Table 3

CVOTs completed after issuance of the FDA 2008 guidance

DPP-4 inhibitorsGLP-1 receptor agonistsSGLT2 inhibitors
SAVOR-TIMI 53 (6) (n = 16,492)EXAMINE (7,59) (n = 5,380)TECOS (8) (n = 14,671)ELIXA (9) (n = 6,068)LEADER (10) (n = 9,340)SUSTAIN-6 (11)* (n = 3,297)EXSCEL (12) (n = 14,752)EMPA-REG OUTCOME (13,60) (n = 7,020)CANVAS Program (14) (n = 10,142)
InterventionSaxagliptin/placeboAlogliptin/placeboSitagliptin/placeboLixisenatide/placeboLiraglutide/ placeboSemaglutide/placeboExenatide QW/placeboEmpagliflozin/placeboCanagliflozin/ placebo
Main inclusion criteriaType 2 diabetes and history of or multiple risk factors for CVDType 2 diabetes and ACS within15–90 days before randomizationType 2 diabetes and preexisting CVDType 2 diabetes and an acute coronary event within 180 days before screeningType 2 diabetes and preexisting CVD, kidney disease, or HF at ≥50 years of age or ≥1 CV risk factor at ≥60 years of ageType 2 diabetes and preexisting CVD, HF, or CKD at ≥50 years of age or ≥1 CV risk factor at ≥60 years of ageType 2 diabetes with or without preexisting CVDType 2 diabetes and preexisting CVD, with BMI ≤45 kg/m2 and eGFR ≥30 mL/min/1.73 m2Type 2 diabetes and preexisting CVD at ≥30 years of age or ≥2 CV risk factors at ≥50 years of age
A1C inclusion criterion (%)≥6.56.5–11.06.5–8.05.5–11.0≥7.0≥7.06.5–10.07.0–10.07.0–10.5
Age (years)65.161.065.460.364.364.66263.163.3
BMI (kg/m2)31.128.730.230.232.532.831.830.732
Diabetes duration (years)10.37.111.69.312.813.91257% >1013.5
Events planned/observed (n)1,040/1,222650/6211,300/1,690844/805≥611/1,302≥122/2541,360/1,744691/772688/1,011
Median follow-up (years)2.11.53.02.13.82.13.23.12.4
Statin use (%)789180937273747775
Prior CVD/CHF (%)78/13100/2874/18100/2281/1860/2473.1/16.299/1065.6/14.4
A1C/A1C change (%)8.0/–0.38.0/–0.37.2/–0.37.7/–0.38.7/–0.48.7/–0.7 or –1.0§8.0/–0.538.1/–0.38.2/–0.58
Year started/reported2010/20132009/20132008/20152010/20152010/20162013/20162010/20172010/20152009/2017
Primary outcome3-point MACE3-point MACE4-point MACE4-point MACE3-point MACE3-point MACE3-point MACE3-point MACE3-point MACE
1.00 (0.89–1.12)0.96 (95% UL ≤1.16)0.98 (0.89–1.08)1.02 (0.89–1.17)0.87 (0.78–0.97)0.74 (0.58–0.95)0.91 (0.83–1.00)0.86 (0.74–0.99)0.86 (0.75–0.97)#
Key secondary outcomeExpanded MACE4-point MACE3-point MACEExpanded MACEExpanded MACEExpanded MACEIndividual components of MACE (see below)4-point MACEAll-cause and CV mortality (see below)
1.02 (0.94–1.11)0.95 (95% UL ≤1.14)0.99 (0.89–1.10)1.00 (0.90–1.11)0.88 (0.81–0.96)0.74 (0.62–0.89)0.89 (0.78–1.01)
CV death1.03 (0.87–1.22)0.85 (0.66–1.10)1.03 (0.89–1.19)0.98 (0.78–1.22)0.78 (0.66–0.93)0.98 (0.65–1.48)0.88 (0.76–1.02)0.62 (0.49–0.77)0.96 (0.77–1.18)**
0.87 (0.72–1.06)#
MI††0.95 (0.80–1.12)1.08 (0.88–1.33)0.95 (0.81–1.11)1.03 (0.87–1.22)0.86 (0.73–1.00)0.74 (0.51–1.08)0.97 (0.85–1.10)0.87 (0.70–1.09)0.89 (0.73–1.09)#
Stroke††1.11 (0.88–1.39)0.91 (0.55–1.50)0.97 (0.79–1.19)1.12 (0.79–1.58)0.86 (0.71–1.06)0.61 (0.38–0.99)0.85 (0.70–1.03)1.18 (0.89–1.56)0.87 (0.69–1.09)#
HF hospitalization1.27 (1.07–1.51)1.19 (0.90–1.58)1.00 (0.83–1.20)0.96 (0.75–1.23)0.87 (0.73–1.05)1.11 (0.77–1.61)0.94 (0.78–1.13)0.65 (0.50–0.85)0.67 (0.52–0.87)#
Unstable angina hospitalization1.19 (0.89–1.60)0.90 (0.60–1.37)0.90 (0.70–1.16)1.11 (0.47–2.62)0.98 (0.76–1.26)0.82 (0.47–1.44)1.05 (0.94–1.18)0.99 (0.74–1.34)
All-cause mortality1.11 (0.96–1.27)0.88 (0.71–1.09)1.01 (0.90–1.14)0.94 (0.78–1.13)0.85 (0.74–0.97)1.05 (0.74–1.50)0.86 (0.77–0.97)0.68 (0.57–0.82)0.87 (0.74–1.01)**
0.90 (0.76–1.07)#
Worsening nephropathy‡‡1.08 (0.88–1.32)0.78 (0.67–0.92)0.64 (0.46–0.88)0.61 (0.53–0.70)0.60 (0.47–0.77)#
  • —, not assessed/reported; 95% UL, upper limit of 95% CI; CHF, congestive heart failure.

