From: DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits
Characteristic | ELIXA (2015) [56] | SUSTAIN-6 (2016) [53] | LEADER (2016) [54] | EXSCEL (2017) [59] | HARMONY (2018) [60] | PIONEER 6 (2019) [61] | REWIND (2019) [62] | AMPLITUDE-O (2021) [63] |
---|---|---|---|---|---|---|---|---|
Drug | Lixisenatide | Semaglutide | Liraglutide | Exenatide | Albiglutide | Semaglutide | Dulaglutide | Efpeglenatide |
Control | Placebo | Placebo | Placebo | Placebo | Placebo | Placebo | Placebo | Placebo |
Median follow-up (years) | 2.1 | 2.1 | 3.5 | 3.2 | 1.6 | 1.3 | 5.4 | 1.81 |
Inclusion criteria | T2DM and acute coronary events within the past 180 d |  ≥ 50 years of age with established CVD, HF (class I or II), CKD (stage 3 +), or ≥ 60 with cardiovascular risk factor |  ≥ 50 years of age with established CVD, HF (class I or II), CKD (stage 3 +), or ≥ 60 with cardiovascular risk factor | T2DM on 0–3 oral or insulin antidiabetic drugs; HbA1c 6.5–10.0% |  ≥ 40 years of age with T2DM; HbA1c > 7.0%; established CVD |  ≥ 50 years; T2DM with established CVD; or ≥ 60 with cardiovascular risk factor |  ≥ 50 years; T2DM with HbA1c ≤ 9.5%; two or less oral glucose-lowering drugs | T2DM with history of CVD or eGFR 25.0 to 59.9 ml/(min‧1.73 m2) |
Exclusion criteria |  < 30 years of age, PCI within past 15 d, CABG for the qualifying event, planned revascularization, eGFR < 30 ml/(min‧1.73 m2), HbA1c < 5.5% or > 11.0% | Treatment with DPP-4i, GLP-1R, or insulin other than basal within 30 d; premixed insulin treatment within 90 d; acute coronary or cerebrovascular event within 90 d; planned coronary intervention | T1DM; use of GLP-1RAs, DPP-4i, or rapid-acting insulin; familial history of medullary thyroid cancer or type 2 endocrine neoplasia; acute coronary or cerebrovascular event within 14 d | T1DM; use of GLP-1RAs; history of gastroparesis, pancreatitis; pregnancy; eGFR < 30 ml/(min‧1.73 m2); planned revascularization | eGFR < 30 ml/(min‧1.73 m2); use of GLP-1RAs; severe gastroparesis; history of pancreatitis, pancreatic tumors, medullary carcinoma of the thyroid; pregnancy, breastfeeding | Use of DPP-4i, GLP-1R; malignant neoplasms; pancreatitis; HF class IV; planned revascularisation; eGFR < 30 ml/(min‧1.73 m2) | eGFR < 15 ml/(min‧1.73 m2); cancer; severe hypoglycemia history; life expectancy < 1 year; coronary or cerebrovascular event within 2 months; planned revascularization | History of GI disease, pancreatitis; hypertension; personal or family history of medullary thyroid cancer; planned coronary procedure; use of DPP-4i, GLP-1R; retinopathy or maculopathy |
Results of primary endpoint (vs. placebo) | Non-inferiority; HR = 1.02 (95% CI 0.89–1.17) | 6.6% vs. 8.9%; HR = 0.74 (95% CI 0.58–0.95); P < 0.001 for non-inferiority; P = 0.02 for superiority | HR = 0.87 (95% CI 0.78–0.97); P < 0.001 for non-inferiority; P = 0.01 for superiority | 11.4% vs. 12.2%; HR = 0.91 (95% CI 0.83–1.00); P = 0.06 for superiority | 7% vs. 9%; HR = 0.78 (95% CI 0.68–0.90); P < 0.0001 for non-inferiority; P = 0.0006 for superiority | 3.8% vs. 4.8%; HR = 0.79 (95% CI 0.57–1.11); P = 0.17* | 12.0% vs. 13.4%; HR = 0.88 (95% CI 0.79–0.99); P = 0.026 for superiority | 7.0% vs. 9.2%; HR = 0.73 (95% CI 0.58–0.92); P < 0.001 for non-inferiority; P = 0.007 for superiority |
HF | HR = 0.96 (95% CI 0.75–1.23) | HR = 1.11 (95% CI 0.77–1.61) | 4.7% vs. 5.3%; HR = 0.87 (95% CI 0.73–1.05) | HR = 0.94 (95% CI 0.78–1.13) | HR = 0.85 (95% CI 0.70–1.04) | 1.3% vs. 1.5%; HR = 0.86 (95% CI 0.48–1.55) | HR = 0.93 (95% CI 0.77–1.12) | HR = 0.61 (95% CI 0.38–0.98) |
Myocardial infarction | HR = 1.03 (95% CI 0.87–1.22) | HR = 0.74 (95% CI 0.51–1.08) | 6.3% vs. 7.3%; HR = 0.86 (95% CI 0.73–1.00) | HR = 0.97 (95% CI 0.85–1.10) | HR = 0.75 (95% CI 0.61–0.90) | HR = 1.18 (95% CI 0.73–1.90) | 4.1% vs. 4.3%; P = 0.65 | HR = 0.75 (95% CI 0.54–1.05) |