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Aim: Many patients with type 1 diabetes mellitus (T1DM) met the histological criteria for non‐alcoholic steatohepatitis (NASH), which leads to cardiovascular disease morbidity and mortality. Matrix metalloproteinase‐14 (MMP‐14) is involved in cardiovascular disease and atherosclerosis. Objectives: To assess the impact of oral dipeptidyl peptidase‐4 inhibitor, vildagliptin, as adjunctive therapy on NASH in adolescents with T1DM and its effect on glycaemic control, MMP‐14 levels and carotid intima media thickness (CIMT). Methods: Sixty adolescents with T1DM and NASH were randomly assigned to receive oral vildagliptin (50 mg once daily) for 6 months or not. Glycated haemoglobin, lipid profile, hepatic steatosis index, triglyceride glucose (TyG) index and MMP‐14 levels were assessed. Transient elastography with controlled attenuation parameter (CAP) was performed together with measuring CIMT. Results: By transient elastography, 12 (20%) patients with T1DM with NASH had elevated liver stiffness ≥7 kPa (F2 stage or higher). Baseline MMP‐14 was positively correlated to insulin dose (p = 0.016), triglycerides and TyG index, CIMT, liver stiffness and CAP levels among the studied patients (p < 0.001 for all). After 6 months, patients with T1DM on vildagliptin therapy had significantly lower glycated haemoglobin, lipid profile, hepatic steatosis index and TyG index, as well as MMP‐14 (p < 0.001). CIMT, liver stiffness and CAP were significantly decreased post‐therapy compared with baseline levels and compared with the control group (p < 0.001). Vildagliptin was safe and well‐tolerated. Conclusions: Administration of vildagliptin for adolescents with T1DM and NASH improved glycaemic control, dyslipidaemia and MMP‐14 levels and decreased liver stiffness and CIMT; hence, reducing subclinical atherosclerosis and disease progression. [ABSTRACT FROM AUTHOR]

Permanent neonatal diabetes mellitus (PNDM) is a genetic disorder, characterized by a decrease in endogenous insulin secretion. Therefore, exogenous insulin supplementation plays a central role in controlling glycemia. Although adding a sulfonylurea can help to discontinue insulin, discontinuation is sometimes difficult when the sulfonylurea is administered at older ages. A 24-year-old woman with longstanding PNDM who had poor glycemic control using insulin (47 U/day) and high-dose glibenclamide (0.6 mg/kg/day), had successfully discontinued insulin after initiating the dipeptidyl peptidase-4 inhibitor sitagliptin (50 mg/day). Additionally, hemoglobin A1c levels decreased by 4.8%. Double dosing of sitagliptin and subsequent switching to the glucagon-like peptide-1 receptor agonist semaglutide (0.25 mg/week followed by 0.5 mg/week) further decreased hemoglobin A1c values, with graded improvements in endogenous insulin secretion. There were no episodes of hypoglycemia during which glibenclamide was titrated down from 0.6 to 0.4 mg/kg/day. Intra- and inter-day glucose variability as assessed by continuous glucose monitoring was also improved. In patients with PNDM, administration and dose escalation of incretin-based drugs, in addition to a high-dose sulfonylurea, could be a useful treatment strategy. This strategy may be helpful for discontinuing insulin, downtitrating sulfonylureas, and subsequent achievement of better glycemic control regarding long-term stability and short-term variability. [ABSTRACT FROM AUTHOR]

Aim: We evaluated the efficacy and safety of cofrogliptin, a novel dipeptidyl peptidase‐4 inhibitor taken once every 2 weeks (Q2W), compared with linagliptin (taken daily) in patients with type 2 diabetes inadequately controlled on metformin in China. Materials and Methods: In this phase 3 randomized, double‐blind, active‐controlled, multicentre study, patients were randomly assigned 1:1:1 to receive cofrogliptin 10 mg Q2W, cofrogliptin 25 mg Q2W, or linagliptin 5 mg daily, all as an add‐on treatment to metformin, for 24 weeks. Eligible patients could enter an open‐label extension period and receive cofrogliptin 25 mg Q2W for an additional 28 weeks. The primary endpoint was change in glycated haemoglobin from baseline to 24 weeks, with a non‐inferiority margin of 0.4% for cofrogliptin versus linagliptin treatment. Results: Overall, 465 patients entered the 24‐week treatment period (median age: 57.0 years). The least‐squares mean (standard error) change in glycated haemoglobin from baseline to week 24 was −0.96 (0.063), −0.99 (0.064) and −1.07 (0.065) for the cofrogliptin 10 mg, cofrogliptin 25 mg and linagliptin 5 mg groups, respectively. The between‐group difference met the predefined margin for non‐inferiority of cofrogliptin (10 and 25 mg) versus linagliptin treatment. The incidence of common adverse events (≥5% patients) during the 24‐week treatment period was similar between treatment groups. There were no serious hypoglycaemic events. Conclusion: In Chinese patients with type 2 diabetes inadequately controlled on metformin, the glucose‐lowering effect of cofrogliptin (Q2W) was non‐inferior to linagliptin (daily), with a similar safety profile maintained over 52 weeks of treatment. [ABSTRACT FROM AUTHOR]

