Dipeptidyl Peptidase‐4 Inhibitors and Cardiovascular Outcomes: Meta‐Analysis of Randomized Clinical Trials with 55,141 Participants

Abstract

Aims:The association between glucose lowering in diabetes mellitus and major cardiovascular (CV) outcomes is weak; indeed, some oral hypoglycemic agents are associated with increased CV events. Dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) are a new class of oral hypoglycemic agent that may have beneficial CV effects. We undertook a systematic review and meta-analysis to appraise the CV safety and efficacy of DPP-4 inhibitors. Methods: Comprehensive search for prospective trials involving DPP-4 inhibitors. Trials included reported at least one of the outcomes examined, recruited minimum 100 patients and minimum follow-up 24 weeks. The risk ratio (RR) was calculated using the MantelHaenszel random-effects model for mortality and major cardiovascular (CV) outcomes. Results: Fifty trials enrolling 55,141 participants were included. Mean follow-up 45.3 weeks. DPP-4 inhibitors compared with all comparators (placebo and active) showed no difference in all-cause mortality (n = 50,982, RR = 1.01, 95% CI 0.91-1.13, P = 0.83), CV mortality (n = 48,151, RR = 0.97, 95% CI 0.85-1.11, P = 0.70), acute coronary syndrome (ACS) (n = 53,034 RR = 0.97, 95% CI 0.87-1.08, P = 0.59), or stroke (n = 42,737, RR = 0.98, 95% CI 0.81-1.18, P = 0.80), and a statistically significant increase in heart failure outcomes (n = 39,953, RR = 1.16, 95% CI 1.01-1.33, P = 0.04). Discussion: Treatment with DPP-4 inhibitors compared with placebo shows no increase in risk with regards to all-cause mortality, CV mortality, ACS, or stroke, but a statistically significant trend toward increased risk of HF outcomes. Conclusion: These findings suggest no cardiovascular harm (or benefit) with DPP-4 inhibitors; further large-scale CV outcome studies will resolve the issue of excess HF risk.

Effect of dipeptidyl peptidase-4 inhibitors on heart failure: A meta-analysis of randomized clinical trials

“…Compared to previous meta-analyses [8,9], our study was larger in size. The studies by Wu et al and Monami et al were conducted with 24 and 37 studies, respectively.…”

“…However, only 54 studies were included into the data analysis while 4,098 studies were excluded. Reasons for exclusion were irrelevance or failure to meet inclusion/exclusion criteria (4,080), post-hoc analysis in nature (8) and data duplication (10). As a result, a total of 54 studies with 74,737 patients were included in the final analysis (9 with alogliptin [7,[21][22][23][24][25][26] A C C E P T E D M A N U S C R I P T…”

“…The SAVOR-TIMI 53 study reported a small, but significant 27% increase in rate of HF related hospitalization in patients treated with saxagliptin compared to placebo [6], while the EXAMINE study showed a numerical excess that did not achieve statistical significance in the risk of HF related hospitalization [7]. These reports were followed by two metaanalyses of randomized, controlled trials evaluating the effects of DPP-4 inhibitors and HF [8,9]. Both metaanalyses showed that DPP-4 inhibitors significantly increased the risk of HF [8,9].…”

“…These reports were followed by two metaanalyses of randomized, controlled trials evaluating the effects of DPP-4 inhibitors and HF [8,9]. Both metaanalyses showed that DPP-4 inhibitors significantly increased the risk of HF [8,9]. However, those two metaanalyses were conducted with key limitations including restrictive inclusion criteria, failure to assess the effect of A C C E P T E D M A N U S C R I P T Subgroup analyses were conducted by several parameters including individual DPP-4 inhibitor (alogliptin, linagliptin, saxagliptin, sitagliptin, or vildagliptin), dose, duration of treatment baseline characteristics of subjects including age (<65 or ≥ 65 years), diabetes duration (<10 or ≥ 10 years), HbA1c at baseline (<8.0% or ≥ 8.0%), and BMI (<30 or ≥ 30 kg/m 2 ).…”

Theeffect of Dipeptidyl Peptidase-4 Inhibitors on Cardiovascular Disease Risk in Type 2 Diabetes Mellitus

“…Contradicting, several other safety trials have shown that DPP-4i do not increase or decrease major adverse CV events over several years of use in individuals with T2DM and CV diseases [21].…”