Introduction
Methods
Results
Literature Review
First author, year of publication | References | Drug(s) assessed | Publication type | Met inclusion criteriaa
|
---|---|---|---|---|
DPP-4 inhibitors | ||||
Abbas, 2016 | [42] | Alogliptin, saxagliptin, and sitagliptin | Meta-analysis | Yes |
Agarwal, 2014 | [33] | Allb
| Meta-analysis | Yes |
Cobble, 2012 | [66] | Saxagliptin | Narrative review | No |
Engel, 2013 | [23] | Sitagliptin | Pooled analysis | Yes |
Frederich, 2010 | [67] | Saxagliptin | Pooled analysis | No |
Iqbal, 2014 | [24] | Saxagliptin | Pooled analysis | Yes |
Johansen, 2012 | [68] | Linagliptin | Pooled analysis | No |
Kongwatcharapong, 2016 | [38] | Allb
| Meta-analysis | Yes |
Kundu, 2016 | [39] | Alogliptin, sitagliptin, and saxagliptin | Meta-analysis | Yes |
Lehrke, 2014 | [22] | Linagliptin | Pooled analysis | Yes |
Li, 2016 | [40] | Allb
| Meta-analysis | Yes |
McInnes, 2015 | [25] | Vildagliptin | Pooled analysis | Yes |
Monami, 2011 | [69] | Allb
| Meta-analysis | No |
Monami, 2012 | [10] | Allb
| Meta-analysis | No |
Monami, 2013 | [29] | Allb
| Meta-analysis | Yes |
Monami, 2014 | [34] | Allb
| Meta-analysis | Yes |
Patil, 2012 | [30] | Allb
| Meta-analysis | Yes |
Rosenstock, 2015 | [21] | Linagliptin | Pooled analysis | Yes |
Savarese, 2015 | [36] | Allb
| Meta-analysis | Yes |
Schweizer, 2010 | [64] | Vildagliptin | Pooled analysis | No |
Udell, 2015 | [37] | Alogliptin and saxagliptin | Meta-analysis | Yes |
von Eynatten, 2013 | [70] | Linagliptin | Pooled analysis | No |
Wang, 2016 | [41] | Allb
| Meta-analysis | Yes |
White, 2013 | [26] | Alogliptin | Pooled analysis | Yes |
Williams-Herman, 2010 | [71] | Sitagliptin | Pooled analysis | No |
Wu, 2013 | [31] | Allb
| Meta-analysis | Yes |
Wu, 2014 | [35] | Allb
| Meta-analysis | Yes |
Zhang, 2014 | [32] | Allb
| Meta-analysis | Yesc
|
GLP-1 receptor agonists | ||||
Ferdinand, 2016 | [54] | Dulaglutide | Pooled analysis | Yes |
Fisher, 2015 | [53] | Albiglutide | Pooled analysis | Yes |
Li, 2016 | [56] | Alld
| Meta-analysis | Yes |
Marso, 2011 | [50] | Liraglutide | Pooled analysis | Yes |
Monami, 2009 | [72] | Alld
| Meta-analysis | No |
Monami, 2011 | [73] | Alld
| Meta-analysis | No |
Monami, 2013 | [12] | Alld
| Meta-analysis | Yes |
Ratner, 2011 | [51] | Exenatide | Pooled analysis | Yes |
Seshasai, 2015 | [52] | Taspoglutide | Pooled analysis | Yes |
Sun, 2012 | [55] | Alld
| Pairwise and network meta-analysis | Yes |
Wang, 2016 | [41] | Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide | Meta-analysis | Yes |
