Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis

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.

Figure 1

Search strategy and trial flow.

Figure 2

Forest plot for heart failure, large versus small trials. Individual and pooled risk ratios (RRs) with 95% confidence intervals (CIs) for randomized controlled trials (RCTs) with a primary outcome that included cardiovascular outcomes and reported the number of patients in each treatment group that were admitted to hospital for heart failure as an adjudicated primary or secondary outcome, as well as smaller RCTs reporting at least 1 patient with heart failure for which outcomes were not necessarily adjudicated and patients not necessarily admitted to hospital. The pooled RRs with 95% CIs were calculated using random-effects models. Weight refers to the contribution of each study to the overall pooled estimate of treatment effect. Each square and horizontal line denotes the point estimate and 95% CI for each trial's RR. The diamonds signify the pooled RR; the diamond's centre denotes the point estimate and width denotes the 95% CI.

Figure 3

Forest plot for heart failure by DPP-4 inhibitor. Individual and pooled risk ratios (RRs) with 95% confidence intervals (CIs) for larger and smaller randomized controlled trials (RCTs) by DPP-4 inhibitor. Interaction p values comparing RRs between pairs of subgroups of RCTs using different DPP-4 inhibitors were all nonsignificant. For the most extreme difference between saxagliptin RCTs and sitagliptin RCTs, interaction p = 0.13 (interaction p = 0.07 comparing RR for only SAVOR-TIMI 53 v. TECOS). The pooled RRs with 95% CI were calculated using random-effects models. Interaction p values were calculated using Z tests. Weight refers to the contribution of each study to the overall pooled estimate of treatment effect. Each square and horizontal line denotes the point estimate and 95% CI for each trial's RR. The diamonds signify the pooled RR; the diamond's centre denotes the point estimate and width denotes the 95% CI.

Figure 4

Forest plot for heart failure requiring hospital admission by previous history of heart failure. Individual and pooled risk ratios (RRs) with 95% confidence intervals (CIs) for the outcome of heart failure requiring hospital admission in subgroups of patients with versus without previous heart failure in SAVOR-TIMI 53 and EXAMINE, the only RCTs that provided these data. Average rates of heart failure requiring hospital admission were 9.9% ([124+ 107 + 63 + 65]/[1056 + 1049 + 771 + 762] = 359/3638) in patients with versus 1.9% ([165 + 121 + 43 + 24]/[7224 + 7163 + 1930 + 1917] = 353/18 234) in patients without a prior history of heart failure. In this analysis, the heterogeneity in the overall analysis (I2 = 43%) is reduced (I2 = 0%) within each subgroup. The pooled RRs with 95% CIs were calculated using random-effects models. Interaction p values were calculated using Z tests. Weight refers to the contribution of each study to the overall pooled estimate of treatment effect. Each square and horizontal line denotes the point estimate and 95% CI for each trial's RR. The diamonds signify the pooled RR; the diamond's centre denotes the point estimate and width denotes the 95% CI.