Composite Primary End Points inCardiovascular Outcomes TrialsInvolving Type 2 Diabetes Patients:Should Unstable Angina BeIncluded in the Primary EndPoint?Diabetes Care 2017;40:1144–1151 | https://doi.org/10.2337/dc17-0068

Reductions in cardiovascular (CV) outcomes in recently reported trials, along with therecent approval by theU.S. Food andDrug Administration of an additional indication forempagliflozin to reduce the risk of CVdeath in type 2 diabetes patientswith evidenceof CV disease, have renewed interest in CV outcome trials (CVOTs) of glucose-lowering drugs. Composite end points are a pragmatic necessity in CVOTs to ensurethat sample size and duration of follow-up remain reasonable. Combining clinicaloutcomes into a composite end point increases the numbers of events ascertainedand thus statistical power and precision. Historically, composite CV end points indiabetes trials have includeda larger numberof components,whilemore recent CVOTsalmost exclusively use a composite of CV death, nonfatal myocardial infarction (MI),and nonfatal strokedthe so-called three-point major adverse CV event (3P-MACE)compositedor add hospitalization for unstable angina (HUA) to these three out-comes (4P-MACE). The inclusion of HUA increases the number of events for analysis,but noteworthy disadvantages include clinical subjectivity in ascertainment of HUAand its lower prognostic relevance compared with CV death, MI, or stroke. Further-more, results from recent CVOTs indicate that glucose-lowering agents seem to haveminimal impact on HUA. Its inclusion therefore potentially favors a shift of the hazardratio (HR) toward the null, which is especially problematic in trials designed to dem-onstrate noninferiority. The primary outcome of 3P-MACEmay offer a better balancethan 4P-MACE between statistical efficiency, operational complexity, the likelihoodof diagnostic precision (and therefore clinical relevance) for each of the componentoutcomes, clinical importance, and the aim to adequately capture any potentialtreatment effect of the intervention. Nevertheless, as individual medications maymechanistically differ in their impact on CV outcomes, no particular individual orcomposite end point can be seen as a “gold standard” for CVOTs of all glucose-lowering drugs.

Cardiovascular (CV) disease is a common comorbidity in type 2 diabetes, andCV-related death remains a leading cause of premature mortality in people withtype 2 diabetes (1). Over the past 15 years, more than 25 CV outcome trials (CVOTs)involving over 200,000 patients with type 2 diabetes have been initiated (2). Thesestudies were designed either to test an intensive versus traditional antihyperglycemictreatment strategy by attempting to achieve ameaningful HbA1c reduction to evaluate

1Department of Internal Medicine I, UniversityHospital Aachen, RWTH Aachen University,Aachen, Germany2Division of Cardiology, Department of InternalMedicine, University of Texas SouthwesternMedical Center, Dallas, TX3The George Institute for Global Health, Univer-sity of Sydney, Sydney, Australia4Boehringer Ingelheim Pharma GmbH & Co. KG,Ingelheim, Germany5Dallas Diabetes Research Center at MedicalCity, Dallas, TX

Corresponding author: Nikolaus Marx, nmarx@ukaachen.de.

Received 20 February 2017 and accepted 26May 2017.

© 2017 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Nikolaus Marx,1 Darren K. McGuire,2

Vlado Perkovic,3 Hans-Juergen Woerle,4

Uli C. Broedl,4 Maximilian von Eynatten,4

Jyothis T. George,4 and Julio Rosenstock5

1144 Diabetes Care Volume 40, September 2017

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SPECTIVES

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its impact on CV events or to investigatespecific glucose-lowering compounds. Inthe latter, the glucose-lowering agent isusually compared with placebo in additionto current standard of care with the pri-mary intention of demonstrating CV safety(i.e., statistical noninferiority), as requiredby international regulatory agencies tosupport approval of diabetes medications.Todate, CVOTs testing intensive antihyper-glycemic strategies have not convincinglydemonstrated improved CV outcomes inpatients with type 2 diabetes. In contrast,the recent BI 10773 (Empagliflozin) Car-diovascular Outcome Event Trial in Type 2Diabetes Mellitus Patients (EMPA-REGOUTCOME)da placebo-controlled trial ofempagliflozin, a sodium–glucose cotrans-porter 2 (SGLT2) inhibitordwas the firstCVOT evaluating a glucose-loweringmed-ication to demonstrate a significant re-duction in CV events (3). Based on thistrial, the U.S. Food and Drug Administra-tion (FDA) recently approved a new indi-cation for empagliflozin to reduce the riskof CV death in adults with type 2 diabe-tes and CV disease (4,5). The Committeefor Medicinal Products for Human Useof the European Medicines Agency hasalso recommended revising the empagliflo-zin label to reflect its beneficial effects onboth glycemic control and CV events (6).In addition, CVOTs of two glucagon-like

