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Abstract

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.
The prevalence of type 2 diabetes mellitus (T2DM) continues to increase, with >12% of US adults and 8.5% of adults worldwide affected.1–3 This growing burden of disease has had tremendous public health consequences because T2DM is accompanied by significant complications such as coronary and cerebrovascular disease, peripheral arterial disease (including lower-limb amputation), heart failure (HF), atrial fibrillation, kidney disease, vision loss, and impaired quality of life.4 T2DM is also one of the most prevalent comorbidities among patients with established cardiovascular disease.5,6
The growing prevalence of T2DM and the emerging awareness of its cardiovascular consequences contributed to a significant increase in the 1990s in the number of drugs approved to treat hyperglycemia. These drugs were granted regulatory approval on the basis of relatively smaller studies that demonstrated usually modest reductions in glycated hemoglobin (HbA1c) concentration. The improvements in glycemic control, as measured by HbA1c, were accepted as a surrogate for a reduction in the risk of microvascular disease,7 but these smaller studies were overall underpowered and of insufficient duration to show any effect on microvascular and macrovascular complications. Signals of increased risk of cardiovascular events were identified with the use of several glucose-lowering therapies, including the sulfonylurea tolbutamide8 and the dual peroxisome proliferator-activated receptor agonist muraglitazar.9 However, it was the identification of a signal for increased myocardial infarction (MI) risk with the thiazolinedione rosiglitazone that spurred the regulatory reassessment of guidance to industry sponsors with regard to the development of glucose-lowering therapies for T2DM.10–13
On the basis of accumulated data up to 2007, questions were raised about the cardiovascular safety of rosiglitazone. A meta-analysis of 43 small short-term trials with relatively low numbers of events suggested a 43% increased risk of MI with the drug (P=0.03), as well as a numerical imbalance in the risk of cardiovascular death (a 64% increased risk of cardiovascular death versus comparator groups; P=0.06).9 These analyses instigated a congressional investigation in which concern was expressed about the role of the US Food and Drug Administration (FDA) in protecting public health related to T2DM glucose-lowering therapies. In response to the safety concern of an increased risk of MI associated with rosiglitazone and safety issues related to other glucose-lowering therapies, the FDA (adopted December 2008)13 and European Medicines Agency (adopted November 2012)12 issued guidance calling for the evaluation of the cardiovascular safety of glucose-lowering therapies. The 2008 FDA guidance required long-term cardiovascular outcome trial (CVOT) evidence (or other equivalent evidence) to rule out increased risk of a major adverse cardiovascular event (MACE) for all new T2DM glucose-lowering therapies (Table 1). As of September 18, 2019, 18 CVOTs have been completed since the issuance of the guidance, and >200 000 patients with T2DM have been studied. Overall, 16 trials were designed as noninferiority trials and 2 as superiority trials (Figure 1). The completed trials conducted in response to the regulatory guidance in patients with T2DM have examined a variety of patient populations and classes of glucose-lowering therapies, including dipeptidyl peptidase-4 (DPP-4) inhibitors,14–19 glucagon-like peptide 1 (GLP-1) receptor agonists,20–29 and sodium-glucose cotransporter-2 (SGLT2) inhibitors30–33 (Table 2). One completed trial evaluated the SGLT2 inhibitor dapagliflozin in patients with established chronic symptomatic HF and reduced ejection fraction regardless of the presence of T2DM.34
Table 1. Main Components of 2008 FDA Guidance for Sponsors on the Evaluation of Cardiovascular Risk of New Glucose-Lowering Drugs13
Outcome trial must exclude HR 1.8 (preapproval) and 1.3 (postapproval)
Patient selection should include high-risk population, including the elderly and those with advanced cardiovascular disease, and some degree of renal impairment
Duration must be at least 2 y
Required cardiovascular events: cardiovascular mortality, myocardial infarction, stroke
Optional cardiovascular events: hospitalization for acute coronary syndrome or urgent revascularization procedures
Cardiovascular events must be adjudicated in a blinded, independent process
FDA indicates US Food and Drug Administration; and HR, hazard ratio.
Table 2. Summary of Completed CVOTs Conducted Under the 2008 FDA Guidance in Patients With T2DM
Trial (n)InterventionMedian Follow-Up, yKey Inclusion CriteriaResults: HR (95% CI)
Primary Outcome*All-Cause MortalityCardiovascular DeathMIStrokeHF HospitalizationUnstable Angina Hospitalization
DPP-4 inhibitors
 SAVOR-TIMI 53 (16 492)14Saxagliptin vs placebo2.1Patients with T2DM (HbA1c ≥6.5%) and age ≥55 y (men) or ≥60 y of age (women) with multiple risk factors for CVD or age ≥40 y with established ASCVD3-Point MACE: 1.00 (0.89–1.11)1.11 (0.96–1.27)1.03 (0.87–1.22)0.95 (0.80–1.12)1.11 (0.88–1.39)1.27 (1.07–1.51)1.19 (0.89–1.60)
 EXAMINE (5380)15Alogliptin vs placebo1.5Patients with T2DM (HbA1c 6.5%–11.0% without insulin, 7.0%–11.0% with insulin) and ACS within 15–90 d before randomization3-Point MACE: 0.96 (upper boundary of the 1-sided repeated CI, 1.16)0.88 (0.71–1.09)0.85 (0.66–1.10)1.08 (0.88–1.33)0.91 (0.55–1.50)1.19 (0.90–1.58)0.90 (0.60–1.37)
 TECOS (14 671)16Sitagliptin vs placebo3.0Patients with T2DM (HbA1c 6.5%–8.0%) and age ≥50 y with established ASCVD4-Point MACE: 0.98 (0.89–1.10)1.01 (0.90–1.14)1.03 (0.89–1.19)1.03 (0.89–1.19)0.97 (0.79–1.19)1.00 (0.83–1.20)0.90 (0.70–1.16)
 CARMELINA (6979)17Linagliptin vs placebo2.2Patients with T2DM (HbA1c 6.5%–10%) and high cardiovascular risk (history of vascular disease and UACR >200 mg/g) and high renal risk (reduced eGFR and microalbuminuria or macroalbuminuria)3-Point MACE: 1.02 (0.89–1.17)0.98 (0.84–1.13)0.96 (0.81–1.14)1.12 (0.90–1.40)0.91 (0.67–1.23)0.90 (0.74–1.08)0.87 (0.57–1.31)
 CAROLINA (6033)18,19Linagliptin vs glimepiride6.3Patients with T2DM (HbA1c 6.5%–8.5%) and high cardiovascular risk, which included documented ASCVD; multiple cardiovascular risk factors; age of at least 70 y; and evidence of microvascular complications3-Point MACE: 0.98 (0.84–1.14)0.91 (0.86–1.14)1.00 (0.81–1.24)1.01 (0.80–1.28)0.87 (0.66–1.15)1.21 (0.92–1.59)1.07 (0.74–1.54)
GLP-1 receptor agonists
 ELIXA (6068)20Lixisenatide vs placebo2.1Patients with T2DM (HbA1c 5.5%–11%) and age ≥40 y, ACS within 180 d before enrollment4-Point MACE: 1.02 (0.89–1.17)0.94 (0.78–1.13)0.98 (0.78–1.22)1.03 (0.87–1.22)1.12 (0.79–1.58)0.96 (0.75–1.23)1.11 (0.47–2.62)
 LEADER (9340)21Liraglutide vs placebo3.8Patients with T2DM (HbA1c ≥7.0%) and preexisting CVD, kidney disease, or HF in patients ≥50 y of age or ≥1 cardiovascular risk factors in patients ≥60 y of age3-Point MACE: 0.87 (0.78–0.97)0.85 (0.74–0.97)0.78 (0.66–0.93)0.86 (0.73–1.00)0.86 (0.71–1.06)0.87 (0.73–1.05)0.98 (0.76–1.26)
 SUSTAIN-6 (3297)22Weekly injectable semaglutide vs placebo2.1Patients with T2DM (HbA1c ≥7.0%) and preexisting CVD, kidney disease, or HF in patients ≥50 y of age or ≥ 1 cardiovascular risk factor in patients ≥60 y of age3-Point MACE: 0.74 (0.58–0.95)1.05 (0.74–1.50)0.98 (0.65–1.48)0.74 (0.51–1.08)0.61 (0.38–0.99)1.11 (0.77–1.61)0.82 (0.47–1.44)
 PIONEER 6 (3183)23,24Oral semaglutide vs placebo1.3Patients with T2DM and age ≥50 y with CVD or moderate (stage 3) CKD or age ≥60 y with ≥1 cardiovascular risk factors3-Point MACE: 0.79 (0.57–1.11)0.51 (0.31–0.84)0.49 (0.27–0.92)1.18, (0.73–1.90)0.74 (0.35–1.57)0.86 (0.49–1.55)1.56 (0.60–4.01)
