Table 1.
Major characteristics of the outcome trials included in the network meta-analysis
| Studies | Year | ClinicalTrials.gov Identifier | Intervention | Patients (Antidiabetic drug/placebo) | Primary endpoints | HRa (95% CI) of MACEb | HR (95% CI) of all-cause mortality |
|---|---|---|---|---|---|---|---|
| GLP-1 RA vs. placebo | |||||||
| ELIXA [24] | 2015 | NCT01147250 | Lixisenatide vs. placebo | 6068 (3034/3034) | A composite of the first occurrence of any of the following: death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina | 1.02 (0.89–1.17) | 0.94 (0.78–1.13) |
| LEADER [9] | 2016 | NCT01179048 | Liraglutide vs. placebo | 9340 (4668/4672) | A composite of the first occurrence of death from cardiovascular causes, nonfatal MI (including silent), or nonfatal stroke | 0.87 (0.78–0.97) | 0.85 (0.74–0.97) |
| SUSTAIN-6 [22] | 2016 | NCT01720446 | Semaglutide vs. placebo | 3297 (1648/1649) | A composite of the first occurrence of death from cardiovascular causes, nonfatal MI (including silent), or nonfatal stroke | 0.74 (0.58–0.95) | 1.05 (0.74–1.50) |
| HARMONY OUTCOMES [12] | 2018 | NCT02465515 | Albiglutide vs. placebo | 9463 (4731/4732) | A composite of death from cardiovascular causes, MI, and stroke | 0.78 (0.68–0.90) | 0.95 (0.79–1.16) |
| EXSCEL [13, 27] | 2018 | NCT01144338 | Exenatide vs. placebo | 10,782 (5394/5388) | A composite of death from cardiovascular causes, nonfatal MI, and nonfatal stroke | 0.90 (0.82–1.00) | 0.88 (0.77–1.00) |
| DPP-4 inhibitor vs. placebo | |||||||
| SAVOR-TIMI 53 [26] | 2013 | NCT01107886 | Saxagliptin vs. placebo | 16,492 (8280/8212) | A composite of cardiovascular death, nonfatal MI, or nonfatal ischaemic stroke | 1.00 (0.89–1.12) | 1.11 (0.96–1.27) |
| EXAMINE [25] | 2013 | NCT00968708 | Alogliptin vs. placebo | 5380 (2701/2679) | A composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke | 0.96 (≤ 1.16)c | 0.98 (0.86–1.12) |
| TECOS [23] | 2015 | NCT00790205 | Sitagliptin vs. placebo | 14,523 (7257/7266) | A composite of the first confirmed event of cardiovascular death, nonfatal MI, nonfatal stroke, or hospitalisation for unstable angina | 0.99 (0.89–1.10) | 1.01 (0.90–1.14) |
| CARMELINA [16] | 2018 | NCT01897532 | Linagliptin vs. placebo | 6979 (3494/3485) | A composite of the first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke | 1.02 (0.89–1.17) | 0.98 (0.84–1.13) |
| SGLT-2 inhibitor vs. placebo | |||||||
| EMPA-REG OUTCOME [10, 28] | 2015 | NCT01131676 | Empagliflozin vs. placebo | 7020 (4687/2333) | A composite of death from cardiovascular causes, nonfatal MI (excluding silent MI), or nonfatal stroke | 0.86 (0.74–0.99) | 0.68 (0.57–0.82) |
| CANVAS [15] | 2017 | NCT01032629 | Canagliflozin vs. placebo | 4330 (2888/1442) | A composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke | 0.88 (0.75–1.03) | 0.84 (0.70–1.01) |
| CANVAS-R [15] | 2017 | NCT01989754 | Canagliflozin vs. placebo | 5812 (2907/2905) | A composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke | 0.82 (0.66–1.01) | 0.92 (0.70–1.21) |
| DECLARE-TIMI 58 [14] | 2018 | NCT01730534 | Dapagliflozin vs. placebo | 17,160 (8582/8578) | A composite of cardiovascular death, MI, or ischaemic stroke | 0.93 (0.84–1.03) | 0.93 (0.82–1.04) |
| CREDENCE [18] | 2019 | NCT02065791 | Canagliflozin vs. placebo | 4401 (2202/2199) | A composite of cardiovascular death, MI, or stroke | 0.80 (0.67–0.95) | 0.83 (0.68–1.02) |
DPP-4: dipeptidyl peptidase-4; GLP-1: glucagon-like peptide-1; HR: hazard ratio; MACE: major adverse cardiovascular events; MI: myocardial infarction; RA: receptor agonist; SGLT-2: sodium-glucose co-transporter 2; 95% CI: 95% confidence interval
aHR (antidiabetic drug vs. placebo) of the outcomes evaluated in each trial
bMACE was defined as the composite of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular mortality
cOnly upper bound of the one-sided 95% CI was reported (α: 0.01)