Identification of Risk Factors for Gliptin-associated Bullous Pemphigoid among Diabetic Patients.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Acute quadruple extremity compartment syndrome due to angio-oedema after polypharmacy overdose including olmesartan medoxomil, telmisartan and vildagliptin.

This case report describes a rare manifestation of acute compartment syndrome (ACS) involving all four extremities, precipitated by angio-oedema in a middle-aged woman who consumed an overdose of multiple medications: nifedipine, azelnidipine, amlodipine besylate, olmesartan medoxomil, telmisartan, esaxerenone and vildagliptin. She presented with haemodynamic instability, necessitating intubation. Despite stabilising haemodynamic parameters within 24 hours, she manifested escalating extremity oedema. At 52 hours after ingestion, mottled skin was observed, along with necrotic alterations in the swollen hands and compartment pressures exceeding 30 mm Hg in all extremities. ACS was diagnosed, leading to fasciotomies. The aetiology is postulated to be drug-induced angio-oedema, possibly intensified by the concurrent overdose of olmesartan medoxomil, telmisartan and vildagliptin, each of which has a risk of angio-oedema even at standard dosages. This scenario is a very rare case caused by drug-induced angio-oedema, which underscores the importance of vigilant monitoring to detect ACS in patients with progressing limb oedema.

Proteomic changes related to actin cytoskeleton function in the skin of vildagliptin-treated mice.

BACKGROUND: Vildagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i) is a widely used type 2 diabetes medication that is associated with an up-to 10-fold increased risk for the development of bullous pemphigoid (BP), an autoimmune skin disease. The mechanism by which vildagliptin promotes the development of BP remains unknown. OBJECTIVE: To elucidate effects of vildagliptin treatment on the mouse cutaneous proteome. METHODS: We analyzed the cutaneous proteome of nondiabetic mice treated for 12 weeks with vildagliptin using label-free shotgun mass spectrometry (MS), two-dimensional difference gel electrophoresis (2D-DIGE), immunohistochemistry, immunoblotting, and quantitative real-time polymerase chain reaction. RESULTS: Although vildagliptin treatment did not cause any clinical signs or histological changes in the skin, separate MS and 2D-DIGE analyses revealed altered cutaneous expression of several proteins, many of which were related to actin cytoskeleton remodeling. Altogether 18 proteins were increased and 40 were decreased in the vildagliptin-treated mouse skin. Both methods revealed increased levels of beta-actin and C->U-editing enzyme APOBEC2 in vildagliptin-treated mice. However, elevated levels of a specific moesin variant in vildagliptin-treated animals were only detected with 2D-DIGE. Immunohistochemical staining showed altered cutaneous expression of DPP-4, moesin, and galectin-1. The changed proteins detected by MS and 2D-DIGE were linked to actin cytoskeleton remodeling, transport, cell movement and organelle assembly. CONCLUSION: Vildagliptin treatment alters the cutaneous proteome of nondiabetic mice even without clinical signs in the skin. Cytoskeletal changes in the presence of other triggering factors may provoke a break of immune tolerance and further promote the development of BP.

A systematic review on the clinical pharmacokinetics of vildagliptin in healthy and disease populations.

INTRODUCTION: Vildagliptin, a dipeptidyl peptidase-4 inhibitor, is indicated to cure type 2 diabetes mellitus (T2DM). This systematic literature search aims to assess the current knowledge about the clinical pharmacokinetics (PK) of vildagliptin to provide recommendations for clinical use to prevent the harmful effects of this drug. METHODS: The PubMed, Science Direct, EBSCO, Cochrane Central Register of Controlled Trials, and Google Scholar databases were screened for articles related to the clinical PK of vildagliptin using systematic search strategies. RESULTS: The literature search identified 2118 records, among which 28 were subsumed in this systematic review that fulfilled the inclusion standards. CONCLUSIONS: This systematic review can help dose optimization among critically ill patients (e.g. renal impairment) without exposing them to the drug's toxic effects.

Dipeptidyl Peptidase-4 Inhibitor-Related Bullous Pemphigoid: Clinical, Laboratory, and Histological Features, and Possible Pathogenesis.