 EXSCEL (14 752)25Weekly exenatide vs placebo3.2Patients with T2DM (HbA1c 6.5%–10.0%) and CVD or multiple risk factors for CVD3-Point MACE: 0.91 (0.83–1.00)0.86 (0.77–0.97)0.88 (0.76–1.02)0.97 (0.85–1.10)0.85 (0.70–1.03)0.94 (0.78–1.13)1.05 (0.94–1.18)
 FREEDOM-CVO (4156)26ITCA 650 (daily continuous subcutaneous delivery of exenatide) vs placebo1.2Patients with T2DM (HbA1c >6.5%) and age ≥40 y with CVD or cardiovascular risk factors3-Point MACE: upper limit of the 95% CI of HR did not exceed 1.8
 Harmony Outcomes (9463)27Albiglutide vs placebo1.6Patients with T2DM (HbA1c >7.0%) and age ≥40 y with vascular disease3-Point MACE: 0.78 (0.68–0.90)0.95 (0.79–1.16)0.93 (0.73–1.19)0.75 (0.61–0.90)0.86 (0.66–1.14)0.85 (0.70–1.04)‡
 REWIND (9,901)28,29Dulaglutide vs placebo5.4Patients with T2DM (HbA1c ≤9.5%) and age ≥50 y with established CVD or ≥2 cardiovascular risk factors3-Point MACE: 0.88 (0.79–0.99)0.90 (0.80–1.01)0.91 (0.78–1.06)0.96 (0.79–1.16)0.76 (0.61–0.95)0.93 (0.77–1.12)§1.14 (0.89–1.54)
SGLT2 inhibitors
 EMPA-REG OUTCOME (7020)30Empagliflozin vs placebo3.1Patients with T2DM (HbA1c 7.0%–10% on background therapy and 7.0%–9.0% for drug naïve) and preexisting CVD, with BMI ≤45 kg/m2 and eGFR ≥30 mL·min−1·1.73 m−23-Point MACE: 0.86 (0.78–0.99)0.68 (0.57–0.82)0.62 (0.49–0.77)0.87 (0.70–1.09)1.18 (0.89–1.56)0.65 (0.50–0.85)0.99 (0.74–1.34)
 CANVAS Program (10 142)31Canagliflozin vs placebo3.6Patients with T2DM (HbA1c 7.0%–10.5%) and preexisting CVD at ≥30 y of age or ≥2 cardiovascular risk factors at ≥50 y of age3-point MACE: 0.86 (0.75–0.97)0.87 (0.74–1.01)0.87 (0.72–1.06)0.89 (0.73–1.09)0.87 (0.69–1.09)0.67 (0.52–0.87)
 DECLARE-TIMI 58 (17 160)32Dapagliflozin vs placebo4.2Patients with T2DM (HbA1c 6.5%–12%) ≥40 y of age with established ASCVD or multiple risk factors for ASCVD3-Point MACE: 0.93 (0.84–1.03) cardiovascular death or HF hospitalization: 0.83 (0.73–0.95)0.93 (0.82–1.04)0.98 (0.82–1.17)0.89 (0.77–1.01)1.01 (0.84–1.21)0.73 (0.61–0.88)
 CREDENCE (4401)33Canagliflozin vs placebo2.62Patients with T2DM, CKD (eGFR 30–<90 mL·min−1·1.73 m−2), and albuminuria (albumin to creatinine ratio >300–5000 mg/g)Renal end point: 0.70 (0.59–0.82; P=0.00001)0.83 (0.68–1.02)0.78 (0.61–1.00; P=0.05)0.61 (0.47–0.80; P<0.001)
 DAPA-HF (4744)34Dapagliflozin1.52Patients with and without T2DM with chronic stable patients with symptomatic HF (NYHA ≥2) and reduced ejection fraction (LVEF ≤40%)Worsening HF (hospitalization or an urgent visit resulting in intravenous therapy for HF) or cardiovascular death: 0.74 (0.65–0.85)0.83 (0.71–0.97)0.82 (0.69–0.98)0.70 (0.59–0.83)
ACS indicates acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CANVAS, Canagliflozin Cardiovascular Assessment Study; CARMELINA, Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; CAROLINA, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; CKD, chronic kidney disease; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; CVD, cardiovascular disease; CVOTs, cardiovascular outcome trials; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; DPP-4, dipeptidyl peptidase-4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EXAMINE, Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; FREEDOM-CVO, Study to Evaluate Cardiovascular Outcomes With ITCA 650 in Patients Treated With Standard of Care for Type 2 Diabetes; eGFR, estimated glomerular filtration rate; FDA, US Food and Drug Administration; GLP-1, glucagon-like peptide 1; HbA1c, glycated hemoglobin; HF, heart failure; HR, hazard ratio; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular event; MI, myocardial infarction; NYHA, New York Heart Association; PIONEER-6, A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes–Thrombolysis in Myocardial Infarction 53; SGLT2, sodium-glucose cotransporter-2; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects with Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes With Sitagliptin; T2DM, type 2 diabetes mellitus; and UACR, urine-albumin creatinine ratio.
*
Three-point MACE: cardiovascular death, nonfatal MI, or nonfatal stroke. Four-point MACE: cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalization for unstable angina.
Composite of fatal and nonfatal events except for the following trials that reported nonfatal events: EXAMINE, ELIXA, SUSTAIN-6, and PIONEER-6.
Composite of cardiovascular death or HF hospitalization.
§
Includes HF hospitalization or urgent HF visit.
End-stage kidney disease (dialysis, transplantation, or a sustained eGFR of <15 mL·min−1·1.73 m−2), a doubling of the serum creatinine level, or death resulting from renal or cardiovascular causes.
Figure 1. Timeline of cardiovascular outcome trials since the 2008 US Food and Drug Administration guidance. AleCardio indicates Aleglitazar to Reduce CV Events in Patients With ACS and Diabetes; CANVAS, Canagliflozin Cardiovascular Assessment Study; CARMELINA, Cardiovascular and Renal Microvascular Outcome Study With Linagliptin; CAROLINA, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes; CREDENCE, Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; DPP-4, dipeptidyl peptidase-4; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; EMPEROR-Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; EXAMINE, Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; FREEDOM-CVO, Study to Evaluate Cardiovascular Outcomes With ITCA 650 in Patients Treated With Standard of Care for Type 2 Diabetes; GLP-1RA, glucagon-like peptide 1 receptor agonist; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; OMNEON, Study to Assess Cardiovascular Outcomes Following Treatment With Omarigliptin (MK-3102) in Participants With Type 2 Diabetes Mellitus; PIONEER-6, A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes; PPAR, peroxisome proliferator-activated receptor agonist; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes–Thrombolysis in Myocardial Infarction 53; SCORED, Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SGLT2, sodium-glucose cotransporter-2; SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects with Type 2 Diabetes; TECOS, Trial Evaluating Cardiovascular Outcomes With Sitagliptin; TOSCA-IT, Thiazolidinediones or Sulfonylureas Cardiovascular Accidents Intervention Trial; and VERTIS-CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.
There were initial concerns that the guidance would inhibit the development of new drugs because of the cost of CVOTs.35 Given the absence of any convincing signal of increased MACE risk in the trials conducted since 2008 (Table 2), some have questioned the need for a continued requirement for CVOTs.36 The demonstration of particular benefits of certain treatments on HF and renal outcomes has also led to questions about the adequacy of the 3-component MACE outcome (cardiovascular death, MI, stroke) or 4-component MACE outcome (unstable angina added) prescribed in the guidance as the primary composite outcome for all trials of glucose-lowering therapies for T2DM.
In February 2018, a think tank with representatives from academia, industry, government, private payers, and regulatory agencies convened to review the impact of the FDA guidance since 2008. The aims of this meeting were to review the experience of CVOTs conducted since the guidance was issued, to evaluate the major issues that have arisen since the implementation of the guidance, and to consider the implications of the knowledge gained over the past decade for future trial designs from the regulatory, industry, and clinical perspectives. This document highlights the discussion around these aims in the context of glucose-lowering CVOT results available before and since the meeting.

