Gliptin-Induced Bullous Pemphigoid: Are Statins and Angiotensin Receptor Blockers the Cause?

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. 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. 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). 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.

The use of dipeptidyl peptidase-4 inhibitors (DPP4i) appears to be associated with a small but significantly elevated risk of bullous pemphigoid (BP). Although the pathogenic mechanism of DPP4i-associated BP remains unclear, this adverse event is reported with multiple gliptins, suggesting a class effect. However, previous studies from various countries showed that vildagliptin had been implicated in most cases. The aim of this study was to illustrate a case series of DPP4i-associated BP in Thai patients. We conducted a retrospective study from consecutive cases of BP in people with type 2 diabetes mellitus (T2DM) from January 2008, the year in which the first DPP4i was introduced in Thailand, until December 2019. During the study period, 10 BP patients with T2DM were identified. A total of 5 DPP4i-associated BP (3 on vildagliptin, 1 on linagliptin, and 1 on sitagliptin) were found. All patients were male with a mean age at BP development of 80.4 years (73–86 years). All patients had a long-standing duration of diabetes (median duration 34 years), and mean A1C was 7.5 ± 1.4%. The median time to BP development after the introduction of DPP4i was 64 months (range 20–128 months). The severity of BP was classified as mild in 2 cases. In all cases, the association between the drug intake and BP onset was classified as “possible” according to the Naranjo causality scale. All of the patients continued taking DPP4i after BP diagnosis, and one patient died of lung cancer 18 months after BP diagnosis. Only 2 patients could achieve complete remission at least 2 months after stopping DPP4i. Our case series demonstrated a potential link between DPP4i and the development of BP, which mainly occurred in very elderly male patients. The latency period from an introduction of DPP-4i could be several years, and the clinical course after DPP4i discontinuation varied. Clinicians prescribing DPP4i should be aware of this association and consider stopping this medication before a refractory disease course ensues.

Disclosure: S. Saad-Omer: None. M. Kinaan: None. N. Sami: None. I. Mansi: None. Introduction: Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are Autoimmune Blistering Disorders (AIBDs). GLP-1 Receptor Agonists (GLP1-RA) and Dipeptidyl peptidase 4 inhibitors (DPP4i) have been noted in various case reports and case control studies to be linked with certain AIBDs; however, their overall role in these diseases is not completely understood, despite the exponential increase in use of these medications. This study aims to be the first study to investigate the association of DPP-4 inhibitors and GLP-1 agonists with incidence of AIBD, PV, and BP in a large cohort of American veterans. Methods: This retrospective cohort study of veterans enrolled in the Veterans Health Administration (VHA) used Corporate Data Warehouse (CDW). We extracted data of patients from fiscal years (FY) 2006 to end of FY 2021 who filled either GLP1-RA or DPP4i prescriptions. CDW is a comprehensive data source that encompasses vital status, demographic data, inpatient and outpatient diagnoses and procedure codes, vital signs, laboratory data, and pharmacy fill data. The study groups included: 1) GLP1-RA group: patients who initiated GLP1-RA; and 2) DPP4i group: patients who initiated DPP4i. Our primary outcome was the incidence of AIBDs. We compared baseline characteristics of patients who experienced the outcome and those who did not among GLP1-RA or DDP4i users. We, thereafter, examined factors associated with incidence of AIBD, PV, and BP among GLP1-RA users and DPP4i users. Results: The initial cohort of GLP1-RA or DPP4i users comprised a total of 415,895 patients, from which we excluded 397 (0.095%) patients with prior bullous skin diseases before starting GLP1-RA or DPP4i medications. Overall, a total of 154 patients developed PV/BP disease after initiation of either DPP4i or GLP1-RA. Of these 154 patients, 123 of these patients were on DPP4i and 31 of these patients were on GLP1-RA. The mean age (SD) of PV/BP patients was 72 (11) years compared to an average age of 66 (10) years in patients who did not develop PV/BP. Patients were also found to be predominately white (77.9%). Factors associated with increased risk of BP were use of DPP4i (Odds Ratio [OR] 1.90, 95% confidence interval [95% CI: 1.14-3.47, p=&amp;lt;0.01), and older age (OR: 1.07, 95%CI: 1.04-1.09, p&amp;lt;0.01). Use of GLP1-RA or DPP4i was not associated with PV incidence. (OR: 1.31, 95% CI: 0.65-2.62, p=&amp;lt;0.45). Conclusion: In conclusion, our study supports existing literature that DPP4i use is associated with an increased risk of developing BP. Our data does not find association with GLP-1 agonists nor DPP4 inhibitors in increasing the risk of PV. Presentation: 6/3/2024