peptide 1 receptor agonists (GLP-1 RAs)have now reported beneficial CV out-comes. The Liraglutide Effect and Actionin Diabetes: Evaluation of CardiovascularOutcome Results (LEADER) trial with thedaily GLP-1 RA liraglutide reported signif-icant reductions in CV events versusplacebo (7). The Trial to Evaluate Cardio-vascular and Other Long-term Outcomeswith Semaglutide in Subjects with Type 2Diabetes (SUSTAIN-6), with the investiga-tional weekly GLP-1 RA semaglutide, alsoreported a reduction in major adverse CVevents (MACE), although this trial was notdesigned to test a superiority hypothesis(8). These three CVOTs used the samecomposite MACE outcome for the pri-mary end point: the time to the first eventof CV death, nonfatal myocardial infarc-tion (MI), or nonfatal stroke, i.e., 3P-MACE. However, other recently concludedCVOTs of a GLP-1 RA and a dipeptidyl pep-tidase 4 (DPP-4) inhibitordEvaluation ofLixisenatide in Acute Coronary Syndrome(ELIXA) and Trial to Evaluate CardiovascularOutcomes after Treatment with Sitagliptin(TECOS), respectivelydused a 4P-MACE

composite primary end point that in-cluded hospitalization for unstable angina(HUA).

Herein, we discuss the necessity ofcomposite end points in CVOTs for type 2diabetes, illustrate their historical evolu-tion, describe the two most commonlyused composite end points for assess-ment of atherosclerotic CV disease out-comes (3P-MACE and 4P-MACE), andhighlight their key strengths and weak-nesses. We also discuss the emerging in-terest in hospitalization for heart failure(HHF) and the issueswith its inclusion as aprimary or secondary end point.

RATIONALE FOR THE USE OFCOMPOSITE END POINTS

Ideally, clinical trials should have a singu-lar (noncomposite) primary end pointthat fully captures the potential effect ofinvestigational therapies, albeit theremay be scenarios in which a compositeend point is more clinically relevantthan a single component of the compos-ite if the intervention can have a similarbeneficial effect on equally importantoutcomes. However, the use of singularend points would require substantiallylarger trial sample sizes and/or longerfollow-up to provide reliable statisticalpower (9,10). Given that extending life isthe ultimate goal of most treatments andthatmortality can be determinedwithoutoutcome ascertainment bias, overall (all-cause) mortality is conceptually an idealprimary end point. Concordant reductionin all-cause mortality (or no increase)would provide reassurance that reduc-tions in CV mortality are not offset bynon-CV deaths. However, mortality ratesin the general population are declin-ing (11), even in high-risk populationssuch as individuals with type 2 diabetes(11–17), possibly as a consequence ofmodern multifactorial approaches tomodify CV risk factors. Consequently, toachieve statistical power for comparisons,trials that focus purely on mortality wouldneedprohibitively largenumbersofpatientsand lengthy follow-up, a concern when oneof the objectives ofmodern CVOTs is to ruleout potential adverse effects of novel med-ications in a timely manner.