Background: This study was aimed to compare the efficacy of two combination tablets of dipeptidyl peptidase-4 (DPP-4) inhibitors and metformin with different dosages, alogliptin/metformin (AM) and vildagliptin/metformin (VM), on glycemic control in patients with type 2 diabetes (T2D). Methods: This was a prospective, multicenter, open-label, randomized, parallel group, comparative trial. After a run-in period of treatment with metformin alone, a total of 59 Japanese outpatients with T2D, aged 20–79 years with glycated hemoglobin (HbA1c) levels of 6.5%–10% were randomly assigned to 12-week AM treatment, alogliptin 25 mg/metformin 500 mg combination tablet orally once a day, or VM treatment, vildagliptin 50 mg/metformin 250 mg combination tablet orally twice a day. The primary endpoints were the changes in HbA1c and fasting plasma glucose (FPG) levels from baseline to week 12 between the two groups. Blinded intermittently scanned continuous glucose monitoring (isCGM) was performed between weeks 10 and 12. The incidence of adverse events during the study was also evaluated. Results: In all, 52 participants were analyzed. Significant decreases in HbA1c and FPG levels from baseline to week 12 were observed in both treatment groups. However, there were no significant differences between the AM and VM groups in the change in HbA1c level (–0.3% and –0.4%, P = 0.309) or the FPG level (–9.0 and –15.0 mg/dL, P = 0.789). The isCGM revealed that both treatments achieved the recommended glycemic target range. No adverse events, such as severe hypoglycemia, were observed in either group. Conclusions: We concluded that there were no significant differences in the efficacy of two combination tablets of DPP-4 inhibitors and metformin with different dosages on glycemic control in patients with T2D. [ABSTRACT FROM AUTHOR]

Abstract Background While the Sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) are widely used for the glycemic control in type 2 diabetes mellitus, the differences in the effects of SGLT2 inhibitors and DPP4 inhibitors on energy intake and diabetes-related indicators are unclear. Methods This was a subanalysis of the CANTABILE study which compared the effects of canagliflozin and teneligliptin on metabolic factors in Japanese patients with Type 2 diabetes. The changes at 24 weeks from the baseline of the diabetes-related indicators including Hemoglobin A1c (HbA1c), energy intake and body weight were compared between the canagliflozin and teneligliptin groups. Results Seventy-five patients in the canagliflozin group and 70 patients in the teneligliptin group were analyzed. A significant decrease in HbA1c was observed in both groups. In the teneligliptin group, although energy intake was significantly reduced, there was no significant change in body weight. Conversely, in the canagliflozin group, although energy intake tended to increase, body weight significantly decreased. Conclusion Canagliflozin and teneligliptin have different effects on the dietary status of patients with Type 2 diabetes. Our result suggests that canagliflozin can manage blood glucose without weight gain, even with increased energy intake.

