sitagliptin-phosphate and Pemphigoid--Bullous

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.. 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.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Linagliptin; Pemphigoid, Bullous; Sitagliptin Phosphate; Vildagliptin

Topics: Aged; Biopsy, Needle; Complement C3-C5 Convertases; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Direct; Follow-Up Studies; Humans; Immunoglobulin G; Immunohistochemistry; Male; Pemphigoid, Bullous; Risk Assessment; Severity of Illness Index; Sitagliptin Phosphate; Withholding Treatment

Although the association between dipeptidyl peptidase-4 (DPP-4) inhibitors and bullous pemphigoid (BP) has begun to be established, some studies have suggested there are risk differences among DPP-4 inhibitors. We conducted a population-based cohort study to examine the risk differences.. Using the claims databases of the Fukuoka Prefecture Wide-Area Association of Latter-Stage Elderly Healthcare between April 1, 2013 and March 31, 2017, we conducted a retrospective cohort study to compare patients receiving one DPP-4 inhibitor with those who were prescribed another antidiabetic drug. The primary outcome was an adjusted hazard ratio (HR) of the development of bullous pemphigoid during a 3-year follow-up. The secondary outcome was the development of BP requiring systemic steroids immediately after the diagnosis. These were estimated using Cox proportional hazards regression models.. The study comprised 33,241 patients, of which 0.26% (n = 88) developed bullous pemphigoid during follow-up. The percentages of patients with bullous pemphigoid who required immediate systemic steroid treatment was 0.11% (n = 37). We analyzed four DPP-4 inhibitors: sitagliptin, vildagliptin, alogliptin, and linagliptin. Vildagliptin and linagliptin raised the risk of BP significantly (primary outcome, vildagliptin, HR 2.411 [95% confidence interval (CI) 1.325-4.387], linagliptin, HR 2.550 [95% CI 1.266-5.136], secondary outcome, vildagliptin HR 3.616 [95% CI 1.495-8.745], linagliptin HR 3.556 [95% CI 1.262-10.024]). A statistically significant risk elevation was not observed with sitagliptin and alogliptin (primary outcome, sitagliptin, HR 0.911 [95% CI 0.508-1.635], alogliptin, HR 1.600 [95% CI 0.714-3.584], secondary outcome, sitagliptin, HR 1.192 [95% CI 0.475-2.992], alogliptin, HR 2.007 [95% CI 0.571-7.053]).. Not all the DPP-4 inhibitors could induce bullous pemphigoid significantly. Therefore, the association warrants further investigations before generalization.

Topics: Aged; Cohort Studies; Delivery of Health Care; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; East Asian People; Humans; Hypoglycemic Agents; Linagliptin; Pemphigoid, Bullous; Retrospective Studies; Sitagliptin Phosphate; Vildagliptin

The use of dipeptidyl peptidase 4 (DPP4) inhibitors, (also known as gliptins), is associated with an increased risk of bullous pemphigoid (BP), an autoimmune blistering skin disease. To explore the mechanism behind gliptin-associated BP we investigated circulating autoantibodies against the major BP autoantigen BP180 in serum samples from patients with type 2 diabetes (T2D) with preceding gliptin medication (n = 136) or without (n = 136). Sitagliptin was the most frequently prescribed gliptin (125/136 patients). Using an ELISA assay, we showed that IgG autoantibodies against the immunodominant NC16A domain of BP180 were found in 5.9% of gliptin treated and in 6.6% of non-gliptin treated T2D patients. We found that 28% of gliptin treated patients had IgG autoantibodies recognizing the native full-length BP180 in ELISA, but among non-gliptin treated the seropositivity was even higher, at 32%. Further ELISA analysis of additional serum samples (n = 57) found no major changes in the seropositivity against BP180 during a follow-up period of about nine years. In immunoblotting, full-length BP180 was recognized by 71% of gliptin treated and 89% of non-gliptin treated T2D patients, but only by 46% of the age-and sex-matched controls. The chemokine stromal derived factor-1(SDF-1/CXCL12) is one of the major substrates of DPP4. Immunostainings showed that the expression of SDF-1 was markedly increased in the skin of BP patients, but not affected by prior gliptin treatment. We found that the use of gliptins decreased the serum level of SDF-1α in both BP and T2D patients. Our results indicate that the autoantibodies against the linear full-length BP180 are common in patients with T2D, but seropositivity is unaffected by the use of sitagliptin.