Composite end points are therefore apragmatic necessity: combining clinicaloutcomes that seem to share commonpathophysiological mechanisms into acomposite end point increases thenumbers of events ascertained and

thus statistical power and precision. In-deed, MACE outcomes allow a CVOT tobe conducted in a more reasonable timeframe while still analyzing important clin-ical outcomes. Furthermore, compositeend points are now a regulatory standardin the realm of CV diseasedas reflectedin the 2008 guidance from the FDA forevaluating the CV risk of novel glucose-lowering therapies (18). Nevertheless,composite end points are not idealfrom a methodological perspective, asheterogeneity of effects on the compo-nent outcomes may be observed, poten-tially diluting the estimate of effect on acomposite. Indeed, adding componentsto a composite end point that are to alesser degree (or not at all) affected bythe intervention, orwhichmaybedifficultto adjudicate, increases the likelihood ofshifting the HR toward the null (19); thisproblem is exacerbatedwhen the primaryanalysis is planned for noninferiority, rais-ing the probability of type II error. This isparticularly true for less well defined andclinically heterogeneous events such asHUA or end points impacted by clinicalor interventional decision-making suchas coronary or peripheral revasculariza-tion (20). In these cases, when the resultsfor the composite end point are notdriven comparably by each of its compo-nents, the addition of more end pointsto a single component such as mortalitymoves the HR of the composite closer tounity (Fig. 1).

COMPOSITE END POINTSIN CVOTS IN PATIENTS WITHTYPE 2 DIABETES

Historically, CVOTs in type 2 diabeteshave included a variable number of cli-nical outcomes within their compositeprimary end points. For example, thecomposite in the UK Prospective DiabetesStudy (UKPDS) (“any diabetes-relatedoutcome”) comprised over 10 differentend points, including vascular and non-vascular intermediate biomarkers ad-mixed with clinical outcomes (21).Similarly, the primary end point in thePROspective pioglitAzone Clinical Trial InmacroVascular Events (PROactive) com-prised seven different outcomes: overallmortality, MI, stroke, acute coronary syn-drome, coronary or peripheral revascu-larization, and amputation above theankle. This heterogeneity clearly shiftedthe results of the composite towardnull, as the between-group difference

care.diabetesjournals.org Marx and Associates 1145

versus placebo failed to achieve nominalstatistical significance even though the“prioritized secondary” outcome of 3P-MACE was significantly superior for pio-glitazone versus placebo (22).

More recent CVOTs in type 2 diabetesalmost exclusively use a much morefocused composite outcome as the pri-mary end point, particularly after the2008 FDA guidance. Although most of

these trials use 3P-MACE, some havealso added HUA to form 4P-MACE.Figure 2 illustrates the change over timein primary end points of CVOTs in type 2diabetes.

Figure 1—Selected end points in the EMPA-REG OUTCOME study of empagliflozin (ref. 3 and Boehringer Ingelheim, data on file), the LEADER study ofliraglutide (7), and the SUSTAIN-6 study of semaglutide (8), each compared with placebo.

1146 Composite End Point Components in CVOTs Diabetes Care Volume 40, September 2017

HUA AS AN END POINT

The inclusion of HUA is a matter of signif-icant and ongoing debate. There arecogent arguments for its inclusion in com-posite primary end points when assessingatherosclerotic vascular disease out-comes. The addition of unstable anginato 3P-MACE may enhance the statisti-cal efficiency of a study by incrementingaccrual of events contributing to the pri-maryendpoint. Furthermore, fromaclinicalperspective, unstable angina and MI bothbelong to the spectrum of pathophysiolog-ical processes collectively describedas acutecoronarysyndromes.TheFDA’s2008guide-line recommends that hospitalization foracute coronary syndrome, urgent revas-cularization, and possibly other endpoints could be added to the 3P-MACEprimary end point (18). However, impor-tant challenges that comewith addingun-stable angina to a composite end pointhave to be considered.First, in contrast to death, nonfatal MI,

or nonfatal stroke, the diagnosis of unsta-ble angina involves significant subjectivity

on the part of the treating clinician, theinvestigator, and adjudication commit-tees (23). To address these challenges,incrementally more specific adjudicationcriteria have been applied to CVOTs inrecent years. These are reflected in a con-sensus document on the adjudication ofHUA for CVOT end points, which requiressymptoms at rest consistent with anginalasting at least 10 min that necessitate anunscheduled visit to a health care facilityand at least an overnight observation, aswell as evidence of ischemia by electrocar-diography or imaging but with no cardiacenzyme elevations (23). Given the hetero-geneous clinical presentation of chestpain syndromes, and despite the wide-spread clinical adoption of highly sensi-tive assays for biomarkers of myocardialinjury such as high-sensitivity troponin(hsTn) assays, central adjudication of un-stable angina remains extremely challeng-ing. Even at the bedside, the distinctionbetween unstable angina and myriad othercauses of chest pain is a clear clinical conun-drum, challenging the specificity of the

diagnosis clinically and the outcome in re-search projectsdwhether as coded by theclinician or investigator or as adjudicatedin a clinical trial. Consequently, concor-dance between the assessment of localclinicians and study investigators andthat of central trial adjudication commit-tees is often quite low (24–26), and bothprocesses have important degrees of im-precision and inaccuracy.