Background: While the Sodium-glucose co-transporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) are widely used for the glycemic control in type 2 diabetes mellitus, the differences in the effects of SGLT2 inhibitors and DPP4 inhibitors on energy intake and diabetes-related indicators are unclear. Methods: This was a subanalysis of the CANTABILE study which compared the effects of canagliflozin and teneligliptin on metabolic factors in Japanese patients with Type 2 diabetes. The changes at 24 weeks from the baseline of the diabetes-related indicators including Hemoglobin A1c (HbA1c), energy intake and body weight were compared between the canagliflozin and teneligliptin groups. Results: Seventy-five patients in the canagliflozin group and 70 patients in the teneligliptin group were analyzed. A significant decrease in HbA1c was observed in both groups. In the teneligliptin group, although energy intake was significantly reduced, there was no significant change in body weight. Conversely, in the canagliflozin group, although energy intake tended to increase, body weight significantly decreased. Conclusion: Canagliflozin and teneligliptin have different effects on the dietary status of patients with Type 2 diabetes. Our result suggests that canagliflozin can manage blood glucose without weight gain, even with increased energy intake. [ABSTRACT FROM AUTHOR]

Aim To investigate the effect of dipeptidyl peptidase-4 inhibitor (DPP-4i) on serum creatinine (Cr) in patients with type 2 diabetes mellitus (T2DM). Methods A systematic search was performed across databases of PubMed, Embase, Cochrane Library and Web of Science, and randomized controlled trials (RCT) of DPP-4i therapy for regulating Cr in T2DM patients was included. A fixed-effect or random-effect model was used for data fitting, heterogeneity was quantitatively evaluated according to the index of I², and sensitivity analysis and publication bias testing were performed by using the standard methods. Results After searching the database through the system, 12 RCTs were included, with a total of 2 276 participants. Due to the potential heterogeneity, a random effect model was used for data fitting. DPP-4i treatment could mildly increase Cr levels in T2DM patients (WMD: 0. 15 mg / L, 95% CI: 0. 03 ~ 0. 27, I² = 18%, P= 0. 02), and the results showed statistical differences. According to sensitivity testing, the results of Meta-analysis were relatively reliable. No publication bias was observed according to Begg’ s and Egger’ s tests. Conclusions The use of DPP-4i for hypoglycemic treatment in T2DM patients may result in mild elevation of blood Cr levels. Further multicenter studies with larger samples are needed in the future to explore the clinical significance of DPP-4i treatment induced changes in Cr levels. [ABSTRACT FROM AUTHOR]

Introduction: Following the introduction of incretin-based drugs to the market, instances of acute pancreatitis have been reported, leading the FDA to mandate a warning label. Incretin-based therapy has been linked to a rare yet significant adverse event known as acute pancreatitis. However, these concerns of use of incretin therapy remained an ongoing debate. Methods: This retrospective cohort study was extracted data from the National Health Insurance (NHI) program in Taiwan focused on those having prior hospitalization history of acute pancreatitis. We identified adult patients with type 2 diabetes, all patients who received new prescriptions one year after the diagnosis of hospitalization for acute pancreatitis for DPP-4 inhibitors (index date). Study participants were divided into two groups: those taking DPP-4 inhibitors (the DPP-4 inhibitors group, n=331) and those not taking DPP-4 inhibitors (the non-DPP-4 inhibitors group, n=918). The outcome of interest is the recurrence of hospitalization of acute pancreatitis. Results: The incidence density (per 1000 person-years) of acute pancreatitis was 23.16 for DPP-4 inhibitors group and 19.88 for non-DPP-4 inhibitor group. The relative risk is 0.86 (95% confidence interval (CI) 0.53-1.38). Results from the Cox proportional hazard model (HR) analysis, the DPP-4 inhibitor was associated with a neutral risk of acute pancreatitis HR 0.68; 95% CI: 0.42-1.09. Conclusions: In this extensive nationwide cohort study conducted in Taiwan, involving a substantial number of newly diagnosed cases, the utilization of DPP-4 inhibitors appears to show no significant correlation with an elevated risk of acute pancreatitis, even among diabetic patients deemed to be at a high risk. These results extend the safety reassurance of incretin-based therapy to individuals considered high-risk for such complications. [ABSTRACT FROM AUTHOR]

Evogliptin is an anti-diabetic drug, which comes under the class of gliptin derivatives for the inhibition of selective dipeptidyl peptidase-4 inhibitor. The developed ultraviolet spectrophotometric method was simple, sensitive, accurate, precise and economic for the development and validation of evogliptin in bulk and tablet dosage form. In this present study, the analytical method validation and development of evogliptin was done using the different parameters of method validation as per International Council for Harmonisation Q2(R1) guidelines. Water using as a solvent and it shows the maximum wavelength at 266 nm and then performed all the parameters of analytical method validation like accuracy, precision, linearity, range, robustness, ruggedness, limit of detection and limit of quantitation. Evogliptin showed linearity over the range of 2-48 µg/ml. The correlation coefficient value obtained was 0.996 with the regression equation y=0.0032x+0.0005. The accuracy studies was done in spiking method and the recoveries ranging from 97.07 %-106.13 %. The percentage relative standard deviation for intra-day precision was 0.44 and inter-day precision was 0.59. The limit of detection was 1.1 µg/ml and limit of quantitation was 3.33 µg/ml respectively. The method has shown good and consistent recoveries and is validated as per International Council for Harmonisation guidelines and can be used for routine quality control analysis of evogliptin in dosage form. [ABSTRACT FROM AUTHOR]