References | Incretin (dosage regimen) | No. of studies | Minimum trial duration (weeks) | Mean trial duration (weeks) | Analysis design |
---|---|---|---|---|---|
Abbas, 2016 [42] | Alogliptin 6.25–25 mg/daya; sitagliptin 100 mg/dayb; saxagliptin 2.5–5 mg/dayc
| 3 | – | 130d
| Post hoc |
Engel, 2013 [23]e
| Sitagliptin (100 mg/day) | 25 | 12 | 34 | Post hoc |
Iqbal, 2014 [24]f
| Saxagliptin (2.5, 5, and 10 mg/day)g
| 20 | 4 | 59 | Post hoc (8 studies) Prespecified (12 studies) |
Kundu, 2016 [39] | Alogliptin 6.25–25 mg/daya; sitagliptin 100 mg/dayb; saxagliptin 2.5–5 mg/dayc
| 3 | – | – | Post hoc |
Lehrke, 2014 [22] | Linagliptin 5 mg/dayh
| 22 | <2i
| 22 | Post hoc |
McInnes, 2015 [25] | Vildagliptin (50 mg od and bd) | 37 | 12 | 50.3 versus 48.7j
| Post hoc |
Rosenstock, 2015 [21] | Linagliptin (≥5 mg/day) | 19 | 12 | 35 | Prespecified |
White, 2013 [26]k
| Alogliptin (≥12.5 mg/day) | 11 | 12 | 29 | Prespecified |
Udell, 2015 [37] | Alogliptin 6.25–25 mg/daya; saxagliptin 2.5–5 mg/dayc
| 2 | – | 93 | Post hoc |
Agarwal, 2014 [33] | DPP-4 inhibitors | 82 | 24 | 44 | Post hoc |
Kongwatcharapong, 2016 [38] | DPP-4 inhibitors | 54 | 12 | 59 | Post hoc |
Li, 2016 [40] | DPP-4 inhibitors | 43 | 12 | 61 | Post hoc |
Monami, 2013 [29] | DPP-4 inhibitors | 63 | 24 | 46 | Post hoc |
Monami, 2014 [34] | DPP-4 inhibitors | 82 | 24 | 47 | Post hoc |
Patil, 2012 [30] | DPP-4 inhibitors | 18 | 24 | 52 | Post hoc |
Savarese, 2015 [36] | DPP-4 inhibitors | 94 | 12 | 29d
| Post hoc |
Wang, 2016 [41] | DPP-4 inhibitors | 68 | 24 | 24–52l
| Post hoc |
Wu, 2013 [31] | DPP-4 inhibitors | 8 | 18 | 43 | Post hoc |
Wu, 2014 [35] | DPP-4 inhibitors | 50 | 24 | 45 | Post hoc |
Zhang, 2014 [32] | DPP-4 inhibitors | 12 | 18 | NR | Post hoc |
Fisher, 2015 [53] | Albiglutide (15–50 mg/week or 30 mg biweekly) | 9 | 16 | 104 | Prespecified |
Ferdinand, 2016 [54] | Dulaglutide (0.1–1.5 mg/week) | 9 | 12 | 45 | Prespecified |
Ratner, 2011 [51] | Exenatide (2.5, 5, and 10 µg bd) | 12 | 12 | 23 | Post hoc |
Marso, 2011 [50]m
| Liraglutide (0.045–3.0 mg/day) | 15 | 26 | NR | Post hoc |
Seshasai, 2015 [52] | Taspoglutide 20 mg/week | 9 | 24 | 52 | Prespecified |
Li, 2016 [56] | GLP-1 receptor agonists | 21 | 16 | 78 | Post hoc |
Monami, 2013 [12] | GLP-1 receptor agonists | 25 | 24 | 42 | Post hoc |
Sun, 2012 [55] | GLP-1 receptor agonists | 45 | 8 | 27 | Post hoc |
Wang, 2016 [41]m
| Albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide | 35 | 24 | 24–156 l
| Post hoc |
