Table 5.
Prespecified MACE and events related to other CV endpoints reported in the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial [28, 45], the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 trial [43], the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS) [44], the Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial [48], and the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial [55]
| Patients with T2DM who had had a recent ACS [28, 45] | ||||
|---|---|---|---|---|
| Endpoint | Alogliptin (N = 2701) | Placebo (N = 2679) | HR for DPP-4 inhibitor (95% CI) | P value |
| n (%) | n (%) | |||
| Composite primary MACE endpoint: CV death, nonfatal MI, or nonfatal stroke | 305 (11.3) | 316 (11.8) | 0.96 (≤1.16) | 0.32 |
| CV death | 89 (3.3) | 111 (4.1) | 0.79 (0.60–1.04) | 0.10 |
| Nonfatal MI | 187 (6.9) | 173 (6.5) | 1.08 (0.88–1.33) | 0.47 |
| Nonfatal stroke | 29 (1.1) | 32 (1.2) | 0.91 (0.55–1.50) | 0.71 |
| Secondary composite MACE endpoint: CV causes, nonfatal MI, nonfatal stroke, or urgent revascularization because of UAP < 24 h after hospital admission | 344 (12.7) | 359 (13.4) | 0.95 (≤1.14) | 0.26 |
| Prespecified exploratory endpoint and first occurrence of components | ||||
| Composite | 433 (16.0) | 441 (16.5) | 0.98 (0.86–1.12) | 0.73 |
| All-cause mortality | 106 (3.9) | 131 (4.9) | 0.80 (0.62–1.03) | 0.08 |
| Nonfatal MI | 171 (6.3) | 155 (5.8) | 1.10 (0.88–1.37) | 0.39 |
| Nonfatal stroke | 28 (1.0) | 29 (1.1) | 0.97 (0.58–1.62) | 0.90 |
| Urgent revascularization because of UAP | 43 (1.6) | 47 (1.8) | 0.90 (0.60–1.37) | 0.63 |
| Hospital admission for HF | 85 (3.1) | 79 (2.9) | 1.07 (0.79–1.46) | 0.66 |
| SAVOR-TIMI 53: Patients with T2DM who had established CV disease or multiple risk factors for vascular disease [43] | ||||
|---|---|---|---|---|
| Endpoint | Saxagliptin (N = 8280) | Placebo (N = 8212) | HR for DPP-4 inhibitor (95% CI) | P value |
| n (%) | n (%) | |||
| Composite primary MACE endpoint: CV death, MI, or stroke | 613 (7.3) | 609 (7.2) | 1.00 (0.89–1.12) | 0.99 |
| Primary secondary endpoint: primary composite endpoint plus hospitalization for HF, coronary revascularization or UAP | 1059 (12.8) | 1034 (12.4) | 1.02 (0.94–1.11) | 0.66 |
| Death from any cause | 420 (4.9) | 378 (4.2) | 1.11 (0.96–1.27) | 0.15 |
| CV death | 269 (3.2) | 260 (2.9) | 1.03 (0.87–1.22) | 0.72 |
| MI | 265 (3.2) | 278 (3.4) | 0.95 (0.80–1.12) | 0.52 |
| Ischemic stroke | 157 (1.9) | 141 (1.7) | 1.11 (0.88–1.39) | 0.38 |
| Hospitalization for UAP | 97 (1.2) | 81 (1.0) | 1.19 (0.89–1.60) | 0.24 |
| Hospitalization for HF | 289 (3.5) | 228 (2.8) | 1.27 (1.07–1.51) | 0.007 |
| Hospitalization for coronary revascularization | 423 (5.2) | 459 (5.6) | 0.91 (0.80–1.04) | 0.18 |
| Doubling of creatinine level, initiation of dialysis, renal transplantation, or creatinine >6.0 mg/dL (530 μmol/L) | 194 (2.2) | 178 (2.0) | 1.08 (0.88–1.32) | 0.46 |
| TECOS: Patients with T2DM and established CV disease [44] | ||||
|---|---|---|---|---|
| Endpoint | Sitagliptin (N = 7257) | Placebo (N = 7266) | HR for DPP-4 inhibitor (95% CI) | P value |
| n (%) | n (%) | |||
| Composite primary MACE endpoint:a CV death, nonfatal MI, nonfatal stroke, or hospitalization for UAP | 695 (9.6) | 695 (9.6) | 0.98 (0.88–1.09) | <0.001 |
| Composite secondary MACE endpoint:a CV death, nonfatal MI, or nonfatal stroke | 609 (8.4) | 602 (8.3) | 0.99 (0.89–1.11) | <0.001 |