Aim: This study assessed the efficacy and safety of co‐administering retagliptin and henagliflozin versus individual agents at corresponding doses in patients with type 2 diabetes mellitus who were inadequately controlled with metformin. Methods: This multicentre, phase 3 trial consisted of a 24‐week, randomized, double‐blind, active‐controlled period. Patients with glycated haemoglobin (HbA1c) levels between 7.5% and 10.5% were randomized to receive once‐daily retagliptin 100 mg (R100; n = 155), henagliflozin 5 mg (H5; n = 156), henagliflozin 10 mg (H10; n = 156), co‐administered R100/H5 (n = 155), or R100/H10 (n = 156). The primary endpoint was the change in HbA1c from baseline to week 24. Results: Based on the primary estimand, the least squares mean reductions in HbA1c at week 24 were significantly greater in the R100/H5 (−1.51%) and R100/H10 (−1.54%) groups compared with those receiving the corresponding doses of individual agents (−0.98% for R100, −0.86% for H5 and −0.95% for H10, respectively; p <.0001 for all pairwise comparisons). Achievement of HbA1c <7.0% at week 24 was observed in 27.1% of patients in the R100 group, 21.2% in the H5 group, 24.4% in the H10 group, 57.4% in the R100/H5 group and 56.4% in the R100/H10 group. Reductions in fasting plasma glucose and 2‐h postprandial glucose were also more pronounced in the co‐administration groups compared with the individual agents at corresponding doses. Decreases in body weight and systolic blood pressure were greater in the groups containing henagliflozin than in the R100 group. The incidence rates of adverse events were similar across all treatment groups, with no reported episodes of severe hypoglycaemia. Conclusions: For patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy, the co‐administration of retagliptin and henagliflozin yielded more effective glycaemic control through 24 weeks compared with the individual agents at their corresponding doses. [ABSTRACT FROM AUTHOR]

Background: Incretin therapies, comprised of the dipeptidyl peptidase-4 inhibitors (DPP-4i) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have been increasingly utilized for the treatment of type 2 diabetes (T2DM). Previous studies have conflicting results regarding risk of pancreatitis associated with these agents—some suggest an increased risk and others find no correlation. Adverse event reporting systems indicate that incretin therapies are some of the most common drugs associated with reports of pancreatitis. Objectives: This study aimed to compare the odds of developing pancreatitis in veterans with T2DM prescribed an incretin therapy versus thiazolidinediones (TZDs: pioglitazone and rosiglitazone) within the Veterans Health Administration (VHA). Methods: This was a retrospective cohort study analyzing veterans with T2DM first prescribed an incretin therapy or a TZD between January 1, 2011, and December 31, 2021. A diagnosis of pancreatitis within 365 days of being prescribed either therapy was counted as a positive case. Data was collected and analyzed utilizing VA's Informatics and Computing Infrastructure (VINCI) and an adjusted odds ratio was calculated. Results: The TZD cohort consisted of 42 912 patients compared with the incretin cohort of 304 811 patients. The TZD cohort had a pancreatitis incidence rate of 1.94 cases per 1000 patients. The incretin cohort had a incidence rate of 2.06 cases per 1000 patients. An adjusted odds ratio found no statistical difference of pancreatitis cases between the TZD and incretin cohorts (adjusted odds ratio [AOR] = 0.94, 95% CI [0.75, 1.18]). Conclusion and Relevance: This retrospective cohort study of national VHA data found a relatively low incidence of pancreatitis in both cohorts, and an adjusted odds ratio found no statistical difference of pancreatitis in patients prescribed an incretin therapy compared with a control group. This data adds to growing evidence that incretin therapies do not seem to be associated with an increased risk of developing pancreatitis. [ABSTRACT FROM AUTHOR]

