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10. Cardiovascular Disease andRisk Management: Standards ofMedical Care in Diabetesd2021Diabetes Care 2021;44(Suppl. 1):S125–S150 | https://doi.org/10.2337/dc21-S010

The American Diabetes Association (ADA) “Standards of Medical Care in Diabetes”includes the ADA’s current clinical practice recommendations and is intended toprovide the components of diabetes care, general treatment goals and guidelines,and tools to evaluate quality of care. Members of the ADA Professional PracticeCommittee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or morefrequently as warranted. For a detailed description of ADA standards, statements,and reports, as well as the evidence-grading system for ADA’s clinical practicerecommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Careare invited to do so at professional.diabetes.org/SOC.

For prevention and management of diabetes complications in children and adoles-cents, please refer to Section 13 “Children andAdolescents” (https://doi.org/10.2337/dc21-S013).

Atherosclerotic cardiovascular disease (ASCVD)ddefined as coronary heart disease(CHD), cerebrovascular disease, or peripheral arterial disease presumed to be ofatherosclerotic origindis the leading cause ofmorbidity andmortality for individualswith diabetes and results in an estimated $37.3 billion in cardiovascular-relatedspending per year associated with diabetes (1). Common conditions coexisting withtype 2 diabetes (e.g., hypertension and dyslipidemia) are clear risk factors for ASCVD,and diabetes itself confers independent risk. Numerous studies have shown theefficacy of controlling individual cardiovascular risk factors in preventing or slowingASCVD in people with diabetes. Furthermore, large benefits are seen when multiplecardiovascular risk factors are addressed simultaneously. Under the current paradigmof aggressive risk factor modification in patients with diabetes, there is evidence thatmeasures of 10-year coronary heart disease (CHD) risk among U.S. adults withdiabetes have improved significantly over the past decade (2) and that ASCVDmorbidity 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). Hypertension isoftenaprecursorofheart failureofeither type, andASCVDcancoexistwitheither type(7), whereas prior myocardial infarction (MI) is often a major factor in HFrEF. Ratesof heart failure hospitalization have been improved in recent trials includingpatients with type 2 diabetes, most of whom also had ASCVD, with sodium–glucosecotransporter 2 (SGLT2) inhibitors (8–10).

This section has received endorsement from theAmerican College of Cardiology.

Suggested citation: American Diabetes Association.10. Cardiovascular disease and risk management:Standards of Medical Care in Diabetesd2021.Diabetes Care 2021;44(Suppl.1):S125–S150

© 2020 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered. More infor-mation is availableathttps://www.diabetesjournals.org/content/license.

American Diabetes Association

Diabetes Care Volume 44, Supplement 1, January 2021 S125

10.CARDIOVASCULA

RDISEA

SEANDRISK

MANAGEM

ENT

https://doi.org/10.2337/dc21-S010https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-SPPChttps://care.diabetesjournals.org/lookup/doi/10.2337/dc21-SPPChttps://care.diabetesjournals.org/lookup/doi/10.2337/dc21-SINThttps://care.diabetesjournals.org/lookup/doi/10.2337/dc21-SINThttps://professional.diabetes.org/content-page/practice-guidelines-resourceshttps://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S013https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S013http://crossmark.crossref.org/dialog/?doi=10.2337/dc21-S010&domain=pdf&date_stamp=2020-11-20https://www.diabetesjournals.org/content/licensehttps://www.diabetesjournals.org/content/license

For prevention and management ofboth ASCVD and heart failure, cardiovas-cular risk factors shouldbe systematicallyassessed at least annually in all patientswith diabetes. These risk factors includeobesity/overweight, hypertension, dysli-pidemia, smoking, a family history of pre-mature coronary disease, chronic kidneydisease, and thepresenceof albuminuria.Modifiable abnormal risk factors shouldbe treated as described in these guide-lines. Notably, the majority of evidencesupporting interventions to reduce cardio-vascular risk indiabetes comes fromtrials ofpatients with type 2 diabetes. Few trialshave been specifically designed to assessthe impact of cardiovascular risk reductionstrategies in patients with type 1 diabetes.

THE RISK CALCULATOR

The American College of Cardiology/American Heart Association ASCVD riskcalculator (Risk Estimator Plus) is gener-ally a useful tool to estimate 10-year riskof a first ASCVD event (available onlineat tools.acc.org/ASCVD-Risk-Estimator-Plus). The calculator includes diabetesas a risk factor, since diabetes itselfconfers increased risk for ASCVD, al-though it should be acknowledged thatthese risk calculators donot account forthe duration of diabetes or the pres-ence of diabetes complications, such asalbuminuria. Although some variabilityin calibration exists in various subgroups,including by sex, race, and diabetes, theoverall risk prediction does not differ inthose with or without diabetes (11–14),validating the use of risk calculators inpeoplewithdiabetes. The10-year risk of afirst ASCVD event should be assessed tobetter stratify ASCVD risk and help guidetherapy, as described below.Recently, risk scores and other cardio-

vascular biomarkershavebeendevelopedfor risk stratification of secondary pre-vention patients (i.e., those who are al-ready high risk because they have ASCVD)but are not yet in widespread use (15,16).Withnewer,moreexpensive lipid-loweringtherapies now available, use of these riskassessments may help target these newtherapies to “higher risk” ASCVD pa-tients in the future.

HYPERTENSION/BLOOD PRESSURECONTROL

Hypertension, defined as a sustained bloodpressure $140/90 mmHg, is common

among patients with either type 1 ortype 2 diabetes. Hypertension is a ma-jor risk factor for both ASCVD and mi-crovascular complications. Moreover,numerous studies have shown thatantihypertensive therapy reducesASCVDevents, 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).

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, including measure-ments on a separate day, todiagnose hypertension. B

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

Blood pressure should be measured atevery routine clinical visit by a trainedindividual and should follow the guide-lines established for the general pop-ulation: 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. Stud-ies of individuals without diabetes foundthat home measurements may bettercorrelate with ASCVD risk than officemeasurements (18,19). Moreover, home

blood pressure monitoring may improvepatient medication adherence and thushelp reduce cardiovascular risk (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 ad-verse effects of antihypertensivemedications, and patient prefer-ences. C

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

10.5 For individualswithdiabetes andhypertension at lower risk forcardiovascular disease (10-yearatherosclerotic cardiovasculardisease risk ,15%), treat to ablood pressure target of,140/90 mmHg. A

10.6 Inpregnantpatientswithdiabetesand preexisting hypertension, ablood pressure target of 110–135/85mmHgis suggested intheinterest of reducing the risk foraccelerated maternal hyperten-sion A and minimizing impairedfetal growth. E

Randomized clinical trials have demon-strated unequivocally that treatment ofhypertension to blood pressure ,140/90 mmHg reduces cardiovascular eventsas well as microvascular complications(21–27). Therefore, patients with type 1or type2 diabeteswhohavehypertensionshould, at aminimum, be treated tobloodpressure targets of,140/90 mmHg. Thebenefits and risks of intensifying anti-hypertensive therapy to target bloodpressures lower than ,140/90 mmHg(e.g.,,130/80 or,120/80 mmHg) havebeen evaluated in large randomized clin-ical trials and meta-analyses of clinicaltrials. Notably, there is an absence ofhigh-quality data available toguidebloodpressure targets in type 1 diabetes.

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https://tools.acc.org/ASCVD-Risk-Estimator-Plushttps://tools.acc.org/ASCVD-Risk-Estimator-Plus

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-mentof thebenefits and risksof 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 bloodpressure control (target systolic bloodpressure ,120 mmHg) did not reducetotalmajor atherosclerotic cardiovascularevents but did reduce the risk of stroke, atthe expense of increased adverse events(Table 10.1). The ACCORD BP results

suggest that blood pressure targetsmore intensive than ,140/90 mmHgare not likely to improve cardiovascularoutcomesamongmost peoplewith type2diabetes but may be reasonable for pa-tients who may derive the most benefitand have been educated about addedtreatment burden, side effects, and costs,as discussed below.

Additional studies, such as the SystolicBlood Pressure Intervention Trial(SPRINT) and the Hypertension OptimalTreatment (HOT) trial, also examinedeffects of intensive versus standard con-trol (Table 10.1), though the relevance oftheir results to people with diabetes isless clear. The Action in Diabetes and

Vascular Disease: Preterax and Diami-cron MR Controlled Evaluation–BloodPressure (ADVANCE BP) trial did notexplicitly test blood pressure targets(29); the achieved blood pressure inthe intervention group was higherthan that achieved in the ACCORD BPintensive arm and would be consistentwith a target blood pressure of ,140/90 mmHg. Notably, ACCORD BP andSPRINT measured blood pressure usingautomated office blood pressure mea-surement, which yields values that aregenerally lower than typical office bloodpressure readings by approximately 5–10 mmHg (30), suggesting that imple-menting the ACCORD BP or SPRINT

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

SBP target:,120 mmHg

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

SBP target:130–140 mmHg

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

c No benefit in primary end point:composite of nonfatal MI,nonfatal stroke, and CVD death

c Stroke risk reduced 41% withintensive control, not sustainedthrough follow-up beyond theperiod of active treatment

c Adverse events more commonin intensive group, particularlyelevated serum creatinine andelectrolyte abnormalities

ADVANCE BP (29) 11,140 participants withT2D aged 55 years andolder with prior evidence ofCVD or multiple cardiovascularrisk factors

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

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

Control: placeboAchieved (mean)

SBP/DBP:141.6/75.2 mmHg

c Intervention reduced risk ofprimary composite end point ofmajor macrovascular andmicrovascular events (9%),death fromany cause (14%), anddeath from CVD (18%)

c 6-year observational follow-upfoundreduction inriskofdeath inintervention group attenuatedbut still significant (198)

HOT (199) 18,790 participants,including 1,501with diabetes

DBP target:#80 mmHg

DBP target:#90 mmHg

c In the overall trial, there was nocardiovascular benefit withmore intensive targets

c In the subpopulation withdiabetes, an intensive DBPtarget was associated witha significantly reducedrisk (51%)of CVD events

SPRINT (40) 9,361 participantswithout diabetes


Achieved (mean):121.4 mmHg


Achieved (mean):136.2 mmHg

c IntensiveSBP target lowered riskof the primary compositeoutcome 25% (MI, ACS, stroke,heart failure, and death due toCVD)

c Intensive target reduced risk ofdeath 27%

c Intensive therapy increased risksof electrolyte abnormalities andAKI

ACCORDBP, Action to Control Cardiovascular Risk inDiabetes BloodPressure trial; ACS, acute coronary syndrome; ADVANCEBP, Action inDiabetes andVascular Disease: Preterax and Diamicron MR Controlled Evaluation–Blood Pressure trial; AKI, acute kidney injury; CVD, cardiovascular disease; DBP,diastolic blood pressure; HOT, Hypertension Optimal Treatment trial; MI, myocardial infarction; SBP, systolic blood pressure; SPRINT, Systolic BloodPressure InterventionTrial; T2D, type2diabetes.Data fromthis table canalsobe found in theADApositionstatement “DiabetesandHypertension” (17).

