;371:203–212106. Rajpathak SN, Kumbhani DJ, Crandall J,Barzilai N, Alderman M, Ridker PM. Statin ther-apy and risk of developing type 2 diabetes: ameta-analysis. Diabetes Care 2009;32:1924–1929107. Sattar N, Preiss D,Murray HM, et al. Statinsand risk of incident diabetes: a collaborativemeta-analysis of randomised statin trials. Lancet2010;375:735–742108. RidkerPM,PradhanA,MacFadyenJG, LibbyP, Glynn RJ. Cardiovascular benefits and diabetesrisks of statin therapy in primary prevention: ananalysis from the JUPITER trial. Lancet 2012;380:565–571109. Mach F, Ray KK,WiklundO, et al.; EuropeanAtherosclerosis Society Consensus Panel. Ad-verse effects of statin therapy: perception vs.the evidence – focus on glucose homeostasis,cognitive, renal and hepatic function, haemo-rrhagic stroke and cataract. Eur Heart J 2018;39:2526–2539110. Heart Protection Study CollaborativeGroup.MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 20,536 high-riskindividuals: a randomisedplacebo-controlled trial.Lancet 2002;360:7–22111. Shepherd J, Blauw GJ, Murphy MB, et al.;PROSPER study group. PROspective Study ofPravastatin in the Elderly at Risk. Pravastatinin elderly individuals at risk of vascular disease(PROSPER): a randomised controlled trial. Lancet2002;360:1623–1630112. Trompet S, van Vliet P, de Craen AJM, et al.Pravastatin and cognitive function in the elderly.Results of thePROSPER study. J Neurol 2010;257:85–90113. Yusuf S, Bosch J, Dagenais G, et al.; HOPE-3Investigators. Cholesterol lowering in interme-diate-risk persons without cardiovascular dis-ease. N Engl J Med 2016;374:2021–2031114. Giugliano RP, Mach F, Zavitz K, et al.;EBBINGHAUS Investigators. Cognitive functionin a randomized trial of evolocumab. N Engl JMed 2017;377:633–643

care.diabetesjournals.org Cardiovascular Disease and Risk Management S121

115. Richardson K, Schoen M, French B, et al.Statins and cognitive function: a systematic re-view. Ann Intern Med 2013;159:688–697116. Baigent C, Blackwell L, Collins R, et al.;Antithrombotic Trialists’ (ATT) Collaboration.Aspirin in the primary and secondary preventionof vascular disease: collaborative meta-analysisof individual participant data from randomisedtrials. Lancet 2009;373:1849–1860117. Perk J, De Backer G, Gohlke H, et al.;European Association for Cardiovascular Preven-tion & Rehabilitation (EACPR); ESC Committee forPracticeGuidelines (CPG). EuropeanGuidelinesoncardiovascular disease prevention in clinical prac-tice (version 2012): The Fifth Joint Task Force ofthe European Society of Cardiology and OtherSocieties on Cardiovascular Disease Prevention inClinical Practice (constituted by representatives ofnine societies and by invited experts). Eur HeartJ 2012;33:1635–1701118. Belch J, MacCuish A, Campbell I, et al. Theprevention of progression of arterial disease anddiabetes (POPADAD) trial: factorial randomisedplacebo controlled trial of aspirin and antiox-idants in patients with diabetes and asymptom-atic peripheral arterial disease. BMJ 2008;337:a1840119. Zhang C, Sun A, Zhang P, et al. Aspirin forprimary prevention of cardiovascular events inpatientswith diabetes: ameta-analysis. DiabetesRes Clin Pract 2010;87:211–218120. De Berardis G, Sacco M, Strippoli GFM,et al. Aspirin for primary prevention of cardio-vascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ2009;339:b4531121. ASCEND Study CollaborativeGroup. Effectsof aspirin for primary prevention in persons withdiabetes mellitus. N Engl J Med 2018;379:1529–1539122. Gaziano JM, Brotons C, Coppolecchia R,et al.; ARRIVE Executive Committee. Use ofaspirin to reduce risk of initial vascular eventsin patients at moderate risk of cardiovasculardisease (ARRIVE): a randomised, double-blind,placebo-controlled trial. Lancet 2018;392:1036–1046123. McNeil JJ,WolfeR,WoodsRL, etal.;ASPREEInvestigator Group. Effect of aspirin on cardio-vascular events and bleeding in the healthyelderly. N Engl J Med 2018;379:1509–1518124. Pignone M, Earnshaw S, Tice JA, PletcherMJ. Aspirin, statins, or both drugs for the primaryprevention of coronary heart disease events inmen: a cost-utility analysis. Ann Intern Med2006;144:326–336125. Pignone M, Alberts MJ, Colwell JA, et al.;American Diabetes Association; American HeartAssociation; American College of CardiologyFoundation. Aspirin for primary prevention ofcardiovascular events in people with diabetes:a position statement of the American DiabetesAssociation, a scientific statement of the Amer-ican Heart Association, and an expert consensusdocument of the American College of Cardiol-ogy Foundation. Diabetes Care 2010;33:1395–1402126. Huxley RR, Peters SAE, Mishra GD,Woodward M. Risk of all-cause mortality andvascular events inwomenversusmenwith type1diabetes: a systematic review andmeta-analysis.Lancet Diabetes Endocrinol 2015;3:198–206

