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Heart Failure Hospitalization with DPP-4 Inhibitors: A Systematic Review and Meta-analysis of Randomized Controlled
Awadhesh Kumar Singh1, Ritu Singh2
1Department of Endocrinology, G.D Hospital and Diabetes Institute, Kolkata, West Bengal, India.
Insights
This meta-analysis found no significant increase in heart failure hospitalizations (hHF) with dipeptyl-dipeptidase-4 inhibitors (DPP-4Is) in patients with type 2 diabetes. Further research is needed due to observed heterogeneity across studies.
Area of Science:
- Cardiology
- Endocrinology
- Pharmacology
Background:
- Dipeptyl-dipeptidase-4 inhibitors (DPP-4Is) use is debated due to potential heart failure hospitalization (hHF) risks, highlighted by the SAVOR-TIMI trial.
- Regulatory agencies have updated labeling for DPP-4Is regarding hHF, creating clinical uncertainty for type 2 diabetes patients with cardiovascular disease risk.
- Conflicting data exists, as some trials (TECOS, CARMELINA) showed no hHF signals, while others indicated a risk.
Purpose of the Study:
- To systematically evaluate the association between DPP-4 inhibitors and hHF in patients with type 2 diabetes.
- To conduct a meta-analysis of dedicated cardiovascular outcome trials and randomized controlled trials assessing hHF as a prespecified endpoint.
Main Methods:
- A comprehensive literature search was performed across PubMed, Embase, Cochrane Central library, ClinicalTrials.gov, and conference presentations up to October 25, 2018.
- Studies with a minimum duration of 52 weeks that explicitly reported hHF as a prespecified endpoint were included.
- Meta-analysis was conducted using comprehensive meta-analysis software, including sensitivity analyses.
Main Results:
- Meta-analysis of four dedicated CV outcome trials (N=43,522) showed no significant increase in hHF with DPP-4Is (RR 1.06; 95% CI, 0.96-1.17; P=0.25).
- Meta-analysis of all eligible randomized controlled trials (N=48,199) also found no significant increase in hHF (OR 1.05; 95% CI 0.95-1.15, P=0.36).
- Heterogeneity was observed across trials (I²=53.95% in CVOTs, I²=43.74% in RCTs), though not statistically significant in all analyses.
Conclusions:
- This meta-analysis indicates no significant increase in hHF associated with DPP-4 inhibitors in type 2 diabetic patients.
- The observed nonsignificant heterogeneity across studies may temper the certainty of this conclusion.
- Clinicians should consider these findings when prescribing DPP-4Is to high-risk cardiovascular patients.
Background:
Heart failure hospitalization (hHF) with dipeptyl-dipeptidase-4 inhibitors (DPP-4Is) remains at the center stage since the publication of Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus - Thrombolysis in Myocardial Infarction (SAVOR-TIMI) in 2013 showing significant increase with saxagliptin, compared to placebo. This outcome led to additional label of hHF to both saxagliptin and alogliptin in April 2016 and eventual labelling of hHF to all the four approved DPP-4Is in United States in August 2017, by US Food Drug Administration. To note, neither Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), nor Cardiovascular and Renal Microvascular Outcome Study with Linagliptin (CARMELINA), showed any signals of hHF with these two agents. These developments have seriously generated an uncertainty among clinicians with regards to hHF effect of DPP-4Is in type 2 diabetic patients with high risk of cardiovascular (CV) disease.
Aims And Objectives:
We systematically searched the database of PubMed, Embase, Cochrane Central library, ClinicalTrials.gov, and International conference presentation from the inception up to October 25, 2018 using MeSH and specific key words. We retrieved all those studies that explicitly looked for hHF as a prespecified end point and were conducted for ≥52 weeks. Subsequently, we conducted the meta-analysis using comprehensive meta-analysis software Version 3, using different sensitivity analysis to study the effect of DPP-4Is on hHF in both dedicated CV outcome trials as well as randomized controlled trials.
Results:
The meta-analysis of four exclusive dedicated CV outcome trials (N = 43,522) did not find significant increase in hHF with DPP-4 inhibitors (Fixed model Relative Risk [RR] 1.06; 95% Confidence Interval [CI], 0.96-1.17; P = 0.25; I2: 53.95%, tau2: 0.012, P = 0.089). Meta-analysis of all randomized controlled trials that explicitly looked for hHF for ≥52 weeks (N = 48,199) also did not show any significant increase in hHF (fixed model peto odds ratio 1.05; 95% CI 0.95-1.15, P = 0.36; I2: 43.74%, tau2: 0.016, P = 0.10).
Conclusions:
This meta-analysis suggests no significant increase in hHF with DPP-4 inhibitors, although a nonsignificant heterogeneity across the trials might limit this observation.
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