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protocols in an outpatient clinic mightrequire a systolic blood pressure tar-get higher than ,120 mmHg, such as,130 mmHg.A number of post hoc analyses have

attempted to explain the apparently di-vergent results of ACCORD BP andSPRINT. Some investigators have arguedthat the divergent results are not due todifferences between people with andwithout diabetes but rather are due todifferences in study design or to charac-teristics other than diabetes (31–33).Others have opined that the divergentresults are most readily explained by thelack of benefit of intensive blood pres-sure control on cardiovascular mortalityin ACCORD BP, which may be due todifferential mechanisms underlying car-diovascular disease in type 2 diabetes, tochance, or both (34). Interestingly, a posthoc analysis has found that intensiveblood pressure lowering increased therisk of incident chronic kidney disease inboth ACCORD BP and SPRINT, with theabsolute risk of incident chronic kidneydisease being higher in individuals withtype 2 diabetes (35).

Meta-analyses of Trials

To clarify optimal blood pressure targetsin patients with diabetes, meta-analyseshave stratified clinical trials by meanbaseline blood pressure or mean bloodpressure attained in the intervention (orintensive treatment) arm.Basedon theseanalyses, antihypertensive treatment ap-pears to be beneficial when mean base-line blood pressure is$140/90mmHg ormean attained intensive blood pressureis $130/80 mmHg (17,21,22,24–26).Among trials with lower baseline orattained blood pressure, antihyperten-sive treatment reduced the risk of stroke,retinopathy, and albuminuria, but effectson other ASCVD outcomes and heartfailurewere not evident. Taken together,these meta-analyses consistently showthat treating patients with baselineblood pressure $140 mmHg to targets,140 mmHg is beneficial, while more-intensive targets may offer additional(though probably less robust) benefits.

Individualization of Treatment Targets

Patients and clinicians should engage in ashared decision-making process to de-termine individual blood pressure tar-gets (17). This approach acknowledgesthat the benefits and risks of intensiveblood pressure targets are uncertain and

may vary across patients and is consis-tent with a patient-focused approach tocare that values patient priorities andprovider judgment (36). Secondary anal-yses of ACCORD BP and SPRINT suggestthat clinical factors can help determineindividualsmore likely to benefit and lesslikely to be harmed by intensive bloodpressure control (37,38).

Absolute benefit from blood pressurereduction correlated with absolute base-line cardiovascular risk in SPRINT and inearlier clinical trials conducted at higherbaseline blood pressure levels (11,38).Extrapolation of these studies suggeststhat patients with diabetes may also bemore likely to benefit from intensiveblood pressure control when theyhave high absolute cardiovascular risk.Therefore, itmay be reasonable to targetblood pressure ,130/80 mmHg amongpatients with diabetes and either clini-cally diagnosed cardiovascular disease(particularly stroke, which was signifi-cantly reduced in ACCORD BP) or10-year ASCVD risk $15%, if it can beattained safely. This approach is consis-tent with guidelines from the AmericanCollege of Cardiology/American HeartAssociation, which advocate a bloodpressure target ,130/80 mmHg for allpatients, with or without diabetes (39).

Potential adverse effects of antihyper-tensive therapy (e.g., hypotension, syn-cope, falls, acute kidney injury, andelectrolyte abnormalities) should alsobe taken into account (28,35,40,41). Pa-tients with older age, chronic kidneydisease, and frailty have been shown tobe at higher risk of adverse effects ofintensive blood pressure control (41). Inaddition, patients with orthostatic hypo-tension, substantial comorbidity, func-tional limitations, or polypharmacy maybeathighriskofadverseeffects,andsomepatientsmaypreferhigher bloodpressuretargets to enhance quality of life. Patientswith low absolute cardiovascular risk (10-yearASCVDrisk,15%)orwithahistoryofadverse 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

There are few randomized controlled trialsof antihypertensive therapy in pregnant

women with diabetes. A 2014 Cochranesystematic review of antihypertensivetherapy 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, orfetaldeath(42).ThemorerecentControlofHypertension in Pregnancy Study (CHIPS)(43) enrolled mostly women with chronichypertension. InCHIPS, targetingadiastolicblood pressure of 85 mmHg during preg-nancy was associated with reduced likeli-hood of developing accelerated maternalhypertension and no demonstrable ad-verse outcome for infants comparedwith targeting a higher diastolic bloodpressure. Themeansystolicbloodpressureachieved in the more intensively treatedgroup was 133.1 6 0.5 mmHg, and themean diastolic blood pressure achieved inthat groupwas85.360.3mmHg.A similarapproach is supported by the InternationalSociety for the Study of Hypertension inPregnancy,which specifically recommendsuse of antihypertensive therapy to main-tain systolic blood pressure between110 and 140 mmHg and diastolic bloodpressure between 80 and 85 mmHg (44).Current evidence supports controllingblood pressure to 110–135/85 mmHg toreduce the risk of accelerated maternalhypertension but also to minimize impair-ment of fetal growth. During pregnancy,treatmentwith ACE inhibitors, angiotensinreceptor blockers, and spironolactone arecontraindicated as they may cause fetaldamage. Antihypertensive drugs known tobe effective and safe in pregnancy includemethyldopa, labetalol, and long-acting ni-fedipine, while hydralzine may be con-sidered in the acute management ofhypertension in pregnancy or severe pre-eclampsia (45). Diuretics are not recom-mended for blood pressure control inpregnancy but may be used during late-stage pregnancy if needed for volumecontrol (45,46). The American College ofObstetricians and Gynecologists also rec-ommends that postpartum patients withgestational hypertension, preeclampsia,andsuperimposedpreeclampsiahavetheirblood pressures observed for 72 h in thehospital and for 7–10 days postpartum.Long-term follow-up is recommended forthese women as they have increased life-time cardiovascular risk (47). See Section


14 “Management of Diabetes in Preg-nancy” (https://doi.org/10.2337/dc21-S014)for additional information.

Treatment Strategies

Lifestyle Intervention

Recommendation

10.7 For patients with blood pres-sure .120/80 mmHg, lifestyleintervention consists of weightloss when indicated, a DietaryApproaches to Stop Hyperten-sion (DASH)-style eating patternincluding reducing sodium andincreasing potassium intake,moderation of alcohol intake,and increasedphysical activity.A

Lifestyle management is an importantcomponent of hypertension treatmentbecause it lowers blood pressure, enhan-ces the effectiveness of some antihyper-tensive medications, promotes otheraspects ofmetabolic and vascular health,and generally leads to few adverse ef-fects. Lifestyle therapy consists of re-ducing excess body weight throughcaloric restriction (see Section 8 “Obe-sity Management for the Treatment ofType2Diabetes,”https://doi.org/10.2337/dc21-S008), restricting sodium intake(,2,300 mg/day), increasing consump-tion of fruits and vegetables (8–10 serv-ings per day) and low-fat dairy products(2–3 servings per day), avoiding exces-sive alcohol consumption (no more than2servingsperday inmenandnomorethan1 serving per day in women) (48), andincreasing activity levels (49).These lifestyle interventions are rea-

sonable for individuals with diabetes andmildly elevated blood pressure (systolic.120 mmHg or diastolic .80 mmHg)and should be initiated along with phar-macologic therapy when hypertension isdiagnosed(Fig.10.1) (49).A lifestyletherapyplan should be developed in collaborationwith the patient and discussed as part ofdiabetes management.

Pharmacologic Interventions

Recommendations

10.8 Patientswith confirmedoffice-based blood pressure $140/90mmHgshould, inaddition 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 additionto lifestyle therapy, havepromptinitiation and timely titration oftwo drugs or a single-pill com-bination of drugs demonstratedto reduce cardiovascular eventsin patients with diabetes. A

10.10 Treatment for hypertensionshould includedrug classes dem-onstrated to reduce cardiovas-cular events in patients withdiabetes. A ACE inhibitors orangiotensin receptor blockersare recommendedfirst-line ther-apy for hypertension in peoplewith diabetes and coronary ar-tery disease. A

10.11 Multiple-drug therapy is gener-ally required to achieve bloodpressure targets. However,combinations of ACE inhibitorsandangiotensinreceptorblock-ers and combinations of ACEinhibitors or angiotensin recep-tor blockers with direct renininhibitors should not beused.A

10.12 AnACE inhibitoror angiotensinreceptor blocker, at the max-imum tolerated dose indicatedfor blood pressure treatment,is the recommended first-linetreatment for hypertension inpatients with diabetes and uri-nary albumin-to-creatinine ra-tio$300 mg/g creatinine A or30–299 mg/g creatinine. B Ifone class is not tolerated, theother should be substituted. B

10.13 Forpatients treatedwithanACEinhibitor, angiotensin receptorblocker, or diuretic, serum cre-atinine/estimated glomerularfiltration rate and serum potas-sium levels should be moni-tored at least annually. B

Initial Number of AntihypertensiveMedications.