Historical Consideration of the 2008 US FDA Guidance

Approval for T2DM medications indicated to lower blood glucose continues to be based primarily on demonstration of reductions in glucose or HbA1c. The duration of trials designed to demonstrate that effect is typically 6 to 12 months or shorter, generally requiring only 300 to 600 patients exposed for 6 months and only 100 exposed for a year. Before 2008, trials were almost always too small and too short and included patients with cardiovascular risk too low to assess effects on cardiovascular or other important safety outcomes; patients with existing cardiovascular disease, including HF, were often excluded.37 A meta-analysis of trials designed to assess the impact of achieving lower versus higher levels of glycemia on cardiovascular outcomes in adult patients with T2DM suggested a 15% relative risk reduction for fatal and nonfatal MI for an ≈1% lower HbA1c38 but with an increased risk of major hypoglycemia.7,39–41 However, a subsequent trial did not demonstrate any incremental cardiovascular benefit from more intensive glucose lowering compared with standard care in patients with T2DM at high cardiovascular risk.42 Furthermore, cardiovascular safety in the trials was generally assessed through investigator-reported adverse events without a blinded, independent adjudication process.
Two controversial meta-analyses evaluating MACE risk of 2 classes of T2DM drugs spurred the development of guidance from the FDA and other regulatory agencies calling for the evaluation of the risk of cardiovascular outcomes with glucose-lowering therapies. A meta-analysis evaluating MACE risk of muraglitazar showed a 2-fold increase in the risk of HF hospitalization and all-cause death.9 Another meta-analysis of 43 trials evaluating rosiglitazone, which had already received FDA approval, reported a 43% increase in the risk of MI (odds ratio, 1.43 [95% CI, 1.03–1.98]; P=0.03) and a numerically high, but nonsignificant, 64% increase in the risk of death resulting from cardiovascular causes (odds ratio, 1.64 [95% CI, 0.98–2.74]; P=0.06).10 Although there was evidence of increased risk of HF with rosiglitazone and the thiazolidinedione pioglitazone, this did not receive the same attention from regulators.11 The ACCORD randomized trial (Action to Control Cardiovascular Risk in Diabetes) compared intensive glucose lowering (target HbA1c ≤6%) with standard therapy (target HbA1c, 7%–7.9%), with a primary composite outcome of nonfatal MI, nonfatal stroke, or death resulting from cardiovascular causes. The primary outcome was not significantly increased in the intensive glucose-lowering arm (hazard ratio [HR], 0.90 [95% CI, 0.78–1.04]), but 257 patients in the intensive therapy arm died compared with 203 patients in the standard-therapy group (HR, 1.22 [95% CI, 1.0–1.46]; P=0.04), a mortality finding that led to early discontinuation of intensive therapy.41
In light of the experience with rosiglitazone and earlier with sulfonylureas, the FDA convened an Endocrinologic and Metabolic Drugs Advisory Committee in July 2008. The committee voted 14 to 2 in favor of recommending a requirement for long-term CVOT evidence (or other equivalent evidence) to rule out increased MACE risk for all new T2DM glucose-lowering therapies. The evidence of no substantial increase in cardiovascular risk would be required at a minimum both before and after marketing approval.13 Specifically, before a therapy could be marketed, the manufacturer would be required to exclude the upper bound of the 95% CI of 1.8 in the analysis of cardiovascular outcomes. If the premarketing results did not rule out the upper bound of the 95% CI of 1.3, then the company would be required to complete another outcome trial after marketing approval to achieve this criterion for the drug to remain on the market.13 A meta-analysis of the phase 2 and phase 3 clinical trials could be used to rule out an upper limit >1.8. If the meta-analysis did not show that the upper bound of the 2-sided 95% CI for the estimated HR was <1.8, then an additional single, large cardiovascular safety trial might need to be conducted before the product could be marketed. If the premarketing data showed that the upper bound of the 2-sided 95% CI for the estimated increased risk (ie, risk ratio) was between 1.3 and 1.8 and the overall risk-benefit analysis otherwise supported approval, a postmarketing trial would be necessary to definitively show that the upper bound of the 2-sided 95% CI for the estimated risk ratio was <1.3. Given that the number of cardiovascular events that occurred during a drug development program generally was too small to rule out an increased risk of cardiovascular outcomes, almost every new drug approved since 2008 has required a dedicated CVOT.43 The guidance stated a preference for the MACE composite of cardiovascular mortality, nonfatal MI, or nonfatal stroke as the preferred cardiovascular safety outcome but was silent on HF safety assessments.

Characteristics of CVOTs since the 2008 Guidance

Comparator Groups

All of the postguidance CVOTs for glucose-lowering therapies have allowed for open-label treatment for T2DM based on regional guidelines to achieve individually appropriate HbA1c targets in all patients. Typically, among trials conducted to demonstrate cardiovascular safety with a noninferiority margin of <1.3, because no previous glucose-lowering drug has a claim or indication of cardiovascular efficacy, CVOTs have used a placebo control arm as the comparator group, and both the study drug and the placebo have been given in addition to standard of care to achieve glycemic control. An exception to the placebo control design is the recently completed CAROLINA trial (Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients With Type 2 Diabetes), which compared linagliptin with glimepiride.18,19 This has generally led to more oral or insulin-based glucose-lowering treatments being added to or having doses intensified in the control groups. Furthermore, there was a modestly lower time-averaged HbA1c percentage in the active therapy group versus control groups in most trials (ranging from 0.2%–1.4%).

Trial Populations

Most studies conducted after the establishment of the guidelines were enriched for participants with atherosclerotic cardiovascular disease (ASCVD) or additional ASCVD risk factors. The recruitment of these patients satisfied the guidance requirement that the safety of studied drugs in the treatment of patients at high cardiovascular risk be ensured and guarantee accrual of adequate numbers of events to be able to rule out the upper bounds of risk. Several studies also enrolled primary prevention patients (i.e., those who did not have preexisting ASCVD but had multiple cardiovascular risk factors).14,17,18,21,22,25,26,28,31,32 The CREDENCE trial (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) enrolled patients with T2DM and albuminuric chronic kidney disease (CKD) both with and without established cardiovascular disease33 (Table 1). These studies have contributed to the evaluation of cardiovascular outcomes among patients with T2DM across a spectrum of moderate to high ASCVD risk.

Trial Outcomes

Most of the CVOTs had the 3-point MACE outcome (cardiovascular death, nonfatal MI, or nonfatal stroke) as the primary outcome. Three trials added hospitalization for unstable angina to create a 4-point MACE outcome as primary: ELIXA (Evaluation of Lixisenatide in Acute Coronary Syndrome),20 TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin),16 and FREEDOM-CVO (Study to Evaluate Cardiovascular Outcomes With ITCA 650 in Patients Treated With Standard of Care for Type 2 Diabetes).26 The DECLARE-TIMI 58 trial32 (Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58) included a dual primary efficacy outcome of cardiovascular death or hospitalization for HF in addition to 3-point MACE after the results of the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) demonstrated reduction in the risk of HF events associated with empagliflozin.30 The primary outcome of the CREDENCE trial was a composite of end-stage kidney disease (dialysis, transplantation or a sustained estimated glomerular filtration rate of <15 mL·min−1·1.73 m−2), a doubling of the serum creatinine level, or death resulting from renal or cardiovascular causes.33

Results of CVOTs Conducted after the 2008 Guidance

Noninferiority and Superiority Outcomes for MACE

To date, the completed CVOTs have all demonstrated noninferiority, and some superiority, of the new drugs compared with placebo for the primary MACE end point. A summary of the completed CVOTs is presented in Table 2, and ongoing trials are summarized in Table 3.
Table 3. Ongoing CVOTs Evaluating Glucose-Lowering Therapies in Patients With and Without T2DM
Trial (n, trial identifier)InterventionKey Inclusion CriteriaPrimary OutcomeRecruitment
SOLOIST-WHF (estimated 4000, NCT03521934)Sotagliflozin vs placeboPatients with T2DM who are admitted to the hospital or have urgent HF visit for worsening HF; those with prior diagnosis of HF(>3 mo) with treatment for HF with a loop diuretic (>30 d); those with BNP ≥150 pg/mL (≥450 pg/mL for patients with atrial fibrillation) or NT-proBNP ≥600 pg/mL (≥1800 pg/mL for patients with AF); and patients with LVEF <40%Cardiovascular death or HF hospitalizationOngoing (estimated completion January 2021)
SCORED (estimated 10 500; NCT03315143)Sotagliflozin vs placeboPatients with T2DM (HbA1c ≥7%) with eGFR ≥25 and ≤60 mL·min−1·1.73 m−2; age ≥18 y with major cardiovascular risk factor or ≥ 55 y with 2 minor cardiovascular risk factorsCoprimary end point: 3-point MACE and cardiovascular death or HF hospitalizationOngoing (March 2022)
VERTIS-CV (8246; NCT01986881)Ertugliflozin vs placeboPatients age ≥40 y with T2DM (HbA1c 7.0%–10.5%) and established ASCVD3-point MACECompleted 2018
EMPEROR-Reduced (estimated 2850; NCT03057977)Empagliflozin vs placeboPatients with chronic HF, NYHA class II–IV, LVEF ≤40%, and elevated NT-proBNP
If LVEF 36%–40%: NT-proBNP ≥2500 pg/mL or patients without AF/atrial flutter and NT-proBNP ≥5000 pg/mL for patients with AF
If LVEF 31%–35%: NT-proBNP ≥ 1000 pg/mL for patients without AF and NT-proBNP ≥2000 pg/mL for patients with AF
If LVEF <31%: NT-proBNP ≥600 pg/mL for patients without AF and NT-proBNP ≥1200 pg/mL for patients with AF
If LVEF ≤40% and hospitalization for HF in the past 12 mo: NT-proBNP ≥600 pg/mL for patients without AF and NT-proBNP ≥1200 pg/mL for patients with AF; and appropriate dose of medical therapy for HF consistent with prevailing local and international cardiovascular guidelines
Cardiovascular death or HF hospitalizationOngoing (June 1, 2020)
EMPEROR-Preserved (estimated 4126, NCT03057951)Empagliflozin vs placeboPatients with chronic HF, NYHA class II–IV, LVEF >40%, and elevated NT-proBNP (>300 pg/mL for patients without AF, or >900 pg/mL for patients with AF), and structural heart disease within 6 mo before visit 1, or documented hospitalization for HF within 12 mo before visit 1Cardiovascular death or HF hospitalizationOngoing (June 1, 2020)
EMPA-KIDNEY (estimated 5000; NCT03594110)Empagliflozin vs placeboPatients with evidence of CKD at risk of kidney disease progression defined by at least 3 mo before and at the time of screening visit and CKD-EPI eGFR ≥20 to <45 mL·min−1·1.73 m−2 or CKD-EPI eGFR ≥45 to <90 mL·min−1·1.73 m−2 with UACR ≥200 mg/g (or protein:creatinine ratio ≥300 mg/g)Time to first occurrence of kidney disease progression (defined as end-stage kidney disease, a sustained decline in eGFR to <10 mL·min−1·1.73 m−2, renal death, or a sustained decline of ≥40% in eGFR from randomization) or cardiovascular deathOngoing (June 30, 2022)
DAPA-CKD (4000; NCT03036150)Dapagliflozin vs placeboPatients with eGFR ≥25 and ≤75 mL·min−1·1.73 m−2 (CKD-EPI formula) and evidence of increased albuminuria 3 mo or more before visit 1 and UACR ≥200 and ≤5000 mg/g at visit 1≥50% Sustained decline in eGFR or reaching end-stage renal disease, cardiovascular death, or renal deathOngoing (November 27, 2020)
DELIVER (estimated 4700; NCT03619213)Dapagliflozin vs placeboPatients ≥40 y of age with symptomatic HF (NYHA class II–IV), LVEF ≥40%, and evidence of structural heart disease with elevated NT-proBNP levelsWorsening HF (emergency department or urgent HF visit) or cardiovascular deathOngoing (June 22, 2021)
AF indicates atrial fibrillation; ASCVD, atherosclerotic cardiovascular disease; BNP, brain natriuretic peptide; CKD, chronic kidney disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; CVOTs, cardiovascular outcome trials; CVD, cardiovascular disease; DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DELIVER, Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; eGFR, estimated glomerular filtration rate; EMPA-KIDNEY, Study of Heart and Kidney Protection With Empagliflozin; EMPEROR-Preserved, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction; HbA1c, glycated hemoglobin; HF, heart failure; LVEF, left ventricular ejection fraction; MACE, major adverse cardiovascular event; MI, myocardial infarction; NT-proBNP, N-terminal B-type natriuretic peptide; NYHA, New York Heart Association; SCORED, Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients With Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk; SOLOIST-WHF, Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure; T2DM, type 2 diabetes mellitus; UACR, urine-albumin creatinine ratio; and VERTIS-CV, Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease.