Second, with the ever-broadening clin-ical adoption of hsTn assays for the diag-nostic assessment of MI, chest pain oranginal-equivalent presentations withnormal hsTn assessments remain catego-rized as possible unstable angina, butwith a wide variety of alternative diagno-ses that are most often not CV related.

Third, unstable angina is ofmuch lowerprognostic relevance than nonfatal strokeor nonfatal MI and, of course, CV deathin the composite. For example, unstable an-gina isdistinguished fromnon–ST-elevationMI by substantially lower risk of mortality(27) and commensurately less absolutebenefit from intensive antiplatelet ther-apy and early invasive treatment (27).

Fourth, all CVOTs in type2 diabetes con-ductedafter theFDA’s2008guidancehavedemonstrated that HUA is a challeng-ing outcome to influence with glucose-lowering agents, thus weighting resultsof composite analyses toward the nulland confounding analyses of noninferior-ity. In these studies, the HRs for HUArange from 0.82 to 1.19 (Table 1). There-fore, inclusion of HUAwithin the compos-ite primary end point is likely to dilute thetreatment effect. Consequently, whilethe addition of HUA may make it morelikely that noninferiority of a medicationis demonstrated, it may also mask poten-tial CV benefit or harm by shifting the HRtoward the null. In summary, while HUAcould be a valuable end point in the as-sessment of some therapies, such as anti-platelet agents, this doesnot seemtobe thecase with glucose-lowering medications.

HEART FAILURE AS AN END POINT

Heart failure is a common complicationof type 2 diabetes, and its prognosticimplicationsdincludinghighmortalitydareoften underappreciated (28,29). A casecould therefore be made for includingheart failure outcomes within the pri-mary composite end point in diabetesCVOTs, as recently suggested (28,29).However, different glucose-loweringmed-ications may have markedly different

Figure 2—Evolution of prospectively planned primary end points in completed CVOTs of antihy-perglycemic treatments for type 2 diabetes, listed in order of year of initiation (3,7,8,21,22,37–47).ACCORD, Action to Control Cardiovascular Risk in Diabetes; ADVANCE, Action in Diabetes andVascular Disease: Preterax and DiamicronModified Release Controlled Evaluation; BARI-2D, BypassAngioplasty Revascularization Investigation in Type 2 Diabetes; EXAMINE, Examination of Cardio-vascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes andAcute Coronary Syndrome; FREEDOM-CVO, Study to Evaluate Cardiovascular Outcomes with ITCA650 in Patients Treatedwith Standard of Care for Type 2 Diabetes; HEART-2D, Hyperglycemia and ItsEffect after Acute Myocardial Infarction on Cardiovascular Outcomes in Patients with Type 2 Di-abetes Mellitus; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; SAVOR-TIMI 53,Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with DiabetesMellitusdThrom-bolysis inMyocardial Infarction 53; VADT, Veterans Affairs Diabetes Trial. *Includes events requiringhospitalization. †Includes fatal and nonfatal events.

care.diabetesjournals.org Marx and Associates 1147

impacts on heart failure; combining suchoutcomes with other end points that havesubstantially disparate pathophysiology ishard to defend, and the results may bedifficult to interpret. Nevertheless, HHFshould always be prospectively captured,adjudicated, and analyzed in CVOTs asa secondary outcome at least. Alterna-tively, HHF can be designated as a primaryoutcome combined with CV mortality instudies of agents whose mechanism ofaction may impact heart failure, such asin the planned studies of the SGLT2 in-hibitors dapagliflozin (30) and empagli-flozin (31).

SHOULD THE FOCUS PURELY BEON THE PRIMARY END POINT?

