Table 3.
CVOTs completed after issuance of the FDA 2008 guidance
| DPP-4 inhibitors |
GLP-1 receptor agonists |
SGLT2 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) | |
| Intervention |
Saxagliptin/placebo |
Alogliptin/placebo |
Sitagliptin/placebo |
Lixisenatide/placebo |
Liraglutide/ placebo |
Semaglutide/placebo |
Exenatide QW/placebo |
Empagliflozin/placebo |
Canagliflozin/ placebo |
| Main inclusion criteria |
Type 2 diabetes and history of or multiple risk factors for CVD |
Type 2 diabetes and ACS within15–90 days before randomization |
Type 2 diabetes and preexisting CVD |
Type 2 diabetes and an acute coronary event within 180 days before screening |
Type 2 diabetes and preexisting CVD, kidney disease, or HF at ≥50 years of age or ≥1 CV risk factor at ≥60 years of age |
Type 2 diabetes and preexisting CVD, HF, or CKD at ≥50 years of age or ≥1 CV risk factor at ≥60 years of age |
Type 2 diabetes with or without preexisting CVD |
Type 2 diabetes and preexisting CVD, with BMI ≤45 kg/m2 and eGFR ≥30 mL/min/1.73 m2 |
Type 2 diabetes and preexisting CVD at ≥30 years of age or ≥2 CV risk factors at ≥50 years of age |
| A1C inclusion criterion (%) |
≥6.5 |
6.5–11.0 |
6.5–8.0 |
5.5–11.0 |
≥7.0 |
≥7.0 |
6.5–10.0 |
7.0–10.0 |
7.0–10.5 |
| Age (years)† |
65.1 |
61.0 |
65.4 |
60.3 |
64.3 |
64.6 |
62 |
63.1 |
63.3 |
| BMI (kg/m2)† |
31.1 |
28.7 |
30.2 |
30.2 |
32.5 |
32.8 |
31.8 |
30.7 |
32 |
| Diabetes duration (years)† |
10.3 |
7.1 |
11.6 |
9.3 |
12.8 |
13.9 |
12 |
57% >10 |
13.5 |
| Events planned/observed (n) |
1,040/1,222 |
650/621 |
1,300/1,690 |
844/805 |
≥611/1,302 |
≥122/254 |
1,360/1,744 |
691/772 |
688/1,011 |
| Median follow-up (years) |
2.1 |
1.5 |
3.0 |
2.1 |
3.8 |
2.1 |
3.2 |
3.1 |
2.4 |
| Statin use (%) |
78 |
91 |
80 |
93 |
72 |
73 |
74 |
77 |
75 |
| Prior CVD/CHF (%) |
78/13 |
100/28 |
74/18 |
100/22 |
81/18 |
60/24 |
73.1/16.2 |
99/10 |
65.6/14.4 |
| A1C/A1C change (%)‡ |
8.0/–0.3 |
8.0/–0.3 |
7.2/–0.3 |
7.7/–0.3 |
8.7/–0.4 |
8.7/–0.7 or –1.0§ |
8.0/–0.53 |
8.1/–0.3‖ |
8.2/–0.58 |
| Year started/reported |
2010/2013 |
2009/2013 |
2008/2015 |
2010/2015 |
2010/2016 |
2013/2016 |
2010/2017 |
2010/2015 |
2009/2017 |
| Primary outcome¶ |
3-point MACE |
3-point MACE |
4-point MACE |
4-point MACE |
3-point MACE |
3-point MACE |
3-point MACE |
3-point MACE |
3-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 outcome¶ |
Expanded MACE |
4-point MACE |
3-point MACE |
Expanded MACE |
Expanded MACE |
Expanded MACE |
Individual components of MACE (see below) |
4-point MACE |
All-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 death¶ |
1.03 (0.87–1.22) |
0.85 (0.66–1.10) |
1.03 (0.89–1.19) |
0.98 (0.78–1.22) |
0.78 (0.66–0.93) |
0.98 (0.65–1.48) |
0.88 (0.76–1.02) |
0.62 (0.49–0.77) |
0.96 (0.77–1.18)** |
| 0.87 (0.72–1.06)# | |||||||||
| MI¶†† |
0.95 (0.80–1.12) |
1.08 (0.88–1.33) |
0.95 (0.81–1.11) |
1.03 (0.87–1.22) |
0.86 (0.73–1.00) |
0.74 (0.51–1.08) |
0.97 (0.85–1.10) |
0.87 (0.70–1.09) |
0.89 (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 hospitalization¶ |
1.27 (1.07–1.51) |
1.19 (0.90–1.58) |
1.00 (0.83–1.20) |
0.96 (0.75–1.23) |
0.87 (0.73–1.05) |
1.11 (0.77–1.61) |
0.94 (0.78–1.13) |
0.65 (0.50–0.85) |
0.67 (0.52–0.87)# |
| Unstable angina hospitalization¶ |
1.19 (0.89–1.60) |
0.90 (0.60–1.37) |
0.90 (0.70–1.16) |
1.11 (0.47–2.62) |
0.98 (0.76–1.26) |
0.82 (0.47–1.44) |
1.05 (0.94–1.18) |
0.99 (0.74–1.34) |
— |
| All-cause mortality¶ |
1.11 (0.96–1.27) |
0.88 (0.71–1.09) |
1.01 (0.90–1.14) |
0.94 (0.78–1.13) |
0.85 (0.74–0.97) |
1.05 (0.74–1.50) |
0.86 (0.77–0.97) |
0.68 (0.57–0.82) |
0.87 (0.74–1.01)** |
| 0.90 (0.76–1.07)# | |||||||||
| 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.