HF and Kidney Outcomes in Patients With T2DM at High Risk for Cardiovascular Disease

HF death and rehospitalization represent a large burden of morbidity in T2DM, and HF is a major cause of death among patients with T2DM and established cardiovascular disease.44,45 As demonstrated by the RECORD trial (Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes)46 and PROACTIVE trial (Prospective Pioglitazone Clinical trial in Macrovascular Events),47 HF hospitalization was increased with both rosiglitazone (HR, 2.6 [95% CI, 1.1–4.1]; P=0.001) and pioglitazone (HR, 1.41 [95% CI, 1.10–1.80]; P=0.007), respectively.48
The 4 completed placebo-controlled randomized clinical trials that evaluated the safety of DPP-4 inhibitors in patients with T2DM have demonstrated conflicting results for the risk of HF hospitalization (Table 2).49–52 The FDA required a label warning about the risk of HF with drugs containing saxagliptin or alogliptin. The warning of HF risk was expanded to sitagliptin product labels despite no increased HF risk observed in TECOS and to linagliptin before the reporting of the CARMELINA trial (Cardiovascular and Renal Microvascular Outcome Study With Linagliptin), which did not show increased risk of HF with linagliptin.51 The expansion of the HF warning appears to reflect a concern about a class effect of the cardiovascular safety of DPP-4 inhibitors by the FDA.
In contrast to the increased HF risk seen with the thiazolidinediones and some DPP-4 inhibitors, results from the completed SGLT2 inhibitor trials have consistently demonstrated a reduction in the risk of HF hospitalizations (Table 2). GLP-1 receptor agonist CVOTs have not demonstrated increased signals of harm with regard to HF risk (Table 2). However, smaller randomized trials have shown that among patients with established HF and reduced ejection fraction, liraglutide (compared with placebo) was associated with signals of increased risk of adverse HF-related outcomes.52,53
In addition to HF outcomes, meta-analyses of the GLP-1 receptor agonists and SGLT2 inhibitor CVOTs of patients with T2DM have demonstrated improvements in various kidney composite outcomes54–56 (Table 4). Ongoing trials evaluating primary renal outcomes are highlighted in Table 3.
Table 4. Kidney Outcomes in CVOTs of GLP-1 Receptor Agonists or SGLT2 Inhibitors in Patients With T2DM at High Cardiovascular Risk
TrialDefinition of Composite Kidney Outcome Including MacroalbuminuriaGlucose-Lowering Therapy, n/N (%)Placebo, n/N (%)HR (95% CI)
GLP-1 receptor agonists
 ELIXA20New-onset macroalbuminuria173/2639 (6.5)203/2647 (7.7)0.84 (0.68–1.02)
 LEADER21New-onset macroalbuminuria, doubling of serum creatinine, eGFR <45 mL·min−1·1.73 m−2, ESKD, death caused by kidney disease268/4668 (5.7)337/4672 (7.2)0.78 (0.67–0.92)
 SUSTAIN-622New-onset macroalbuminuria, doubling of serum creatinine, eGFR <45 mL·min−1·1.73 m−2, ESKD, death caused by kidney disease62/1648 (3.8)100/1649 (6.0)0.64 (0.46–0.88)
 EXSCEL25≥40% worsening of eGFR, ESKD, death caused by kidney disease, new-onset persistent macroalbuminuria366/6256 (5.8)407/6222 (6.5)0.88 (0.76–1.01)
 REWIND29New-onset macroalbuminuria, ≥30% worsening of eGFR, ESKD848/4949 (17.1)970/4952 (19.6)0.85 (0.77–0.93)
SGLT2 inhibitors
 EMPA-REG OUTCOME30Progression to macroalbuminuria, doubling of the serum creatinine level accompanied by an eGFR of ≤45  mL·min−1·1.73 m−2, initiation of renal replacement therapy, or death resulting from renal disease525/4124 (12.7)388/2061 (18.8)0.61 (0.53–0.70)
 CANVAS31Sustained and adjudicated doubling in serum creatinine, ESKD, or death resulting from renal causes1.5/1000 patient-y*2.8/1000 patient-y*0.53 (0.33–0.84)
 DECLARE-TIMI 5832≥40% worsening of eGFR, ESKD, death caused by kidney disease127/8582 (1.5)238/8578 (2.8)0.53 (0.43–0.66)
CANVAS indicates Canagliflozin Cardiovascular Assessment Study; CVOTs, cardiovascular outcome trials; DECLARE-TIMI 58, Dapagliflozin Effect on Cardiovascular Events–Thrombolysis in Myocardial Infarction 58; ELIXA, Evaluation of Lixisenatide in Acute Coronary Syndrome; EMPA-REG OUTCOME, BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; eGFR, estimated glomerular filtration rate; ESKD, end-stage kidney disease; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; GLP-1, glucagon-like peptide 1; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; REWIND, Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SGLT2, sodium-glucose cotransporter-2; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects with Type 2 Diabetes; and T2DM, type 2 diabetes mellitus.
Results not reported for PIONEER-6 (A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes) or Harmony Outcomes.
*
Reported as patient-years.

Other Adverse Outcomes

In the CANVAS trials (Canagliflozin Cardiovascular Assessment Study) program, an unexpected finding was an increased risk of amputation with canagliflozin (HR, 1.97 [95% CI, 1.41–2.75]). Amputations were primarily at the level of the toe or metatarsal, but the point estimate of increased risk was similar for amputations at or above the ankle.31 Although potentially underpowered to detect a modest difference in lower-limb amputation risk, the CREDENCE trial of canagliflozin did not find an increase in the risk of lower-limb amputation (HR, 1.11 [95% CI, 0.79–1.56]). An analysis of the FDA Adverse Event Reporting System showed that the frequency of amputation associated with canagliflozin was significantly higher than for non-SGLT2 inhibitor drugs.57 An increased incidence of amputation has also been observed in clinical trials with ertugliflozin, another SGLT2 inhibitor.58 Confirmatory data from the CVOT (VERTIS-CV [Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease]) are not yet available. Increased amputation risk was not seen in post hoc analysis of trial data for empagliflozin59 or dapagliflozin.32 There was a numerically higher rate of amputations among patients with peripheral arterial disease associated with dapagliflozin (8.4% dapagliflozin versus 5.6% placebo; HR, 1.51 [95% CI, 0.94–2.42]).60
The CVOTs evaluating the cardiovascular safety of GLP-1 receptor agonists also identified a potential increase in the risk of diabetic retinopathy outcomes. In the LEADER trial (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results), liraglutide was associated with a numerical increase in the risk of diabetic retinopathy compared with placebo (HR, 1.15 [95% CI, 0.87–1.52]).21 In SUSTAIN-6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects with Type 2 Diabetes), semaglutide compared with placebo was associated with an increased risk of severe diabetic retinopathy complications (HR, 1.76 [95% CI, 1.11–2.78]; P = 0.002).22 Increased risk of diabetic retinopathy was not reported in PIONEER-6 (A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes), which excluded patients with a history of diabetic retinopathy.