A single component of a composite endpoint often disproportionately affects thetreatment outcome compared with theother components. However, even if allcomponents contribute relatively equallyfor a clinically significant composite butnot enough for each individually to beclinically significant, it is usually not validto conclude efficacy for a single compo-nent based on the findings for the com-posite (32). Furthermore, Pocock andStone (33) recently made the followingpertinent observation: “There is a naturaltendency to simplify the findings of a clin-ical trial into a binary conclusion: ‘Wasthere a positive outcomedor not?’ In or-der to address this question with someobjectivity, attention is typically focusedon whether the prespecified measure ofsuccess for the primary outcome hasbeen metdthat is, whether a P value ofless than 0.05 has been achieved forthe difference in treatments. In reality, amore nuanced interpretation requires a

thorough examination of the totality ofthe evidence, including secondary endpoints, safety issues, and the size andquality of the trial.” One recent exampleis the EMPA-REG OUTCOME trial (3),where the primary end point (3P-MACE)was drivenby a substantially reduced rateof CV death (n 5 309 events; HR 0.62;95% CI 0.49, 0.77; P , 0.001) and wasstrengthened by similar findings for all-cause mortality (n 5 463 events; HR0.68; 95% CI 0.57, 0.82; P , 0.001) andHHF (n 5 221 events; HR 0.65; 95% CI0.50, 0.85; P5 0.002) (3). However, therewas no significant effect onnonfatalMI ornonfatal stroke. This example also illus-trates the importance of separating outHHF from 3P-MACE as a stand-aloneend point, because of both the heteroge-neity of efficacy that a therapy may haveon HHF compared with MACE outcomesand the disparate underlying pathobiol-ogy of heart failure compared with ath-erosclerotic vascular disease.

3P-MACE: A SUITABLE COMMONSTANDARD FOR CVOTS INDIABETES?

In light of the above considerations, 3P-MACE appears to be the most suitableend point for evaluating CV outcomes inlarge CVOTs with glucose-lowering medi-cations. The 3P-MACE composite endpoint best captures clinically relevant CVoutcomes, has individual componentsthat are reasonably straightforward to ad-judicate (thus ensuring precision of the di-agnosis), is relatively easy to implement,and is well accepted by regulatory author-ities. For these reasons, the large majorityof ongoing CVOTs in type 2 diabetesrequired by regulatory authorities use

3P-MACE as their primary end point(Table 2). Indeed, a recent FDA recom-mendation is to prefer the use of 3P-MACE to more reliably exclude a CV riskupper margin of 1.3 (34). In the absenceof regulatory or academic consensus onend points, this alignment of primaryend points across CVOTs should makebetween-study comparisonsdincludingmeta-analysesdmore robust and en-hance the clinical relevance of thesemegatrials, which demand substantialtime, effort, and resources from clinicalinvestigators, patients, and study spon-sors. Nevertheless, even 3P-MACE itselfsuffers from potential problems with het-erogeneity of effects on the componentoutcomes, as the mechanism of actionof a glucose-loweringmedicationmay dif-ferentially impact the three componentsof this end point. This phenomenonoccurred in the EMPA-REG OUTCOMEstudy, as discussed above, in which em-pagliflozin significantly reduced the inci-dence of CV death (HR 0.62; 95% CI 0.49,0.77) but not that of nonfatalMI (HR 0.87;95% CI 0.70, 1.09) or nonfatal stroke (HR1.24; 95% CI 0.92, 1.67), which thusdiluted the estimate of the overall treat-ment effect as measured by the 3P-MACEprimary end point (HR 0.86; 95% CI 0.74,0.99) (3). Similarly, the incidence of CVdeath (HR 0.78; 95% CI 0.66, 0.93) wassignificantly reduced with liraglutide inthe LEADER study, but not that of non-fatal MI (HR 0.88; 95% CI 0.75, 1.03) ornonfatal stroke (HR 0.89; 95% CI 0.72,1.11) (7). In the selection of compositeend points, therefore, sufficient consider-ation needs to be given to the question ofwhether individual components are likelyto be differentially impacted.

