Table 1.
Summary of major large-scale clinical trials with GLP-1RAs
| ELIXA [24] | LEADER [16] | SUSTAIN-6 [17] | EXSCEL [36] | Harmony Outcomes [18] | REWIND [19] | PIONEER-6 [59] | AMPLITUDE-O [20] | SELECT [25] | FLOW [31] | |
|---|---|---|---|---|---|---|---|---|---|---|
| Drug | Lixisenatide | Liraglutide | Semaglutide (s.c. injection) | Exenatide | Albiglutide | Dulaglutide | Semaglutide (oral) | Efpeglenatide | Semaglutide (s.c. injection) | Semaglutide (s.c. injection) |
| Dose | 10 or 20 μg per day | 1.8 mg per day | 0.5 or 1.0 mg per week | 2.0 mg per week | 30 or 50 mg per week | 1.5 mg per week | 14 mg per day | 4 or 6 mg per week | 2.4 mg per week | 1.0 mg per week |
| Number | 6068 | 9340 | 3297 | 14,752 | 9463 | 9903 | 3183 | 4076 | 17,604 | 3533 |
| Population | T2DM and history of acute coronary syndrome within 180 days | T2DM with high cardiovascular risk* | T2DM with high cardiovascular risk* | T2DM with or without previous CVD | T2DM with previous CVD | T2DM with previous CVD or risk factors of CVD | T2DM with high cardiovascular risk* | T2DM with previous CVD, or CKD and additional risk of CVD | BMI ≥ 27 kg/m2 and previous CVD without diabetes | T2DM and CKD |
| Observation period, years | 2.1 | 3.8 | 3.1 | 3.2 | 1.6 | 5.4 | 1.3 | 1.8 | 3.3 | 3.4 |
| Age, years | 60 | 64 | 65 | 62 | 64 | 66 | 66 | 65 | 62 | 67 |
| BMI, kg/m2 | 30.1 | 32.5 | 32.8 | 32.7 | 32.3 | 32.3 | 32.3 | 32.7 | 33.3 | 32.0 |
| HbA1c, % | 7.7 | 8.7 | 8.7 | 8 | 8.7 | 7.4 | 8.2 | 8.9 | 5.8 | 7.8 |
| History of CVD, % | 100 | 81 | 60 | 73.1 | 71 | 32 | 85 | 90 | 100 | 22.9 |
| History of CHF, % | 22 | 18 | 24 | 16.2 | 20 | 9 | 12 | 18 | 24 | 19.2 |
| SGLT2i use at baseline, % | – | – | 0.2 |
0.9 (ITT population) |
6.1 | – | 10 | 15.2 | – | 15.6 |
| MACE, HR (95% CI) |
1.02** (0.89–1.17) |
0.87 (0.78–0.97) |
0.74 (0.58–0.95) |
0.91 (0.83–1.00) |
0.78 (0.68–0.90) |
0.88 (0.79–0.99) |
0.79 (0.57–1.11) |
0.73 (0.58–0.92) |
0.80 (0.72–0.90) |
0.82 (0.68–0.98) |
| Cardiovascular 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) |
0.93 (0.73–1.19) |
0.91 (0.78–1.06) |
0.49 (0.27–0.92) |
0.72 (0.50–1.03) |
0.85 (0.71–1.01) |
0.71 (0.56–0.89) |
| 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) |
0.75 (0.61–0.90) |
0.96 (0.79–1.15) |
1.18 (0.73–1.90) |
0.78 (0.55–1.10) |
0.72 (0.61–0.85) |
0.80 (0.55–1.15) |
| 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) |
0.86 (0.66–1.14) |
0.76 (0.61–0.95) |
0.74 (0.35–1.57) |
0.80 (0.48–1.31) |
0.93 (0.74–1.15) |
1.22 (0.84–1.77) |
| HHF, HR (95% CI) |
0.96 (0.75–1.23) |
0.87 (0.73–1.05) |
1.11 (0.77–1.61) |
0.94 (0.78–1.13) |
0.85*** (0.70–1.04) |
0.93 (0.77–1.12) |
0.86 (0.48–1.55) |
0.61 (0.38–0.98) |
0.79 (0.60–1.13) |
- |
| All cause death, 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) |
0.95 (0.79–1.16) |
0.90 (0.80–1.01) |
0.51 (0.31–0.84) |
0.78 (0.58–1.06) |
0.81 (0.71–0.93) |
0.80 (0.67–0.95) |
| Composite kidney events, HR (95% CI) | – |
0.78 (0.67–0.92) |
0.64 (0.46–0.88) |
– | – |
0.85 (0.77–0.93) |
– |
0.68 (0.57–0.79) |
0.78 (0.63–0.96) |
0.76**** (0.66–0.88) |
BMI body mass index, CI confidence interval, CHF congestive heart failure, CVD cardiovascular disease, GLP-1RA glucagon-like peptide-1 receptor agonist, HHF heart failure hospitalization, HR hazard ratio, ITT intention-to-treat, MACE major adverse cardiovascular events, MI myocardial infarction, s.c. subcutaneous, SGLT2i sodium-glucose cotransporter 2 inhibitor, T2DM type 2 diabetes mellitus
*Age of 50 years or more with at least one cardiovascular condition, or age of 60 years or more with at least one cardiovascular risk factor, ** 4-point MACE, *** Composite endpoint of CV death or HHF, **** Excluding macroalbuminuria