DPP-4 Inhibitors and Respiratory Infection: A Systematic Review and Meta-analysis of the Cardiovascular Outcomes Trials

Abstract

From before the coronavirus disease 2019 (COVID-19) pandemic, the effect of dipeptidyl peptidase 4 inhibitors (DPP4i) on respiratory infections (RI) remains unclear. The meta-analysis of Yang et al. (1) specifically assessed the risk of infection with DPP-4i. However, cardiovascular outcomes trials (CVOTs) did not appear in theirmeta-analysis for RI (1). In addition, themeta-analyses of CVOTs did not report assessment of RI for DPP-4i. Meta-analyses and pharmacovigilance studies showed some discrepancies (2). Recently published practical recommendations did not suggest discontinuation of DPP-4i because of the COVID-19 pandemic (3,4). The dipeptidyl peptidase 4 enzyme could be a target for treating COVID-19 (2). We aimed to provide a powerful and less biased estimate of the effect of DPP-4i on the overall risk of RI and thus verify the validity of the recent recommendations for themanagement of diabetes during the COVID-19 pandemic (3,4). We updated a previous systematic review and meta-analysis, focusing our primary analysis on RI in placebocontrolled CVOTs assessing a DPP-4i in patients with type 2 diabetes, using PubMed and Cochrane Central Register of Controlled Trials (CENTRAL), up to 27 January 2020. In linewith the previous meta-analysis of Yang et al. (1), our primary outcome was “any respiratory infection” (defined as influenza, nasopharyngitis, sinusitis, pharyngotonsillitis, pharyngitis, bronchitis, respiratory tract infection [RTI], upper RTI, lower RTI, or pneumonia). Secondary outcomes were any upper RI, any lower RI, and each of their components. Our primary analysis included placebo-controlled CVOTs only to avoid the risk of “small study effects” and the potential heterogeneity of different comparators. We added a sensitivity analysis integrating 1) the combined non-CVOTs from the previous metaanalysis of Yang et al. (1) and 2) an active-control CVOT identifiedduring the systematic review. We estimated treatment effect using risk ratio and 95% CI. A Pvalue,0.05wasconsideredsignificant. Analyseswere performedwith R.We used a fixed-effects model when I was ,50% and random-effects model otherwise. The full report is available on medRxiv (5). Five trials with 47,714 patients were included. At baseline, mean 6 SD age ranged from61to65.869.1years,HbA1c from 7.2 6 0.5 to 8.0 6 0.9%, and BMI from 28.7 to 31.3 6 5.3 kg z m; 62.9– 70.7% were male; 78.4–95.4% had arterial hypertension; and 10.2–14.4% were current smokers. The risk of bias regarding the reporting of RI was unclear for all the included studies. The primary analysis included 47,714 patients; 4,369 participants were affected by an event of the primary outcome (rate: 9.2%). DPP-4i were not associated with either an increased or a decreased risk of overall RI compared with placebo (risk ratio0.99[95%CI0.93;1.04], I50%) (Fig. 1).Thesensitivityanalysis integratingnonCVOT studies and the active-controlled CVOT reached 82,644 participants and 11,349 events (rate: 13.7%). The risk of overall RI with DPP-4i was neither increased nor decreased (1.00 [0.97; 1.03]) (Fig. 1). Regarding secondary outcomes, DPP-4i were not associated with a different risk of 1) any upper RI (1.00 [0.93; 1.08]), 2) any lower RI (0.96 [0.87; 1.06]), or 3) any components themselves (influenza 1.08 [0.91; 1.28], nasopharyngitis 0.96 [0.86; 1.08], sinusitis 0.84 [0.17; 4.09], pharyngotonsillitis not estimable, pharyngitis 2.98 [0.12; 73.01], bronchitis 0.93 [0.66; 1.30], RTI 0.62 [0.24; 1.59], upper RTI 1.01 [0.89; 1.13], lower RTI 0.90 [0.41; 2.01], and pneumonia 1.05 [0.90; 1.23]). Our updated meta-analysis provides the most powerful and least biased estimation of the association of DPP-4i and