Withdrawn and Terminated Studies

The TIDE trial (Thiazolidinedione Intervention With Vitamin D Evaluation), which sought to assess the effects of thiazolidinediones (rosiglitazone and pioglitazone) on cardiovascular outcomes, was stopped prematurely because of regulatory concerns relating to inadequate consideration of accrued data.61 Two studies evaluating the cardiovascular safety of aleglitazar, a dual activator of proliferator-activated receptor-α and -γ agonist, were terminated prematurely because of safety concerns.62,63 OMNEON (Study to Assess Cardiovascular Outcomes Following Treatment With Omarigliptin [MK-3102] in Participants With Type 2 Diabetes Mellitus) compared once-weekly omarigliptin (a DPP-4 inhibitor) with placebo in 4202 patients with T2DM and cardiovascular disease; the study was terminated by the sponsor, Merck, as a result of a business decision.64 The 8-trial program of fasiglifam, a novel G-protein–coupled receptor 40 agonist for the treatment of T2DM, was stopped prematurely because of liver toxicity.65 A study investigating taspoglutide (a GLP-1 receptor agonist) was discontinued because of an increase in unacceptable adverse effects, including nausea/vomiting, injection-site reactions, and systemic allergic reactions.66

Efficacy of SGLT2 Inhibitors in Patients With HF and Reduced Ejection Fraction

The DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) evaluated the efficacy of dapagliflozin compared with placebo to reduce the risk of the composite of worsening HF (HF hospitalization or urgent visit requiring intravenous therapy for HF) or cardiovascular death among patients with symptomatic, chronic stable HF with reduced ejection fraction (defined as left ventricular ejection fraction ≤40%).34 Patients were to be on optimally tolerated guideline-directed HF therapy. The DAPA-HF trial demonstrated that compared with placebo, dapagliflozin reduced the risk of the composite of worsening HF or cardiovascular death (HR, 0.74 [95% CI, 0.65–0.85]). Dapagliflozin compared with placebo also reduced the risk of cardiovascular death (HR, 0.82 [95% CI, 0.69–0.98]) and all-cause mortality (HR, 0.83 [95% CI, 0.71–0.97]), in addition to worsening HF (HR, 0.70 [95% CI, 0.59–0.83]). The efficacy of dapagliflozin in reducing the risk of the primary composite outcome was seen among patients with T2DM (HR, 0.75 [95% CI, 0.63–0.90]) and without diabetes mellitus (HR, 0.73 [95% CI, 0.60–0.88]).34 Additional ongoing trials evaluating the role of SGLT-2 inhibitors are presented in Table 3.

Issues for Current CVOTs

The postguidance CVOTs have provided significant reassurance of MACE safety for most new glucose-lowering therapies and supported their use to improve glycemic control without increasing MACE risk. More recent evidence of cardiovascular benefit with empagliflozin, canagliflozin, dapagliflozin, liraglutide, albiglutide, dulaglutide, and possibly semaglutide was not the anticipated result of these CVOTs. The results from these CVOTs have already changed clinical practice consensus recommendations. The increased HF risk identified with some DPP-4 inhibitors would not have emerged, or would have emerged much later in the product life cycle, in the absence of CVOTs. The demonstration of reductions in HF hospitalization and potential renal benefits with SGLT2 inhibitors has led to many new trials studying these and an SGLT1/2 inhibitor in patients with established HF and more advanced CKD, including, in both sets of studies, patients without diabetes mellitus.

Cost, Clinical Resources, and Delay in Regulatory Approval

Because none of the completed CVOTs demonstrated an increased risk of fatal or nonfatal ASCVD outcomes, one might ask whether they are still necessary to demonstrate safety for ASCVD events, as was mandated by the 2008 FDA guidance. Because the cost of taking a new therapy from discovery to market may exceed US $2 billion in total67 and phase 3 registration trials alone (including CVOTs for T2DM)35 often cost hundreds of millions of dollars, there is concern from the pharmaceutical industry that this enormous investment might act as a disincentive to the development of new treatments and thus lead to fewer options for patients with diabetes mellitus. Venture funding of US companies in T2DM is 24 times below oncology funding, and there has been a 50% decline in the trial initiation for T2DM programs over the past decade.35 On the other hand, recent favorable effects of some drugs on cardiovascular outcomes (or harm in the case of HF and other noncardiovascular outcomes) associated with various glucose-lowering therapies would not have been identified without dedicated CVOTs. The significant cost of conducting the CVOTs may well be offset by the important new identified benefits that could markedly affect choice of treatments. This may lead to significant market advantage as therapies with cardiovascular benefit become a part of standard of care. The recent increase in the number of CVOTs evaluating glucose-lowering therapies in patients with and without T2DM across disease states (such as HF and CKD) suggests a market interest in further exploring the findings from trials that have demonstrated cardiovascular and HF benefit.30–32

Generalizability of Current CVOTs

Although findings of cardiovascular safety in high-risk patient populations might reasonably be extrapolated to lower-risk groups, the demonstration of cardiovascular benefit in populations at high ASCVD risk may not be translatable to the larger population of patients with diabetes mellitus. Even if the benefit were maintained, fewer events would be prevented, potentially changing the benefit/risk consideration of these therapies. Among the completed SGLT2 inhibitor trials, 34% of the CANVAS trial program participants and 59% in DECLARE-TIMI 58 were primary prevention patients. There was no suggestion of an effect of canagliflozin in reducing the risk of the primary MACE end point among the primary prevention groups (HR, 0.98 [95% CI, 0.74–1.30]), but the secondary prevention groups (HR, 0.82 [95% CI, 0.72–0.95]) showed a significant benefit. Although there was no evidence of statistical heterogeneity between the groups, the FDA product-labeled indication stated that the demonstration of canagliflozin benefits in reducing risk of 3-point MACE was robust only among patients with prevalent ASCVD.68 In the LEADER trial, liraglutide lowered cardiovascular risk primarily in people with established ASCVD (HR, 0.83 [95% CI, 0.74–0.93]), not among patients without cardiovascular disease (HR, 1.20 [95% CI, 0.86–1.67]; unadjusted interaction P=0.04). This result is reflected in the FDA label for liraglutide in which the cardiovascular reduction indication is only for patients with T2DM who have established cardiovascular disease.69 More than half of DECLARE-TIMI 58 trial participants (59%) were without cardiovascular disease but with cardiovascular risk factors (primary prevention group). There was no statistical heterogeneity in the reduction of risk for the primary efficacy outcome of the composite of cardiovascular death or HF hospitalization associated with dapagliflozin between the primary prevention groups (HR, 0.84 [95% CI, 0.67–1.04]) and secondary prevention groups (HR, 0.83 [95% CI, 0.71–0.98]; interaction P=0.99).32 How the FDA responds to the results of these trials with labeling for patients with and without established cardiovascular disease remains to be determined.

Duration of Studies

The strategy in some CVOTs of enrolling very high-risk patients has tended to result in studies of relatively short duration, providing limited exposure and fewer general safety data. The REWIND trial (Researching Cardiovascular Events With a Weekly Incretin in Diabetes), which enrolled 67% of patients without ASCVD, had a median follow-up of 5.4 years, the longest of the CVOTs in the GLP-1 receptor agonist class. The top-line results as reported thus far showed superiority for MACE compared with placebo.29 Several lines of evidence argue for the importance of longer-term follow-up. The UKPDS (UK Prospective Diabetes Study) had long-term follow-up of a median of 10 years (median follow-up for the sulfonylurea-insulin and metformin groups, 10.0 and 10.7 years, respectively70). With an additional 10 years of passive observational posttrial follow-up, the study was able to show lower MACE rates and all-cause mortality outcomes in patients with early, more intensive glycemic control, despite cessation of trial-based glucose control strategies. Long follow-up would also allow assessment of the full effects of glucose-lowering therapies on the worsening of diabetic nephropathy, a critical complication of diabetes mellitus. The current CVOT design is generally unable to provide objective information about longer-term risk of therapies (ie, >5 years of use), which is pertinent even among drugs with short-term cardioprotective benefits.

Choice of Comparator

To date, a limited number of CVOTs have compared a new glucose-lowering therapy with another therapy.10,19,71 Active comparator trials may provide more evidence on which glucose-lowering therapies should be recommended by guideline committees. Furthermore, the choice of active comparator instead of placebo needs to be considered in light of the glucose-lowering therapies that demonstrate a reduction in cardiovascular outcomes. In general, placebo-controlled CVOTs of novel glucose-lowering agents may be conducted on a background of SGLT2 inhibitors, GLP-1 receptor agonists, or both; whether it would be possible to demonstrate efficacy of a new agent in a noninferiority study, with use of background therapies that have proven cardiovascular benefit, needs to be considered. However, the ethics of denying the active group a drug with proven cardiovascular benefit may pose a problem, suggesting that add-on studies may be needed.

