Subodh Verma1, Ronald M Goldenberg1, Deepak L Bhatt1, Michael E Farkouh1, Adrian Quan1, Hwee Teoh1, Kim A Connelly1, Lawrence A Leiter1, Jan O Friedrich1. 1. Divisions of Cardiac Surgery (Verma, Quan, Teoh), Endocrinology and Metabolism (Teoh, Leiter) and Cardiology (Connelly), and Departments of Surgery (Verma), Medicine (Connelly, Leiter, Friedrich) and Critical Care (Friedrich), Li Ka Shing Knowledge Institute of St. Michael's Hospital; Departments of Surgery (Verma), Medicine (Farkouh, Connelly, Leiter, Friedrich), Nutritional Sciences (Leiter) and Interdepartmental Division of Critical Care (Friedrich), University of Toronto, Toronto, Ont.; LMC Diabetes & Endocrinology (Goldenberg), Thornhill, Ont.; Brigham and Women's Hospital Heart & Vascular Center and Harvard Medical School (Bhatt), Boston, Mass.; Peter Munk Cardiac Centre (Farkouh), University Health Network, Toronto, Ont.
Abstract
BACKGROUND: Given recent discrepant results from randomized controlled trials (RCTs), we examined the totality of RCT evidence assessing the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and heart failure. METHODS: MEDLINE, Embase and ClinicalTrials.gov were searched without language restrictions to August 2016 for RCTs comparing DPP-4 inhibitors to placebo or no therapy for a period of 24 weeks or more. We included all heart failure outcomes when listed either as a serious adverse event or adverse event. Pooled analyses used random-effects. RESULTS: We identified 100 RCTs (n = 79 867) - 3 large cardiovascular-safety RCTs (SAVOR-TIMI 53[saxagliptin]/n = 16 492, EXAMINE[alogliptin]/n = 5380, and TECOS[sitagliptin]/n = 14 735), and 97 smaller RCTs with a primary outcome that was usually change in glycated hemoglobin. Virtually all RCTs were high-quality, multicentre, placebo-controlled trials. A total of 96% (1192/1244) of heart failure events were prespecified, blindly adjudicated and required hospital admission. Pooled results suggested a 13% increase in heart failure (relative risk [RR] 1.13, 95% confidence interval [CI] 1.01-1.26, I2 = 0%; 32 RCTs, n = 54 640, 1244 events). When including only the 3 large RCTs, the increase was similar, but not significant (RR 1.14, 95% CI 0.97-1.32; 3 RCTs, n = 36 543, 1169 adjudicated events; number needed to harm 246) owing to heterogeneity (I2 = 42%), which lead to wider CIs, because SAVOR-TIMI 53 showed increased heart failure (RR 1.26, 95% CI 1.06-1.49) and TECOS showed no effect (RR 1.00, 95% CI 0.83-1.19). INTERPRETATION: Despite pooled data from 79 867 patients, whether DPP-4 inhibitors increase heart failure overall or exhibit within-class differences remains unresolved. Our results highlight the importance of ongoing trials that are comparing DPP-4 inhibitors to placebo, although no large cardiovascular-safety RCTs are comparing different DPP-4 inhibitors to each other; consequently, these will address the overall but not class-difference question.
BACKGROUND: Given recent discrepant results from randomized controlled trials (RCTs), we examined the totality of RCT evidence assessing the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and heart failure. METHODS: MEDLINE, Embase and ClinicalTrials.gov were searched without language restrictions to August 2016 for RCTs comparing DPP-4 inhibitors to placebo or no therapy for a period of 24 weeks or more. We included all heart failure outcomes when listed either as a serious adverse event or adverse event. Pooled analyses used random-effects. RESULTS: We identified 100 RCTs (n = 79 867) - 3 large cardiovascular-safety RCTs (SAVOR-TIMI 53[saxagliptin]/n = 16 492, EXAMINE[alogliptin]/n = 5380, and TECOS[sitagliptin]/n = 14 735), and 97 smaller RCTs with a primary outcome that was usually change in glycated hemoglobin. Virtually all RCTs were high-quality, multicentre, placebo-controlled trials. A total of 96% (1192/1244) of heart failure events were prespecified, blindly adjudicated and required hospital admission. Pooled results suggested a 13% increase in heart failure (relative risk [RR] 1.13, 95% confidence interval [CI] 1.01-1.26, I2 = 0%; 32 RCTs, n = 54 640, 1244 events). When including only the 3 large RCTs, the increase was similar, but not significant (RR 1.14, 95% CI 0.97-1.32; 3 RCTs, n = 36 543, 1169 adjudicated events; number needed to harm 246) owing to heterogeneity (I2 = 42%), which lead to wider CIs, because SAVOR-TIMI 53 showed increased heart failure (RR 1.26, 95% CI 1.06-1.49) and TECOS showed no effect (RR 1.00, 95% CI 0.83-1.19). INTERPRETATION: Despite pooled data from 79 867 patients, whether DPP-4 inhibitors increase heart failure overall or exhibit within-class differences remains unresolved. Our results highlight the importance of ongoing trials that are comparing DPP-4 inhibitors to placebo, although no large cardiovascular-safety RCTs are comparing different DPP-4 inhibitors to each other; consequently, these will address the overall but not class-difference question.
Authors: Benjamin M Scirica; Deepak L Bhatt; Eugene Braunwald; P Gabriel Steg; Jaime Davidson; Boaz Hirshberg; Peter Ohman; Robert Frederich; Stephen D Wiviott; Elaine B Hoffman; Matthew A Cavender; Jacob A Udell; Nihar R Desai; Ofri Mosenzon; Darren K McGuire; Kausik K Ray; Lawrence A Leiter; Itamar Raz Journal: N Engl J Med Date: 2013-09-02 Impact factor: 91.245
Authors: Robert G Moses; Elizabeth Round; Yue Shentu; Gregory T Golm; Edward A O'neill; Ira Gantz; Samuel S Engel; Keith D Kaufman; Barry J Goldstein Journal: J Diabetes Date: 2016-02-03 Impact factor: 4.006
Authors: L Olansky; C Reasner; T L Seck; D E Williams-Herman; M Chen; L Terranella; A Mehta; K D Kaufman; B J Goldstein Journal: Diabetes Obes Metab Date: 2011-09 Impact factor: 6.577
Authors: F J Lavalle-González; A Januszewicz; J Davidson; C Tong; R Qiu; W Canovatchel; G Meininger Journal: Diabetologia Date: 2013-09-13 Impact factor: 10.122
Authors: Ling Li; Sheyu Li; Ke Deng; Jiali Liu; Per Olav Vandvik; Pujing Zhao; Longhao Zhang; Jiantong Shen; Malgorzata M Bala; Zahra N Sohani; Evelyn Wong; Jason W Busse; Shanil Ebrahim; German Malaga; Lorena P Rios; Yingqiang Wang; Qunfei Chen; Gordon H Guyatt; Xin Sun Journal: BMJ Date: 2016-02-17
Authors: Flory T Muanda; Matthew A Weir; Lavanya Bathini; Kristin K Clemens; Vlado Perkovic; Manish M Sood; Eric McArthur; Jessica M Sontrop; Richard B Kim; Amit X Garg Journal: Clin J Am Soc Nephrol Date: 2020-11-25 Impact factor: 8.237