Background/Objectives: Patients with diabetes mellitus face increased risk of severe outcomes and mortality from COVID-19. Dipeptidyl peptidase-4 (DPP-4) inhibitors, widely used antidiabetic agents, are hypothesized to affect COVID-19 outcomes via anti-inflammatory and immune-modulating mechanisms. However, real-world evidence, especially in Korean populations, remains limited. Methods: We conducted a retrospective cohort study using Korea’s nationwide Health Insurance Review and Assessment (HIRA) database. Adults with diabetes hospitalized for confirmed COVID-19 between 1 March 2021, and 28 February 2022, were included and stratified by DPP-4 inhibitor use. The primary outcome was 30-day all-cause mortality. Cox proportional hazards models adjusted for age, sex, and comorbidities estimated hazard ratios (HRs). Subgroup analyses examined angiotensin receptor blocker (ARB) and insulin use. Results: Among 16,134 eligible patients, 7082 received DPP-4 inhibitors. The 30-day mortality rate was lower in DPP-4 inhibitor users than non-users (4.3% vs. 10.3%, p < 0.0001). Adjusted analyses showed DPP-4 inhibitor use was associated with reduced mortality risk (adjusted HR: 0.455; 95% CI: 0.414–0.499). Subgroup analyses yielded consistent results across ARB and insulin users. Kaplan-Meier curves demonstrated higher survival probability in the DPP-4 inhibitor group. Conclusions: In this nationwide Korean cohort, DPP-4 inhibitor use was associated with lower mortality among hospitalized diabetic patients with COVID-19. While these findings suggest a potential benefit, causality cannot be confirmed due to the observational design. Prospective studies are needed to verify these associations and explore underlying mechanisms.

Recent studies suggest that dipeptidyl peptidase 4 (DPP-4) inhibitors are associated with an increased risk of developing bullous pemphigoid (BP). Population-based studies on the association between DPP-4 inhibitors and BP are limited. To characterize the potential association between the use of DPP-4 inhibitors and an increased risk of developing BP. This retrospective, nationwide, population-based, case-control study using Korean insurance claims data from January 1, 2012, to December 31, 2016, included patients with newly diagnosed BP and diabetes. Control patients with diabetes (and without BP) were randomly obtained after matching for age, sex, and year of diagnosis within the same period. The number of patients with newly diagnosed BP and diabetes per year and annual changes in the proportion of patients with diabetes among all patients with BP were measured. The association between use of DPP-4 inhibitors and risk of developing BP was analyzed using univariate and multivariate logistic regression analyses. The study included 670 case patients (with diabetes and BP) and 670 control patients (with only diabetes) (mean [SD] age, 75.3 [10.0] years in each group; 342 [51.0%] male in each group). The number of patients with diabetes and BP more than doubled during the study period (from 77 in 2012 to 206 in 2016). The proportion of patients with diabetes among all patients with BP also increased (from 0.18 in 2012 to 0.33 in 2016). The use of DPP-4 inhibitors was associated with a significant increase in the risk of developing BP (adjusted odds ratio [aOR], 1.58; 95% CI, 1.25-2.00; P < .001); among all DPP-4 inhibitors used in Korea, the highest aOR was associated with the use of vildagliptin (aOR, 1.81; 95% CI, 1.31-2.50; P < .001). Subgroup analyses revealed a significant association in male patients (aOR, 1.91; 95% CI, 1.39-2.63; P < .001) and that vildagliptin was the most high-risk DPP-4 inhibitor (aOR, 2.70; 95% CI, 1.73-4.34; P < .001). The findings suggest that DPP-4 inhibitors are associated with a significantly increased risk of the development of BP in patients with diabetes. Of the DPP-4 inhibitors available in Korea, vildagliptin was associated with the highest risk, particularly in male patients. Practitioners should consider that DPP-4 inhibitors, particularly vildagliptin, may be associated with the development of BP in patients with diabetes. These nationwide, population-based results may serve as a foundation for further studies seeking to understand how DPP-4 inhibitors contribute to the development of BP.

