The Risk of Immune-Mediated Skin Disease Under Dipeptidyl-Peptidase IV Inhibitor - A Global Population-Based Study

Q: What question does the study address?

It evaluates the risk of 14 immune-mediated skin diseases in adults with type 2 diabetes treated with DPP4 inhibitors compared with those treated with SGLT-2 inhibitors or thiazolidinediones.

Q: Which skin diseases showed a significantly increased risk with DPP4 inhibitors?

Bullous pemphigoid and atopic dermatitis were significantly increased after DPP4 inhibitor use, based on hazard ratios reported in the study.

Q: How was the study population and comparison group defined?

The study used a retrospective cohort from the TriNetX Global Collaborative Network, including adults initiating either a DPP4i or SGLT-2i/thiazolidinedione, matched 1:1 by propensity scores and excluding patients exposed to both drug classes.

Sep 30, 2026

Uploaded by Quinn Holloway

Dipeptidyl peptidase-4 inhibitors (DPP4i) are second-line oral antidiabetic drugs, and their immunoregulatory target CD26 may influence immune responses. A retrospective cohort study used TriNetX Global Collaborative Network records from 718,046 adults with type 2 diabetes to assess 14 immune-mediated skin diseases after DPP4i initiation versus SGLT-2 inhibitors or thiazolidinediones. DPP4i increased bullous pemphigoid risk (HR 1.84) and atopic dermatitis risk (HR 1.15), while other studied conditions showed no significant elevation. Temporal analysis indicated persistent BP risk, with AD and alopecia areata significance emerging from three years.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages3

Reading Time8 min

AccessFree to download

Background and Rationale

Study Design and Data Source

Outcomes and Statistical Methods

Key Results

Temporal Findings

International Journal of Dermatology SHORT COMMUNICATION OPEN ACCESS The Risk of Immune-Mediated Skin Disease Under Dipeptidyl-Peptidase IV Inhibitor: A Global Population-Based Study Noor Mruwat1 | Noga Givon-Lavi2,3 | Ralf J. Ludwig4,5 | Khalaf Kridin1,4,6 1Unit of Dermatology and Skin Research Laboratory, Galilee Medical Center, Nahariya, Israel | 2Soroka University Medical Center, Beer Sheva, Israel | 3Ben Gurion University of the Negev, Beer Sheva, Israel | 4Lübeck Institute of Experimental Dermatology, University of Lübeck, Lübeck, Germany | 5Department of Dermatology, University of Lübeck, Lübeck, Germany | 6Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel Correspondence: KhalafKridin ([dr_kridin@hotmail.com](dr_kridin@hotmail.com)) Received: 6 April 2025 | Revised: 31 May 2025 | Accepted: 6 June 2025 Funding: The authors received no specific funding for this work. Keywords: autoimmune skin diseases | dipeptidyl-peptidase IV inhibitor | SGLT-2 | thiazolidinedione Dipeptidyl peptidase-4 inhibitors (DPP4i), also known as gliptins, are widely used second-line oral antidiabetic drugs in managing type 2 diabetes mellitus (T2DM) . These drugs work by preventing degradation of incretin hormones, such as glucagon-like peptide-1 (GLP-1), thereby enhancing insulin secretion and improving glycemic control [1] . DPP4, however, is also a surface protein (CD26) involved in immune regulation, expressed on various immune cells, including T cells and macrophages. As such, its inhibition may impact immune responses, potentially triggering autoimmune conditions [2] . Bullous pemphigoid (BP), an autoimmune blistering skin disease, has been the most consistently linked adverse dermatological effect of DPP4i use [3]. Yet, the broader implications of DPP4ion autoimmune skin diseases remain underexplored. This study evaluated the risk of 14 immune-mediated skin diseases (IMSD) in T2DM patients treated with DPP4i compared to those managed with sodium-glucose cotransporter-2 inhibitors (SGLT-2i) or thiazolidinediones. A retrospective cohort study was conducted using the TriNetX Global Collaborative Network, aggregating de-identified electronic health records from over 117 million patients worldwide. Adults with T2DM initiating either DPP4i (sitagliptin, linagliptin, saxagliptin, vildagliptin, and alogliptin) or SGLT-2i/ thiazolidinediones were included. Patients exposed to both drug classes were excluded. The two treatment groups were matched 1:1 using propensity scores, accounting for age, sex, race, body mass index (BMI), smoking status, and significant comorbidities (e.g., ischemic heart diseases, hypertension, hyperlipidemia, obesity, chronic kidney disease, depression, cerebral infarction, cirrhosis) . The primary outcomes were incident diagnoses of 14 IMSD, including BP, atopic dermatitis (AD), alopecia areata (AA), pemphigus foliaceus (PF), and 10 additional IMSDs. Follow-up began on the date of drug initiation. Cox proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). A Bonferroni-corrected significance threshold of p < 0.004 was used to adjust for multiple comparisons. A total of 718,046 patients were analyzed, with 359,023 individuals in each treatment group (Table 1) . DPP4i use was associated with a significantly increased risk of BP (HR, 1.84; 95% CI, 1.52–2.22; p < 0.001) and AD (HR, 1.15; 95% CI, 1.08–1.23; p < 0.001) . No significant risk elevation was observed for the other IMSDs (Table 2) . Temporal analysis showed that BP risk was elevated across all time intervals, with the highest risk occurring 1–3 years | Noor Mruwat and Noga Givon-Lavi contributed equally to this work.
Ralf J. Ludwig and Khalaf Kridin contributed equally to this work. | | --- | | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, pro

FAQs

What question does the study address?

It evaluates the risk of 14 immune-mediated skin diseases in adults with type 2 diabetes treated with DPP4 inhibitors compared with those treated with SGLT-2 inhibitors or thiazolidinediones.

Which skin diseases showed a significantly increased risk with DPP4 inhibitors?

Bullous pemphigoid and atopic dermatitis were significantly increased after DPP4 inhibitor use, based on hazard ratios reported in the study.

How was the study population and comparison group defined?

The study used a retrospective cohort from the TriNetX Global Collaborative Network, including adults initiating either a DPP4i or SGLT-2i/thiazolidinedione, matched 1:1 by propensity scores and excluding patients exposed to both drug classes.

Sep 30, 2026

Uploaded by Quinn Holloway