Dipeptidyl peptidase-4 inhibitor (DPP4i) is a widely used antidiabetic agent. Emerging cases of DPP4i-associated bullous pemphigoid (DBP), whose pathogenesis remains unclear, have been reported. Thus, a retrospective study was conducted from January 2016 to June 2021 to determine the clinical, laboratory, and histopathological features of DBP and idiopathic bullous pemphigoid (IBP). We set up in vitro experiments using vildagliptin-treated HaCaT keratinocytes to validate what we found by analyzing published RNA sequencing data about the genes related to the dermal-epidermal junction. We also observed IL-6 expression by HaCaT cells treated with vildagliptin. We enrolled 20 patients with DBP and 40 patients with IBP. The total Bullous Pemphigoid Disease Area Index (BPDAI) score was similar in both groups. However, the BPDAI score of erosions and blisters in DBP was significantly higher than that in IBP (24.6 vs. 16.68, p = 0.0189), and the score for urticaria and erythema was lower in DBP (12 vs. 19.05, p = 0.0183). The pathological features showed that the mean infiltrating eosinophil number per high-power field was significantly lower in DBP than in IBP (16.7 vs. 27.08, p = 0.023). The expression of LAMA3, LAMB3, LAMC2, DST, and COL17A1 decreased significantly in vildagliptin-treated human keratinocytes. On the other hand, IL-6, the hallmark cytokine of bullous pemphigoid (BP) severity, was found to be upregulated in HaCaT cells by vildagliptin. These experimental findings imply less of a requirement for eosinophil infiltration to drive the inflammatory cascades in DBP blistering. Both immunologic and non-immunologic pathways could be employed for the development of DBP. Our findings may help explain the higher incidence of non-inflammatory BP that was observed in DBP.

Gliptin-induced bullous pemphigoid: withdrawal of gliptin allows for faster control of the disease

Background: Gliptins, also called dipeptidyl peptidase-4 inhibitors, have been incriminated in the development of bullous pemphigoid (BP). To date, there are no recommendations regarding the therapeutic approach for BP during gliptin intake. Objectives: The aim of this retrospective study was to evaluate the evolution of BP after three months relative to continuation or discontinuation of gliptin. Materials & Methods: From a series of 372 patients with BP, 40 taking gliptin were included (January 2009 to December 2019). The primary endpoint was complete response, three months after BP diagnosis based on gliptin continuation or discontinuation. The secondary endpoints were complete response after one month and six months. Results: Of BP patients, 67.5% were taking vildagliptin. BP was diagnosed at a mean period of 28.8 months after gliptin initiation. Gliptin was continued and discontinued each in 20 patients. Three months after diagnosis, patients who stopped gliptin had a significatively better clinical status (p = 0.0006). Thirteen patients had complete response when gliptin was stopped, compared to one patient when gliptin was continued. This difference was maintained after six months (p = 0.0031). There was no difference between the treatments received by patients who stopped gliptin and those who continued treatment (p = 0.7515). Conclusion: In this retrospective study, two groups were compared; one that continued gliptin and the other that stopped the drug. The results obtained suggest that stopping gliptin allows for a complete response rate at three months and six months, whereas gliptin maintenance did not allow for complete response.

Efficacy of vildagliptin on 10-year cardiovascular risk reduction in Thai patients with type 2 diabetes mellitus: A real-world observational study.

BACKGROUND AND AIMS: This study aimed to assess the effects of vildagliptin on the prevention of cardiovascular diseases in Thai patients with type 2 diabetes mellitus using the Thai Cardiovascular Risk Score. METHODS: All patients with type 2 diabetes mellitus who used vildagliptin at a secondary hospital in Thailand were screened and recruited. The relevant variables were obtained from patient medication charts at the first visit on which the patients were prescribed vildagliptin and from the 6-month, 12-month, and 18-month post-treatment visits. The Thai Cardiovascular Risk Score was calculated and monitored as a primary outcome, whereas changes in separate cardiometabolic parameters were assessed as secondary outcomes. RESULTS: Of the 321 patients screened, only 95 were recruited for the analysis. The average 10-year cardiovascular risks of patients increased from 19.65% at baseline to 20.74%, 20.69%, and 23.78% at 6, 12, and 18 months post treatment, respectively. However, a better trend of reduction in cardiovascular risk was observed in patients with a high baseline cardiovascular risk. The glucose-lowering effects of vildagliptin were significantly observed 12 months of treatment onwards, but non-significant changes were found in lipid and blood pressure levels as well as body mass index. CONCLUSION: Vildagliptin provided a promising glucose-lowering effect in Thai patients with type 2 diabetes mellitus. However, the mean 10-year cardiovascular risk did not significantly decrease. However, a negative correlation between cardiovascular risk reduction and baseline cardiovascular risk was observed in this study. Low sample size was a major limitation of this study.

