Dipeptidyl peptidase‐4 inhibitors and bullous pemphigoid: A systematic review and adjusted meta‐analysis

Abstract

Background/Objective There have been a number of case reports and small clinical series reporting the potential association between dipeptidyl peptidase‐4 inhibitors (DPPIs) for diabetes and the onset of bullous pemphigoid (BP). The aim of this study was to assess the association between DPPI use and BP, and whether this varied according to DPPI type. Methods We performed a systematic review and meta‐analysis according to PRISMA guidelines. We identified five studies with cases and controls. We performed unadjusted and adjusted meta‐analyses to assess the potential association. Results Adjusted meta‐analysis revealed significant association between DPPI use and BP (OR 2.13, 95% CI 1.59–2.86, I2 = 46%, P < 0.00001). This association was stronger between vildagliptin and BP (OR 5.08, 95% CI 1.70–15.19, P = 0.004) compared to linagliptin (OR 2.87, 95%CI 1.06–7.79, P = 0.04), and no association was found between sitagliptin and BP (OR 1.29, 95%CI 0.79–2.08, P = 0.31). Subgroup analysis demonstrated that the association between DPPI use and BP remained significant in males (OR 2.35, 95% CI 1.46–3.78, P = 0.0005) and females (OR 1.88, 95%CI 1.10–3.22, P = 0.02). Conclusions Limitations were that studies reviewed were retrospective by design which are susceptible to bias and lack of randomisation. Our adjusted analysis supports a significant association between DPPI use and onset of bullous pemphigoid. Vildagliptin had the highest odds of BP. These findings have clinical implications for dermatologists and the management of patients with diabetes and being treated with DPPI agents.

Increased risk of bullous pemphigoid in dipeptidyl peptidase 4 inhibitors: A nationwide, population‐based, cohort study in Taiwan

“…The recent meta‐analysis study reported that the association between DPP‐4 inhibitors and BP was significant in both males and females (OR, 2.35; P = 0.0005; and OR, 1.88; P = 0.02; respectively) . Subgroup analysis conducted in our study also showed that the higher risks of BP in DPP‐4 inhibitor users were found in both male and female patients with DM (aHR, 2.198; P = 0.018; and aHR, 2.676; P = 0.001; respectively).…”

“…A recent meta‐analysis study of five case–control studies showed a significant association between DPP‐4 inhibitors and BP (OR, 2.13; 95% CI, 1.59–2.86; P < 0.00001) . The study also reported a strong association between vildagliptin and BP (OR, 5.08; 95% CI, 1.70–15.19; P = 0.004), followed by linagliptin (OR, 2.87; 95% CI, 1.06–7.79; P = 0.04), but not in sitagliptin (OR, 1.29; 95% CI, 0.79–2.08; P = 0.31).…”

“…A recent meta-analysis study of five case-control studies showed a significant association between DPP-4 inhibitors and BP (OR, 2.13; 95% CI, 1.59-2.86; P < 0.00001). 19 The study also reported a strong association between vildagliptin and BP (OR, 5.08; 95% CI, 1.70-15.19; P = 0.004), followed by linagliptin (OR, 2.87; 95% CI, 1.06-7.79; P = 0.04), but not in sitagliptin (OR, 1.29; 95% CI, 0.79-2.08; P = 0.31). In Asia, a Korean retrospective, nationwide, case-control study of 670 case patients (DM and BP) and 670 control patients (DM only) showed that DPP-4 inhibitors are associated with a significant risk of BP (adjusted odds ratio [aOR], 1.58; 95% CI, 1.25-2.00; P < 0.001).…”

The role of Dipeptidyl Peptidase‐4 in cutaneous disease

“…Emerging evidence has established a relationship between DPP4i and the development of BP (OR, 2.13-97.69; Table S1). [42][43][44][45][46][47][48][49][50][51][52][53][54][55] Vildagliptin is the leading DPP4i to confer increased risk of BP The extracellular domain comprises dipeptidyl peptidase activity which selectively removes the X-proline or X-alanine dipeptide residues in the penultimate position from the NH 2 -terminus of polypeptide substrates. The extracellular catalytic domain of DPP4 serves as a binding site for substrates and inhibitors.…”

“…Adapted from Ohnuma et al 2 and anagliptin (111.07), which are less frequently used, 43,45,56 and omarigliptin (OR, 557.20), teneligliptin (OR, 29.23-161.9), and trelagliptin (OR, 178.18), which are available in fewer countries, such as Japan, Argentina, Korea, and India. 42,45,57 Whilst individual studies found no significant risk associated with sitagliptin use, a recent meta-analysis of randomized controlled trials involving sitagliptin, saxagliptin and linagliptin identified a significant association (OR, 7.38) 12,46,47 In addition to BP, DPP4i appear to predispose towards mucous membrane pemphigoid (MMP) development. In a study examining gliptin accountability in a cohort of 313 MMP patients, 17 of 24 gliptin-treated diabetic MMP patients were considered gliptin-induced MMP due to onset within <12 weeks.…”