Table 3.
Incidence of MACE in the integrated analyses of DPP-4 inhibitors and GLP-1 receptor agonists trialled in randomized controlled studies
| Reference, active intervention | No. of enrolled patients (D/C)a | MACE definition | No. of events (D/C) | Exposure-adjusted incidence rates per 100 patient-years (D/C) | Adjudicated |
|---|---|---|---|---|---|
|
White, 2013 [26] Alogliptin |
6028 (41,628/1860) | Composite of CV death, nonfatal MI, and nonfatal stroke |
MACE, 13/10 CV death, 5/1 MI, 6/4 Stroke, 2/5 |
MACE, 0.64/1.04 CV death, 0.25/0.10 MI, 0.30/0.41 Stroke, 0.10/0.52 |
Yes |
|
Lehrke, 2014 [22] Linagliptin |
7400 (4810/2590) | CV AEs |
Cardiac disorder AEs, 153/83 ACS, 3/2 MI, 9/3 Narrow SMQ HF, 21/8 HF, 11/7 |
HF, 0.045/0.046 | No |
|
Rosenstock, 2015 [21] Linagliptin |
9459 (5847/3612) | Composite of CV death, nonfatal stroke, nonfatal MI, and hospitalization for UAP |
MACE, 60/62 CV death, 11/8 MI, 23/20 Stroke, 9/19 UAP, 22/16 |
MACE, 1.34/1.89 CV death, 0.24/0.24 MI, 0.51/0.61 Stroke, 0.2/0.58 UAP, 0.49/0.48 |
Yes |
|
Iqbal, 2014 [24] Saxagliptin |
9156 (5701/3455) | Composite of CV death, MI, stroke, and cardiac ischemic events (derived from post hoc and prospective adjudication of MedDRA preferred terms) |
MACE, 43/31 CV death, 17/15 MI, 19/12 Stroke, 16/10 |
MACE, 0.85/1.12 CV death, 0.34/0.54 MI, 0.40/0.45 Stroke, 0.27/0.36 |
Yes |
|
Engel, 2013 [23] Sitagliptin |
14,611 (7726/6885) | Composite of ischemic events reported as AEs with a MedDRA (version 14.1) term in a 39-item list and CV deaths reported as AEs with a MedDRA (version 14.1) term in an 11-item list |
MACE, 40/38 CV death, 12/10 |
MACE, 0.65/0.74 CV death, 0.25/0.25 |
No |
|
McInnes, 2015 [25] Vildagliptin 50 mg od and bd |
17,446 (9599/7847) | Composite of CV death, nonfatal MI, and nonfatal stroke |
MACE, 83/85 CV death, 25/28 MI, 38/35 Stroke, 24/25 |
MACE, 0.90/1.16 CV death, 0.27/0.38 MI, 0.41/0.48 Stroke, 0.26/0.34 |
Yes |
|
Udell, 2015 [37] Alogliptin and saxagliptin |
21,872 (10,981/10,891) | None | HF, 395/317 | NR | Yes |
|
Abbas, 2016 [42] Alogliptin, saxagliptin, and sitagliptin |
36,543 (18,313/18,230) |
Composite of CV death, nonfatal MI, and nonfatal stroke Secondary: hospitalization for HF |
MACE, 1663/1671 CV death, 671/664 MI, 737/745 Stroke, 333/332 HF, 602/536 |
NR | Yes |
|
Kundu, 2016 [39] Alogliptin, saxagliptin, and sitagliptin |
36,543 (18,313/18,230) |
Secondary: composite of CV death, nonfatal MI, and nonfatal stroke Primary: hospitalization for HF |
MACE, 1663/1671 HF, 623/546 |
NR | Yes |
| Wang, 2016 [41] | Individual components of MACE: (1) all-cause death; (2) CV death; (3) nonfatal MI; (4) nonfatal stroke; (5) HF; (6) unstable angina; and (7) arrhythmia | NR | NR | No | |
|
Alogliptin Linagliptin Saxagliptin Sitagliptin Vildagliptin |
11,002 7987 23,073 30,558 6906 |
||||
|
Agarwal, 2014 [33] DPP-4 inhibitors |
73,678 (40,749/32,592) | Composite of CV death, MI, and strokeb | NR | NR | No |
|
Kongwatcharapong, 2016 [38] DPP-4 inhibitors |
74,737 (39,776/34,961) | Any occurrence of HF and HF-related hospitalizations | 726/635 | NR | No |
|
Li, 2016 [40] DPP-4 inhibitors |
28,292 (15,701/12,591) 37,028 (18,554/18,474) |
Co-primary: HF Co-primary: Hospital admission for HF |
42/33 622/522 |
NR | No |
|
Monami, 2013 [29] DPP-4 inhibitors |
40,071 (23,562/16,509) | Composite of CV death, nonfatal MI, stroke, ACS, and/or HF reported as serious AEs |
MACE, 263/232 CV death, 26/26 MI, 61/59 Stroke, 41/33 |
MACE, 1.12/1.37 CV death, 0.11/0.15 Acute MI, 0.26/0.35 Stroke, 0.17/0.19 |
