Table 2 Summary of main CVOTs for DPP-4i
From: DPP-4 inhibitors and GLP-1RAs: cardiovascular safety and benefits
Characteristic | EXAMINE (2013) [48] | SAVOR-TIMI53 (2015) [49] | TECOS (2015) [47] | CARMELINA (2019) [57] | CAROLINA (2019) [58] |
|---|---|---|---|---|---|
Drug | Alogliptin | Saxagliptin | Sitagliptin | Linagliptin | Linagliptin |
Comparative agent | Placebo | Placebo | Placebo | Placebo | Glimepiride |
Median follow-up period (years) | 1.5 | 2.1 | 3 | 2.2 | 6.3 |
Inclusion criteria |  ≥ 18 years with T2DM who are receiving mono or combination therapy (excluding GLP-1RAs or DPP-4i); HbA1c levels between 6.5 and 11.0%; History of ACS within 15–90 days of screening | T2DM with HbA1c between 6.5 and 12.0% and an established cardiovascular disease or multiple vascular risk factors |  ≥ 50 years of age with T2DM; HbA1c 6.5 and 8.0% when treated with OAD or insulin; established cardiovascular disease | T2DM with HbA1c of 6.5–10.0%; high cardiovascular risk; high renal risk: eGFR 45–75 ml/(min‧1.73 m2) and UACR ≥ 200 mg/g, or eGFR 15–45 ml/(min‧1.73 m2) | Age 40–85 years; T2DM with increased cardiovascular risk or established CVD; HbA1c of 6.5–8.5%; BMI ≤ 45 kg/m2 |
Exclusion criteria | T1DM; currently on GLP-1RAs; taken DPP-4i for > 14 d or within past 3 months; unstable cardiovascular disorder; dialysis; severe immunodeficiency | Treatment with incretins in the past 6 months; dialysis; prior renal transplant; or serum creatinine higher than 6.0 mg per deciliter | Prior treatment with GLP-1RAs, DPP-4i, thiazolidinedione within the last 3 months; two or more hypoglycemia episodes in the past 12 months; eGFR < 30 ml/(min‧1.73 m2) | T1DM; prior use of GLP-1RAs or DPP-4i; eGFR < 15 ml/(min‧1.73 m2) or requiring maintenance dialysis; liver disease; bariatric surgery; nursing or pregnant women | T1DM; insulin therapy; prior use of DPP-4i, GLP-1RAs, or thiazolidinedione; uncontrolled hyperglycemia; liver disease; HF class III or IV |
Results of primary endpoint (vs. placebo/control) | HR = 0.96 (upper boundary of the one-sided repeated CI 1.16; P = 0.32 for superiority; P < 0.001 for non-inferiority) | HR = 1.00 (95% CI 0.89–1.12; P = 0.99 for superiority; P < 0.001 for non-inferiority) | HR = 0.98 (95% CI 0.88–1.09; P < 0.001 for non-inferiority; intention-to-treat analysis: 0.98; 95% CI 0.89–1.08; P = 0.65 for superiority) | HR = 1.02 (95% CI 0.89–1.17); P < 0.001 for non-inferiority | 11.8% vs. 12.0%; HR = 0.98 (95% CI 0.84–1.14; P < 0.001 for non-inferiority; P = 0.76 for superiority) |
HF hospitalization | HR = 1.07 (95% CI 0.79–1.46) | 3.5% vs. 2.8%; HR = 1.27 (95% CI 1.07–1.51; P = 0.007) | 3.1% vs. 3.1%; HR = 1.00 (95% CI 0.83–1.20); P = 0.98 | 6.0% vs. 6.5%; HR = 0.90 (95% CI 0.74–1.08); P = 0.26 | HR = 1.21 (95% CI 0.92–1.59); P = 0.18 |
Myocardial infarction | 6.5% vs. 6.9%; HR = 1.08 (95% CI 0.88–1.33) | HR = 0.95 (95% CI 0.80–1.12); P = 0.52 | HR = 0.95 (95% CI 0.81–1.11); P = 0.49 | HR = 0.78 (95% CI 0.36–1.72); P = 0.54* | HR = 1.03 (95% CI 0.82–1.29); P = 0.82 |
All-cause mortality | 6.5% vs. 5.7%; HR = 0.88 (95% CI 0.71 – 1.09) | HR = 1.11 (95% CI 0.96–1.27); P = 0.15 | HR = 1.01 (95% CI 0.90–1.14); P = 0.88 | 10.5% vs. 10.7%; HR = 0.98 (95% CI 0.84–1.13); P = 0.74 | HR = 0.91 (95% CI 0.78–1.06); P = 0.23 |