CV Risk of DPP-4 Inhibitors
Pooled Analyses
Features
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 |
MACE Incidence Rates
MACE Risk
MACE Components
First author [reference] | Drug | CV event category | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
CV death | MI | Stroke | ACS | Arrhythmia | TIA | Heart failure | All death | UAP | ||
White, 2013 [26] | Alogliptin | NR | NR | NR | NR | NR | NR | NR | NR | NR |
Iqbal, 2014 [24]a
| Saxagliptin | 0.61 (>1) | 0.87 (>1) | 0.75 (>1) | NR | NR | NR | 0.55 (>1) | NR | NR |
Engel, 2013 [23] | Sitagliptin | 0.95 (0.40–2.30) | NR | NR | NR | NR | NR | NR | NR | NR |
Rosenstock, 2015 [21] | Linagliptin | 1.04 (0.42–2.60) | 0.86 (0.47–1.56) | 0.34 (0.15–0.75) | NR | NR | 0.09 (0.01–0.75) | NR | 0.89 (0.45–1.75) | 1.08 (0.56–2.06)b
|
McInnes, 2015 [25] | Vildagliptin 50 mg od and bd | 0.77 (0.45–1.31) | 0.97 (0.56–1.38) | 0.84 (0.47–1.50) | NR | NR | NR | 1.08 (0.68–1.70) | NR | NR |
Wang, 2016 [41] | Alogliptin | 0.78 (0.59–1.03) | 1.06 (0.86–1.31) | 0.86 (0.54–1.36) | NR | 1.25 (0.44–3.52) | NR | 1.22 (0.92–1.60) | 0.86 (0.69–1.07) | 0.86 (0.58–1.28) |
Linagliptin | 1.85 (0.56–6.08) | 0.90 (0.45–1.78) | 0.49 (0.24–1.00) | NR | 1.47 (0.64–3.42) | NR | 1.87 (0.84–4.15) | 0.94 (0.38–2.33) | 1.58 (0.52–4.76) | |
Saxagliptin | 1.00 (0.84–1.19) | 0.93 (0.79–1.10) | 1.12 (0.90–1.40) | NR | 1.14 (0.47–2.78) | NR | 1.23 (1.03–1.46) | 1.09 (0.95–1.26) | 1.18 (0.88–1.58) | |
Sitagliptin | 1.03 (0.89–1.19) | 0.98 (0.83–1.15) | 0.91 (0.73–1.13) | NR | 1.14 (0.54–2.41) | NR | 0.98 (0.82–1.18) | 1.00 (0.89–1.13) | 0.86 (0.68–1.10) | |
Vildagliptin | 2.19 (0.53–9.01) | 0.20 (0.04–1.00) | 0.26 (0.08–0.84) | NR | 0.91 (0.34–2.45) | NR | 0.80 (0.16–4.09) | 0.95 (0.35–2.60) | NR | |
Udell, 2015 [37] | Alogliptin and saxagliptin | NR | NR | NR | NR | NR | NR | 1.25 (1.08–1.45) | NR | NR |
Abbas, 2016 [42] | Alogliptin, saxagliptin, and sitagliptin | 1.01 (0.91–1.12) | 0.99 (0.89–1.09) | 1.00 (0.86–1.16) | NR | NR | NR | 1.12 (1.00–1.25) | NR | NR |
Kundu, 2016 [39] | Alogliptin, saxagliptin, and sitagliptin | NR | NR | NR | NR | NR | NR | 1.14 (0.97–1.34)b
| NR | NR |
Agarwal, 2014 [33] | DPP-4 inhibitors | 0.95 (0.82–1.09) | 0.98 (0.86–1.10) | 0.92 (0.77–1.11) | NR | NR | NR | NR | 1.00 (0.90–1.13) | NR |
Kongwatcharapong, 2016 [38] | DPP-4 inhibitors | NR | NR | NR | NR | NR | NR | 1.106 (0.995–1.228) | NR | NR |
Li, 2016 [40] | DPP-4 inhibitors | NR | NR | NR | NR | NR | NR | 0.97 (0.61–1.56) 1.13 (1.00–1.26)b
| NR | NR |
