DPP4 inhibitors and respiratory infection, a systematic review and meta-analysis of the CardioVascular Outcomes Trials conducted before the pandemic and implications for the management of diabetes during COVID-19
Authors: Grenet Guillaume , Mekhaldi Samia , Mainbourg Sabine , Auffret Marine , Cornu Catherine , Cracowski Jean-Luc , Gueyffier François , Lega Jean-Christophe , Cucherat Michel 
Published: July 2020

SummaryBackgroundAssociation between DPP4 inhibitors and respiratory infection remains unclear. CardioVascular Outcomes Trials (CVOTs) conducted before the COVID-19 pandemic are available. We aimed to estimate the effect of DPP4 inhibitors on the risk of respiratory infections.MethodsWe updated a previous systematic review and meta-analysis, searching for CVOTs assessing a DPP4 inhibitor in patients with type 2 diabetes mellitus. We focused on placebo-controlled CVOTs. Our primary outcome was ‘any respiratory infection’. We added a sensitivity analysis integrating non-CVOTs and active-controlled CVOTs.FindingsWe included 47 714 patients in five placebo-controlled CVOTs. Median follow-up ranged from 1·5 years to 3 years. 4 369 events of overall respiratory infection were reported (rate of 9·2%). DPP4 inhibitors were not associated with a different risk compared to placebo (RR = 0·99 [95% CI: 0·93; 1·04]). The sensitivity analysis integrating the non-CVOTs studies and the active-controlled CVOT reached 11 349 events among 82 644 participants (rate of 13·7%). DPP4 inhibitors were not associated with a different risk of overall respiratory infection (RR = 1·00 [95% CI: 0·97; 1·03]).InterpretationOur up-dated meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. We did not find any effect of the DPP4 inhibitors on the risk of respiratory infection. Our results support the recently published practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.FundingNo source of fundingPanel: Research in contextEvidence before this studyFrom before the COVID19 pandemic, respiratory infections are considered potential adverse effects of DPP4 inhibitors. Randomized trials assessing DPP4 inhibitors in patients with type 2 diabetes (T2D), their meta-analyses and pharmacovigilance studies reported conflicting results. Since the last meta-analyses assessing the risk of infections with DPP4 inhibitors, powerful cardiovascular outcomes randomized trials (CVOTs) became available. Recent practical recommendations for the management of diabetes during COVID-19 suggested that DPP4 inhibitors could be continued. We updated our previous meta-analysis of CVOTs and focused to the overall risk of respiratory infection associated with DPP4 inhibitors. We searched for published and unpublished CVOTs in Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), and ClinicalTrials.gov, up to January 27, 2020, using key word as “diabetes mellitus”, “hypoglycemic agents”, “glucose control”, “randomized controlled trial”, “cardiovascular diseases”.Added value of this studyWe included CVOTs comparing a DPP4 inhibitor versus placebo, in people with T2D, and analysed the risk of respiratory infection with DPP4 inhibitors. We focused on placebo-controlled CVOTs to avoid the pitfalls of small study effect and heterogeneous comparators. We added a sensitivity analysis integrating non-CVOTs and non-placebo CVOTs to challenge our results and to increase the statistical power. Our meta-analysis provides the most powerful and least biased estimation of the association of DPP4 inhibitors and the risk of overall (non COVID-19) respiratory infection. Our analyses integrated 11 349 events of any respiratory infections through 82 644 patients from randomized trials. Our results did not find any association between DPP4 inhibitors use and risk of non-COVID respiratory infections.Implications of all the available evidenceThe current COVID-19 pandemic has raised some questions about pros and cons of certain cardiovascular drugs. Our results support the recent practical recommendations for the management of diabetes in patients with COVID-19, suggesting that DPP4 inhibitors should not be discontinued regarding the COVID-19 pandemic.