Initial treatment for people with diabetesdependsontheseverityofhypertension(Fig.10.1). Those with blood pressure between140/90 mmHg and 159/99 mmHg maybeginwith a single drug. For patientswithblood pressure $160/100 mmHg, initialpharmacologic treatment with two anti-hypertensive medications is recommendedinorder tomoreeffectivelyachieveadequateblood pressure control (50–52). Single-pill

antihypertensive combinations may im-prove medication adherence in somepatients (53).

Classes of Antihypertensive Medications.

Initial treatment for hypertension shouldinclude any of the drug classes demon-strated to reduce cardiovascular eventsin patients with diabetes: ACE inhibitors(54,55), angiotensin receptor blockers(ARBs) (54,55), thiazide-like diuretics (56),or dihydropyridine calciumchannel block-ers (57). In patients with diabetes andestablished coronary artery disease, ACEinhibitors orARBs are recommendedfirst-line therapy for hypertension (58–60). Forpatients with albuminuria (urine albumin-to-creatinine ratio [UACR] $30 mg/g),initial treatment should include an ACEinhibitor or ARB in order to reduce therisk of progressive kidney disease (17)(Fig. 10.1). In the absence of albumin-uria, risk of progressive kidney disease islow, and ACE inhibitors and ARBs have notbeen found to afford superior cardiopro-tection when compared with thiazide-likediuretics or dihydropyridine calcium channelblockers (61).b-Blockers are indicated in thesetting of prior MI, active angina, or HfrEFbut have not been shown to reduce mor-tality as blood pressure–lowering agents inthe absence of these conditions (23,62,63).

Multiple-Drug Therapy. Multiple-drugtherapy is often required to achieveblood pressure targets (Fig. 10.1), par-ticularly in the setting of diabetic kid-ney disease. However, the use of bothACE inhibitors and ARBs in combination,or the combination of an ACE inhibitor orARB and a direct renin inhibitor, is notrecommended given the lack of addedASCVD benefit and increased rate of ad-verse eventsdnamely, hyperkalemia, syn-cope, and acute kidney injury (AKI) (64–66).Titrationofand/oradditionof furtherbloodpressure medications should be made in atimely fashion to overcome therapeuticinertia in achieving blood 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 randomizedclinicaltrials foundasmallbenefitofeveningversus morning dosing of antihypertensivemedications with regard to blood pressurecontrol but had no data on clinical effects(67). In two subgroup analyses of a sin-gle subsequent randomized controlledtrial, moving at least one antihypertensive


https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S014https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S008https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S008http://care.diabetesjournals.org

medication tobedtimesignificantly reducedcardiovascular events, but results werebased on a small number of events (68).

Hyperkalemia and Acute Kidney Injury.

Treatment with ACE inhibitors or ARBs

can cause AKI and hyperkalemia, whilediuretics can cause AKI and either hypo-kalemia or hyperkalemia (depending onmechanism of action) (69,70). Detectionand management of these abnormalities

is importantbecauseAKIandhyperkalemiaeach increase the risks of cardiovascularevents and death (71). Therefore, serumcreatinine and potassium should be mon-itored during treatment with an ACE

Figure 10.1—Recommendationsfor thetreatmentofconfirmedhypertension inpeoplewithdiabetes.*AnACEinhibitor (ACEi)orangiotensinreceptorblocker (ARB)is suggested to treat hypertension for patients with coronary artery disease (CAD) or urine albumin-to-creatinine ratio 30–299 mg/g creatinine and stronglyrecommended for patientswith urine albumin-to-creatinine ratio$300mg/g creatinine. **Thiazide-like diuretic; long-acting agents shown to reduce cardiovascularevents, suchaschlorthalidoneandindapamide,arepreferred.***Dihydropyridinecalciumchannelblocker(CCB).BP,bloodpressure.AdaptedfromdeBoeretal. (17).


inhibitor, ARB, or diuretic, particularlyamong patients with reduced glomerularfiltration who are at increased risk ofhyperkalemia and AKI (69,70,72).

Resistant Hypertension

Recommendation

10.14 Patients with hypertension whoare not meeting blood pressuretargets on three classes of an-tihypertensive medications (in-cluding a diuretic) should beconsidered for mineralocorti-coid receptor antagonist ther-apy. B

Resistant hypertension is defined asblood pressure $140/90 mmHg despitea therapeutic strategy that includes ap-propriate lifestyle management plus adiuretic 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 effects)should be identified and addressed (Fig.10.1). Mineralocorticoid receptor antag-onists are effective for management ofresistant hypertension in patients withtype 2 diabetes when added to existingtreatment with an ACE inhibitor or ARB,thiazide-like diuretic, and dihydropyri-dine calcium channel blocker (73). Min-eralocorticoid receptor antagonists alsoreduce albuminuria and have additionalcardiovascular benefits (74–77). How-ever, adding a mineralocorticoid recep-tor antagonist to a regimen including anACE inhibitororARBmay increase the riskfor hyperkalemia, emphasizing the im-portanceof regularmonitoring for serumcreatinine and potassium in these pa-tients, and long-term outcome studiesare needed to better evaluate the role ofmineralocorticoid receptor antagonistsin blood pressure management.

LIPID MANAGEMENT

Lifestyle Intervention

Recommendations

10.15 Lifestyle modification focusingon weight loss (if indicated);applicationofaMediterraneanstyle or Dietary Approaches to

Stop Hypertension (DASH) eat-ing pattern; reduction of satu-rated fat and trans fat; increaseof dietary n-3 fatty acids, vis-cous fiber, and plant stanols/sterols intake; and increasedphysical activity should be rec-ommendedto improve the lipidprofile and reduce the risk ofdeveloping atherosclerotic car-diovascular disease in patientswith 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 (78), increased physical activity, andmedical nutrition therapy, allows somepatients to reduce ASCVD risk factors.Nutrition intervention should be tailoredaccording to each patient’s age, diabetestype, pharmacologic treatment, lipid lev-els, and medical conditions.

Recommendations should focus onapplication of a Mediterranean stylediet (79) or Dietary Approaches toStop Hypertension (DASH) eating pat-tern, reducing saturated and trans fatintake and increasing plant stanols/sterols, n-3 fatty acids, and viscous fiber(such as in oats, legumes, and citrus)intake (80). Glycemic control may alsobeneficially modify plasma lipid levels,particularly in patients with very hightriglycerides and poor glycemic control.See Section 5 “Facilitating BehaviorChange and Well-being to ImproveHealth Outcomes” (https://doi.org/10.2337/dc21-S005) for additional nutri-tion information.

OngoingTherapyandMonitoringWithLipid Panel

Recommendations

10.17 In adults not taking statins orother lipid-lowering therapy,it is reasonable to obtain alipid profile at the time ofdiabetes diagnosis, at an ini-tial medical evaluation, andevery 5 years thereafter if un-der the age of 40 years, ormore frequently if indicated. E

10.18 Obtain a lipid profile at initi-ation of statins or other lipid-lowering therapy, 4–12 weeksafter initiation or a change indose, and annually thereafteras it may help to monitor theresponse to therapy and in-formmedication adherence. E

In adultswith diabetes, it is reasonable toobtain a lipid profile (total cholesterol,LDL cholesterol, HDL cholesterol, andtriglycerides) at the time of diagnosis,at the initial medical evaluation, and atleast every 5 years thereafter 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 beforeinitiating statin therapy. Once a patientis taking a statin, LDL cholesterol levelsshould be assessed 4–12 weeks afterinitiation of statin therapy, after anychange in dose, and on an individualbasis (e.g., to monitor for medica-tion adherence and efficacy). If LDLcholesterol levels are not respondingin spite of medication adherence, clin-ical judgment is recommended to de-termine the need for and timing of lipidpanels. In individual patients, the highlyvariable LDL cholesterol–lowering re-sponse seen with statins is poorly un-derstood (81). Clinicians should attemptto find a dose or alternative statin thatis tolerable if side effects occur. Thereis evidence for benefit from even ex-tremely low, less than daily statin doses(82).

STATIN TREATMENT

Primary Prevention

Recommendations

10.19 For patients with diabetesaged 40–75 years without ath-erosclerotic cardiovasculardis-ease, use moderate-intensitystatin therapy in addition tolifestyle therapy. A

10.20 For patients with diabetesaged 20–39 years with addi-tional atherosclerotic cardio-vascular disease risk factors,itmay be reasonable to initiatestatin therapy in addition tolifestyle therapy. C


https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S005https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S005http://care.diabetesjournals.org

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

10.22 In adults with diabetes and10-year atherosclerotic car-diovascular disease risk of20% or higher, it may bereasonable to add ezetimibeto maximally tolerated statintherapy to reduce LDL cho-lesterol levels by 50% ormore. C

Secondary Prevention

Recommendations

10.23 For patients of all ages withdiabetes and atheroscleroticcardiovascular disease, high-intensity statin therapy shouldbeadded to lifestyle therapy.A

10.24 For patients with diabetesand atherosclerotic cardio-vascular disease consideredvery high risk using specificcriteria, if LDL cholesterol is$70 mg/dL on maximally tol-erated statin dose, consideradding additional LDL-loweringtherapy (such as ezetimibe orPCSK9 inhibitor). A Ezetimibemay be preferred due to lowercost.