127. Peters SAE, Huxley RR, Woodward M. Di-abetes as risk factor for incident coronary heartdisease in women compared with men: a sys-tematic review and meta-analysis of 64 cohortsincluding 858,507 individuals and 28,203coronary events. Diabetologia 2014;57:1542–1551128. Kalyani RR, Lazo M, Ouyang P, et al. Sexdifferences in diabetes and risk of incidentcoronary artery disease in healthy young andmiddle-aged adults. Diabetes Care 2014;37:830–838129. Peters SAE, Huxley RR, Woodward M. Di-abetes as a risk factor for stroke in womencompared with men: a systematic review andmeta-analysis of 64 cohorts, including 775,385individuals and 12,539 strokes. Lancet 2014;383:1973–1980130. Dimitriu-Leen AC, Scholte AJHA, vanRosendael AR, et al. Value of coronary computedtomography angiography in tailoring aspirintherapy for primary prevention of atheroscle-rotic events in patients at high risk with diabetesmellitus. Am J Cardiol 2016;117:887–893131. Mora S, Ames JM, Manson JE. Low-doseaspirin in the primary prevention of cardiovas-cular disease: shared decision making in clinicalpractice. JAMA 2016;316:709–710132. Campbell CL, Smyth S, Montalescot G,Steinhubl SR. Aspirin dose for the preventionof cardiovascular disease: a systematic review.JAMA 2007;297:2018–2024133. Davı G, Patrono C. Platelet activation andatherothrombosis. N Engl JMed 2007;357:2482–2494134. Larsen SB, Grove EL, Neergaard-Petersen S,WurtzM,HvasA-M,KristensenSD.Determinantsof reduced antiplatelet effect of aspirin in pa-tients with stable coronary artery disease. PLoSOne 2015;10:e0126767135. Zaccardi F, Rizzi A, Petrucci G, et al. In vivoplatelet activation and aspirin responsiveness intype 1 diabetes. Diabetes 2016;65:503–509136. Bethel MA, Harrison P, Sourij H, et al.Randomized controlled trial comparing im-pact on platelet reactivity of twice-daily withonce-daily aspirin in peoplewith type 2 diabetes.Diabet Med 2016;33:224–230137. Rothwell PM, Cook NR, Gaziano JM, et al.Effects of aspirin on risks of vascular events andcancer according to bodyweight and dose: anal-ysis of individual patient data from randomisedtrials. Lancet 2018;392:387–399138. Vandvik PO, Lincoff AM, Gore JM, et al.Primary and secondary prevention of cardiovas-cular disease: Antithrombotic Therapy and Pre-vention of Thrombosis, 9th ed: American Collegeof Chest Physicians Evidence-Based Clinical Prac-tice Guidelines [published correction appearsinChest 2012;141:1129]. Chest 2012;141(Suppl.):e637S–e668S139. Bhatt DL, Bonaca MP, Bansilal S, et al.Reduction in ischemic events with ticagrelorin diabetic patients with prior myocardial in-farction in PEGASUS-TIMI 54. J Am Coll Cardiol2016;67:2732–2740140. Bax JJ, Young LH, Frye RL, Bonow RO,Steinberg HO, Barrett EJ. Screening for coronaryarterydisease inpatientswith diabetes.DiabetesCare 2007;30:2729–2736141. Boden WE, O’Rourke RA, Teo KK, et al.;COURAGETrial ResearchGroup.Optimalmedical