Background: Dipeptidyl peptidase-4 inhibitors (DPP-4is) are the most widely used oral hypoglycemic drugs in Japan. However, once-daily oral semaglutide has been reported to reduce glycated hemoglobin (HbA1c) and body weight (BW) without causing significant hypoglycemia. Here, we aimed to evaluate the efficacy and safety of switching from a DPP-4i to oral semaglutide in Japanese patients with type 2 diabetes (T2D). Methods: We performed a single-center retrospective study of the changes in HbA1c and BW in 68 patients with T2D who were switched from a DPP-4i and took oral semaglutide for ≥ 6 months, without changes in any other oral hypoglycemic agent. Results: Mean HbA1c decreased from 7.8 to 7.0% (p < 0.001) and BW decreased from 74.2 to 71.2 kg (p < 0.001) over 6 months. The decrease in HbA1c was more pronounced in participants with high baseline HbA1c (r = − 0.542, p < 0.001). There was also a trend (r = 0.236, p = 0.052) toward a decrease in BW in individuals with shorter disease duration. There were reductions in either HbA1c or BW in 65 participants (95.6%). In addition, the larger the decrease in HbA1c was, the greater was the decrease in BW (r = 0.480, p < 0.001). Eighteen participants (20.1%) discontinued the drug within 6 months, of whom 10 (11.6% of the total) did so because of suspected adverse effects and the discontinuation rate was the highest in older, non-obese patients. Conclusions: Switching from a DPP-4i to oral semaglutide may be useful for Japanese patients with T2D who have inadequate glycemic or BW control. However, its utility may be limited by gastrointestinal adverse effects in certain patients. [ABSTRACT FROM AUTHOR]

Aims: To assess the glycemic control of once-weekly (QW) and other administration frequencies for dipeptidyl peptidase-4 inhibitors (DPP-4i) in patients with type 2 diabetes in a real-world setting. Methods: A retrospective cohort study used Japanese medical claims data and medical check-up data between December 2015 and February 2020. Patients with type 2 diabetes had been newly prescribed a DPP-4i regimen of once-daily (QD), twice-daily (BID), or QW administration and had hemoglobin A1c (HbA1c) values from regular medical check-ups. HbA1c values and proportion of patients achieving their HbA1c target were assessed. Multivariable analyses were conducted to examine the association between DPP-4i regimen and achievement of HbA1c target. Results: Of the analysis population (N = 7229), 6098 patients were prescribed the QD regimen, 772 BID, and 359 QW. Mean HbA1c before exposure to DPP-4i was 7.31 ± 1.20% (mean ± standard deviation) for QD, 7.64 ± 1.47% for BID, and 7.06 ± 0.96% for QW, decreasing after DPP-4i exposure to 6.71 ± 0.78%, 6.77 ± 0.84%, and 6.59 ± 0.67%, respectively. HbA1c < 7% was achieved in 72.1% of patients for QD, 69.0% for BID, and 79.1% for QW. On multivariable analysis, the odds ratio (95% confidence interval) for HbA1c < 7.0% in patients < 65 years of age was 0.97 (0.73–1.30) for BID and 0.90 (0.57–1.42) for QW compared to QD. Similar achievement of HbA1c target was noted in each regimen for patients age ≥ 65 years and for age ≥ 65 years with multimorbidity. Conclusion: In this study under real-world conditions, glycemic control for the DPP-4i QW regimen was similar to that for QD and BID. [ABSTRACT FROM AUTHOR]

Aims: Assess medication persistence and adherence for dipeptidyl peptidase-4 inhibitors (DPP-4i) administered once weekly (QW), once daily (QD), and twice daily (BID) among patients with type 2 diabetes (T2D), and explore factors associated with discontinuation and non-adherence for DPP-4i regimens. Methods: This retrospective T2D cohort study used medical claims data for three DPP-4i regimens in patients newly prescribed DPP-4i between December 2016 and February 2019. Medication persistence rates were calculated at 3, 6, and 12 months by the Kaplan–Meier method. Adherence was measured as Proportion of Days Covered (PDC). We used Cox proportional hazards models for DPP-4i discontinuation and logistic regression models for non-adherence. Results: In the analysis population of 52,762 patients, DPP-4i prescriptions were 84.2% QD, 11.8% BID, and 4.0% QW. Medication persistence rates were similar up to 6 months for all regimens: approximately 90% at 3 and 80% at 6 months. The 12-month persistence rates for QD, BID, and QW were 74.8%, 67.5%, and 68.0%, respectively. Median PDC was 94.0% for QD, 91.8% for BID, and 93.2% for QW. Five specific factors were associated with discontinuation: BID or QW regimen, younger age, no concomitant medications, comorbid dementia, and comorbid chronic pulmonary disease. Non-adherence was associated with those factors plus male sex and treatment at clinics with 0–19 beds. Conclusions: The 12-month medication persistence rates were highest for QD, followed by QW and then BID. Adherence was similar for all three regimens. Medication persistence for DPP-4i may be improved by tailoring regimens to patient characteristics and needs. [ABSTRACT FROM AUTHOR]