10.25 For patients who do not tol-erate the intended intensity,the maximally tolerated statindose should be used. E

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

10.27 In adults with diabetes aged.75 years, it may be reason-able to initiate statin therapyafter discussion of potentialbenefits and risks. C

10.28 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 dem-onstrated the beneficial effects of statintherapy on ASCVD outcomes in subjects

with and without CHD (83,84). Subgroupanalyses of patients with diabetes inlarger trials (85–89) and trials in patientswith diabetes (90,91) showed significantprimary and secondary prevention ofASCVD events and CHD death in patientswith diabetes. Meta-analyses, includingdata from over 18,000 patients withdiabetes from 14 randomized trials ofstatin therapy (mean follow-up 4.3years), demonstrate a 9% proportionalreduction in all-cause mortality and 13%reduction in vascular mortality for each1 mmol/L (39 mg/dL) reduction in LDLcholesterol (92).

Accordingly, statins are the drugs ofchoice for LDL cholesterol lowering andcardioprotection. Table 10.2 shows thetwo statin dosing intensities that arerecommended for use in clinical practice:high-intensity statin therapy will achieveapproximately a $50% reduction in LDLcholesterol, and moderate-intensity sta-tin regimens achieve 30–49% reductionsin LDL cholesterol. Low-dose statin ther-apy is generally not recommended inpatients with diabetes but is sometimesthe only dose of statin that a patient cantolerate. Forpatientswhodonot toleratethe intended intensity of statin, themaximally tolerated statin dose shouldbe used.

As in those without diabetes, absolutereductions in ASCVD outcomes (CHDdeath and nonfatal MI) are greatest inpeople with high baseline ASCVD risk(known ASCVD and/or very high LDLcholesterol levels), but the overall bene-fits of statin therapy in people with di-abetes at moderate or even low risk forASCVD are convincing (93,94). The rela-tive benefit of lipid-lowering therapy hasbeen uniform across most subgroupstested (84,92), including subgroupsthat varied with respect to age and otherrisk factors.

Primary Prevention (Patients Without

ASCVD)

For primary prevention, moderate-dosestatin therapy is recommended for those40 years and older (86,93,94), 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 thosewith ASCVD. As such,recent guidelines recommend that inpatients with diabetes who are at higherrisk, especially those with multipleASCVD risk factors or aged 50–70 years,it is reasonable to prescribe high-intensitystatin therapy (12,95). Furthermore,for patients with diabetes whose ASCVDrisk is $20%, i.e., an ASCVD risk equiv-alent, the samehigh-intensity statin ther-apy is recommended as for those withdocumented ASCVD (12). In those indi-viduals, it may also be reasonable to addezetimibe to maximally tolerated statintherapy if needed to reduce LDL choles-terol levels by 50% or more (12). Theevidence is lower for patients aged.75years; relatively few older patients withdiabetes have been enrolled in primaryprevention trials. However, heterogene-ity by age has not been seen in therelative benefit of lipid-lowering therapyin trials that included older participants(84,91,92), and because older age con-fers higher risk, the absolute benefitsare actually greater (84,96). Moderate-intensity statin therapy is recommendedinpatientswithdiabeteswhoare75yearsor older. However, the risk-benefit pro-file should be routinely evaluated in thispopulation, with downward titration of

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

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

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

Atorvastatin 40–80 mg Atorvastatin 10–20 mg

Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg

Simvastatin 20–40 mg

Pravastatin 40–80 mg

Lovastatin 40 mg

Fluvastatin XL 80 mg

Pitavastatin 1–4 mg

*Once-daily dosing. XL, extended release.


dose performed as needed. See Section12 “Older Adults” (https://doi.org/10.2337/dc21-S012) for more details onclinical considerations for this population.

Age

patients with diabetes, comprising11,031 patients (40% of the trial) (104).In the ODYSSEY OUTCOMES trial (Eval-

uation of Cardiovascular Outcomes Afteran Acute Coronary Syndrome DuringTreatment With Alirocumab), 18,924 pa-tients (28.8%ofwhomhaddiabetes)withrecent acute coronary syndrome wererandomized to the PCSK9 inhibitor alir-ocumab or placebo every 2 weeks in ad-dition tomaximally tolerated statin therapy,with alirocumab dosing titrated between75 and 150 mg to achieve LDL cholesterollevels between 25 and 50 mg/dL (105).Over amedian follow-upof 2.8 years, a

composite primary end point (compris-ing death from coronary heart disease,nonfatal MI, fatal or nonfatal ischemicstroke, or unstable angina requiring hos-pital admission) occurred in 903 patients(9.5%) in the alirocumab group and in1,052 patients (11.1%) in the placebogroup (HR 0.85 [95% CI 0.78–0.93]; P ,0.001). Combination therapy with aliro-cumab plus statin therapy resulted in agreater absolute reduction in the inci-dence of theprimary endpoint in patientswithdiabetes (2.3% [95%CI0.4–4.2]) thanin thosewith prediabetes (1.2% [0.0–2.4])or normoglycemia (1.2% [–0.3 to 2.7])(106).

Treatment of Other LipoproteinFractions or Targets

Recommendations

10.29 Forpatientswith fasting triglyc-eride levels$500 mg/dL, eval-uate for secondary causes ofhypertriglyceridemia and con-sidermedical therapy to reducethe risk of pancreatitis. C

10.30 In adults with moderate hyper-triglyceridemia (fasting or non-fasting triglycerides 175–499mg/dL),cliniciansshouldaddressand treat lifestyle factors (obe-sity and metabolic syndrome),secondary factors (diabetes,chronic liver or kidney diseaseand/ornephrotic syndrome,hy-pothyroidism), andmedicationsthat raise triglycerides. C

10.31 In patients with atheroscle-rotic cardiovascular disease orother cardiovascular risk factorson a statin with controlledLDL cholesterol but elevatedtriglycerides (135–499 mg/dL),the addition of icosapent ethyl

can be considered to reducecardiovascular risk. A

Hypertriglyceridemia should be addressedwith dietary and lifestyle changes includ-ing weight loss and abstinence fromalcohol (107). Severe hypertriglyceride-mia (fasting triglycerides $500 mg/dLand especially .1,000 mg/dL) may war-rant pharmacologic therapy (fibric acidderivatives and/or fish oil) and reductionin dietary fat to reduce the risk of acutepancreatitis. Moderate- or high-intensitystatin therapy should also be used as in-dicated to reduce risk of cardiovascularevents (see STATIN TREATMENT). In patientswith moderate hypertriglyceridemia, life-style interventions, treatment of secondaryfactors, and avoidance of medications thatmight raise triglycerides are recommended.

TheReductionofCardiovascular Eventswith Icosapent Ethyl–Intervention Trial(REDUCE-IT) enrolled 8,179 adults receiv-ing statin therapy with moderately el-evated triglycerides (135–499 mg/dL,median baseline of 216 mg/dL) who hadeither established cardiovascular disease(secondarypreventioncohort)ordiabetesplus at least one other cardiovascular riskfactor (primary prevention cohort). Pa-tientswere randomized to icosapentethyl4 g/day (2 g twice daily with food) versusplacebo. The trial met its primary endpoint, demonstrating a 25% relative riskreduction (P, 0.001) for the primary endpoint composite of cardiovascular death,nonfatal myocardial infarction, nonfatalstroke, coronary revascularization, or un-stable angina. This reduction in risk wasseeninpatientswithorwithoutdiabetesatbaseline. The composite of cardiovasculardeath, nonfatal myocardial infarction, ornonfatal stroke was reduced by 26%(P , 0.001). Additional ischemic endpoints were significantly lower in theicosapent ethyl group than in the placebogroup, including cardiovascular death,which was reduced by 20% (P 50.03). The proportions of patients expe-riencing adverse events and serious ad-verse events were similar between theactive and placebo treatment groups. Itshould benoted that data are lackingwithother n-3 fatty acids, and results of theREDUCE-IT trial should not be extrapo-lated to other products (108).

Low levels of HDL cholesterol, oftenassociated with elevated triglyceride lev-els, are the most prevalent pattern of

dyslipidemia in individuals with type 2 di-abetes. However, the evidence for the useof drugs that target these lipid fractions issubstantially less robust than that for statintherapy (109). In a large trial in patientswithdiabetes, fenofibrate failed to reduceoverall cardiovascular outcomes (110).

Other Combination Therapy

Recommendations

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

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

Statin and Fibrate Combination Therapy

Combination therapy (statin and fibrate)is associated with an increased risk forabnormal transaminase levels, myositis,and rhabdomyolysis. The risk of rhabdo-myolysis is more common with higherdoses of statins and renal insufficiencyandappears tobehigherwhenstatinsarecombined with gemfibrozil (comparedwith fenofibrate) (111).

In the ACCORD study, in patients withtype 2 diabetes who were at high risk forASCVD, the combination of fenofibrateandsimvastatindidnot reduce the rateoffatal cardiovascular events, nonfatal MI,or nonfatal stroke as compared withsimvastatin alone. Prespecified subgroupanalyses suggested heterogeneity intreatment effects with possible benefitfor men with both a triglyceride level$204 mg/dL (2.3 mmol/L) and an HDLcholesterol level #34 mg/dL (0.9 mmol/L)(112). A prospective trial of a newer fibratein this specific population of patients isongoing (113).