Table 1—Hazard ratio for HUA in recently completed CVOTs in type 2 diabetes, listed in approximate order of completion fromearliest to most recent

CVOT (reference) Glucose-lowering drug Class Hazard ratio 95% CI

SAVOR-TIMI 53 (44) Saxagliptin DPP-4 inhibitor 1.19 0.89, 1.60

EXAMINE (48) Alogliptin DPP-4 inhibitor 0.90* 0.60, 1.37

ELIXA (45) Lixisenatide GLP-1 RA 1.11 0.47, 2.62

TECOS (46) Sitagliptin DPP-4 inhibitor 0.90 0.70, 1.16

EMPA-REG OUTCOME (3) Empagliflozin SGLT2 inhibitor 0.99 0.74, 1.34

LEADER (7) Liraglutide GLP-1 RA 0.98 0.76, 1.26

SUSTAIN-6 (8) Semaglutide GLP-1 RA 0.82 0.47, 1.44

FREEDOM-CVO (47) ITCA 650 (exenatide minipump) GLP-1 RA Not yet available Not yet available

EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care in Patients with Type 2 Diabetes and Acute CoronarySyndrome; FREEDOM-CVO, Study to Evaluate Cardiovascular Outcomes with ITCA 650 in Patients Treated with Standard of Care for Type 2 Diabetes;SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes MellitusdThrombolysis in Myocardial Infarction 53.*Urgent revascularization due to unstable angina.

1148 Composite End Point Components in CVOTs Diabetes Care Volume 40, September 2017

In conclusion, as individual drugs maymechanistically differ in their impact onCV outcomes, no particular end point canbe seen as a “gold standard” for all CVOTsof glucose-lowering drugs. However,3P-MACE is generally likely (albeit notguaranteed) to offer the best balance be-tween statistical efficiency andoperationalcomplexity, to ensure diagnostic precision(and therefore clinical relevance) for eachof its components, and to adequately cap-ture any potential treatment effect of theintervention. In this regard, 3P-MACE ap-pears to be superior to its variants thatinclude HUA (4P-MACE), HHF, revasculari-zation, or other CV outcomes.Consequently, the steering commit-

tees of two ongoing CVOTs of the DPP-4 inhibitor linagliptindCardiovascularOutcome Study of Linagliptin versusGlimepiride in Patients with Type 2 Dia-betes (CAROLINA) and Cardiovascu-lar and Renal Microvascular OutcomeStudy with Linagliptin in Patients withType 2 Diabetes Mellitus (CARMELINA)(clinical trial reg. nos. NCT01243424and NCT01897532, respectively,clinicaltrials.gov)dwhich include the au-thors, have unanimously decided toadopt 3P-MACE as the primary end pointof these studies, replacing the originallyplanned primary end point of 4P-MACElong before these studies are finalized.The 4P-MACE end point will remain a pre-defined end point of both trials followinganalyses of 3P-MACE.

There is clear precedent for such ac-tions from other large CVOTs, where con-cerns emergedduring the studies that theinclusion of components less affected bythe treatment may dilute the treatmenteffect or may mask the true treatment ef-fect. A notable example is the Study ofHeart and Renal Protection (SHARP), inwhich the primary composite CV end pointwas similarly revised from a broader oneto amore focused one during trial conduct(35). An absolute prerequisite for such amodification in study analysis during trialconduct is that the decision is made with-out access to unblinded data. Indeed, therespective steering committees and spon-sor of CAROLINA and CARMELINA had ab-solutely no access to any interim resultsfrom these two ongoing CVOTs and, at thetime of protocol modifications of the pri-mary composite end points, the studiesremained fully blinded to the steeringcommittees, sponsor, trial teams, investi-gators, and participants. The adoption of3P-MACE as the primary end point willalign these two trials with other ongoingand completed CVOTs in type 2 diabetes(Table 2).

Finally, the position taken here is di-rectly supported in a recent opinionpaperon the assessment of CV safety profilesof novel pharmacotherapies, in whichthe Cardiovascular Working Party of theEuropeanMedicines Agency’s Committeefor Medicinal Products for Human Useexpressed a preference for 3P-MACE as

the primary safety end point in meta-analyses and dedicated CVOTs (36).