  • *Powered to rule out an HR upper margin ≥1.8; superiority hypothesis not prespecified.

  • †Age and BMI were reported as means in all trials except EXAMINE, which reported medians; diabetes duration was reported as means in all but four trials, with SAVOR-TIMI 58, EXAMINE, and EXSCEL reporting medians and EMPA-REG OUTCOME reporting as percentage of population with diabetes duration >10 years.

  • ‡For TECOS, LEADER, EXSCEL, and the CANVAS Program, A1C difference was updated over time; for SAVOR-TIMI 53, EXAMINE, ELIXA, SUSTAIN-6, and EMPA-REG OUTCOME, A1C difference was at study end.

  • §A1C change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide.

  • ‖A1C change of 0.30 in EMPA-REG OUTCOME is based on pooled results for both doses (i.e., 0.24% for 10 mg and 0.36% for 25 mg of empagliflozin).

  • ¶Outcomes reported as HR (95% CI) unless otherwise noted.

  • #Nontruncated integrated data (refers to pooled data from CANVAS, including before 20 November 2012 plus CANVAS-R).

  • **Truncated integrated data set (refers to pooled data from CANVAS after 20 November 2012 plus CANVAS-R; prespecified in treating hierarchy as the principal data set for analysis for superiority of all-cause mortality and CV death in the CANVAS Program).

  • ††Reported for fatal and nonfatal events in all trials except EXAMINE, ELIXA, and SUSTAIN-6, which reported for nonfatal events only.

  • ‡‡Worsening nephropathy was defined as doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL (530 μmol/L) in SAVOR-TIMI 53; as the new onset of macroalbuminuria (urine albumin creatinine ratio >300 mg/g) or a doubling of the serum creatinine level and an eGFR of ≤45 mL/min/1.73 m2, the need for continuous renal-replacement therapy, or death from renal disease in LEADER, SUSTAIN-6, and EMPA-REG OUTCOME; and as 40% reduction in eGFR, renal-replacement therapy, or death from renal causes in CANVAS. Worsening nephropathy was a prespecified exploratory adjudicated outcome in SAVOR-TIMI 53, LEADER, SUSTAIN-6, and CANVAS but not in EMPA-REG OUTCOME.