Statin and Niacin Combination Therapy

The Atherothrombosis Intervention inMetabolic Syndrome With Low HDL/High Triglycerides: Impact on GlobalHealth Outcomes (AIM-HIGH) trial ran-domized over 3,000 patients (aboutone-third with diabetes) with estab-lished ASCVD, low LDL cholesterol levels


(,180 mg/dL [4.7 mmol/L]), low HDLcholesterol levels (men ,40 mg/dL[1.0 mmol/L] and women ,50 mg/dL[1.3 mmol/L]), and triglyceride levels of150–400 mg/dL (1.7–4.5 mmol/L) tostatin therapy plus extended-release ni-acin or placebo. The trial was halted earlydue to lack of efficacy on the primaryASCVD outcome (first event of the com-posite of death from CHD, nonfatal MI,ischemic stroke, hospitalization for anACS, or symptom-driven coronary orcerebral revascularization) andapossibleincrease in ischemic stroke in those oncombination therapy (114).The much larger Heart Protection

Study 2–Treatment of HDL to Reducethe Incidence of Vascular Events (HPS2-THRIVE) trial also failed to show a benefitof adding niacin to background statintherapy (115). A total of 25,673 patientswithprior vascular diseasewere random-ized to receive 2 g of extended-releaseniacin and 40 mg of laropiprant (anantagonist of the prostaglandin D2 re-ceptor DP1 that has been shown toimprove adherence to niacin therapy)versus a matching placebo daily andfollowed for a median follow-up periodof 3.9 years. There was no significantdifference in the rate of coronary death,MI, stroke, or coronary revascularizationwith the addition of niacin–laropiprantversus placebo (13.2% vs. 13.7%; rateratio 0.96; P5 0.29). Niacin–laropiprantwas associated with an increased inci-dence of new-onset diabetes (absoluteexcess, 1.3 percentage points; P, 0.001)and disturbances in diabetes controlamong those with diabetes. In addition,there was an increase in serious adverseevents associated with the gastrointes-tinal system, musculoskeletal system,skin, and, unexpectedly, infection andbleeding.Therefore, combination therapywith a

statin and niacin is not recommendedgiven the lack of efficacy onmajor ASCVDoutcomes and increased side effects.

Diabetes Risk With Statin UseSeveral studies have reported amodestlyincreased risk of incident diabetes withstatin use (116,117), which may be lim-ited to those with diabetes risk factors.An analysis of one of the initial studiessuggested that although statin use wasassociated with diabetes risk, the cardio-vascular event rate reductionwith statinsfar outweighed the risk of incident

diabetes even for patients at highestrisk for diabetes (118). The absoluterisk increase was small (over 5 yearsof follow-up, 1.2% of participants onplacebo developed diabetes and 1.5%on rosuvastatin developed diabetes)(118). A meta-analysis of 13 randomizedstatin trials with 91,140 participantsshowed an odds ratio of 1.09 for anew diagnosis of diabetes, so that (onaverage) treatment of 255 patients withstatins for 4 years resulted in one addi-tional case of diabetes while simulta-neously preventing 5.4 vascular eventsamong those 255 patients (117).

Lipid-Lowering Agents and CognitiveFunctionAlthough concerns regarding a potentialadverse impact of lipid-lowering agentson cognitive function have been raised,several lines of evidence point againstthis association, as detailed in a 2018 Eu-ropean Atherosclerosis Society Consen-sus Panel statement (119). First, thereare three large randomized trials of statinversus placebo where specific cognitivetests were performed, and no differ-ences were seen between statin andplacebo (120–123). In addition, nochange in cognitive function has beenreported in studies with the additionof ezetimibe (96) or PCSK9 inhibitors(99,124) to statin therapy, includingamong patients treated to very lowLDL cholesterol levels. In addition, themost recent systematic review of theU.S. Food and Drug Administration’s(FDA’s) postmarketing surveillance da-tabases, randomized controlled trials,and cohort, case-control, and cross-sectional studies evaluating cognition inpatients receiving statins found thatpublished data do not reveal an adverseeffect of statins on cognition (125).Therefore, a concern that statins orother lipid-lowering agents might causecognitive dysfunction or dementia is notcurrently supported by evidence andshould not deter their use in individualswith diabetes at high risk for ASCVD(125).

ANTIPLATELET AGENTS

Recommendations

10.34 Use aspirin therapy (75–162mg/day) as a secondary pre-vention strategy in thosewith diabetes and a history of

atherosclerotic cardiovasculardisease. A

10.35 For patients with atheroscle-rotic cardiovascular disease anddocumented aspirin allergy,clopidogrel (75mg/day) shouldbe used. B

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

10.37 Long-term treatment with dualantiplatelet therapy should beconsidered for patients withprior coronary intervention,high ischemic risk, and lowbleeding risk to prevent majoradverse cardiovascular events.A

10.38 Combination therapy with as-pirin plus low-dose rivaroxa-ban should be considered forpatients with stable coronaryand/or peripheral arterydiseaseand low bleeding risk to pre-vent major adverse limb andcardiovascular events. A

10.39 Aspirin therapy (75–162 mg/day) may be considered as aprimary prevention strategy inthose with diabetes who are atincreased cardiovascular risk,after a comprehensive discus-sion with the patient on thebenefits versus the comparableincreased risk of bleeding. A

Risk ReductionAspirin has been shown to be effective inreducing cardiovascular morbidity andmortality in high-risk patients with pre-viousMI or stroke (secondary prevention)and is strongly recommended. In primaryprevention,however,amongpatientswithno previous cardiovascular events, its netbenefit is more controversial (126,127).

Previous randomized controlled trialsof aspirin specifically in patients withdiabetes failed to consistently show asignificant reduction in overall ASCVDend points, raising questions about theefficacy of aspirin for primary preventioninpeoplewithdiabetes, althoughsomesexdifferences were suggested (128–130).

The Antithrombotic Trialists’ Collabo-ration published an individual patient–level meta-analysis (126) of the six largetrials of aspirin for primary prevention in



the general population. These trials col-lectively enrolled over 95,000 participants,including almost 4,000 with diabetes.Overall, they found that aspirin reducedthe risk of serious vascular events by 12%(relative risk 0.88 [95% CI 0.82–0.94]).The largest reduction was for nonfatalMI, with little effect on CHD death (rel-ative risk 0.95 [95%CI0.78–1.15]) or totalstroke.Most recently, the ASCEND (A Study of

Cardiovascular Events iN Diabetes) trialrandomized 15,480 patients with diabe-tes but no evident cardiovascular diseaseto aspirin 100 mg daily or placebo (131).The primary efficacy end point was vas-cular death, MI, or stroke or transientischemic attack. The primary safetyoutcome was major bleeding (i.e., in-tracranial hemorrhage, sight-threateningbleeding in the eye, gastrointestinalbleeding, or other serious bleeding).During a mean follow-up of 7.4 years,there was a significant 12% reduction inthe primary efficacy end point (8.5% vs.9.6%; P 5 0.01). In contrast, majorbleeding was significantly increasedfrom 3.2% to 4.1% in the aspirin group(rate ratio 1.29; P 5 0.003), with mostof the excess being gastrointestinalbleeding and other extracranial bleed-ing. There were no significant differ-ences by sex, weight, or duration ofdiabetes or other baseline factors in-cluding ASCVD risk score.Two other large randomized trials of

aspirin for primary prevention, in pa-tients without diabetes (ARRIVE [Aspirinto Reduce Risk of Initial Vascular Events])(132) and in the elderly (ASPREE [Aspirinin Reducing Events in the Elderly]) (133),which included 11%with diabetes, foundno benefit of aspirin on the primaryefficacy end point and an increased riskof bleeding. In ARRIVE, with 12,546 pa-tients over a period of 60 months follow-up, the primary end point occurred in4.29% vs. 4.48% of patients in the aspirinversus placebo groups (HR 0.96 [95% CI0.81–1.13]; P 5 0.60). Gastrointestinalbleeding events (characterized as mild)occurred in0.97%ofpatients in theaspiringroup vs. 0.46% in the placebo group (HR2.11 [95% CI 1.36–3.28]; P 5 0.0007). InASPREE, including 19,114 individuals, forcardiovascular disease (fatal CHD, MI,stroke, or hospitalization for heart failure)after a median of 4.7 years of follow-up,the rates per 1,000 person-years were10.7 vs. 11.3 events in aspirin vs. placebo

groups (HR 0.95 [95% CI 0.83–1.08]). Therate of major hemorrhage per 1,000 per-son-years was 8.6 events vs. 6.2 events,respectively (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 risk ofgastrointestinal bleeding. The excess riskmay be as high as 5 per 1,000 per year inreal-world settings. However, for adultswith ASCVD risk .1% per year, thenumber of ASCVD events preventedwill be similar to the number of episodesofbleeding induced, although thesecom-plications do not have equal effects onlong-term health (134).

Recommendations for using aspirin asprimary prevention include both menand women aged $50 years with di-abetes and at least one additional majorrisk factor (family history of prematureASCVD, hypertension, dyslipidemia,smoking, or chronic kidney disease/albuminuria) who are not at increasedrisk of bleeding (e.g., older age, anemia,renal disease) (135–138). Noninvasiveimaging techniques such as coronarycalcium scoring may potentially helpfurther tailor aspirin therapy, particularlyin those at low risk (139,140). For pa-tients over the age of 70 years (with orwithout diabetes), the balance appearsto have greater risk than benefit(131,133). Thus, for primary prevention,the use of aspirin needs to be carefullyconsidered and may generally not berecommended. Aspirin may be consid-ered in the context of high cardiovascularrisk with low bleeding risk, but generallynot in older adults. Aspirin therapy forprimary preventionmaybe considered inthe context of shared decision-making,which carefully weighs the cardiovascu-lar benefits with the fairly comparableincrease in risk of bleeding. For patientswith documented ASCVD, use of aspirinfor secondary prevention has far greaterbenefit than risk; for this indication,aspirin is still recommended (126).

