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DPP-4 inhibitors and COVID-19 outcomes

The French CORONADO study provides reassuring data about the safety of dipeptidyl peptidase-4 inhibitors in the context of the pandemic, and suggests that prescribing practice need not be changed.

Concerns had previously arisen about a possible link between dipeptidyl peptidase-4 (DPP-4) inhibitor use and adverse outcomes of COVID-19 infection. The DPP-4 protein itself is recognised as a coronavirus receptor and is also involved in immune regulation, with effects on T cells and cytokines, amongst others. The cytokine storm that characterises severe COVID-19 disease, and the potential role of DPP-4 within it, had led to some calls for caution when using DPP-4 inhibitors to treat type 2 diabetes during the pandemic.

Conversely, it has also been hypothesised that DPP-4 inhibition could both block SARS-CoV-2 entry into cells and reduce inflammation and cytokine release, thus improving outcomes (Scheen, 2020). Healthcare professionals, therefore, have received mixed messages about DPP-4 inhibitor use during the pandemic. This analysis from the CORONADO study (Roussel et al, 2021) goes some way towards clarifying the uncertainty.

The authors evaluated data on 2449 people with type 2 diabetes hospitalised for COVID-19 in 68 centres in France. Of these, 596 were being prescribed DPP-4 inhibitors. The primary outcome, a composite of mechanical ventilation or death at 1 week after admission, occurred at similar rates between DPP-4 inhibitor users and those being treated with other diabetes drugs (27.7% vs 28.6%; P=0.68). The findings were similar when examining the individual components of the primary outcome and when outcomes were reassessed at 28 days after admission. Indeed, at 28 days, there was a non-significant trend towards reduced mortality with DPP-4 inhibitors (18.1% vs 21.8%; P=0.056).

As DPP-4 inhibitor use was associated with a number of factors known to affect COVID-19 outcomes, the authors also used a propensity score analysis, accounting for factors including age, sex, comorbidities known to be associated with COVID outcomes and other treatments. This model also showed no link between DPP-4 inhibitor use and the primary outcome, even after further adjustment for kidney function, diabetes duration or HbA1c.

These findings are reassuring about the safety of DPP-4 inhibitors in the context of the pandemic, and the authors conclude that the class is safe and should not be discontinued. Previous studies have even suggested a beneficial effect in terms of mortality (Mirani  et al, 2020; Solerte et al, 2020). However, these were limited by small sample sizes and limited adjustment for the factors accounted for in the current study. All of the studies, including the present, were limited by their observational designs. In the absence of randomised controlled trials, it would appear premature to prescribe DPP-4 inhibitors to improve COVID-19 outcomes; however, the message is clear that the drugs are safe and that prescribing practice should not change.

Mirani M, Favacchio G, Carrone F et al (2020) Impact of comorbidities and glycemia at admission and dipeptidyl peptidase 4 inhibitors in patients with type 2 diabetes with COVID-19: a case series from an academic hospital in Lombardy, Italy. Diabetes Care 43: 3042–9

Roussel R, Darmon P, Pichelin M et al; CORONADO investigators (2021) Use of dipeptidyl peptidase-4 inhibitors and prognosis of COVID-19 in hospitalized patients with type 2 diabetes: a propensity score analysis from the CORONADO study. Diabetes Obes Metab 2 Feb [Epub ahead of print]. https://doi.org/10.1111/dom.14324

Scheen AJ (2020) DPP-4 inhibition and COVID-19: from initial concerns to recent expectations. Diabetes Metab 47: 101213

Solerte SB, D’Addio F, Trevisan R et al (2020) Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study. Diabetes Care 43: 2999–3006

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