| CV deathb | 380 (5.2) | 366 (5.0) | 1.03 (0.89–1.19) | 0.71 |
| Hospitalization for UAPb | 116 (1.6) | 129 (1.8) | 0.90 (0.70–1.16) | 0.42 |
| Fatal or nonfatal MIb | 300 (4.1) | 316 (4.3) | 0.95 (0.81–1.11) | 0.49 |
| Fatal or nonfatal strokeb | 178 (2.4) | 183 (2.5) | 0.97 (0.79–1.19) | 0.76 |
| Death from any causeb | 547 (7.5) | 537 (7.3) | 1.01 (0.90–1.14) | 0.88 |
| Hospitalization for HFb | 228 (3.1) | 229 (3.1) | 1.00 (0.83–1.20) | 0.98 |
| Hospitalization for HF or CV deathb | 538 (7.3) | 525 (7.2) | 1.02 (0.90–1.15) | 0.74 |
| ELIXA: Patients with T2DM who had had a recent ACS [48] | ||||
|---|---|---|---|---|
| Endpoint | Lixisenatide (N = 3034) | Placebo (N = 3034) | HR for GLP-1 RA (95% CI) | P value |
| n (%) | n (%) | |||
| Composite primary MACE endpoint: CV death, nonfatal MI, nonfatal stroke, or hospitalization for UAP | 399 (13.2) | 406 (13.4) | 1.02 (0.89–1.17) | 0.81 |
| CV death | 93 (3.1) | 88 (2.9) | ||
| Nonfatal MI | 247 (8.1) | 255 (8.4) | ||
| Nonfatal stroke | 49 (1.6) | 54 (1.8) | ||
| UAP | 10 (0.3) | 9 (0.3) | ||
| Primary endpoint event or hospitalization for HF | 469 (15.5) | 456 (15.0) | 0.97 (0.85–1.10) | 0.63 |
| Primary endpoint event, hospitalization for HF, or revascularization | 659 (21.7) | 661 (21.8) | 1.00 (0.90–1.11) | 0.96 |
| Hospitalization for HF | 127 (4.2) | 122 (4.0) | 0.96 (0.75–1.23) | 0.75 |
| Death from any cause | 223 (7.4) | 211 (7.0) | 0.94 (0.78–1.13) | 0.50 |
| LEADER: Patients with T2DM who were at high risk for CV events [57] | ||||
|---|---|---|---|---|
| Endpoint | Liraglutide (N = 4668) | Placebo (N = 4672) | HR for GLP-1 RA (95% CI) | P value |
| n (%) | n (%) | |||
| Primary composite outcome: death from CV causes, nonfatal MI, or nonfatal stroke | 608 (13.0) | 694 (14.9) | 0.87 (0.78–0.97) | 0.01 |
| Expanded composite outcome: death from CV causes, nonfatal MI, nonfatal stroke, coronary revascularization, or hospitalization for UAP or HF | 948 (20.3) | 1062 (22.7) | 0.88 (0.81–0.96) | 0.005 |
| Death from any cause | 381 (8.2) | 447 (9.6) | 0.85 (0.74–0.97) | 0.02 |
| Death from CV causes | 219 (4.7) | 278 (6.0) | 0.78 (0.66–0.93) | 0.007 |
| Death from non-CV causes | 162 (3.5) | 169 (3.6) | 0.95 (0.77–1.18) | 0.66 |
| MI | 292 (6.3) | 339 (7.3) | 0.86 (0.73–1.00) | 0.046 |
| Fatal | 17 (0.4) | 28 (0.6) | 0.60 (0.33–1.10) | 0.10 |
| Nonfatal | 281 (6.0) | 317 (6.8) | 0.88 (0.75–1.03) | 0.11 |
| Silent | 62 (1.3) | 76 (1.6) | 0.86 (0.61–1.20) | 0.37 |
| Stroke | 173 (3.7) | 199 (4.3) | 0.86 (0.71–1.06) | 0.16 |
| Fatal | 16 (0.3) | 25 (0.5) | 0.64 (0.34–1.19) | 0.16 |
| Nonfatal | 159 (3.4) | 177 (3.8) | 0.89 (0.72–1.11) | 0.30 |
| TIA | 48 (1.0) | 60 (1.3) | 0.79 (0.54–1.16) | 0.23 |
| Coronary revascularization | 405 (8.7) | 441 (9.4) | 0.91 (0.80–1.04) | 0.18 |
| Hospitalization for UAP | 122 (2.6) | 124 (2.7) | 0.98 (0.76–1.26) | 0.87 |
| Hospitalization for HF | 218 (4.7) | 248 (5.3) | 0.87 (0.73–1.05) | 0.14 |
| Microvascular event | 355 (7.6) | 416 (8.9) | 0.84 (0.73–0.97) | 0.02 |
| Retinopathy | 106 (2.3) | 92 (2.0) | 1.15 (0.87–1.52) | 0.33 |
| Nephropathy | 268 (5.7) | 337 (7.2) | 0.78 (0.67–0.92) | 0.003 |
CV cardiovascular, DPP-4 dipeptidyl peptidase-4, GLP-1 RA glucagon-like peptide-1 receptor agonist, HF heart failure, HR hazard ratio, MI myocardial infarction, TIA transient ischemic attack, UAP unstable angina pectoris
aPer-protocol analysis
bIntention-to-treat analysis