Table 1.
Key features of cardiovascular outcome trials of long-acting GLP-1RAs
| LEADER (n = 9340) | SUSTAIN-6 (n = 3297) | EXSCEL (n = 14,752) | Harmony Outcomes (n = 9463) | REWIND (n = 9901) | PIONEER-6 (n = 3183) | |
|---|---|---|---|---|---|---|
| ID code | NCT01179048 | NCT01720446 | NCT01144338 | NCT02465515 | NCT01394952 | NCT02692716 |
| Key inclusion criteria | HbA1c ≥ 7.0%; age ≥ 50 years with CVD, CHF (NYHA class II or III), CKD (stage 3 or higher), or age ≥ 60 years with at least one CV risk factor | HbA1c ≥ 7.0%; age ≥ 50 years with CVD, CHF (NYHA class II or III), CKD (stage 3 or higher), or age ≥ 60 years with at least one CV risk factor | HbA1c 6.5–10.0%; established CVD and primary prevention; age ≥ 18 years | HbA1c ≥ 7.0%; age ≥ 40 years with ASCVD | HbA1c ≤ 9.5%; age ≥ 50 years with established CVD or age ≥ 60 years with at least two CV risk factors; BMI ≥ 23 kg/m2 | Aged ≥ 50 years with established CVD, moderate CKD (stage 3), or aged ≥ 60 years with at least one CV risk factor |
| Intervention | Liraglutide vs. placebo | Semaglutide vs. placebo | Exenatide vs. placebo | Albiglutide vs. placebo | Dulaglutide vs. placebo | Semaglutide vs. placebo |
| Usage | SI 1.8 mg, once daily | SI 0.5 or 1.0 mg, once weekly | SI 2 mg, once weekly | SI 30 mg, once weekly | SI 1.5 mg, once weekly | Oral 14 mg, once daily |
| Dose strategy | Forced increase | Forced increase | Single dose | Clinical titration | Single dose | Increased if tolerated |
| Follow-up (median) | 3.8 years | 2.1 years | 3.2 years | 1.6 years | 5.4 years | 15.9 months |
| Phase | III | III | III/IV | IV | III | III |
| Female sex | 3339 (35.7%) | 1294 (39.2%) | 5605 (38.0%) | 2886 (30.5%) | 4589 (46.4%) | 1005 (31.9%) |
| White | 7430 (79.5%) | 2736 (83.0%) | 11,175 (75.8%) | 8024 (84.8%) | 7498 (75.7%) | 2300 (72.3%) |
| Asian | 1256 (13.4%) | 272 (8.2%) | 1453 (9.8%) | 464 (4.9%) | 4.4% | 19.8% |
| Mean baseline HbA1c (%) | 8.7 ± 1.6 | 8.7 ± 1.5 | 8.1 ± 1.0 | 8.7 ± 1.5 | 7.3 ± 1.1 | 8.2 ± 1.6 |
| DM duration (years) | 12.7 ± 8.0 | 13.9 ± 8.1 | 12.0 (7.0, 17.0) | 14.1 ± 8.7 | 10.0 ± 7.2 years | 14.9 ± 8.5 years |
| Baseline BMI (kg/m2) | 32.5 ± 6.3 | 32.8 ± 6.0 | 31.8 (28.2, 36.2) | 32.3 ± 5.9 | 32.3 ± 5.7 | 32.3 ± 6.6 |
| ≥ 30 kg/m2 | 5753 (61.6%) | 2115 (64.1%) | 9338 (63.3%) | 5834 (61.6%) | 6068 (61.3%) | 1902 (59.8%) |
| < 30 kg/m2 | 3587 (38.4%) | 1182 (35.9%) | 5414 (36.7%) | 3629 (38.4%) | 3833 (38.7%) | 1279 (40.2%) |
| Baseline SBP (mmHg) | 135.9 ± 17.7 | 135.6 ± 17.0 | 135 (124, 145) | 134.7 ± 16.6 | 137.2 ± 16.8 | 135.6 ± 17.6 |
| LDL (mmol/L) | 2.3 ± 0.9 | 2.13 ± 1.19 | 2.4 ± 1.0 | 2.1 | 2.56 ± 0.98 | 2.2 ± 0.9 |
| Prior established CVD | 81% | 83% | 73% | 100% | 31.4% | 84.6% |
| Prior heart failurea | 14.0% | 23.6% | 16.2% | 20% | 8.6% | 12.2% |
| Pre-existing retinopathy | 17% | 29.4% | NA | 18.5% | 9.0% | 27.2% |
| Primary outcome | Three point-MACE | Three point-MACE | Three point-MACE | Three point-MACE | Three point-MACE | Three point-MACE |
| Number of events in long-acting GLP-1RAs group | 608 | 108 | 839 | 334 | 594 | 61 |
| HR (95% CI) | 0.87 (0.78, 0.97); P < 0.001 for non-inferiority; P = 0.01 for superiority | 0.74 (0.58, 0.95); P < 0.001 for non-inferiority; P = 0.02 for superiority | 0.91 (0.83, 1.00); P < 0.001 for non-inferiority; P = 0.06 for superiority | 0.78 (0.68, 0.90); P < 0.0001for non-inferiority; P = 0.0006 for superiority | 0.88 (0.79, 0.99); P = 0.026 | 0.79 (0.57, 1.11); P < 0.001 for non-inferiority |
| Completion | December 2015 | March 2016 | May 2017 | March 2018 | August 2018 | September 2018 |
Data are n, %, or mean (SD), unless otherwise specified. GLP-1RAs glucagon-like peptide 1 receptor agonists, BMI body mass index, HbA1c glycated hemoglobin, CVD cardiovascular disease, CV cardiovascular, CHF chronic heart failure, CKD chronic kidney disease, ASCVD arteriosclerotic cardiovascular disease, SI subcutaneous injections, MACE major adverse cardiovascular events, HR hazard ratio, CI confidence interval, NYHA New York Heart Association functional classification
aHeart failure with NYHA II–III