Dipeptidyl peptidase-4 (DPP-4) inhibitor and mortality in coronavirus disease 2019 (COVID-19) – A systematic review, meta-analysis, and meta-regression

The association between statins and subsequent risk of bullous pemphigoid: A population-based cohort study

The association of bullous pemphigoid (BP) with the use of dipeptidyl-peptidase 4 (DPP-4) inhibitors among patients with diabetes has recently emerged. The risk of developing BP during treatment with new DPP-4 inhibitor agents like linagliptin is yet to be established. The clinical features and the prognostic outcomes of patients with DPP-4 inhibitor-associated BP are yet to be established. Primarily to estimate the association between DPP-4 inhibitor exposure and the development of BP, and secondarily to characterize the clinical features and history of patients with DPP-4 inhibitor-associated BP. A retrospective case-control study of the intake of different DPP-4 inhibitor agents and metformin and occurrence of BP among patients with diabetes in a tertiary care referral center for autoimmune bullous diseases in northern Israel. Included were 82 consecutive patients with diabetes and immunopathologically validated BP diagnosed between January 1, 2011, and December 31, 2017, and 328 age-, sex-, and ethnicity-matched control participants with diabetes but without BP. Patients with diabetes and BP and exposure to DPP-4 inhibitors were followed up for a median of 2.0 years and compared with other patients with diabetes and BP who were not exposed to DPP-4 inhibitors regarding clinical and immunological features, laboratory analyses, treatments, and clinical outcomes. Eighty-two patients with BP and 328 age- and sex-matched control participants were enrolled; mean (SD) age, 79.1 (9.1) years; and 44 patients were female (53.7%). Overall, DPP-4 inhibitor intake was associated with a 3-fold increased risk for BP (adjusted odds ratio [OR], 3.2; 95% CI, 1.9-5.4). The adjusted ORs for vildagliptin and linagliptin were 10.7 (95% CI, 5.1-22.4) and 6.7 (95% CI, 2.2-19.7), respectively. The association of DPP-4 inhibitor use with BP was independent of the use of metformin and was stronger among male (OR, 4.46; 95% CI, 2.11-9.40) than female (OR, 1.88; 95%, CI 0.92-3.86) patients and strongest in patients younger than 70 years (OR, 5.59; 95% CI, 1.73-18.01). Patients with DPP-4 inhibitor-associated BP presented with higher mucosal involvement (22.2% vs 6.5%; P = .04) and lower mean (SD) peripheral eosinophil counts (399.8 [508.0] vs 1117.6 [1847.6] cells/μL; P = .01) than those with BP who had not been exposed to DPP-4 inhibitor. Discontinuation of DPP-4 inhibitor treatment was followed by improved clinical outcomes. Vildagliptin and, to a lesser extent, linagliptin are associated with an increased risk of BP. This may partly explain the increasing incidence of BP in Israel. Discontinuation of DPP-4 inhibitor treatment in patients with diabetes should be considered when BP is diagnosed.