Topics: Autoantibodies; Chemokine CXCL12; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Humans; Immunodominant Epitopes; Immunoglobulin G; Non-Fibrillar Collagens; Pemphigoid, Bullous; Sitagliptin Phosphate

Topics: Autoantibodies; Autoantigens; Dystonin; Enzyme-Linked Immunosorbent Assay; Humans; Laminin; Non-Fibrillar Collagens; Pemphigoid, Bullous; Sitagliptin Phosphate

The clinical and immunological profile of patients with dipeptidyl peptidase-4 inhibitor (DPP4i)-associated bullous pemphigoid (BP) is inconsistent in the current literature.. The aims were to investigate the clinical and immunological features of patients with DPP4i-associated BP and to examine whether there are intraclass differences between different DPP4i agents.. A retrospective cohort study was conducted, including all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral center.. The study encompassed 273 patients with BP (mean age at diagnosis 79.1 ± 9.9 years), of whom 24 (8.8%) were associated with DPP4i. Sitagliptin was the prescribed agent for 17 patients (70.8%), and vildagliptin was prescribed in seven patients (29.2%). Relative to other patients with BP, patients with DPP4i-associated BP had more prominent truncal involvement (95.8% vs. 73.9%; P = 0.017), greater erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) subscore (29.8 ± 17.4 vs. 20.6 ± 14.4; P = 0.018), and lower levels of anti-BP180 NC16A (279.2 ± 346.1 vs. 572.2 ± 1352.0 U/ml; P = 0.009) and anti-BP230 (25.5 ± 47.8 vs. 128.6 ± 302.9 U/ml; P = 0.009) antibodies. Relative to patients with sitagliptin-associated BP, those with vildagliptin-associated BP had a lower seropositivity rate (57.1% vs. 94.1%, P = 0.031) and lower levels (96.7 ± 139.0 vs. 354.5 ± 376.5; P = 0.023) of anti-BP180 NC16A antibodies, and tended to present with higher erosion/blister BPDAI subscore (36.3 ± 9.6 vs. 25.8 ± 19.7; P = 0.095).. DPP4i-associated BP is characterized by a more severe blistering and erosive presentation despite lower levels of typically pathogenic antibodies.

Topics: Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Collagen Type XVII; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Female; Humans; Male; Middle Aged; Non-Fibrillar Collagens; Pemphigoid, Bullous; Retrospective Studies; Severity of Illness Index; Sitagliptin Phosphate; Skin; Vildagliptin

Bullous pemphigoid (BP) has been associated with dipeptidyl peptidase-4 inhibitors (DPP4i). Clinical features, outcomes, and risk of BP for new DPP4i (linagliptin, saxagliptin, and alopgliptin) are not well established. Comparison of risk of BP appearance for DPP4i and other oral antidiabetic drugs (OADs) such as sodium glucose cotransporter 2 inhibitors has not been studied to date.. To describe the prevalence, sociodemographic, clinical, and histopathological characteristics, and outcome after drug withdrawal in DPP-4i-associated BP cases from our hospital. To review all Spanish spontaneous notifications of BP where DPP4i or OADs were included as suspected drugs and calculate the reporting odds ratios (RORs).. A retrospective observational study was performed examining the association between DDP4i and BP. Clinical features and RORs were analyzed. Data from the Spanish Pharmacovigilance System (SEFV) are included.. In our center, 28 of 89 patients with BP (31.5%) were under DPP4i treatment; 53.6% were male, and mean age was 80.8 years. BP debuted the first year after DPP4i in 57.2%. BP control was achieved within 3.7 months after drug withdrawal. Regarding SEFV, 22 of 972 spontaneous notifications were related to BP and DPP4i. RORs were superior for DPP4i compared to other OADs. Vildagliptin had the highest ROR.. We present the largest DPP4i-induced BP case series in a single center, with a detailed study of the sociodemographic, clinical, and histopathological characteristics of each patient, and their treatment and outcome. Vildagliptin had the highest risk. DPP4i-associated BP does not seem to have specific clinical characteristics.

Topics: Aged; Aged, 80 and over; Databases, Factual; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Pharmacovigilance; Retrospective Studies; Sitagliptin Phosphate; Sodium-Glucose Transporter 2 Inhibitors; Spain; Vildagliptin

Recent studies revealed the risk of bullous pemphigoid (BP) in patients with diabetes mellitus (DM) taking dipeptidyl peptidase 4 (DPP-4) inhibitors. To clarify the relationship between taking DPP-4 inhibitors and the risk of BP among patients with DM, we conducted a cohort study by using the National Health Insurance Research Database of Taiwan from 1 January 2009 to 31 December 2015. We identified 6340 patients with DM taking DPP-4 inhibitors and 25 360 DM patients who had not taken DPP-4 inhibitors during the 7-year follow-up period. Compared with the non-DPP-4 inhibitor group, patients taking DDP-4 inhibitors had a higher risk of BP (adjusted hazard ratio [aHR], 2.382; 95% confidence interval (CI), 1.163-4.883; P = 0.017]. Among the DPP-4 inhibitors available in Taiwan, vildagliptin showed the highest risk of BP (aHR, 2.849; 95% CI, 1.893-4.215; P < 0.001), followed by saxagliptin (aHR, 2.657; 95% CI, 1.770-3.934; P < 0.001). Subgroup analysis revealed that the higher risk of BP was observed in patients older than 65 years (aHR, 2.403; 95% CI, 1.590-3.627; P < 0.001). This study revealed that treatment with DPP-4 inhibitors, especially vildagliptin, was significantly associated with an increased risk of BP among DM patients.