No |
|
Monami, 2014 [34] DPP-4 inhibitors |
69,615 (29,788/22,776) | None | Acute HF, 448/361 | NR | No |
|
Patil, 2012 [30] DPP-4 inhibitors |
8544 (4998/3546) | Composite of death from CV causes, nonfatal MI or ACS, stroke, arrhythmias, and HF reported as AEs |
MACE, 45/56 ACS, 11/17 |
MACE, 0.14/0.14c ACS, 0.03/0.05c |
No |
|
Savarese, 2015 [36] DPP-4 inhibitors |
85,224 (48,486/36,738) | All-cause death, CV death, MI, stroke, and new onset of HF | NR | NR | No |
|
Wu, 2013 [31] DPP-4 inhibitors |
7778 | Composite of death from CV causes, nonfatal MI or ACS, stroke, arrhythmias, and heart failure reported as AEs | MACE, 6/18d; 10/12e | NR | No |
|
Wu, 2014 [35] DPP-4 inhibitors |
55,141 | None |
All-cause mortality, 627/601 CV death, 408/410 ACS, 621/610 Stroke, 222/219 HF, 424/352 |
NR | No |
|
Zhang, 2014 [32] DPP-4 inhibitors |
10,982 (5505/5477) | CV AEs | CE, 25/43f | NR | No |
|
Fisher, 2015 [53], Albiglutide |
5107 (2524/2583) |
Composite of CV death, nonfatal MI, and nonfatal stroke, or hospitalization for UAP Secondary: MACE |
MACE or UAP, 58/58 MACE, 52/53 |
1.19/1.11 1.07/1.02 |
Yes |
|
Ferdinand, 2016 [54] Dulaglutide |
6010 (3885/2125) | Composite of CV death, nonfatal MI, nonfatal stroke, or hospitalization for UAP |
MACE, 26/25 CV death, 3/5 MI, 9/14 Stroke, 12/4 UAP, 3/6 |
MACE, 0.66/1.13 CV death, 0.08/0.23 MI, 0.23/0.63 Stroke, 0.31/0.18 UAP, 0.08/0.27 |
Yes |
|
Ratner, 2011 [51], Exenatide bd |
3945 (2316/1629) | Composite of CV death, MI, stroke, ACS, and revascularization procedures | MACE, 20/18 | 1.87/2.31 | Yes |
|
Marso, 2011 [50], Liraglutide |
6638 (4257/2381) | Composite of CV death, MI, and stroke reported as AEs using MedDRA terms | NR | NR | Yes |
|
Seshasai, 2015 [52] Taspoglutide |
7056 (4275/2781) | Composite of CV death, acute MI, stroke, and hospitalization for UAP | MACE, 40/27 |
CV death, 0.21/0.22 MI, 0.37/0.37 Stroke, 0.15/0.26 UAP, 0.1/0.15 All-cause mortality, 0.27/0.37 |
Yes |
|
Li, 2016 [56] GLP-1 receptor agonists |
11,758 (7441/4317) | HF | 17/19 | NR | No |
| Wang, 2016 [41] | Individual components of MACE: (1) all-cause death; (2) CV death; (3) nonfatal MI; (4) nonfatal stroke; (5) HF; (6) unstable angina; and (7) arrhythmia | NR | NR | No | |
|
Albiglutide Dulaglutide Exenatide Liraglutide Lixisenatide |
3286 2052 6283 4161 8607 |
||||
|
Monami, 2013 [12] GLP-1 receptor agonists |
15,398 (8619/6779) |
Composite of CV death, nonfatal MI, stroke, ACS, and/or HF reported as serious AEs |
NR | NR | No |
AEs adverse events, ACS acute coronary syndrome, bd twice daily, C comparator, CCV cardiovascular and cerebrovascular, CEC clinical events committee, D drug, HF heart failure, MedDRA Medical Dictionary for Regulatory Activities, MI myocardial infarction, NR not reported, od once daily, SMQ standardized Medical Dictionary for Regulatory Activities query, TIA transient ischemic attack, UAP unstable angina pectoris
aSome trials reported zero events and so the sum of the number of drug and comparator patients does not always equal the total number of enrolled patients
bSecondary outcome measure because of non-uniform reporting across the trials. The individual endpoints comprising MACE were the co-primary endpoints [33]
cMetric calculated by dividing the total number events in each group by total patient-years and multiplying by 100
dDPP-4 inhibitor monotherapy versus metformin monotherapy
eDPP-4 inhibitor plus metformin versus metformin monotherapy
fDPP-4 inhibitor monotherapy versus sulfonylurea therapy