Dipeptidyl peptidase‐4 inhibitor treatment and the risk of bullous pemphigoid and skin‐related adverse events: A systematic review and meta‐analysis of randomized controlled trials

Aims This meta‐analysis aimed to evaluate the risk of developing bullous pemphigoid (BP) and other skin‐related adverse events (AEs) in patients with type 2 diabetes (T2DM) undergoing dipeptidyl peptidase‐4 inhibitor (DPP‐4i) treatment in randomized controlled trials (RCTs). Methods In this meta‐analysis, the MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases were searched for RCTs, which involve patients with T2DM reporting skin‐related AEs. RCTs that comparatively evaluated the effects of DPP‐4i treatment and placebo on patients with T2DM and reported skin‐related AEs were included in the analysis. The odds ratio (OR) and 95% confidence interval (CI) were calculated using the Peto's methods. The GRADE approach was used to rate the quality of evidence. Results A total of 46 randomized placebo‐controlled trials, including 3 trials with reports of BP (n = 38 011), that reported skin‐related AEs were included (n = 59 332). Compared to the placebo group, the risk of developing BP was significantly higher in the DPP‐4i treatment group (OR = 7.38, 95% CI 2.00‐27.25, I2 = 0%, P = .003; quality rating: very low). Additionally, DPP‐4i treatment was associated with an increased overall risk of developing skin‐related AEs (OR = 1.22, 95% CI 1.02‐1.46, I2 = 32%, P = .03; quality rating: moderate). Conclusions This meta‐analysis suggested that treatment with DPP‐4is, including sitagliptin, saxagliptin, and linagliptin, was associated with an increased risk of developing BP. Additionally, the risk of developing skin‐related AEs increased when all DPP‐4is were combined. Skin lesion, especially BP, should be monitored in patients with diabetes undergoing DPP‐4i treatment. Future studies should evaluate the susceptible population and develop strategies for early detection of skin‐related AEs.