Table 4.
Major cardiovascular and renal outcome trials of GLP-1 receptor agonists
| Trial (Year) | Population | Drug | Primary outcome | Key findings |
|---|---|---|---|---|
| ELIXA (2015) | DM2 + recent acute coronary syndrome | Lixisenatide | 3-point MACE | Demonstrated cardiovascular safety but no significant reduction in MACE |
| LEADER (2016) | DM2 + high CV risk | Liraglutide | 3-point MACE | 13% reduction in MACE; 22% reduction in CV death |
| SUSTAIN-6 (2016) | DM2 + high CV risk | Semaglutide (s.c.) | 3-point MACE | 26% reduction in MACE; significant reduction in stroke |
| EXSCEL (2017) | DM2 with or without CVD | Exenatide (weekly) | 3-point MACE | Demonstrated CV safety; non-significant trend toward reduced MACE |
| REWIND (2019) | DM2 with or without CVD | Dulaglutide | 3-point MACE | Significant reduction in MACE; benefit extended to primary prevention population |
| FLOW (2024) | DM2 + CKD | Semaglutide (s.c.) 1 mg | Renal composite (eGFR decline ≥ 50%, ESKD, renal/CV death) | 24% reduction in primary renal composite; first dedicated renal outcomes trial for GLP-1 RAs |
| SELECT (2023) | No diabetes; established CVD; BMI ≥ 27 kg/m2 | Semaglutide (s.c.) 2.4 mg | 3-point MACE (CV death, MI, stroke) | 20% reduction in MACE (HR 0.80); first GLP-1 RA CVOT in non-diabetic patients; benefits independent of weight loss magnitude |
| STEP-HFpEF (2023) | HFpEF (LVEF ≥ 45%); BMI ≥ 30 kg/m2; no diabetes | Semaglutide (s.c.) 2.4 mg | KCCQ-CSS change and body weight change (dual primary) | KCCQ-CSS improved by 7.8 points vs. placebo; body weight reduced by 10.7%; first pharmacological therapy to significantly improve symptoms in obesity-related HFpEF |
| HARMONY-OUTCOMES (2018) | T2DM + established CVD | Albiglutide | 3-point MACE | 22% reduction in MACE (HR 0.78); negligible weight effect supports weight-independent CV protection |
| AMPLITUDE-O (2021) | T2DM + high CV risk or CKD | Efpeglenatide | 3-point MACE + renal composite | 27% reduction in MACE (HR 0.73); significant reduction in composite renal outcome |
| PIONEER-6 (2019) | T2DM + high CV risk | Oral semaglutide 14 mg | 3-point MACE | CV safety established; non-significant 21% MACE reduction (HR 0.79) |
| SOUL (2025) | T2DM + ASCVD and/or CKD (n = 9,650; ~31% on SGLT2i) | Oral semaglutide 14 mg | 3-point MACE | Significant 14% reduction in CV composite; benefit consistent regardless of baseline SGLT2i use |