Aspirin Use in People

this period. Evidence supports use ofeither ticagrelor or clopidogrel if nopercutaneous coronary interventionwas performed and clopidogrel, ticagre-lor, or prasugrel if a percutaneous cor-onary intervention was performed (148).In patients with diabetes and prior MI(1–3 years before), adding ticagrelor toaspirin significantly reduces the risk ofrecurrent ischemic events including car-diovascular and CHD death (149). Simi-larly, the addition of ticagrelor to aspirinreduced the risk of ischemic cardiovas-cular events compared with aspirinalone in patients with diabetes and stablecoronary artery disease (150,151). How-ever, a higher incidence of major bleed-ing, including intracranial hemorrhage,wasnotedwithdual antiplatelet therapy.The net clinical benefit (ischemic benefitvs. bleeding risk) was improved withticagrelor therapy in the large prespe-cified subgroup of patients with historyof percutaneous coronary intervention,while no net benefit was seen in patientswithout prior percutaneous coronary in-tervention (151).

Combination Antiplatelet andAnticoagulation TherapyCombination therapy with aspirin pluslow dose rivaroxabanmay be consideredfor patients with stable coronary and/orperipheral artery disease to preventmajor adverse limb and cardiovascularcomplications. In the COMPASS (Cardio-vascularOutcomes for PeopleUsingAnti-coagulation Strategies) trial of 27,395patientswith established coronary arterydisease and/or peripheral artery disease,aspirin plus rivaroxaban 2.5 mg twicedaily was superior to aspirin plus placeboin the reduction of cardiovascular ische-mic events including major adverse limbevents. The absolute benefits of combi-nation therapy appeared larger in pa-tientswith diabetes,whocomprised10,341of the trial participants (152,153). A similartreatment strategy was evaluated in theVascular Outcomes Study of ASA (acetyl-salicylic acid) Along with Rivaroxaban inEndovascular or Surgical Limb Revascu-larization for Peripheral Artery Disease(VOYAGER PAD) trial (154), in which6,564 patients with peripheral artery dis-ease who had undergone revasculariza-tion were randomly assigned to receiverivaroxaban2.5mg twicedailyplus aspirinorplaceboplusaspirin. Rivaroxaban treat-ment in this group of patients was also

associated with a significantly lower in-cidenceof ischemiccardiovascularevents,including major adverse limb events.However,an increasedriskofmajorbleed-ing was noted with rivaroxaban added toaspirin treatment in both COMPASS andVOYAGER PAD.

The risks and benefits of dual antipla-telet or antiplatelet plus anticoagulanttreatment strategies should be thor-oughly discussed with eligible patients,and shared decision-making should beused to determine an individually appro-priate treatment approach.

CARDIOVASCULAR DISEASE

Screening

Recommendations

10.40 In asymptomatic patients, rou-tine screening for coronaryartery disease is not recom-mended as it does not improveoutcomes as long as athero-sclerotic cardiovascular dis-ease risk factors are treated. A

10.41 Consider investigations for cor-onaryarterydisease inthepres-ence of any of the following:atypical cardiac symptoms(e.g., unexplained dyspnea,chest discomfort); signs orsymptoms of associated vas-cular disease including carotidbruits, transient ischemic at-tack, stroke, claudication, orperipheral arterial disease; orelectrocardiogram abnormalities(e.g., Q waves). E

Treatment

Recommendations

10.42 Among patients with type 2diabetes who have estab-lished atherosclerotic cardio-vascular disease or establishedkidney disease, a sodium–glucose cotransporter 2 inhibitoror glucagon-like peptide 1 re-ceptor agonist with demon-strated cardiovascular diseasebenefit (Table 10.3B and Table10.3C) is recommended as partof the comprehensive cardio-vascular risk reduction and/orglucose-lowering regimens. A

10.42a In patients with type 2 diabetesand established atheroscleroticcardiovasculardisease,multiple

atherosclerotic cardiovasculardisease risk factors, or diabetickidney disease, a sodium–glucose cotransporter 2 inhibitorwith demonstrated cardiovas-cular benefit is recommendedto reduce the risk of majoradverse cardiovascular eventsand/or heart failure hospital-ization. A

10.42b Inpatientswithtype2diabetesandestablishedatheroscleroticcardiovascular disease or mul-tiple risk factors for atheroscle-rotic cardiovascular disease, aglucagon-like peptide 1 recep-tor agonist with demonstratedcardiovascular benefit is rec-ommended to reduce the riskofmajor adverse cardiovascu-lar events. A

10.43 In patients with type 2 di-abetes and established heartfailure with reduced ejectionfraction, a sodium–glucosecotransporter 2 inhibitor withproven benefit in this patientpopulation is recommendedto reduce risk of worseningheart failure and cardiovascu-lar death. A

10.44 In patients with known ath-erosclerotic cardiovasculardisease, particularly coronaryartery disease, ACE inhibitoror angiotensin receptor blockertherapy is recommended toreduce the risk of cardiovascu-lar events. A

10.45 In patients with prior myo-cardial infarction, b-blockersshould be continued for 3 yearsafter the event. B

10.46 Treatment of patients withheart failure with reducedejection fraction shouldinclude a b-blocker withproven cardiovascular out-comes benefit, unless oth-erwise contraindicated. A

10.47 Inpatientswith type2diabeteswith stable heart failure, met-formin may be continued forglucose lowering if esti-mated glomerular filtrationrate remains .30 mL/min/1.73m2but shouldbeavoidedin unstable or hospitalizedpatients with heart failure. B



CARDIAC TESTINGCandidates for advanced or invasive car-diac testing include those with 1) typicalor atypical cardiac symptoms and 2)an abnormal resting electrocardiogram(ECG). Exercise ECG testing without or

with echocardiography may be used asthe 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 or

nuclear imaging should be consideredin individuals with diabetes in whomresting ECG abnormalities preclude ex-ercise stress testing (e.g., left bundlebranch block or ST-T abnormalities). Inaddition, individuals who require stress

Table 10.3A—Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed after theissuance of the FDA 2008 guidelines: DPP-4 inhibitors

SAVOR-TIMI 53 (194)(n 5 16,492)

EXAMINE (200)(n 5 5,380)

TECOS (196)(n 5 14,671)

CARMELINA(197,201)

(n 5 6,979)

CAROLINA(173,202)

(n 5 6,042)

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

Main inclusion criteria Type 2 diabetes andhistory of ormultiple riskfactors for CVD

Type 2 diabetes and ACSwithin 15–90 daysbefore randomization

Type 2 diabetes andpreexisting CVD

Type2diabetes andhigh CV andrenal risk

Type 2 diabetes andhigh CV risk

A1C inclusion criteria(%) $6.5 6.5–11.0 6.5–8.0 6.5–10.0 6.5–8.5

Age (years) †† 65.1 61.0 65.4 65.8 64.0

Race (% White) 75.2 72.7 67.9 80.2 73.0

Sex (% male) 66.9 67.9 70.7 62.9 60.0

Diabetes duration(years)†† 10.3 7.1 11.6 14.7 6.2

Median follow-up(years) 2.1 1.5 3.0 2.2 6.3

Statin use (%) 78 91 80 71.8 64.1

Metformin use (%) 70 66 82 54.8 82.5

Prior CVD/CHF (%) 78/13 100/28 74/18 57/26.8 34.5/4.5

Mean baseline A1C(%) 8.0 8.0 7.2 7.9 7.2

Mean difference inA1C betweengroups at end oftreatment (%) 20.3̂ 20.3̂ 20.3̂ 20.36̂ 0

Year started/reported 2010/2013 2009/2013 2008/2015 2013/2018 2010/2019

Primary outcome§ 3-point MACE 1.00(0.89–1.12)

3-point MACE 0.96(95% UL #1.16)

4-point MACE 0.98(0.89–1.08)

3-point MACE 1.02(0.89–1.17)

3-point MACE 0.98(0.84–1.14)

Key secondaryoutcome§

Expanded MACE1.02 (0.94–1.11)

4-point MACE 0.95(95% UL #1.14)

3-point MACE 0.99(0.89–1.10)

Kidney composite(ESRD, sustained$40% decreasein eGFR, or renaldeath) 1.04(0.89–1.22)

4-point MACE 0.99(0.86–1.14)

Cardiovasculardeath§ 1.03 (0.87–1.22) 0.85 (0.66–1.10) 1.03 (0.89–1.19) 0.96 (0.81–1.14) 1.00 (0.81–1.24)

MI§ 0.95 (0.80–1.12) 1.08 (0.88–1.33) 0.95 (0.81–1.11) 1.12 (0.90–1.40) 1.03 (0.82–1.29)

Stroke§ 1.11 (0.88–1.39) 0.91 (0.55–1.50) 0.97 (0.79–1.19) 0.91 (0.67–1.23) 0.86 (0.66–1.12)

HF hospitalization§ 1.27 (1.07–1.51) 1.19 (0.90–1.58) 1.00 (0.83–1.20) 0.90 (0.74–1.08) 1.21 (0.92–1.59)

Unstable anginahospitalization§ 1.19 (0.89–1.60) 0.90 (0.60–1.37) 0.90 (0.70–1.16) 0.87 (0.57–1.31) 1.07 (0.74–1.54)

All-cause mortality§ 1.11 (0.96–1.27) 0.88 (0.71–1.09) 1.01 (0.90–1.14) 0.98 (0.84–1.13) 0.91 (0.78–1.06)

Worseningnephropathy§||

1.08 (0.88–1.32) d d Kidney composite(see above)

__

d, not assessed/reported; ACS, acute coronary syndrome; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; DPP-4,dipeptidyl peptidase 4; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GLP-1, glucagon-like peptide 1; HF, heart failure;MACE, major adverse cardiac event; MI, myocardial infarction; UL, upper limit. Data from this table was adapted from Cefalu et al. (203) in the January2018 issue of Diabetes Care. ††Age was reported as means in all trials except EXAMINE, which reported medians; diabetes duration was reported asmeans in all trials except SAVOR-TIMI 53 and EXAMINE, which reported medians. §Outcomes reported as hazard ratio (95% CI). ||Worseningnephropathy is defined as as doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine.6.0mg/dL (530mmol/L) in SAVOR-TIMI 53.Worseningnephropathywas a prespecified exploratory adjudicated outcome in SAVOR-TIMI 53.̂ Significant difference in A1Cbetween groups(P , 0.05).