Funding. Editorial assistance, supported finan-cially by Boehringer Ingelheim, was provided byGiles Brooke of Envision Scientific Solutionsduring the preparation of this manuscript.Duality of Interest. N.M. has served as a consul-tant to AstraZeneca, Amgen, Bristol-MyersSquibb, Boehringer Ingelheim, Merck, NovoNordisk, Roche, and Sanofi; has receivedgrant support from Merck and BoehringerIngelheim; and has served as a speaker forAstraZeneca, Amgen, Bayer, Bristol-MyersSquibb, Boehringer Ingelheim, Lilly, Merck,Mitsubishi Tanabe Pharma Corporation, Novartis,Novo Nordisk, Pfizer, Roche, and Sanofi .D.K.M. has received support for clinical trialleadership from Eisai, Esperion, Novo Nordisk,AstraZeneca, Boehringer Ingelheim, Merck &Co., Lexicon, GlaxoSmithKline, Janssen, and EliLilly and consultancy fees from Lexicon, NovoNordisk, Sanofi, Janssen, Boehringer Ingelheim,AstraZeneca, and Merck & Co. V.P. has re-ceived fees for advisory services to BoehringerIngelheim. H.-J.W., U.C.B., M.v.E., and J.T.G. areemployees of Boehringer Ingelheim. J.R. hasserved on scientific advisory boards and re-ceived honoraria or consulting fees fromSanofi, Novo Nordisk, Eli Lilly, Daiichi Sankyo,Janssen, AstraZeneca, Boehringer Ingelheim,and Lexicon and has also received grants/research support from Merck, Pfizer, Sanofi,Novo Nordisk, Bristol-Myers Squibb, Eli Lilly,GlaxoSmithKline, Takeda, Janssen, Daiichi Sankyo,Hanmi Pharmaceutical, Lexicon, and BoehringerIngelheim.

References1. Seshasai SR, Kaptoge S, Thompson A, et al.;Emerging Risk Factors Collaboration. Diabetes

Table 2—Primary end points in ongoing CVOTs of glucose-lowering drugs for type 2 diabetes reporting after 2016, listed in orderof trial start date from earliest to most recent

CVOT Glucose-lowering drug Class Primary end point ClinicalTrials.gov identifier

TOSCA.IT Pioglitazone Thiazolidinedione 3P-MACE plus unplanned coronaryrevascularization

NCT00700856

CANVAS Canagliflozin SGLT2 inhibitor 3P-MACE NCT01032629

EXSCEL Exenatide (once weekly) GLP-1 RA 3P-MACE NCT01144338

CAROLINA Linagliptin DPP-4 inhibitor 3P-MACE NCT01243424

REWIND Dulaglutide GLP-1 RA 3P-MACE NCT01394952

DECLARE-TIMI 58 Dapagliflozin SGLT2 inhibitor 3P-MACE NCT01730534

CARMELINA Linagliptin DPP-4 inhibitor 3P-MACE NCT01897532

DEVOTE Insulin degludec Basal insulin 3P-MACE NCT01959529

VERTIS CV Ertugliflozin SGLT2 inhibitor 3P-MACE NCT01986881

HARMONY Albiglutide GLP-1 RA 3P-MACE NCT02465515

PIONEER 6 Semaglutide (oral) GLP-1 RA 3P-MACE NCT02692716

3P-MACE: CV death, nonfatal MI, nonfatal stroke. CANVAS, CANagliflozin cardioVascular Assessment Study; DECLARE-TIMI 58, Dapagliflozin Effect onCardiovascuLAR Events; DEVOTE, A Trial Comparing Cardiovascular Safety of Insulin Degludec versus Insulin Glargine in Subjects with Type 2 Diabetes atHigh Risk of Cardiovascular Events; EXSCEL, EXenatide Study of Cardiovascular Event Lowering trial; HARMONY, Effect of Albiglutide, When Added toStandard BloodGlucose Lowering Therapies, onMajor Cardiovascular Events in Patientswith Type 2DiabetesMellitus; PIONEER 6, A Trial Investigating theCardiovascular Safety of Oral Semaglutide in Subjects with Type 2 Diabetes; REWIND, Researching cardiovascular Events with a Weekly INcretin inDiabetes; TOSCA.IT, ThiazolidinedionesOr Sulphonylureas and CardiovascularAccidents.Intervention Trial; VERTIS CV, CardiovascularOutcomes FollowingErtugliflozin Treatment in Type 2 Diabetes Mellitus Participants with Vascular Disease.

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