TABLE 1.
Cardiovascular outcomes of randomized multicentre clinical trials in T2D patients.
| Study | Patient no/follow up | Patient history | Comparison | Parameter | HR (95% CI) |
| Metformin | |||||
| UKPDS34 (UKPDS Group, 1998; Holman et al., 2008) | 753/10.7 years | T2D, no HF or MI | Metformin vs. diet | T2D-EP* | 0.68 (0.53–0.87) |
| All-cause mortality | 0.64 (0.45–0.91) | ||||
| MI | 0.61 (0.41–0.89) | ||||
| Intensive therapy# vs. diet | T2D-EP* | 0.93 (0.77–1.12) | |||
| All-cause mortality | 0.92 (0.71–1.18) | ||||
| MI | 0.79 (0.60–1.05) | ||||
| SAVOR TIMI 53 (Bergmark et al., 2019): Post hoc analysis | 12,156/2.1 years | T2D, CVD HF history (21% metformin vs. 11% non-metformin) | Metformin vs. never taken metformin | All-cause mortality | 0.75 (0.59–0.95) |
| 3P-MACE | 0.92 (0.76–1.11) | ||||
| CV death | 0.68 (0.51–0.91) | ||||
| MI | 1.23 (0.92–1.65) | ||||
| 2447 pairs of patients§ /2.1 years | T2D, CVD HF history (16% both groups) | Metformin vs. never taken metformin | All-cause mortality | 0.73 (0.59–0.91) | |
| 3P-MACE | 0.92 (0.78–1.10) | ||||
| CV death | 0.77 (0.59–0.99) | ||||
| MI | 1.24 (0.95–1.62) | ||||
| GLP1 receptor agonists | |||||
| LEADER (Marso et al., 2016b) | 9,340/3.8 years | T2D, CVD (81%) HF history (18%) | Liraglutide vs. placebo | All-cause mortality | 0.85 (0.74–0.97) |
| 3P-MACE | 0.87 (0.78–0.97) | ||||
| CV death | 0.78 (0.66–0.93) | ||||
| MI | 0.86 (0.73–1.00) | ||||
| HHF | 0.87 (0.73–1.05) | ||||
| SUSTAIN-6 (Marso et al., 2016a) | 3,297/2 years | T2D, CVD (83%) HF history (24%) | Semaglutide (subcutaneous) vs. placebo | All-cause mortality | 1.05 (0.74–1.50) |
| 3P-MACE | 0.74 (0.58–0.95) | ||||
| CV death | 0.98 (0.65–0.93) | ||||
| MI | 0.81 (0.57–1.16) | ||||
| HHF | 1.11 (0.77–1.61) | ||||
| PIONEER 6 (Husain et al., 2019) | 3,183/1.3 years | T2D, CVD (85%) HF history (12%) | Semaglutide (oral) vs. placebo | All-cause mortality | 0.51 (0.31–0.84) |
| 3P-MACE | 0.79 (0.57–1.11) | ||||
| CV death | 0.49 (0.27–0.92) | ||||
| MI | 1.18 (0.73–1.90) | ||||
| HHF | 0.86 (0.48–1.44) | ||||
| Harmony Outcomes (Hernandez et al., 2018) | 9,463/1.5 years | T2D, CVD (100%) HF history (20%) | Albiglutide vs. placebo | All-cause mortality | 0.95 (0.79–1.16) |
| 3P-MACE | 0.78 (0.68–0.90) | ||||
| CV death | 0.93 (0.73–1.19) | ||||
| MI | 0.75 (0.61–0.90) | ||||
| HHF | 0.71 (0.53–0.94) | ||||
| REWIND (Gerstein et al., 2019) | 9,901/5.4 years | T2D, CVD (31%) HF history (9%) | Dulaglutide vs. placebo | All-cause mortality | 0.90 (0.80–1.01) |
| 3-P MACE | 0.88 (0.79–0.99) | ||||
| CV death | 0.91 (0.78–1.06) | ||||
| MI | 0.96 (0.79–1.15) | ||||
| HHF | 0.93 (0.77–1.12) | ||||
| EXSCEL (Holman et al., 2017) | 14,752/3.2 years | T2D, CVD (73%) HF history (16%) | Exenatide vs. placebo | All-cause mortality | 0.86 (0.77–0.97) |
| 3P-MACE | 0.91 (0.83–1.00) | ||||
| CV death | 0.88 (0.76–1.02) | ||||
| MI | 0.97 (0.85–1.10) | ||||
| HHF | 0.94 (0.78–1.13) | ||||
| Elixa (Pfeffer et al., 2015) | 6,068/2 years | T2D, CVD (100%) HF history (22%) | Lixisenatide vs. placebo | All-cause mortality | 0.94 (0.78–1.13) |
| 3P-MACE | 1.02 (0.89–1.17) | ||||