Table

10.3B—Cardiova

scularandca

rdiorenal

outcomestrialsofava

ilable

antihyp

erg

lyce

mic

med

icationsco

mpletedaftertheissu

ance

oftheFD

A2008guidelines

:GLP-1

rece

ptor

agonists

ELIXA(183

)LEADER

(178

)SU

STAIN-6

(179)*

EXSCEL

(184

)Harmony

Outcom

es(181)

REW

IND(182)

PIONEER-6

(180

)(n

56,06

8)(n

59,340)

(n5

3,29

7)(n

514

,752

)(n

59,46

3)(n

59,90

1)(n

53,18

3)

Interven

tion

Lixisenatide/placebo

Liraglutide/placebo

Semaglutides.c.

injection/placebo

Exen

atideQW/

placebo

Albiglutide/placebo

Dulaglutide/

placebo

Semaglutideoral/

placebo

Maininclusioncriteria

Type2diabetes

and

history

ofACS

(,18

0days)

Type2diabetes

and

preexistingCVD,

CKD

,orHFat

$50

yearsofageorCV

risk

at$60

yearsof

age

Type2diabetes

andpreexisting

CVD,HF,

orCKD

at$50

yearsof

ageorCVrisk

at$60

yearsofage

Type2diabetes

withorwithou

tpreexistingCVD

Type2diabetes

with

preexistingCVD

Type2diabetes

andpriorA

SCVD

even

torrisk

factors

for

ASCVD

Type2diabetes

andhighCVrisk

(age

of$50

yearswith

established

CVD

orC

KD,orage

of

$60

yearswith

CVrisk

factors

only)

A1C

inclusion

criteria

(%)

5.5–11

.0$7.0

$7.0

6.5–10

.0$7.0

#9.5

None

Age

(years)††

60.3

64.3

64.6

6264

.166

.266

Race(%

White)

75.2

77.5

83.0

75.8

84.8

75.7

72.3

Sex(%

male)

69.3

64.3

60.7

6269

.453

.768

.4

Diabetes

duration

(years)††

9.3

12.8

13.9

1213

.810

.514

.9

Med

ianfollow-up

(years)

2.1

3.8

2.1

3.2

1.6

5.4

1.3

Statin

use

(%)

9372

7374

84.0

6685

.2(alllipid-

lowering)

Metform

inuse

(%)

6676

7377

73.6

8177.4

PriorCVD/CHF(%

)10

0/22

81/18

60/24

73.1/16.2

100/20

.232

/984

.7/12.2

MeanbaselineA1C

(%)

7.7

8.7

8.7

8.0

8.7

7.4

8.2

Meandifference

inA1C

betweengroupsat

endoftreatm

ent(%

)20.3̂

20.4̂

20.7or21.0̂†

20.53̂

20.52̂

20.61̂

20.7

Year

started/rep

orted

2010/2015

2010/2016

2013/2016

2010/2017

2015/2018

2011/2019

2017/2019

Prim

aryoutcome§

4-pointMACE1.02

(0.89–1.17)

3-pointMACE0.87

(0.78–0.97)

3-pointMACE0.74

(0.58–0.95)

3-pointMACE0.91

(0.83–1.00

)3-pointMACE0.78

(0.68–0.90)

3-pointMACE0.88

(0.79–0.99)

3-pointMACE0.79

(0.57–1.11)

Con

tinu

edon

p.S140



Table

10.3B—Continued

ELIXA(183

)LEADER

(178

)SU

STAIN-6

(179)*

EXSCEL

(184

)Harmony

Outcom

es(181)

REW

IND(182)

PIONEER-6

(180

)(n

56,06

8)(n

59,340)

(n5

3,29

7)(n

514

,752

)(n

59,46

3)(n

59,90

1)(n

53,18

3)

Keysecondary

outcome§

Expanded

MACE

(0.90–1.11)

Expanded

MACE0.88

(0.81–0.96)

Expanded

MACE

0.74

(0.62–0.89)

Individual

componen

tsof

MACE(see

below)

Expanded

MACE(w

ith

urgen

trevascularizationfor

unstable

angina)

0.78

(0.69–0.90)

CVdeath

orHF

hospitalization0.85

(0.70–1.04)

Individual

componen

tsof

MACE(see

below)

Composite

microvascular

outcome(eye

or

renal

outcome)

0.87

(0.79–0.95)

Expanded

MACEor

HF

hospitalization

0.82

(0.61–1.10

)

Cardiovascular

death§

0.98

(0.78–1.22)

0.78

(0.66–0.93

)0.98

(0.65–1.48)

0.88

(0.76–1.02)

0.93

(0.73–1.19)

0.91

(0.78–1.06

)0.49

(0.27–0.92)

MI§

1.03

(0.87–1.22)

0.86

(0.73–1.00

)0.74

(0.51–1.08)

0.97

(0.85–1.10)

0.75

(0.61–0.90)

0.96

(0.79–1.15

)1.18

(0.73–1.90)

Stroke§

1.12

(0.79–1.58)

0.86

(0.71–1.06

)0.61

(0.38–0.99)

0.85

(0.70–1.03)

0.86

(0.66–1.14)

0.76

(0.61–0.95

)0.74

(0.35–1.57)

HFhospitalization§

0.96

(0.75–1.23)

0.87

(0.73–1.05

)1.11

(0.77–1.61)

0.94

(0.78–1.13)

d0.93

(0.77–1.12

)0.86

(0.48–1.55)

Unstable

angina

hospitalization§

1.11

(0.47–2.62)

0.98

(0.76–1.26

)0.82

(0.47–1.44)

1.05

(0.94–1.18)

d1.14

(0.84–1.54

)1.56

(0.60–4.01)

All-cause

mortality§

0.94

(0.78–1.13)

0.85

(0.74–0.97

)1.05

(0.74–1.50)

0.86

(0.77–0.97)

0.95

(0.79–1.16)

0.90

(0.80–1.01

)0.51

(0.31–0.84)

Worsen

ing

nep

hropathy§||

d0.78

(0.67–0.92

)0.64

(0.46–0.88)

dd

0.85

(0.77–0.93

)d

d,notassessed/rep

orted

;ACS,acutecoronarysyndrome;ASCVD,atheroscleroticcardiovasculard

isease;CHF,congestiveheartfailure;CKD

,chronickidney

disease;CV,cardiovascular;CVD,cardiovasculard

isease;

GLP-1,glucagon-likepep

tide1;HF,heartfailure;M

ACE,majoradversecardiaceven

t;MI,myocardialinfarction.D

atafrom

thistablewas

adaptedfrom

Cefaluet

al.(203)intheJanuary2018

issueofD

iabetesCare.

*Powered

toruleoutahazardratioof1.8;superiority

hypothesisnotprespecified

.††Age

was

reported

asmeansinalltrials;diabetes

durationwas

reported

asmeansinalltrialsexceptEXSCEL,w

hichreported

med

ians.†A1C

change

of0.66

%with0.5mgand1.05%with1mgdose

ofsemaglutide.§O

utcomes

reported

ashazardratio(95%

CI).||W

orsen

ingnep

hropathyisdefi

ned

asthenew

onsetofurinealbumin-to-

creatinineratio.300mg/gcreatinineora

doublingoftheserumcreatininelevelandan

estimated

glomerularfiltrationrateof,

45mL/min/1.73m

2,the

needforcontinuousrenalreplacemen

ttherapy,ordeathfrom

renaldisease

inLEADER

andSU

STAIN-6

andas

new

macroalbuminuria,asustained

declineinestimated

glomerularfiltrationrate

of30

%ormore

from

baseline,orchronicrenalreplacemen

ttherapyinREW

IND.

Worsen

ingnep

hropathywas

aprespecified

exploratory

adjudicated

outcomein

LEADER

,SU

STAIN-6,andREW

IND.Ŝignificantdifference

inA1C

betweengroups(P

,0.05).


Table 10.3C—Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed afterthe issuance of the FDA 2008 guidelines: SGLT2 inhibitors

EMPA-REG OUTCOME (8)(n 5 7,020)

CANVAS Program (9)(n 5 10,142)

DECLARE-TIMI 58 (176)(n 5 17,160)

CREDENCE (174)(n 5 4,401)

DAPA-HF (177)(n 5 4,744; 1,983with diabetes)

Intervention Empagliflozin/placebo Canagliflozin/placebo Dapagliflozin/placebo Canagliflozin/placebo

Dapagliflozin/placebo

Main inclusioncriteria

Type 2 diabetes andpreexisting CVD

Type 2 diabetes andpreexisting CVD at $30years of age or .2 CV riskfactors at$50 years of age

Type 2 diabetes andestablished ASCVD ormultiple risk factors forASCVD

Type 2 diabetes andalbuminurickidney disease

NYHA class II, III, or IVheart failure andan ejectionfraction #40%,with or without

diabetes

A1C inclusioncriteria (%) 7.0–10.0 7.0–10.5 $6.5 6.5–12 __

Age (years)†† 63.1 63.3 64.0 63 66

Race (% White) 72.4 78.3 79.6 66.6 70.3

Sex (% male) 71.5 64.2 62.6 66.1 76.6

Diabetes duration(years)†† 57% .10 13.5 11.0 15.8 N/A

Median follow-up(years) 3.1 3.6 4.2 2.6 1.5

Statin use (%) 77 75 75 (statin or ezetimibe use) 69 __

Metformin

use (%)

74 77 82 57.8 51.2% (of patients

with diabetes)

PriorCVD/CHF (%) 99/10 65.6/14.4 40/10 50.4/14.8 100% with CHF

Mean baseline A1C

(%) 8.1 8.2 8.3 8.3 __

Mean difference inA1C betweengroups at end oftreatment (%) 20.3̂ ‡ 20.58̂ 20.43̂ 20.31 N/A

