Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

Table 3 Summary of the pharmacovigilance and population-based studies reporting dipeptidyl peptidase-4 inhibitor induced bullous pemphigoid

Ref.	Country	Population	Pooled odds ratio	Individual DPP-4i	Remarks
Reolid et al[55], 2020	Spanish Pharmacovigilance System	Overall reported adverse events	NA	ROR: linagliptin 69.42 (95%CI: 21.17–227.57), saxagliptin 46.45 (6.26-344.25), vildagliptin 123.38 (95%CI: 68.72–221.15), sitagliptin 12.42 (95%CI: 3.89–39.63)	Vildagliptin was the DPP-4i that most frequently induced BP
García et al[56], 2016	European pharmacovigilance database	Overall reported adverse events	NA	PRR: Vildagliptin 85.98 (95%CI: 70.98–104.15), sitagliptin 4.55 (95%CI: 3.32–6.24), saxagliptin 8.36 (95%CI: 3.14–22.28), linagliptin 24.32 (95%CI: 14.11–41.92)	Alogliptin was not associated with development of BP
Lee et al[57], 2019	Korea (Retrospective, nationwide, population-based, case-control study)	670 patients with diabetes with BP and 670 control patients with only diabetes	aOR, 1.58 (95%CI: 1.25-2.00)	Vildagliptin aOR 1.81 (95%CI: 1.31-2.50), sitagliptin aOR, 1.70 (95%CI: 1.19-2.43), linagliptin aOR 1.64 (95%CI: 1.15-2.33)	Male gender was associated with higher risk of development of BP
Carnovale et al[58], 2019	World Health Organization global Individual Case Safety Reports database	Overall reported adverse events	ROR 179.48 (95%CI: 166.41–193.58)	Teneligliptin 975.04 (95%CI: 801.70–1185.87), sitagliptin 46.52 (95%CI: 40.57–53.36), vildagliptin 399.70 (95%CI: 362.26–441.02), linagliptin 143.23 (95%CI: 122.60–167.33)	The highest ROR was found for teneligliptin
Béné et al[59], 2016	French Pharmacovigilance Database	Among 1297 spontaneous ADR reports, 42 were DPP-4i induced BP	ROR 67·5 (95%CI: 47.1-96.9)	Vildagliptin ROR 225·3 (95%CI: 148.9-340.9), sitagliptin ROR 17.0 (95%CI: 8.9-32.5), saxagliptin ROR 16.5 (95%CI: 2.3-119.1)	Vildagliptin had higher ROR
Varpuluoma et al[60], 2018	Finland (Nationwide Registry Study)	3397 BP cases and 12941 controls	aOR 2.13 (95%CI: 1.51–3.00)	aOR vildagliptin 8.66 (95%CI: 4.06-18.50), aOR sitagliptin 1.36 (95%CI: 0.93-1.99)	A significantly increased risk of BP after the use of vildagliptin
Hung et al[61], 2020	Taiwan (Nationwide, population-based, cohort study)	6340 patients with DM on DPP-4i and 25360 DM patients without DPP-4i	aHR 2.382 (95%CI: 1.163-4.883)	Vildagliptin aHR, 2.849 (95%CI: 1.893-4.215), saxagliptin aHR, 2.657 (95%CI: 1.770-3.934), sitagliptin aHR, 2.585 (95%CI: 1.723–3.829), linagliptin aHR, 2.360 (95%CI: 1.567–3.477), alogliptin aHR, 1.450 (95%CI: 0.965–2.152)	Vildagliptin was significantly associated with an increased risk of BP, and alogliptin was not associated with development of BP
Arai et al[49], 2018	Japanese Adverse Drug Event Report database	392 BP cases in DPP-4i user and 12811 without BP as control	ROR 87.56 (95%CI: 72.61–105.59)	ROR: alogliptin 8.02 (95%CI: 4.87–13.22), anagliptin 10.84 (95%CI: 3.46–33.96), sitagliptin 12.59 (95%CI: 9.86–16.06), trelagliptin 13.77 (95%CI: 3.40–55.85), saxagliptin 15.85 (95%CI: 5.87–42.79), linagliptin 28.96 (95%CI: 21.38–39.23), omarigliptin 43.79 (95%CI: 5.85–327.70), teneligliptin 58.52 (95%CI: 42.75–80.10), vildagliptin 105.33 (95%CI: 88.54–125.30)	The highest ROR was found with vildagliptin
MolinaGuarneros et al[70], 2020	Spain (pharmacovigilance data)	Case/non-case analysis (1998 DPP-4i induced ADR where 45 were DPP-4i induced BP)	ROR 70.0 (47.1–104.1)	Vildagliptin 113.9 (95%CI: 73.4–177), linagliptin 55.2 (95%CI: 28.2–108.0), sitagliptin 9.1 (95%CI: 3.7–22.6), saxagliptin 27.4 (95%CI: 3.7–200.1)	Highest risk of BP with vildagliptin
Douros et al[80], 2019	United Kingdom Clinical Practice Research Datalink	Cohort study among 168774 patients started on antidiabetic drugs	HR 2.21 (95%CI: 1.45-3.38)	Linagliptin HR 4.90 (95%CI: 2.68–8.96), vildagliptin HR 4.56 (95%CI: 1.42–14.64), saxagliptin HR 2.16 (95%CI: 0.86–5.46), sitagliptin HR 1.42 (95%CI: 0.79–2.53)	HRs for development of BP gradually increased with longer durations of DPP-4i use

ADR: Adverse drug reaction; aHR: Adjusted hazard ratio; aOR: Adjusted odds ratio; BP: Bullous pemphigoid; CI: Confidence interval; DPP-4i: Dipeptidyl peptidase-4 inhibitor; DM: Diabetes mellitus; NA: Not available; PRR: Proportional reporting ratio; ROR: Reporting odds ratio.