| CV death | 0.98 (0.78–1.22) | ||||
| MI | 1.03 (0.87–1.22) | ||||
| HHF | 0.96 (0.75–1.23) | ||||
| DPP4 inhibitors | |||||
| Carmelina (Rosenstock et al., 2019) | 6,979/2.2 years | T2D, CVD (57%) | Linagliptin vs. placebo | All-cause mortality | 0.98 (0.84–1.13) |
| 3P-MACE | 1.02 (0.89–1.17) | ||||
| CV death | 0.96 (0.81–1.14) | ||||
| MI | 1.12 (0.90–1.40) | ||||
| HHF | 0.90 (0.74–1.08) | ||||
| Tecos (Green et al., 2015) | 14,671/3.0 years | T2D, CVD (100%) | Sitagliptin vs. placebo | All-cause mortality | 1.01 (0.90–1.14) |
| 3P-MACE | 0.99 (0.89–1.11) | ||||
| CV death | 1.03 (0.89–1.19) | ||||
| MI | 0.95 (0.81–1.11) | ||||
| HHF | 1.00 (0.83–1.20) | ||||
| Savor timi 53 (Scirica et al., 2013) | 16,492/2.1 years | T2D, CVD (78%) | Saxagliptin vs. placebo | All-cause mortality | 1.11 (0.96–1.27) |
| 3P-MACE | 1.00 (0.89–1.12) | ||||
| CV death | 1.03 (0.87–1.22) | ||||
| MI | 0.95 (0.80–1.12) | ||||
| HHF | 1.27 (1.07–1.51) | ||||
| Examine (White et al., 2013; Zannad et al., 2015) | 5,380/1.5 years | T2D, CVD (100%), | Alogliptin vs. placebo | All-cause mortality | 0.80 (0.62–1.03) |
| acute coronary event | 3P-MACE | 0.96 (≤ 1.16) | |||
| within 15-90 days | CV death | 0.85 (0.66–1.10) | |||
| MI | 1.10 (0.88–1.37) | ||||
| HHF | 1.19 (0.90–1.58) | ||||
| SGLT2 inhibitors | |||||
| Empareg-outcome (Zinman et al., 2015) | 7,020/3.1 years | T2D, CVD (100%), HF (10%) | Empagliflozin vs. placebo | All-cause mortality | 0.68 (0.57–0.82) |
| 3P-MACE | 0.86 (0.74–0.99) | ||||
| CV death | 0.62 (0.49–0.77) | ||||
| MI | 0.87 (0.70–1.09) | ||||
| HHF | 0.65 (0.50–0.85) | ||||
| Canvas (Neal et al., 2017) | 10,142/3.6 years | T2D, CVD (66%), HF (14%) | Canagliflozin vs. placebo | All-cause mortality | 0.87 (0.74–1.01) |
| 3P-MACE | 0.86 (0.75–0.97) | ||||
| CV death | 0.87 (0.72–1.06) | ||||
| MI | 0.89 (0.73–1.09) | ||||
| HHF | 0.67 (0.52–0.87) | ||||
| Declare-timi 58 (Wiviott et al., 2019) | 17,160/4.2 years | T2D, CVD (41%), HF (10%) | Dapagliflozin vs. placebo | All-cause mortality | 0.93 (0.82–1.04) |
| 3P-MACE | 0.93 (0.84–1.03) | ||||
| CV death | 0.98 (0.82–1.17) | ||||
| MI | 0.89 (0.77–1.01) | ||||
| HHF | 0.73 (0.61–0.88) | ||||
| Credence (Perkovic et al., 2019) | 4,401/2.6 years | T2D, CKD (GFR 30 | Canagliflozin vs. | All-cause mortality | 0.83 (0.68–1.02) |
| to ≤ 90 mL/min per | placebo | 3P-MACE | 0.80 (0.67–0.90) | ||
| 1.73 m2) | CV death | 0.78 (0.61–1.00) | |||
| HHF | 0.61 (0.47–0.80) | ||||
*T2D endpoint (T2D-EP, diabetes related endpoint): sudden death, death from hypo- or hyperglycaemia, fatal or nonfatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation, vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction. #Intensive therapy: therapy with chloropropamide, glibenclamide, insulin. §Propensity matched patients (2,447 patients with metformin vs. 2,447 patients never taken metformin). 3P-MACE, 3-point major adverse cardiovascular events; CI, confidence interval; CKD, chronic kidney disease; CV death, cardiovascular death; CVD, cardiovascular disease; HHF, hospitalization for heart failure; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; T2D, type 2 diabetes mellitus.