Pharmacokinetics and Bioequivalence of a Generic Fixed-Dose Combination Tablet of Metformin Hydrochloride/Vildagliptin Versus a Branded Product in Healthy Chinese Subjects Under Fed and Fasting Conditions.

The purpose of this study was to compare the bioequivalence and safety of test and reference preparations of fixed-dose combination tablets of metformin hydrochloride/vildagliptin 850 mg/50 mg in healthy volunteers under fasting and fed conditions for marketing authorization in China. A single-dose, randomized, open-label, 2-way crossover study was conducted. Blood samples were collected up to 36 hours after dosing in each period with a 7-day washout. Pharmacokinetic parameters, including maximum plasma concentration (Cmax ), time to reach Cmax , area under the plasma concentration-time curve (AUC) from time 0 to the last time point of the measurable concentration, AUC from time 0 to infinity, terminal elimination half-life, and apparent clearance, were calculated using noncompartmental methods and compared between the 2 formulations. Safety profiles were assessed, including significant findings of vital signs, electrocardiogram, laboratory tests, physical examination, and adverse events. A total of 30 healthy subjects (19 men, 11 women) were randomized, and 29 subjects were treated under fasting conditions. Likewise, 30 subjects (24 men, 6 women) were randomized and treated under fed conditions. The geometric mean ratio and corresponding 90% confidence intervals of Cmax , AUC from time 0 to the last time point of the measurable concentration , and AUC from time 0 to infinity for both metformin hydrochloride and vildagliptin between the 2 fixed-dose combination formulations were within the bioequivalence acceptance range of 80% to 125% under fasting or fed conditions. Therefore, the generic and branded formulations were bioequivalent and well tolerated in healthy Chinese subjects.

The association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors: a ten-year prospective observational study.

BACKGROUND: Bullous pemphigoid is the most common bullous chronic autoimmune skin disease. Recent studies have suggested dipeptidyl-peptidase 4 inhibitors as possible predisposing agents of bullous pemphigoid. The objective of our study was to prospectively estimate the association between gliptins and the development of bullous pemphigoid. METHODS: We conducted a prospective study which included all patients diagnosed with biopsy-proven bullous pemphigoid in the Dermatology Department of our hospital between April 1, 2009 and December 31,2019. The diagnosis of bullous pemphigoid was based on specific clinical, histological and immunological features. RESULTS: Overall 113 consecutive patients (age 75 ± 13 years, 62 females) with the diagnosis of bullous pemphigoid were enrolled. Seventy-six patients (67.3%) suffered from type 2 Diabetes and 52 (46%) were treated with dipeptidyl-peptidase 4 inhibitors. The most frequent prescribed gliptin was vildagliptin, being administered to 45 cases (39.8% of total patients enrolled, 86.5% of the patients treated with gliptins). Gliptins were withdrawn immediately after the diagnosis of bullous pemphigoid, which together with steroid administration led to remission of the rash. CONCLUSIONS: This study revealed that treatment with dipeptidyl-peptidase 4 inhibitors, especially vildagliptin, is significantly associated with an increased risk of bullous pemphigoid development.

The impact of vildagliptin on the daily glucose profile and coronary plaque stability in impaired glucose tolerance patients with coronary artery disease: VOGUE-A multicenter randomized controlled trial.

BACKGROUND: The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT). METHODS: This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention. RESULTS: A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was - 18.8 mg/dl (95% confidence interval, - 30.8 to - 6.8) (p = 0.0064) for the MAGE (vildagliptin, - 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), - 22.8° (- 40.6° to - 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, - 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 µm (15.3 to 70.1 µm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 µm vs. control, - 15.1 ± 25.2 µm). CONCLUSIONS: Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058.

Vildagliptin vs. insulin treatment alone in diabetic acute coronary syndrome patients.