Interim Analyses and Demonstration of Safety

Given the number of diabetes mellitus drug CVOTs that have demonstrated benefit on cardiovascular outcomes and the totality of trials failing to demonstrate any increased risk of atherothrombotic outcomes associated with newer medications, the value of continuing to conduct noninferiority studies at the currently predefined 1.8 margin to demonstrate MACE safety to gain regulatory approval for marketing warrants further consideration. However, demonstration of cardiovascular safety remains critical given the concerns for cardiovascular safety, HF outcomes, lower-limb amputation, and other adverse outcomes raised with some glucose-lowering therapies.8–10,14,31,41 Demonstrating MACE safety for the 1.8 and subsequently 1.3 safety thresholds can be done in a single trial; however, some programs attempting this strategy have come across challenges. Canagliflozin was first granted FDA approval on the basis of interim data from CANVAS. However, as a result of including publicly unmasked interim cardiovascular outcome data in the regulatory filing documents, the CANVAS-R (CANVAS–Renal)72 study was required.73 This example highlights the challenges with public unmasking of interim unblinded data.74

Outcome Components

The role of the primary 3-point MACE outcome (cardiovascular death, nonfatal MI, or nonfatal stroke) endorsed by the FDA should be re-evaluated given the absence of harm for the MACE outcome in any of the postguidance CVOTs thus far. To date, the only completed postregulatory trial that incorporated HF as a component of the dual primary efficacy outcome was DECLARE-TIMI 58. Without powering for non-MACE cardiovascular outcomes such as HF, CVOTs may miss important signals of harm or benefit.

2018 FDA Advisory Committee Meeting

In October 2018, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee met to discuss the 2008 guidance (Table 5). The primary question raised was whether an unacceptable increase in cardiovascular risk needed to be excluded for all new drugs to improve glycemic control in patients with T2DM, regardless of the presence or absence of a signal for cardiovascular risk in the development program. As highlighted by the advisory committee meeting, the assessment of cardiovascular risk as recommended by the guidance has led to greater assurance of cardiovascular safety of glucose-lowering therapies and additional data in a population of patients who were not well represented previously. As an example, saxagliptin, liraglutide, and alogliptin were under review as the 2008 guidance was being issued. On the basis of the narrower custom query developed for review of these products in 2008, there were a total of 40, 38, and 18 cardiovascular events in the saxagliptin, liraglutide, and alogliptin programs, respectively. The manufacturers subsequently were required to conduct postmarketing studies. The number of events accrued in the CVOTs for these 3 products was 1222 in SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes–Thrombolysis in Myocardial Infarction 53; saxagliptin), 1302 in LEADER (liraglutide), and 621 in EXAMINE (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care; alogliptin). The significantly increased number of clinical cardiovascular events allowed for greater certainty in assessments of the relative risk associated with each drug program.75
Table 5. Summary of 2018 FDA Advisory Committee and 2018 Think Tank Discussion
Issue2018 FDA Advisory Committee Meeting2018 Think Tank
Goal of meeting• Discuss whether an unacceptable increase in cardiovascular risk needed to be excluded for all new drugs to improve glycemic control in patients with T2DM, regardless of the presence or absence of a signal for cardiovascular risk in the development program• Review the major issues that have arisen since the implementation of the guidance and evaluate implications of the experience to date on future trial designs from the regulatory, industry, and clinical perspectives
Continue guidance recommendation of excluding unacceptable increases in cardiovascular risk for all new glucose-lowering therapies• FDA advisory committee voted 10 to 9 to continue the guidance recommendation to exclude unacceptable increases in cardiovascular risk for all new glucose-lowering therapies• Recommend at least 1 adequately powered CVOT, with outcomes that might include heart failure and/or kidney disease, to ensure absence of unacceptable increase in cardiovascular risk for all new glucose-lowering therapies
2-Step approach of conducting premarket studies to exclude 1.8 upper bound of CI for cardiovascular risk and postmarketing CVOT to exclude 1.3 upper bound of CI for cardiovascular risk• Preapproval programs could be modified to rule out increased risk early on
• Majority of the committee advocated to replace the 2-step approach
• In certain situations, the 1.8 noninferiority requirement to obtain preliminary FDA approval could be waived provided that a CVOT demonstrating cardiovascular safety at the 1.3 noninferiority safety margin is completed in a timely manner
Single premarketing study to exclude 1.5 upper bound of CI for cardiovascular risk• Some support from individuals on the FDA advisory committee for an approach whereby a single premarket CVOT to rule out unacceptable cardiovascular risk at a 1.5 upper bound of CI could be considered• Limited support for a single premarket 1.5 upper bound of CI
• A potential 50% increase in cardiovascular risk would be challenging to accept given that therapies exist that can now reduce the risk of cardiovascular events
Can cardiovascular safety findings from certain members of a drug class be applied to all members of the drug class?• No consensus reached• Given the potential heterogeneity of trial results, for each new glucose-lowering therapy, at least 1 large-scale CVOT should be continued to enable greater confidence in the cardiovascular efficacy/safety profiles
• 1 Large-scale CVOT for each new glucose-lowering agent would enable a better assessment of within-class differences relating to efficacy and adverse events
CVOT study design• Advocated the use of novel study design to streamline and reduce trial costs and potentially to lengthen follow-up• Leverage pragmatic study design such as use of electronic health records, digital technology, and streamlined safety and clinical event adjudication
Populations to be enrolled• Advocated the inclusion of more diverse populations within clinical trials• Consider mandating or recommending the enrollment of a certain percentage of underrepresented patients
• Broaden the inclusion criteria to capture wider range of comorbidities
• Target populations tailored to the anticipated benefits of the drug being tested, eg, patients with HF or CKD
• Tailor CVOT end points tailored to the study population
• Leverage pragmatic study design to improve inclusion of diverse populations
CKD indicates chronic kidney disease; CVOT, cardiovascular outcome trial; FDA, US Food and Drug Administration; HF, heart failure; and T2DM, type 2 diabetes mellitus.
The advisory committee narrowly voted 10 to 9 in favor of continuing to exclude unacceptable increases in cardiovascular risk for all new glucose-lowering therapies.76 Of note, the vote was nonbinding and does not necessarily reflect the opinion of the FDA. Given the vast size of the market for patients with T2DM, increased cardiovascular risk must be explicitly excluded. However, the advisory committee generally agreed that the scope of CVOTs and regulatory safety thresholds should be modified. Potentially, instead of requiring large and long CVOTs after approval, perhaps preapproval programs could be modified to rule out increased risk earlier.77 The majority of the advisory committee members advocated to replace the 2-step approach of ruling out the premarket setting (ie, the upper bound of the CI for the HR <1.8) and the lower level of risk in the postmarketing CVOT (ie, the upper bound of the CI for the HR <1.3). There was support among some advisory committee members to consider a single premarket upper bound of 1.5. The endocrinologists at the advisory committee generally felt that the guidance was too strict. Furthermore, among the cardiologists at the advisory committee, the 1.3 upper bound seemed more stringent than needed for ascertainment of cardiovascular safety of new glucose-lowering therapies. In our think tank meeting, there was limited support for a single premarket upper bound of 1.5. Our discussion highlighted that in certain situations the 1.8 noninferiority requirement to obtain preliminary FDA approval can be waived. However, in this situation, the completion of a postmarketing trial demonstrating safety at the 1.3 noninferiority safety margin in a timely fashion should be required.
The FDA advisory committee also discussed whether cardiovascular safety findings from certain members of a drug class should be applied to all members of the drug class. No consensus was achieved for this question. Several advisory committee members commented that each drug should be considered individually and that results should not be applied across all members of a drug class (ie, a class effect). A few of the advisory committee members stated that cardiovascular safety findings for a drug during a trial may support the cardiovascular safety for other members of the drug class in the absence of any cardiovascular safety signals in the phase 2 and phase 3 trials of the other drugs in the class. Given the potential heterogeneity of trial results, our think thank discussion recommended that for each new glucose-lowering therapy, the totality of data needed to be considered, and the requirement of at least 1 large-scale CVOT should be continued to enable greater confidence in the cardiovascular efficacy/safety profiles of these new therapies.
There was further support from the FDA advisory committee for using novel study designs such as pragmatic open-label study designs to streamline and reduce costs, thus allowing lower-cost, longer-term follow-up. In addition, there was support for encouraging the inclusion of more diverse patient populations. These are positions that our think tank meeting also advocated. This vote was nonbinding, and whether the FDA modifies the current version of the guidance remains to be seen.

Directions and Strategies Moving Forward

Overall Reevaluation of Current Regulatory Guidance

Given the significant knowledge that has been gained about the cardiovascular benefit of certain glucose-lowering therapies (and the absence of adverse MACE outcomes), the question arose among the think tank attendees as to whether the 2008 FDA guidance should be modified.78 The consensus (based on discussion and postmeeting surveys) of the group was that the guidance should be modified to take into account lessons from CVOTs to date and to take a more individualized approach to establishing the cardiovascular safety and efficacy profile of each new diabetes mellitus drug (Figure 2).
Figure 2. Issues and recommendations regarding (A) methodological issues and (B) real-world applicability issues surrounding cardiovascular outcome trials for glucose-lowering therapies. MACE indicates major adverse cardiovascular event; and RCT, randomized, controlled trial.