Bullous pemphigoid (BP) is an autoimmune skin disorder characterized by the production of autoantibodies. Several recent reports have described the occurrence of BP in diabetic patients treated with dipeptidyl peptidase-4 (DPP-4) inhibitors. However, the clinical features of BP in diabetic patients, particularly in those treated with DPP-4 inhibitors, have not yet been examined. The aim of this study was to clarify clinical characteristics of BP in elderly type 2 diabetic patients. We found cases of BP in 15 elderly type 2 diabetic patients (11 men, 4 women) and 20 non-diabetic patients (8 men, 12 women) from September, 2012 to September, 2016. These patients had all been treated with corticosteroid therapy. We investigated the participants' basic clinical characteristics and the course of BP treatment. The differences in variables between the two groups were analyzed using Wilcoxon's test and the chi-square test. The mean age of type 2 diabetes patients with BP was 81.1±5.5 years. The mean HbA1c was 7.3±1.6%. A total of 87% of diabetic patients had been treated with DPP-4 inhibitors for 11.7 months prior to the BP onset. The diabetic patients had a lower prevalence of neurogenerative disease, severe ADL disabilities, and dementia than the non-diabetic patients. Furthermore, the diabetic patients with BP tended to be younger and more frequently male than those without diabetes. After stopping the DPP-4 inhibitors, the skin lesions were successfully treated with systemic corticosteroid therapy, and glycemic control was achieved using intensive insulin therapy. DPP-4 inhibitors were used in all cases where the aniti-BP180NC16a antibody showed negative conversion. BP in patients with type 2 diabetes had different clinical features from that in non-diabetic patients, suggesting an association between BP and the use of DPP-4 inhibitors.

Objective: The rare risk association of bullous pemphigoid (BP) with use of dipeptidyl peptidase-4 inhibitors (DPP-4i) had been reported including genetic association with HLA variants. We assessed genetic susceptibility of BP associated with DPP-4i use in patients with type 2 diabetes (T2D) . Methods: In a prospective cohort of 30,129 Chinese patients with T2D enrolled in the Hong Kong Diabetes Register between 1995 to 2018, we curated multiple case-control cohorts with available genotype data to explore the genetic associations of major histocompatibility complex (MHC) region with DDP-4i-associated BP. Results: During a median follow period of 9 years, 60 patients developed BP (incidence of 2.cases per 10,000 patient-years) . 20 patient developed BP after DPP-4i use, with median exposure to DPP-4i of 1.7 years (incidence of 4.76 cases per 10,000 patient-years) and an adjusted odds ratio of 1.1 (95% CI 0.5-1.6) . 32 patients developed BP and were not exposed to DPP-4i (incidence of 2.87 cases per 10,000 patient-years) . In 1:2 matched case:control cohort of patients who tolerated DPP-4i and did not develop of BP, multiple variants in the second intron of HLA-DQB1 exhibited strong association with DPP4i-associated BP, including the well-reported HLA-DQB1*03: (OR 12.00; 95% CI 1.99-72.35; P-value 6.71e-03) and a novel single nucleotide polymorphism rs281863580 (OR 11.96; 95% CI 4.14-34.54; P-value 4.53e-06) . We additionally identified variants located in other HLA regions that were associated with BP in non-DPP4i users. Conclusion: Multiple genetic polymorphisms in the second intron of HLA-DQB1 were associated with increased susceptibility to incident BP in DPP-4i users. Further exploration of the extended MHC region beyond HLA alleles might identify a combination panel for assessing the genetic risk of BP rather than a single HLA allele. Disclosure M.Shi: None. A.Yang: None. E.Chow: Research Support; Hua Medicine, Medtronic, Powder Pharmaceuticals Inc., Speaker's Bureau; Novartis AG, Sanofi. E.S.Lau: None. C.H.Tam: None. R.C.Ma: Other Relationship; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; AstraZeneca, Bayer AG, Novo Nordisk A/S, Pfizer Inc., Tricida, Inc. M.Cheung: None. J.C.Chan: Board Member; Asia Diabetes Foundation, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Celltrion, Merck Sharp &amp; Dohme Corp., Roche Diabetes Care, Viatris Inc., Research Support; Applied Therapeutics, AstraZeneca, Eli Lilly and Company, Hua Medicine, Servier Laboratories, Stock/Shareholder; GemVCare Ltd. W.Chan: None. Funding The Hong Kong Government Research Grants Committee Theme-based Research Scheme (T12-402/13N) .2) Impact Research Impact Fund (R4012-18) .

