Table 10.3B.
Cardiovascular and cardiorenal outcomes trials of available antihyperglycemic medications completed after the issuance of the FDA 2008 guidelines: GLP-1 receptor agonists
| ELIXA (208) | LEADER (203) | SUSTAIN-6 (204)* | EXSCEL (209) | REWIND (207) | PIONEER-6 (205) | |
|---|---|---|---|---|---|---|
| (n = 6,068) | (n = 9,340) | (n = 3,297) | (n = 14,752) | (n = 9,901) | (n = 3,183) | |
| Intervention | Lixisenatide/placebo | Liraglutide/placebo | Semaglutide s.c. injection/placebo | Exenatide QW/ placebo | Dulaglutide/placebo | Semaglutide oral/ placebo |
| Main inclusion criteria | Type 2 diabetes and history of ACS (<180 days) | Type 2 diabetes and preexisting CVD, CKD, or HF at ≥50 years of age or CV risk at ≥60 years of age | Type 2 diabetes and preexisting CVD, HF, or CKD at ≥50 years of age or CV risk at ≥60 years of age | Type 2 diabetes with or without preexisting CVD | Type 2 diabetes and prior ASCVD event or risk factors for ASCVD | Type 2 diabetes and high CV risk (age of ≥50 years with established CVD or CKD, or age of ≥60 years with CV risk factors only) |
| A1C inclusion criteria (%) | 5.5–11.0 | ≥7.0 | ≥7.0 | 6.5–10.0 | ≤9.5 | None |
| Age (years)† | 60.3 | 64.3 | 64.6 | 62 | 66.2 | 66 |
| Race (% White) | 75.2 | 77.5 | 83.0 | 75.8 | 75.7 | 72.3 |
| Sex (% male) | 69.3 | 64.3 | 60.7 | 62 | 53.7 | 68.4 |
| Diabetes duration (years)† | 9.3 | 12.8 | 13.9 | 12 | 10.5 | 14.9 |
| Median follow-up (years) | 2.1 | 3.8 | 2.1 | 3.2 | 5.4 | 1.3 |
| Statin use (%) | 93 | 72 | 73 | 74 | 66 | 85.2 (all lipid-lowering) |
| Metformin use (%) | 66 | 76 | 73 | 77 | 81 | 77.4 |
| Prior CVD/CHF (%) | 100/22 | 81/18 | 60/24 | 73.1/16.2 | 32/9 | 84.7/12.2 |
| Mean baseline A1C (%) | 7.7 | 8.7 | 8.7 | 8.0 | 7.4 | 8.2 |
| Mean difference in A1C between groups at end of treatment (%) | −0.3‡^ | −0.4‡ | −0.7 or −1.0^ | −0.53‡^ | −0.61‡ | −0.7 |
| Year started/reported | 2010/2015 | 2010/2016 | 2013/2016 | 2010/2017 | 2011/2019 | 2017/2019 |
| Primary outcome§ | 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) |
| Key secondary outcome§ | Expanded MACE 1.02 (0.90–1.11) | Expanded MACE 0.88 (0.81–0.96) | Expanded MACE 0.74 (0.62–0.89) | Individual components of MACE (see below) | Composite microvascular outcome (eye or renal outcome) 0.87 (0.79–0.95) | Expanded MACE or HF hospitalization 0.82 (0.61–1.10) |
| Cardiovascular death§ | 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) |
| Ml§ | 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) |
| Stroke§ | 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 (0.61–0.95) | 0.74 (0.35–1.57) |
| HF hospitalization§ | 0.96 (0.75–1.23) | 0.87 (0.73–1.05) | 1.11 (0.77–1.61) | 0.94 (0.78–1.13) | 0.93 (0.77–1.12) | 0.86 (0.48–1.55) |
| Unstable angina hospitalization§ | 1.11 (0.47–2.62) | 0.98 (0.76–1.26) | 0.82 (0.47–1.44) | 1.05 (0.94–1.18) | 1.14 (0.84–1.54) | 1.56 (0.60–4.01) |
| All-cause mortality§ | 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) |
| Worsening nephropathy§ǁ | — | 0.78 (0.67–0.92) | 0.64 (0.46–0.88) | — | 0.85 (0.77–0.93) | — |
—, not assessed/reported; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; CVD, cardiovascular disease; GLP-1, glucagon-like peptide 1; HF, heart failure; MACE, major adverse cardiovascular event; Ml, myocardial infarction. Data from this table was adapted from Cefalu et al. (238) in the January 2018 issue of Diabetes Care.
Powered to rule out a hazard ratio of 1.8; superiority hypothesis not prespecified.
Age was reported as means in all trials; diabetes duration was reported as means in all trials except EXSCEL, which reported medians.
Significant difference in A1C between groups (P < 0.05).
AIC change of 0.66% with 0.5 mg and 1.05% with 1 mg dose of semaglutide.
Outcomes reported as hazard ratio (95% Cl).
Worsening nephropathy is defined as the new onset of urine albumin-to-creatinine ratio >300 mg/g creatinine or a doubling of the serum creatinine level and an estimated glomerular filtration rate of <45 mL/min/1.73 m2, the need for continuous renal replacement therapy, or death from renal disease in LEADER and SUSTAIN-6 and as new macroalbuminuria, a sustained decline in estimated glomerular filtration rate of 30% or more from baseline, or chronic renal replacement therapy in REWIND. Worsening nephropathy was a prespecified exploratory adjudicated outcome in LEADER, SUSTAIN-6, and REWIND.