Year started/reported 2010/2015 2009/2017 2013/2018 2017/2019 2017/2019

Primary outcome§ 3-point MACE0.86 (0.74–0.99)

3-point MACE0.86 (0.75–0.97)§

3-point MACE 0.93(0.84–1.03)

ESRD, doubling ofcreatinine, ordeath from renal

or CV cause 0.70(0.59–0.82)

Worsening heartfailure or deathfrom CV causes

0.74 (0.65–0.85)Results did not differ

by diabetes status

CV death or HF hospitalization

0.83 (0.73–0.95)

Key secondaryoutcome§

4-point MACE0.89 (0.78–1.01)

All-cause and CV mortality(see below)

Death from any cause 0.93(0.82–1.04)

CV death or HFhospitalization0.69 (0.57–0.83)

3-point MACE 0.80(0.67–0.95)

CV death or HFhospitalization0.75 (0.65–0.85)Renal composite ($40%

decrease in eGFR rateto ,60 mL/min/1.73 m2,new ESRD, or death fromrenal or CV causes 0.76(0.67–0.87)

Cardiovasculardeath§ 0.62 (0.49–0.77) 0.87 (0.72–1.06) 0.98 (0.82–1.17) 0.78 (0.61–1.00) 0.82 (0.69–0.98)

MI§ 0.87 (0.70–1.09) 0.89 (0.73–1.09) 0.89 (0.77–1.01) __ __

Stroke§ 1.18 (0.89–1.56) 0.87 (0.69–1.09) 1.01 (0.84–1.21) __ __

HF hospitalization§ 0.65 (0.50–0.85) 0.67 (0.52–0.87) 0.73 (0.61–0.88) 0.61 (0.47–0.80) 0.70 (0.59–0.83)

Unstable anginahospitalization§ 0.99 (0.74–1.34) d d __ __

All-cause

mortality§ 0.68 (0.57–0.82) 0.87 (0.74–1.01) 0.93 (0.82–1.04) 0.83 (0.68–1.02) 0.83 (0.71–0.97)

Worseningnephropathy§||

0.61 (0.53–0.70) 0.60 (0.47–0.77) 0.53 (0.43–0.66) (See primaryoutcome)

0.71 (0.44–1.16)

d, not assessed/reported; CHF, congestive heart failure; CV, cardiovascular; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate;ESRD,end-stage renal disease;HF, heart failure;MACE,major adverse cardiacevent;MI,myocardial infarction; SGLT2, sodium–glucose cotransporter 2;NYHA, New York Heart Association. Data from this table was adapted from Cefalu et al. (203) in the January 2018 issue of Diabetes Care. ††Age wasreported as means in all trials; diabetes duration was reported as means in all trials except EMPA-REG OUTCOME, which reported as percentage ofpopulationwith diabetes duration.10 years, andDECLARE-TIMI 58, which reportedmedian. ‡A1C change of 0.30 in EMPA-REGOUTCOME is based onpooled results for both doses (i.e., 0.24% for 10mg and 0.36% for 25mgof empagliflozin). §Outcomes reported as hazard ratio (95%CI). ||Definitions ofworsening nephropathy differed between trials. Ŝignificant difference in A1C between groups (P , 0.05).



testing and are unable to exercise shouldundergo pharmacologic stress echocar-diography or nuclear imaging.

SCREENING ASYMPTOMATICPATIENTS

The screening of asymptomatic patientswith high ASCVD risk is not recommen-ded (155), in part because these high-riskpatients should already be receiving in-tensive medical therapydan approachthat provides similar benefit as invasiverevascularization (156,157). There is alsosome evidence that silent ischemia mayreverse over time, adding to the contro-versy concerning aggressive screeningstrategies (158). 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 (159–161). However, arandomized observational trial demon-strated no clinical benefit to routinescreening of asymptomatic patientswith type 2 diabetes and normal ECGs(162). Despite abnormal myocardialperfusion imaging in more than onein five patients, cardiac outcomeswereessentially equal (and very low) inscreened versus unscreened patients.Accordingly, indiscriminate screening isnot considered cost-effective. Studieshave found that a risk factor–basedapproach to the initial diagnostic eval-uation and subsequent follow-up forcoronary artery disease fails to identifywhich patients with type 2 diabetes willhave silent ischemia on screening tests(163,164).Any benefit of newer noninvasive cor-

onary artery disease screening methods,such as computed tomography calciumscoring and computed tomography an-giography, to identify patient subgroupsfor different treatment strategies re-mains unproven in asymptomatic pa-tients with diabetes, though researchis ongoing. Although asymptomatic pa-tientswith diabeteswith higher coronarydisease burden havemore future cardiacevents (159,165,166), the role of thesetests beyond risk stratification is notclear.While coronary artery screening

methods, such as calcium scoring, may

improve cardiovascular risk assessmentinpeoplewith type2diabetes (167), theirroutine use leads to radiation exposureand may result in unnecessary invasivetesting suchas coronary angiography andrevascularization procedures. The ulti-mate balance of benefit, cost, and risksof such an approach in asymptomaticpatients remains controversial, particu-larly in the modern setting of aggressiveASCVD risk factor control.

LIFESTYLE AND PHARMACOLOGICINTERVENTIONS

Intensive lifestyle intervention focusingon weight loss through decreased caloricintake and increased physical activity asperformed in the Action for Health inDiabetes (Look AHEAD) trial may beconsidered for improving glucose con-trol, fitness, and some ASCVD risk factors(168). Patients at increased ASCVD riskshould receive statin, ACE inhibitor, orARB therapy if the patient has hyperten-sion, and possibly aspirin, unless thereare contraindications to a particular drugclass. Clear benefit exists for ACE inhib-itor or ARB therapy in patients withdiabetic kidney disease or hypertension,and these agents are recommended forhypertension management in patientswithknownASCVD (particularly coronaryartery disease) (59,60,169). b-Blockersshould be used in patients with activeangina or HFrEF and for 3 years afterMI in patients with preserved left ventric-ular function (170,171).

GLUCOSE-LOWERING THERAPIESAND CARDIOVASCULAROUTCOMES

In 2008, the FDA issued a guidance forindustry to perform cardiovascular out-comes trials for all new medications forthe treatment for type 2 diabetes amidconcerns of increased cardiovascularrisk (172). Previously approved diabetesmedications were not subject to theguidance. Recently published cardiovas-cular outcomes trials have provided ad-ditional data on cardiovascular and renaloutcomes in patients with type 2 diabe-tes with cardiovascular disease or at highrisk for cardiovascular disease (see Table10.3A, Table 10.3B, and Table 10.3C). Anexpanded review of the effects of glu-cose-lowering therapy in patients withchronic kidney disease is included inSection 11 “Microvascular Complications

and Foot Care” (https://doi.org/10.2337/dc21-S011).

Cardiovascular outcomes trials of di-peptidyl peptidase 4 (DPP-4) inhibitorshave all, so far, not shown cardiovascularbenefits relative to placebo. In addition,the CAROLINA (Cardiovascular OutcomeStudy of Linagliptin Versus Glimepiridein Type 2 Diabetes) study demonstratednoninferioritybetweenaDPP-4 inhibitor,linagliptin, and a sulfonylurea, glimepir-ide, on cardiovascular outcomes despitelower rates of hypoglycemia in the lina-gliptin treatment group (173). However,results from other new agents haveprovided a mix of results.

SGLT2 Inhibitor TrialsThe BI 10773 (Empagliflozin) Cardiovas-cular Outcome Event Trial in Type 2 Di-abetes Mellitus Patients (EMPA-REGOUTCOME) was a randomized, double-blind trial that assessed the effect ofempagliflozin, an SGLT2 inhibitor, versusplacebo on cardiovascular outcomes in7,020 patients with type 2 diabetes andexisting cardiovascular disease. Studyparticipants had a mean age of 63 years,57%haddiabetes formore than10 years,and 99% had established cardiovasculardisease. EMPA-REG OUTCOME showedthatover amedian follow-upof 3.1 years,treatment reduced the composite out-come of MI, stroke, and cardiovasculardeath by 14% (absolute rate 10.5% vs.12.1% in the placebo group, HR in theempagliflozin group 0.86 [95% CI 0.74–0.99]; P 5 0.04 for superiority) andcardiovascular death by 38% (absoluterate 3.7% vs. 5.9%, HR 0.62 [95% CI 0.49–0.77]; P , 0.001) (8). The FDA added anindication for empagliflozin to reduce therisk of major adverse cardiovascular deathin adults with type 2 diabetes and car-diovascular disease.

Two large outcomes trials of the SGLT2inhibitor canagliflozin that separatelyassessed 1) the cardiovascular effectsof treatment in patients at high riskfor major adverse cardiovascular events,and2) the impact of canagliflozin therapyon cardiorenal outcomes in patients withdiabetes-related chronic kidney diseasehave been conducted (174). First, theCanagliflozin Cardiovascular AssessmentStudy (CANVAS) Program integrateddatafrom two trials. The CANVAS trial thatstarted in 2009 was partially unblindedprior to completion because of the needto file interim cardiovascular outcomes


https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S011https://care.diabetesjournals.org/lookup/doi/10.2337/dc21-S011

data for regulatory approval of the drug(175). Thereafter, the postapproval CANVAS-Renal (CANVAS-R) trial was started in2014. Combining both of these trials,10,142 participants with type 2 diabeteswere randomized to canagliflozin or pla-cebo and were followed for an average3.6 years. The mean age of patients was63 years, and 66% had a history ofcardiovascular disease. The combinedanalysis of the two trials found thatcanagliflozin significantly reduced thecomposite

10. cardiovascular disease and risk management: standards ......measures of 10-year coronary heart...

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