Modification of the 1.8 Noninferiority Margin for Initial Approval of a Diabetic Medication

If a commitment is made to confirm the composite MACE end point (cardiovascular death, nonfatal MI, nonfatal stroke) safety by a 1.3 margin in a CVOT, then preliminary approval by the FDA should be considered, in some situations, without having to attain the 1.8 margin compared with placebo. This might be the case, for example, when other glucose-lowering therapies of the same class have established cardiovascular safety and if there is no other particular reason for concern based on preclinical and phase 2 experience. Modifying the need to demonstrate noninferiority using the 1.8 margin may result in a number of unanticipated consequences that must be considered. The early glucose-lowering therapies within a therapeutic class may be subjected to greater regulatory scrutiny compared with therapies that come later. It is unclear whether there would be pressure to describe a therapy as being a part of a particular class for which there is more established evidence to avoid the 1.8 noninferiority margin. If the 1.8 margin requirement remains, then it could include the following considerations: The 1.8 noninferiority margin should be demonstrated for specific events, depending on the safety and cardiovascular profile of the class, rather than only the 3-point MACE for all agents; and if the 1.8 noninferiority is demonstrated by an interim analysis, the only information that should be reported to the FDA is whether the upper bound of effect (analyzed by the independent biostatistician of the data monitoring committee) was <1.8, to preserve integrity of the ongoing trial. Public sharing of unblinded trial data may result in potential unanticipated consequences such as perceived loss of equipoise by patients and clinicians.74

Outcome Selection in Cardiovascular Safety Studies

As highlighted, the guidance currently endorses 3-point MACE (cardiovascular death, nonfatal MI, nonfatal stroke) as the primary end point of the CVOTs. Given the modest number of completed trials, it is still possible, particularly for new classes of glucose-lowering therapies, that such a risk could be found. Given the favorable findings of some drugs on important outcomes, allowing flexibility to consider clinically relevant outcomes may be pertinent for each agent. Because HF and kidney outcomes are significant sources of morbidity and mortality among patients with T2DM, depending on the glucose-lowering agent in question, the inclusion of these outcomes in the primary composite outcome of clinical trials remains warranted, especially if evidence from a previous CVOT provides supportive hypothesis-generating results. This occurred with the DECLARE-TIMI 58 study, which added cardiovascular death or HF hospitalization as a dual coprimary outcome in addition to 3-point MACE.32 Dedicated CVOTs in the particular population such as HF or CKD (several are currently underway) should also be considered. Hospitalization for unstable angina, given the inherent imprecision in the diagnosis, should be carefully considered before being included in any primary composite end point for diabetes mellitus drug CVOTs.79

Comparator Groups in CVOTs

If a novel class of glucose-lowering therapy is being evaluated against placebo for cardiovascular safety, then the background therapy in both placebo and active treatment arms should include patients on maximally tolerated evidence-based therapies that should include glucose-lowering agents with cardiovascular benefit. For new agents within a class of therapies that have demonstrated cardiovascular benefit, the use of placebo-controlled trials in the population to be studied would generally not be considered ethical, although a trial in a clearly different population might be acceptable. Other considerations may include the expected clinical benefit of the established agents (eg, large mortality benefit versus benefit on a softer clinical outcome such as revascularization or symptoms), the plausibility of previous data and whether results align across multiple trials, and whether previous agents with cardiovascular benefit are being routinely used in practice and are suggested by consensus practice recommendations. There are also practical issues in terms of what is considered standard of care; newer and more expensive therapies may not be available to all countries of all patients, and it may not be acceptable in many jurisdictions for sponsors to pay for the background therapies that are then withdrawn at the end of the trial.
If there is a lack of equipoise, then an active comparator trial must be considered. The new agent would be compared with the established agent in the same class because it would be unethical to withhold a therapy that has established cardiovascular benefit in the study population, especially if those established therapies are recommended by consensus practice documents and used routinely. These active comparator studies would need to be powered either for a superiority outcome for the novel therapy or for a noninferiority outcome. However, establishing noninferiority of a new therapy against an established therapy with cardiovascular benefit may be challenging. The evidence-based lower boundary of the 95% CI and demonstration of preserving 50% of that benefit would be difficult because the 95% confidence limit is not far from 1.0 and would require at least several thousand events.80
A new agent can also be evaluated in a clinical population in which equipoise still exists such as in populations without ASCVD, prediabetes, HF, or CKD. This strategy was used in the study of statins, which were initially evaluated in patients with MI and then eventually shifted to primary prevention patient populations.
In clinical practice, glucose-lowering therapies are usually added on top of one another. Another important question remains as to whether a glucose-lowering therapy with cardiovascular benefit has additive benefit to another therapy that also has cardiovascular benefit. For example, it is unclear whether liraglutide and empagliflozin have a greater effect together than each alone. If placebo is chosen as the comparator for a new drug in a class with other agents known to reduce cardiovascular risk, permission or provision of background therapy with beneficial glucose-lowering therapies from other classes might address this issue.

Metformin as First-Line Therapy

Whether metformin should continue to be considered first-line therapy for T2DM remains unclear.81 Metformin use was not a specified eligibility criterion for any of the CVOTs,81 and 17% to 47% of patients enrolled in CVOTs of glucose-lowering therapies completed to date were not treated with metformin at baseline. In clinical practice, most patients will eventually require >1 drug to maintain adequate glycemic control, and usually metformin will be a part of that therapy. In addition, the newer drug classes with demonstrated cardiovascular benefit may be added to metformin monotherapy without increasing the risk of hypoglycemia.

Priorities of Future CVOTs

Five potential priorities were identified for future CVOTs: (1) continuing to demonstrate cardiovascular safety compared with standard of care; (2) establishing cardiovascular superiority compared with standard of care; (3) shedding light on safety, efficacy, and outcomes in understudied populations such as those with CKD or HF or those without established cardiovascular disease; (4) assessing the effects of combinations of new glucose-lowering therapies (eg, combination of GLP-1 receptor agonists and SGLT2 inhibitors); and (5) and head-to-head comparisons of different new glucose-lowering therapies (Figure 2). The requirement to assess each new glucose-lowering therapy in at least 1 large-scale CVOT should continue so that healthcare providers can have greater confidence in the cardiovascular efficacy/safety profiles of these therapies.82 There is need for the evaluation of glucose-lowering therapies to be expanded to patients with HF because these patients have low tolerability for drugs that affect blood pressure and renal function.48 Currently, only 1 outcome trial is investigating the effect of a glucose-lowering medication, sotagliflozin, in patients with T2DM after hospitalization for worsening HF: the SOLOIST-WHF trial (Effect of Sotagliflozin on Cardiovascular Events in Patients With Type 2 Diabetes Post Worsening Heart Failure; NCT03521934). The priorities suggested reflect the opinion that the current focus of the FDA guidance, which is on establishing traditional MACE safety of glucose-lowering therapies, should be expanded.

Strategies to Streamline and Simplify CVOTs

Several pragmatic strategies could be considered to improve the efficiency of conducting CVOTs. Given the cost of conducting these trials, we would encourage the collection of only serious adverse events, suspected unexpected serious adverse reactions, and adverse events of special interest, as was done in the Harmony Outcomes, EXSCEL (Exenatide Study of Cardiovascular Event Lowering), and TECOS trials. Enabling the use of novel technologies and electronic medical records to capture outcomes in a cost-effective manner warrants further evaluation.83,84
Developing long-term registries that follow randomized patients over protracted periods of time could enable extended evaluation of efficacy or safety in low-risk populations and would better represent expected duration of use in clinical practice.85 Similarly, among primary prevention patients with T2DM, provisional market approval may be granted with a short-term cardiovascular safety study with the commitment to conduct a longer-term pragmatic registry-based follow-up of randomized patients.
In addition to the conduct of clinical trials, standardizing outcome definitions across CVOTs of glucose-lowering therapies as much as possible would improve comparability between trials. Emerging consensus definitions for outcomes in cardiovascular trials can be considered and extended to CVOTs of glucose-lowering therapies.86

Real-World Randomized Clinical Trials

The increased availability of registries, electronic medical records, insurance-based claims data, and computing technology has led to increasing calls for pragmatic or real-world studies to establish the efficacy of a therapy.87 However, research is needed first to evaluate the reliability and appropriateness of using evidence that is based on registries and unselected populations in studies assessing cardiovascular safety. Furthermore, real-world evidence does not simply refer to observational data but includes randomization in general practice settings. Real-world observational studies cannot completely eliminate the issue of confounding, which can significantly bias observational findings, and randomization serves as the gold standard in demonstrating the efficacy of therapies. Real-world data (eg, electronic medical records and claims-based data) can be leveraged to optimize and potentially streamline the conduct of CVOTs. Understanding how real-world evidence can make the conduct of randomized controlled trials more streamlined and cost-effective should remain a priority for regulatory agencies, academia, and industry.

Enrollment of Underrepresented Populations in Diabetes Mellitus Drug CVOTs

Women, minorities, and older patients have been underrepresented in trials to evaluate cardiovascular effects of glucose-lowering therapies. To address this, a potential approach is to mandate the enrollment of a certain percentage of underrepresented patients. Broadening the inclusion criteria to capture comorbidities (eg, atrial fibrillation, HF, peripheral arterial disease, and CKD) that are often present in women, minorities, and older patients may help encourage enrollment of these underrepresented groups. One possibility is that pragmatic studies could enroll a more diverse patient population.