Topics: Adamantane; Adult; Age Factors; Aged; Case-Control Studies; Databases, Factual; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Incidence; Linagliptin; Male; Middle Aged; Pemphigoid, Bullous; Piperidines; Risk Factors; Sitagliptin Phosphate; Taiwan; Uracil; Vildagliptin; Young Adult

Topics: Administration, Intravenous; Aged, 80 and over; Dipeptidyl-Peptidase IV Inhibitors; Disseminated Intravascular Coagulation; Fatal Outcome; Humans; Iatrogenic Disease; Immunoglobulins; Male; Pemphigoid, Bullous; Recurrence; Sitagliptin Phosphate

Bullous pemphigoid (BP) is an autoimmune blistering skin disorder. Recently, BP induced by dipeptidyl peptidase-4 (DPP-4) inhibitors has been a concern. Although DPP-4 inhibitors are commonly used in the Asian population because of their safety and efficacy, BP associated with DPP-4 inhibitors is sometimes seen in clinical settings. Here, we report five Japanese cases of BP associated with the agents. In the present cases, BP occurred in older adults using four different DPP-4 inhibitors, which showed various clinical manifestations in terms of latency period for BP, sex, glycemic control and diabetes duration. Withdrawal of DPP-4 inhibitors was effective in improving BP, and achieved remission even in cases requiring oral steroid administration and intravenous immunoglobulin therapy. Clinicians should note the importance of early diagnosis of this clinical condition and initiate prompt withdrawal of DPP-4 inhibitors.

Topics: Aged, 80 and over; Asian People; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Japan; Linagliptin; Male; Pemphigoid, Bullous; Pyrimidines; Sitagliptin Phosphate

Topics: Adamantane; Aged; Aged, 80 and over; Autoantibodies; Autoantigens; Collagen Type XVII; Dipeptidyl-Peptidase IV Inhibitors; Epitopes; Female; Humans; Immunoglobulin A; Immunoglobulin E; Immunoglobulin G; Linagliptin; Male; Membrane Glycoproteins; Middle Aged; Nitriles; Non-Fibrillar Collagens; Pemphigoid, Bullous; Piperidines; Pyrrolidines; Sitagliptin Phosphate; Uracil; Vildagliptin

Dipeptidyl peptidase-4 (DPP-4) inhibitors have increasingly been identified as causative agents of bullous pemphigoid. The clinical and immunological characteristics of this pemphigoid variant are still unclear. The objective of our study was to analyze the clinical and immunological features of patients with pemphigoid induced by DPP-4 inhibitors.. All patients diagnosed with DPP-4 inhibitor-associated bullous pemphigoid at dermatology departments in three Spanish centers during the period 2013 to 2015 were included. ELISA assays for the NC16A domain of BP180 and BP230 were performed. Immunoblot studies using epidermal/dermal extracts and the C-terminal, NC16A and LAD-1 regions of BP180 were also carried out.. A total of eight patients were identified (5 treated with vildagliptin, 2 with linagliptin, and one with sitagliptin). Of these, four presented the classical inflammatory phenotype of bullous pemphigoid and four a noninflammatory phenotype. The ELISA for BP180 (NC16A domain) was positive in six patients at diagnosis. Most patients reacted to more than one BP180 antigenic site (LAD-1 and/or C-terminal domain) on the immunoblot. Two patients showed no reaction against the NC16A domain of BP180 on either the ELISA or immunoblot but recognized either LAD-1 or both LAD-1 and the C-terminal domain. Only one of the NC16A-negative patients had a noninflammatory subtype of bullous pemphigoid.. Patients with DPP-4 inhibitor-induced BP may present either an inflammatory or a noninflammatory phenotype of BP. IgG response against other BP180 regions different from the NC16A domain, such as LAD-1 and the C-terminal domain, could be pathogenically relevant to the onset of DPP-4 inhibitor-induced BP.

Topics: Adamantane; Aged; Aged, 80 and over; Autoantigens; Collagen Type XVII; Dipeptidyl-Peptidase IV Inhibitors; Dystonin; Female; Humans; Immunoglobulin G; Linagliptin; Male; Nitriles; Non-Fibrillar Collagens; Pemphigoid, Bullous; Phenotype; Pyrrolidines; Sitagliptin Phosphate; Vildagliptin

A 78-year-old man presented with cutaneous blisters of the limbs and abdominal distension. He had been treated for various diseases, including liver cirrhosis. He had begun receiving sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for diabetes mellitus three years before the hospitalization. A skin biopsy demonstrated bullous pemphigoid. Ultrasonography (US) revealed multiple liver tumors, although he had been receiving regular US studies. We stopped sitagliptin and started insulin and corticosteroids. However, his renal dysfunction progressed, and he died 14 days after the hospitalization. We should therefore be careful of various complications, including bullous pemphigoid and progression of tumors, when using DPP-4 inhibitors.

Topics: Aged; Carcinoma, Hepatocellular; Diabetes Mellitus; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Liver Cirrhosis; Liver Neoplasms; Male; Pemphigoid, Bullous; Sitagliptin Phosphate

Topics: Adamantane; Aged; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Male; Nitriles; Pemphigoid, Bullous; Pyrazines; Pyrrolidines; Sitagliptin Phosphate; Triazoles; Vildagliptin