Monami, 2013 [29] | DPP-4 inhibitors | 0.67 (0.39–1.14) | 0.64 (0.44–0.94)c
| 0.77 (0.48–1.24) | NR | NR | NR | NR | 0.60 (0.41–0.88) | NR |
Monami, 2014 [34] | DPP-4 inhibitors | NR | NR | NR | NR | NR | NR | 1.19 (1.03–1.30)d
| NR | NR |
Patil, 2012 [30] | DPP-4 inhibitors | NR | NR | NR | 0.40 (0.18–0.88)e
| NR | NR | NR | NR | NR |
Savarese, 2015 [36] | DPP-4 inhibitors (STFU) | 1.03 (0.51–2.07) | 0.58 (0.36–0.94)f
| 0.66 (0.36–1.21) | NR | NR | NR | 0.67 (0.32–1.40) | 1.064 (0.56–2.00) | NR |
DPP-4 inhibitors (LTFU) | 0.962 (0.84–1.10) | 0.94 (0.84–1.06) | 0.95 (0.79–1.14) | NR | NR | NR | 1.16 (1.01–1.33)g
| 1.01 (0.91–1.13) | NR | |
Wu, 2013 [31] | DPP-4 inhibitors | NR | NR | NR | NR | NR | NR | NR | NR | NR |
Wu, 2014 [35] | DPP-4 inhibitors | 0.97 (0.85–1.11) | NR | 0.98 (0.81–1.18) | 0.97 (0.87–1.08) | NR | NR | 1.16 (1.01–1.33)h
| 1.01 (0.91–1.13) | NR |
Zhang, 2014 [32] | DPP-4 inhibitors | NR | NR | NR | NR | NR | NR | NR | NR | NR |
Fisher, 2015 [53] | Albiglutide | 1.06 (0.55–2.06) | 0.96 (0.52–1.76) | 1.02 (0.45–2.33) | NR | NR | NR | NR | NR | 0.77 (0.25–2.37)b
|
Ferdinand, 2016 [54] | Dulaglutide | 0.35 (0.07–1.87)i
| 0.35 (0.13–0.95)i
| 1.61 (0.42–6.20)i
| NR | NR | NR | 2.02 (0.41–9.88)b, i
| 0.50 (0.18– 1.38)i
| 0.28 (0.05–1.46)b, i
|
Ratner, 2011 [51] | Exenatide bd | NR | NR | NR | NR | NR | NR | NR | NR | NR |
Marso, 2011 [50] | Liraglutide | NR | NR | NR | NR | NR | NR | NR | NR | NR |
Seshasai, 2015 [52] | Taspoglutide | NR | NR | NR | NR | NR | NR | NR | 0.89 (0.38–2.07) | NR |
Wang, 2016 [41] | Albiglutide | NR | 1.20 (0.57–2.51) | 0.57 (0.19–1.69) | NR | 2.01 (0.70–5.73) | NR | 0.45 (0.17–1.17) | 0.56 (0.12–2.59) | 0.87 (0.32–2.38) |
Dulaglutide | NR | 0.21 (0.04–0.98) | 2.83 (0.60–13.28) | NR | NR | NR | NR | NR | NR | |
Exenatide | 1.68 (0.28–9.87) | 0.81 (0.29–2.25) | 1.56 (0.45–5.41) | NR | 2.83 (1.06–7.57) | NR | 1.92 (0.39–9.50) | 1.17 (0.47–2.89) | 0.83 (0.22–3.08) | |
Liraglutide | NR | 1.03 (0.43–2.47) | 1.06 (0.33–3.37) | NR | 0.74 (0.20–2.77) | NR | 5.52 (0.90–33.95) | 0.47 (0.02–8.88) | NR | |
Lixisenatide | 0.98 (0.78–1.23) | NR | 2.74 (0.38–19.50) | NR | 4.50 (0.24–84.78) | NR | NR | 1.06 (0.87–1.29) | NR | |
Li, 2016 [56] | GLP-1 receptor agonists | NR | NR | NR | NR | NR | NR | 0.62 (0.31–1.22) | NR | NR |
Monami, 2013 [12] | GLP-1 receptor agonists | 0.63 (0.24–1.66) | 0.87 (0.48–1.56) | 0.87 (0.37–2.05) | NR | NR | NR | NR | 0.89 (0.46–1.70) | NR |
Meta-analyses
Features
MACE Risk
Randomized Controlled Trial Data
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 |