Conclusions

Given the societal burden of T2DM and its associated morbidities and mortality risk, ensuring the cardiovascular safety and efficacy for clinical outcomes of glucose-lowering therapies remains a high priority. The 2008 FDA guidance and guidance from other regulatory agencies for glucose-lowering drug development have greatly increased clinicians’ confidence in the cardiovascular safety of new glucose-lowering therapies. Several completed studies have shown cardiovascular benefit of some therapies and have alleviated concerns of cardiovascular harm for others. However, emerging outcomes of interest have arisen, specifically the impact of newer therapies on the risk of HF and renal disease progression. Furthermore, unexpected safety signals (eg, lower-limb amputations with canagliflozin) have also emerged. These trials have demonstrated the critical importance of randomized controlled CVOTs rather than relying on surrogate outcomes.
As we pass the 10-year anniversary of the issuance of the guidance, the principles underlying the guidance are being re-evaluated to determine whether the recommendations can or should be modified in the current era of diabetes mellitus CVOTs. Several strategies can be considered to optimize trial conduct in light of the past decade of experience with glucose-lowering therapies. Therapies that do not demonstrate any interim cardiovascular safety signal receive conditional approval with a postmarketing requirement to demonstrate safety at the 1.3 noninferiority safety margin in a timely fashion (ie, the current standard). Relevant outcomes such as HF or renal disease progression could be added to or substituted for the primary composite outcome of registration trials, but all trials should have sufficient events to demonstrate safety at the designated level (hazard ratio <1.3). Pragmatic trial designs may facilitate trial conduct and more extended follow-up ascertainment. A further area of interest is whether cardiovascular benefits seen with glucose-lowering therapies in individual trials are additive when these therapies are used together. Studies in specialized populations such as those with CKD or at lower risk for cardiovascular disease should be considered, as should greater enrollment of underrepresented patients in trials. As newer glucose-lowering therapies emerge, guidance that offers flexibility while ensuring cardiovascular safety will enable accurate and efficient gathering of evidence needed to benefit patients with T2DM.

Acknowledgments

The authors thank Carolyn Moore Arias of the Duke Clinical Research Institute for assistance in organizing the think tank and Peter Hoffmann of the Duke Clinical Research Institute for editorial support. Dr Holman is an Emeritus National Institute for Health Research Senior Investigator. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the US Department of Health and Human Services.

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Circulation
Pages: 843 - 862
PubMed: 31992065

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Published online: 29 January 2020
Published in print: 10 March 2020

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Keywords

  1. cardiovascular disease
  2. diabetes mellitus, type 2
  3. heart failure
  4. United States Food and Drug Administration

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Authors

Affiliations

Abhinav Sharma, MD [email protected]
Division of Cardiology, McGill University Health Centre, Montreal, QC, Canada (A.S.).
Division of Cardiovascular Medicine, Stanford University School of Medicine, CA (A.S.).
Neha J. Pagidipati, MD, MPH
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.).
Robert M. Califf, MD
Verily Life Sciences and Duke University School of Medicine, Durham, NC (R.M.C.).
Darren K. McGuire, MD
UT Southwestern, Dallas (D.K.M.).
Jennifer B. Green, MD
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.).
Dave Demets, PhD
University of Wisconsin, Madison (D.D.).
Jyothis Thomas George, MBBS, PhD
Boehringer-Ingelheim International, Ingelheim am Rhein, Germany (J.T.G.).
Hertzel C. Gerstein, MD, MSc
McMaster University, Hamilton, ON, Canada (H.C.G.).
Todd Hobbs, MD
Novo Nordisk, Plainsboro, NJ (T.H.).
Rury R. Holman, FMedSci
Diabetes Trials Unit, University of Oxford, UK (R.R.H.).
Francesca C. Lawson, MD
Sanofi US, Bridgewater, NJ (F.C.L.).
Lawrence A. Leiter, MD
University of Toronto, ON, Canada (L.A.L.).
Marc A. Pfeffer, MD, PhD
Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA (M.A.P.).
Jane Reusch, MD
University of Colorado School of Medicine, Denver (J.R.).
Jeffrey S. Riesmeyer, MD
Eli Lilly & Co, Indianapolis, IN (J.S.R.).
Matthew T. Roe, MD, MHS
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.).
Yves Rosenberg, MD, MPH
National Heart, Lung, and Blood Institute, Bethesda, MD (Y.R.).
Robert Temple, MD
Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD (R.T.).
Stephen Wiviott, MD
TIMI Study Group, Harvard Medical School, Boston, MA (S.W.).
John McMurray, MD
University of Glasgow, Scotland, UK (J.M.).
Christopher Granger, MD
Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (N.J.P., J.B.G., M.T.R., C.G.).

Notes

Abhinav Sharma, MD, McGill University Health Centre, 1001 Decarie Blvd, Montreal, QC, Canada H4A3J1. Email [email protected]

Disclosures

Dr Sharma reports personal support from the Fonds de Recherche Sante - Quebec (FRSQ) Junior 1 clinician scientist award, McGill University Lucien Award, Bayer-Canadian Cardiovascular Society, Alberta Innovates Health Solution, Roche Diagnostics, Takeda, Boehringer-Ingelheim, and Akcea. Dr Pagidipati has disclosures listed at https://dcri.org/about-us/conflict-of-interest/. Dr Califf was the commissioner of food and drugs for the FDA from February 2016 to January 2017 and deputy commissioner for medical products and tobacco for the FDA from February 2015 to January 2016. Dr Califf serves on the corporate board for Cytokinetics and is the board chair for the People-Centered Research Foundation. He also reports receiving consulting fees from Merck, Biogen, Genentech, Eli Lilly, and Boehringer Ingelheim and is employed as a scientific advisor by Verily Life Sciences (Alphabet). Dr McGuire reports personal fees from Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi US, Merck Sharp and Dohme Corp, Eli Lilly and Co, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon, Eisai Inc, Esperion, Metavant, Pfizer, and Applied Therapeutics. Dr Green reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Merck, Sharpe & Dohme, and Sanofi; grants from GlaxoSmithKline, Intarcia Therapeutics, and Janssen; and personal fees from Daiichi Sankyo and NovoNordisk. Dr Demets reports personal fees from Sanofi, GlaxoSmithKline, Johnson & Johnson, and AstraZeneca. Dr George is an employee of Boehringer Ingelheim. Dr Gerstein reports grants and personal fees from Sanofi, Eli Lilly, AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Merck, and Abbott, as well as personal fees from Janssen. Dr Hobbs is an employee of Novo Nordisk. Dr Holman reports grants and personal fees from AstraZeneca, Bayer AG, and Merck Sharp & Dohme; personal fees from Novartis and Novo Nordisk; and service on an Independent Data Monitoring Committee for GlaxoSmithKline and Janssen. Dr Lawson is an employee of Sanofi. Dr Leiter reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi; personal fees from Servier; and grant support from GlaxoSmithKline. Dr Pfeffer reports grant support from Novartis; consulting fees from AstraZeneca, Corvidia, DalCor, GlaxoSmithKline, MyoKardia, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Servier, and Takeda; and stock options in DalCor. Dr Reusch reports grant support from Merck and nonfinancial support from the American Diabetes Association. Dr Riesmeyer is an employee of Eli Lilly and Co. Dr Roe reports grant support from the American College of Cardiology, American Heart Association, AstraZeneca, Familial Hypercholesterolemia Association, Ferring Pharmaceuticals, Janssen Pharmaceuticals, Myokardia, Patient Centered Outcomes Research Institute, and Sanofi-Aventis, as well as consulting fees from Amgen, Ardea Biosciences, AstraZeneca, Eli Lilly & Co, Elsevier Publishers, Flatiron, Janssen Pharmaceuticals, Novo Nordisk, Pfizer, Regeneron, Roche-Genentech, Sanofi-Aventis, and Signal Path. Dr Wiviott reports grants from Amgen, Arena, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi-Aventis, as well as consulting fees from ARENA, AstraZeneca, Aegerion, Allergan, Angelmed, Boehringer-Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Icon Clinical, Janssen, Lexicon, Merck, Servier, St Jude Medical, and Xoma. His spouse is an employee of Merck. Dr McMurray reports service as a steering committee member for trials funded by Abbvie, Vifor-Fresenius Pharma, Kidney Research UK, Bayer, Cardiorentis, Amgen, Oxford University/Bayer, DalCor, Bristol-Myers Squibb, GlaxoSmithKline, and Novartis; as a principal investigator for trials funded by Theracos, AstraZeneca, GlaxoSmithKline, and Novartis; and as a Data Safety Monitoring Committee member for trials funded by Pfizer and Merck. Dr Granger has disclosures listed at https://dcri.org/about-us/conflict-of-interest/. Drs Rosenberg and Temple report no conflicts.

Sources of Funding

Funding support for the meeting from which this consensus document was generated was provided through registration fees from Amgen, Inc; AstraZeneca; Bayer Pharma AG; Boehringer Ingelheim Pharma GmbH & Co KG; Eli Lilly and Co; Janssen, Pharmaceuticals Companies of Johnson & Johnson; Novo Nordisk; Pfizer Inc; and Sanofi. No government funds were used for this meeting. Role of the think tank meeting sponsors: This think tank was funded by industry sponsors with representation at the meeting. The first draft of the manuscript was written independently of sponsor input. Industry representatives were able to provide comments on subsequent drafts of the manuscript. The ultimate decision to include these comments rested with the primary and senior authors.

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Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus
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