therapy with or without PCI for stable coronarydisease. N Engl J Med 2007;356:1503–1516142. BARI 2D Study Group, Frye RL, August P,et al. A randomized trial of therapies for type 2diabetes and coronary artery disease. N Engl JMed 2009;360:2503–2015143. Wackers FJT, Chyun DA, Young LH, et al.;Detectionof Ischemia inAsymptomaticDiabetics(DIAD) Investigators. Resolution of asymptom-atic myocardial ischemia in patients with type 2diabetes in the Detection of Ischemia in Asymp-tomatic Diabetics (DIAD) study. Diabetes Care2007;30:2892–2898144. Elkeles RS, Godsland IF, Feher MD, et al.;PREDICT Study Group. Coronary calcium mea-surement improves prediction of cardiovascularevents in asymptomatic patients with type 2diabetes: the PREDICT study. Eur Heart J 2008;29:2244–2251145. Raggi P, Shaw LJ, Berman DS, Callister TQ.Prognostic value of coronary artery calciumscreening in subjects with and without diabetes.J Am Coll Cardiol 2004;43:1663–1669146. Anand DV, Lim E, Hopkins D, et al. Riskstratification in uncomplicated type 2 diabetes:prospective evaluation of the combined use ofcoronary artery calcium imaging and selectivemyocardial perfusion scintigraphy. Eur Heart J2006;27:713–721147. Young LH, Wackers FJT, Chyun DA, et al.;DIAD Investigators. Cardiac outcomes afterscreening for asymptomatic coronary arterydisease in patients with type 2 diabetes: theDIAD study: a randomized controlled trial. JAMA2009;301:1547–1555148. Wackers FJT, Young LH, Inzucchi SE, et al.;Detectionof Ischemia inAsymptomaticDiabeticsInvestigators. Detection of silent myocardial is-chemia in asymptomatic diabetic subjects: theDIAD study. Diabetes Care 2004;27:1954–1961149. Scognamiglio R, Negut C, Ramondo A,Tiengo A, Avogaro A. Detection of coronaryartery disease in asymptomatic patients withtype 2 diabetes mellitus. J Am Coll Cardiol 2006;47:65–71150. Hadamitzky M, Hein F, Meyer T, et al.Prognostic value of coronary computed tomo-graphic angiography in diabetic patients with-out known coronary artery disease. DiabetesCare 2010;33:1358–1363151. Choi E-K,ChunEJ, Choi S-I, et al.Assessmentof subclinical coronary atherosclerosis in asymp-tomatic patients with type 2 diabetes mellituswith single photon emission computed tomog-raphy and coronary computed tomography an-giography. Am J Cardiol 2009;104:890–896152. Malik S, Zhao Y, Budoff M, et al. Coronaryartery calcium score for long-term risk classificationin individuals with type 2 diabetes and metabolicsyndrome from the Multi-Ethnic Study of Athero-sclerosis. JAMA Cardiol 2017;2:1332–1340153. Wing RR, Bolin P, Brancati FL, et al.; LookAHEAD Research Group. Cardiovascular effectsof intensive lifestyle intervention in type 2 di-abetes. N Engl J Med 2013;369:145–154154. Braunwald E, Domanski MJ, Fowler SE,et al.; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronaryartery disease. N Engl J Med 2004;351:2058–2068155. Telmisartan Randomised AssessmeNt Studyin ACE iNtolerant subjects with cardiovascular

S122 Cardiovascular Disease and Risk Management Diabetes Care Volume 42, Supplement 1, January 2019

Disease (TRANSCEND) Investigators, Yusuf S, TeoK, etal. Effectsof theangiotensin-receptorblockertelmisartan on cardiovascular events in high-riskpatients intolerant to angiotensin-convertingenzyme inhibitors: a randomised controlledtrial. Lancet 2008;372:1174–1183156. Kezerashvili A, Marzo K, De Leon J. Betablocker use after acute myocardial infarction inthe patientwith normal systolic function:when is it“ok” todiscontinue?Curr Cardiol Rev 2012;8:77–84157. U.S. FoodandDrugAdministration. Guidancefor industry. Diabetes mellitusdevaluating cardio-vascular risk in new antidiabetic therapies to treattype2diabetes [Internet]. Silver Spring,MD,2008.Available from http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf).Accessed3November2017158. Neal B, Perkovic V, Matthews DR, et al.;CANVAS-R Trial Collaborative Group. Rationale,design and baseline characteristics of theCANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab 2017;19:387–393159. Marso SP, Daniels GH, Brown-Frandsen K,et al.; LEADER Steering Committee; LEADER TrialInvestigators. Liraglutide and cardiovascular out-comes in type 2 diabetes. N Engl JMed 2016;375:311–322160. Marso SP, Bain SC, Consoli A, et al.;SUSTAIN-6 Investigators. Semaglutide and car-diovascular outcomes in patients with type 2diabetes. N Engl J Med 2016;375:1834–1844161. Pfeffer MA, Claggett B, Diaz R, et al.; ELIXAInvestigators. Lixisenatide in patientswith type 2diabetes and acute coronary syndrome. N EnglJ Med 2015;373:2247–2257

