TABLE 3.
Summary of the GLP-1RA CV Outcomes Trials
| ELIXA (77) | LEADER (14) | SUSTAIN-6* (15) | EXSCEL (78) | REWIND (16) | PIONEER-6 (79) | |
|---|---|---|---|---|---|---|
| Patients enrolled | 6,068 | 9,340 | 3,297 | 14,752 | 9,901 | 3183 |
| Drug | Lixisenatide | Liraglutide | Semaglutide SQ | Exenatide QW | Dulaglutide | Semaglutide oral |
| Dose | 10 mcg or 20 mcg per day | 1.8 mg or max tolerated dose per day | 0.5 mg or 1 mg per week | 2 mg per week | 1.5 mg per week | 14 mg or max tolerated dose per day |
| Median follow-up (years) | 2.1 | 3.8 | 2.1 | 3.2 | 5.4 | 1.3 |
| Baseline HbA1c | 7.7 | 8.7 | 8.7 | 8.0 | 7.2 | 8.2 |
| Mean duration of diabetes (years) | 9.3 | 12.8 | 13.9 | 12.0 | 9.5 | 14.9 |
| Baseline statin use (%) | 93 | 72 | 73 | 74 | 66 | 85 |
| Baseline prevalence of ASCVD†/HF (%) | 100 | 81 | 72 | 73 | 31 | 85 |
| Baseline prevalence of HF (%) | 22 | 18 | 24 | 16 | 9 | NR |
| Primary outcome, HR (95% CI)‡ | 4-point MACE 1.02 (0.89-1.17) | 3-point MACE 0.87 (0.78-0.97) | 3-point MACE 0.74 (0.58-0.95) | 3-point MACE 0.91 (0.83-1.00) | 3-point MACE 0.88 (0.79-0.99) | 3-point MACE 0.79 (0.57-1.11) |
| CV death, HR (95% CI) | 0.98 (0.78-1.22) | 0.78 (0.66-0.93) | 0.98 (0.65-1.48) | 0.88 (0.76-1.02) | 0.91 (0.78-1.06) | 0.49 (0.27-0.92) |
| Fatal or nonfatal MI, HR (95% CI)§ | 1.03 (0.87-1.22) | 0.86 (0.73-1.00) | 0.74 (0.51-1.08) | 0.97 (0.85-1.10) | 0.96 (0.79-1.15) | 1.18 (0.73-1.90) |
| Fatal or nonfatal stroke, HR (95% CI)§ | 1.12 (0.79-1.58) | 0.86 (0.71-1.06) | 0.61 (0.38-0.99) | 0.85 (0.70-1.03) | 0.76 (0.62-0.94) | 0.74 (0.35-1.57) |
| All-cause mortality, HR (95% CI) | 0.94 (0.78-1.13) | 0.85 (0.74-0.97) | 1.05 (0.74-1.50) | 0.86 (0.77-0.97) | 0.90 (0.80-1.01) | 0.51 (0.31-0.84) |
| HF hospitalization, HR (95% CI)∥ | 0.96 (0.75-1.23) | 0.87 (0.73-1.05) | 0.86 (0.48-1.55) | 0.94 (0.78-1.13) | 0.93 (0.77-1.12)∥ | 1.11 (0.77-1.61) |
| Renal composite outcome¶ | 0.84 (0.68-1.02) | 0.78 (0.67-0.92) | 0.64 (0.46-0.88) | 0.88 (0.76-1.01) | 0.85 (0.77-0.93) | 0.64 (0.46-0.88) |
As noted in the text, SUSTAIN-6 was designed and powered as a noninferiority trial. Testing for superiority for the primary CV outcome was not prespecified.
SUSTAIN-6 reported that 72.2% of patients had established CV disease with or without chronic kidney disease, and 10.7% had chronic kidney disease without ASCVD.
Three-point MACE is a composite of CV death, MI, or stroke. The 4-point MACE used in the ELIXA trial was a composite of CV death, MI, stroke, or hospitalization for unstable angina.
The risk estimates and 95% CIs for ELIXA, SUSTAIN-6, and PIONEER 6 are for nonfatal MI (excluding fatal MI) or nonfatal stroke (excluding fatal stroke). The effect estimates for the composite endpoints of fatal or nonfatal MI and fatal or nonfatal stroke were not available in the primary manuscripts.
Urgent HF visit or hospitalization for HF.
The renal composite outcome reported in a recent meta-analysis was a composite of the development of macroalbuminuria, doubling of serum creatinine, a ≥40% decline in eGFR, development of end-stage kidney disease, or death due to renal causes (81). For SUSTAIN-6, the renal composite was persistent macroalbuminuria, persistent doubling of serum creatinine with an eGFR <45 ml/min/1.73 m2 or need for continuous renal replacement therapy.
CI = confidence interval; CV = cardiovascular; ELIXA = Evaluation of CV Outcomes in Patients With T2D After Acute Coronary Syndrome During Treatment With AVE0010 (Lixisenatide); EXSCEL = Exenatide Study of CV Event Lowering Trial; GLP-1RA = glucagon-like peptide-1 receptor agonists; HbA1c = hemoglobin A1c; HF = heart failure; HR = hazard ratio; LEADER = Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results; MACE = major adverse cardiovascular event; MI = myocardial infarction; NR = not reported; PIONEER-6 = A Trial Investigating the CV Safety of Oral Semaglutide in Subjects With T2D; QW = once weekly; REWIND = Researching Cardiovascular Events With a Weekly Incretin in Diabetes; SQ = subcutaneous; SUSTAIN-6 = Trial to Evaluate CV and Other Long-term Outcomes With Semaglutide in Subjects With T2D.