HLA-DQB1*03:01 as a Biomarker for Genetic Susceptibility to Bullous Pemphigoid Induced by DPP-4 Inhibitors

Dipeptidyl peptidase-4 inhibitors (DPP4is), drugs used to treat type 2 diabetes mellitus (DM2), show a significant association with bullous pemphigoid (BP) development. In this retrospective cohort study, we evaluated the clinical course and development of BP among patients with DM2 treated with DPP4is. This retrospective cohort study included all the patients with BP and comorbid DM2 who visited Sheba hospital during 2015-2020. Among 338 patients with BP, 153 were included in our study. In 92 patients, BP diagnosis was attributed to the use of DPP4is. DPP4i-associated BP patients had fewer neurological and cardiovascular comorbidities and higher blistered body surface area (BSA) at first presentation, with noticeable upper and lower limb involvement. These patients were younger and more responsive to treatment, with a greater reduction in the BSA score after two months of treatment. The clinical features of patients with BP treated with DPP4is were initially more severe; however, during follow-up, a marked clinical improvement was noticed, especially among patients who had ceased the drug. Therefore, although withdrawal of the drug may not impose disease remission, it can alleviate the disease course and avert the need for treatment escalation.

AimTo evaluate the association between the use of dipeptidyl peptidase-4 inhibitors (DPP4I) and clinical and laboratory findings of bullous pemphigoid (BP) in patients treated at the European Reference Network – Skin Reference Centre in Croatia.MethodsThis retrospective study enrolled 82 patients treated for BP at the Department of Dermatovenereology, University Hospital Center Zagreb from January 2015 to December 2019. Clinical features of BP, presence of comorbidities, and laboratory findings of anti-BP antibodies and eosinophilia were analyzed in three groups of BP patients: 1) diabetes mellitus (DM) type II patients treated with DPP4I, 2) DM type II patients not treated with DPP4I, and 3) non-DM type II patients.ResultsThe average age and anti-BP180 titer were similar in all three groups. DPP4I group had a slightly lower eosinophil level in both peripheral blood (4.89%) and biopsy specimens (87.5%), but the difference was not significant. The prevalence of inflammatory BP in DPP4I group was 76.5%. DPP4I group had significantly higher percentage of patients with chronic renal failure and dementia (52.9% and 11.8%, respectively) compared with non-DPP4I DM (14.3% and 0%, respectively) and non-DM type II patients (15.7% and 0%, respectively).ConclusionBP patients treated with DPP4I and those not treated with DPP4Is did not significantly differ in laboratory findings. However, DPP4I treatment was associated with an inflammatory subtype of BP and a higher prevalence of dementia and chronic renal failure. These findings warrant further research into the association of BP and DM with dementia and chronic renal failure.

Bullous pemphigoid (BP) has been associated with dipeptidyl peptidase-4 inhibitor (DDP-4i) use in patients with diabetes mellitus (DM). The prevalence and association of DM in BP patients independent of DPP-4i use has not been investigated by meta-analysis. To perform a systematic review and meta-analysis on the association between diabetes and bullous pemphigoid. The goal was to determine the prevalence and pooled odds ratio of BP patients with DM in the absence of DDP-4i use compared to the general population prevalence of diabetes mellitus. OVID Medline, EMBASE, Cochrane Central and Web of Science were searched for relevant studies published from inception to April 2020. Case-control, case-series, cohort, and cross-sectional studies that included the association of BP and DM without DDP-4i's, in any language. PRISMA guidelines were followed for data extraction and the Newcastle-Ottawa Scale for risk of bias evaluation. Three reviewers independently performed data extraction. Pooled odds ratio and prevalence were calculated using the random effects model. The odds ratio and prevalence of BP patients with DM. Overall, 8 studies out of 856 identified publications through data base searches were included. The pooled prevalence of diabetes in patients with BP was 20.0% [95% CI 14%-26%; p = 0.00]. Within the comparative non-BP control population, 13% had diabetes. BP patients were more likely to have diabetes compared to a control population without BP [OR 2.10, 95% CI 1.22-3.60; p = 0.01]. This study found that twice the number of BP patients have DM (20%) compared to the general population reported as 10.5%, warranting monitoring of blood glucose levels in BP patients who may have yet undeclared or undiagnosed DM when initiating systemic steroids.

Rate of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Use and the Number of COVID-19–Confirmed Cases and Deaths