162. Holman RR, Bethel MA, Mentz RJ, et al.;EXSCEL Study Group. Effects of once-weeklyexenatide on cardiovascular outcomes in type2 diabetes. N Engl J Med 2017;377:1228–1239163. Hernandez AF, Green JB, Janmohamed S,et al.; Harmony Outcomes committees and in-vestigators. Albiglutide and cardiovascular out-comes in patients with type 2 diabetes andcardiovascular disease (Harmony Outcomes):a double-blind, randomised placebo-controlledtrial. Lancet 2018;392:1519–1529164. Kannel WB, Hjortland M, Castelli WP.Role of diabetes in congestive heart failure:the Framingham study. Am J Cardiol 1974;34:29–34165. Dormandy JA, Charbonnel B, Eckland DJA,et al.; PROactive Investigators. Secondary pre-vention of macrovascular events in patientswith type 2 diabetes in the PROactive Study(PROspective pioglitAzone Clinical Trial InmacroVascular Events): a randomised con-trolled trial. Lancet 2005;366:1279–1289166. Singh S, Loke YK, Furberg CD. Long-termrisk of cardiovascular events with rosiglitazone:a meta-analysis. JAMA 2007;298:1189–1195167. Lincoff AM,Wolski K, Nicholls SJ, Nissen SE.Pioglitazone and risk of cardiovascular events inpatients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA 2007;298:1180–1188168. Scirica BM, Bhatt DL, Braunwald E, et al.;SAVOR-TIMI 53 Steering Committee and Inves-tigators. Saxagliptin and cardiovascular outcomesin patients with type 2 diabetes mellitus. N Engl JMed 2013;369:1317–1326169. U.S. Food and Drug Administration. FDADrug Safety Communication: FDA adds warn-ings about heart failure risk to labels of type 2

diabetes medicines containing saxagliptin andalogliptin [Internet], 2016. Available fromhttp://www.fda.gov/Drugs/DrugSafety/ucm486096.htm. Accessed 24 September 2018170. Zannad F, Cannon CP, Cushman WC, et al.;EXAMINE Investigators. Heart failure and mor-tality outcomes in patients with type 2 diabetestaking alogliptin versus placebo in EXAMINE:a multicentre, randomised, double-blind trial.Lancet 2015;385:2067–2076171. Green JB, BethelMA, Armstrong PW, et al.;TECOS Study Group. Effect of sitagliptin on car-diovascular outcomes in type 2 diabetes. N Engl JMed 2015;373:232–242172. Fitchett D, Butler J, van de Borne P, et al.Effects of empagliflozin on risk for cardiovasculardeath and heart failure hospitalization across thespectrum of heart failure risk in the EMPA-REGOUTCOME trial. Eur Heart J 2017;39:363–370173. Hansson L, Zanchetti A, Carruthers SG,et al.; HOT Study Group. Effects of intensiveblood-pressure lowering and low-dose aspirin inpatients with hypertension: principal results ofthe Hypertension Optimal Treatment (HOT)randomised trial. Lancet 1998;351:1755–1762174. Zoungas S, Chalmers J, Neal B, et al.;ADVANCE-ON Collaborative Group. Follow-up ofblood-pressure lowering and glucose control intype 2 diabetes. N Engl JMed 2014;371:1392–1406175. White WB, Cannon CP, Heller SR, et al.;EXAMINE Investigators. Alogliptin after acutecoronary syndrome in patients with type 2 di-abetes. N Engl J Med 2013;369:1327–1335176. Cefalu WT, Kaul S, Gerstein HC, et al.Cardiovascular outcomes trials in type 2 diabe-tes: where do we go from here? Reflectionsfrom a Diabetes Care Editors’ Expert Forum.Diabetes Care 2018;41:14–31

care.diabetesjournals.org Cardiovascular Disease and Risk Management S123