BACKGROUND: Vildagliptin, an oral antidiabetic of the dipeptidyl peptidase-4 (DPP-4) inhibitor drugs, exhibits an overall low risk of hypoglycemia with less frequent hypoglycemic events in type 2 diabetes mellitus (T2DM) patients than other antidiabetic drugs. We hypothesized that among hospitalized acute coronary syndrome (ACS) patients, the addition of vildagliptin to subcutaneous insulin therapy would reduce the risk of hypoglycemic events. METHODS: One hundred ACS T2DM adult patients naive to DPP-4 inhibitors were enrolled during admission to the ICCU. Patients were divided into two randomized controlled groups: a subcutaneous rapid-acting insulin-only therapy group and an oral vildagliptin plus subcutaneous insulin group. The trial was open label with no placebo arm. Mean glucose values, insulin values given for correction per hospitalization, and the number of hypoglycemic events (glucose < 70 mg/dL) were documented. RESULTS: Eight hypoglycemia events occurred in the insulin-only group and none in the insulin plus DPP-4 inhibitor group (P < 0.001). Patients with acute myocardial infarction experienced a higher number of hypoglycemic events compared with unstable angina diagnosed patients. No significant differences were found regarding glucose level (P = 0.462) and administered insulin units (P = 0.639). CONCLUSIONS: In T2DM patients, the addition of DPP-4 inhibitors to routine subcutaneous insulin therapy may significantly reduce hypoglycemic events while maintaining acceptable recommended ranges of glucose. Further studies on a larger scale are required to verify these results and to support that DPP-4 inhibitors added to today's standard insulin-only treatment in hospitalized diabetic ACS patients may improve overall glycemic control and provide a potential treatment option in this challenging clinical setting.

More Severe Erosive Phenotype Despite Lower Circulating Autoantibody Levels in Dipeptidyl Peptidase-4 Inhibitor (DPP4i)-Associated Bullous Pemphigoid: A Retrospective Cohort Study.

BACKGROUND: The clinical and immunological profile of patients with dipeptidyl peptidase-4 inhibitor (DPP4i)-associated bullous pemphigoid (BP) is inconsistent in the current literature. OBJECTIVES: 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. METHODS: A retrospective cohort study was conducted, including all consecutive patients diagnosed with BP throughout the years 2009-2019 in a tertiary referral center. RESULTS: 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). CONCLUSIONS: DPP4i-associated BP is characterized by a more severe blistering and erosive presentation despite lower levels of typically pathogenic antibodies.

A case of anti-BP230 antibody-positive bullous pemphigoid receiving DPP-4 inhibitor.

Bullous pemphigoid (BP) is a cutaneous autoimmune blistering disorder. Recently, it has been reported that dipeptidyl peptidase-4 inhibitors (DPP4i) is associated with the development of BP (DPP4i-BP). Patients with DPP4i-BP have autoantibodies (autoAbs) preferentially targeting full-length BP180, but not the BP180NC16a domain. In this report, we described a case of anti-BP230 antibody (Ab)-positive BP receiving DPP4i. A 78-year-old male with a medical history of type 2 diabetes receiving vildagliptin at 100 mg daily for 38 months was referred to our hospital with itching blisters on his body and extremities. Skin biopsy showed subepidermal bulla with eosinophil infiltration. Direct immunofluorescence staining revealed a linear staining pattern with complement C3 and IgG at the subepidermal basement membrane zone. By laboratory testing, autoAbs against BP180NC16a and full-length BP180 were negative by enzyme-linked immunosorbent assay (ELISA); however, anti-BP230 Abs were positive by ELISA (index: 123.91). His HLA genotype was DQB1*04:01 and 05:01. Based on these results, we diagnosed the patient with anti-BP230 Abs-positive BP associated with DPP4i. To the best of our knowledge, this is the first case of DPP4i-BP with only anti-BP230 Abs. Further accumulation of DPP4i-BP cases is needed to clarify the relationship between overall features of DPP4i-BP and anti-BP230 Abs.

Reprotoxic activities of vildagliptin administration in male Wistar rats

Vildagliptin is an oral hypoglycemic agent used in the management of diabetes. Some oral antidiabetic drugs have been implicated in reproductive toxicity.The objective of this study was to investigate the effects of daily administration of vildagliptin at different dosages (0.35 mg/kg B.W., 0.70 mg/kg B.W. and 1.40 mg/kg B.W.) to male Wistar rats for 8 weeks. Sperm parameters, serum concentrations of testosterone, follicle stimulating hormone and luteinizing hormone and the histology of the testis of the rats were assessed. Another set of rats were also treated for 8 weeks and allowed to recover and the same parameters were assessed in them. Fertility study was conducted by determining their litter size. The results showed that vildagliptin administration significantly reduced sperm count and motility of the treated rats. It also significantly increased the number of abnormal sperms. Serum level of testosterone was significantly decreased while luteinizing hormone and follicle stimulating hormone levels showed no significant change. The histoarchitecture of the testis of the treated rats appeared visibly normal. The litter size was also significantly reduced. Most of the changes observed were dose dependent. However, these parameters were restored towards normal in the recovery group. Our results suggest that vildagliptin adversely affected sperm parameters, affected litter size and disrupted the pituitary - gonadal axis. These changes were however reversed upon cessation of drug administration.