Aim: Dipeptidyl peptidase‐4 (DPP‐4) inhibitors suppress the inactivation of incretin hormones and lower blood glucose levels by inhibiting DPP‐4 function. Sodium‐glucose cotransporter 2 (SGLT2) inhibitors lower blood glucose levels in an insulin‐independent manner by inhibiting renal reabsorption of glucose. DPP‐4 and SGLT2 inhibitors each have the potential to improve hepatic steatosis; however, their combined effects remain unclear. In this study, we examined the effects of the combination of these drugs on hepatic steatosis using high‐fat diet‐fed mice. Method: C57BL/6J male mice were fed a 60% high‐fat diet for 2 months to induce hepatic steatosis. Mice were divided into four groups (control; DPP‐4 inhibitor anagliptin; SGLT2 inhibitor luseogliflozin; anagliptin and luseogliflozin combination), and the effects of each drug and their combination on hepatic steatosis after a 4‐week intervention were evaluated. Results: There were no differences in blood glucose levels among the four groups. Anagliptin suppresses inflammation‐ and chemokine‐related gene expression. It also improved macrophage fractionation in the liver. Luseogliflozin reduced body weight, hepatic gluconeogenesis and blood glucose levels in the oral glucose tolerance test. The combination treatment improved hepatic steatosis without interfering with the effects of anagliptin and luseogliflozin, respectively, and fat content and inflammatory gene expression in the liver were significantly improved in the combination group compared with the other groups. Conclusion: The combination therapy with the DPP‐4 inhibitor anagliptin and the SGLT2 inhibitor luseogliflozin inhibits fat deposition in the liver via anti‐inflammatory effects during the early phase of diet‐induced liver steatosis. [ABSTRACT FROM AUTHOR]

The increasing occurrence of childhood overweight and obesity has been followed by a substantial increase in youth-onset type 2 diabetes (T2D). Pharmacological treatment options for youth-onset T2D remain limited, with a clear unmet need for additional oral agents. This summary of research reports on the efficacy and safety of empagliflozin and linagliptin on glycaemic control in children and adolescents aged 10–17 years with T2D in the randomised, double-blind, parallel group, phase 3 DINAMO trial. Empagliflozin provided a clinically relevant, statistically significant, and durable improvement in glycaemic control; however, linagliptin did not. The safety profile of both empagliflozin and linagliptin was comparable to those observed in studies in adults. These results suggest that empagliflozin could be a new oral therapy option for youth-onset T2D. [ABSTRACT FROM AUTHOR]

Abstract Background The prognosis of dipeptidyl peptidase‐4 inhibitor‐associated bullous pemphigoid (DPP‐4i‐BP) is variable, with some cases showing spontaneous remission after drug cessation and others showing worsening BP or developing infectious complications, termed infectious immune reconstitution inflammatory syndrome (IRIS), after DPP‐4i cessation. We recently demonstrated that the neutrophil‐to‐lymphocyte ratio measured at baseline and during treatment predicts the eventual development of infectious IRIS. Objectives To identify key molecular immune parameters that correlate with, and potentially shape, subsequent immune responses after DPP‐4i cessation. Methods This retrospective observational study examined DPP‐4i‐BP patients who were treated at our hospital for 4 years. Patients selected for this study were those who developed BP after initiation of DPP‐4i and were followed up at least 90 days after DPP‐4i cessation, if information and the relevant parameters were available from the medical records. The patients were divided into two cohorts: a spontaneous remission group and an exacerbation group showing worsening BP or developing infectious IRIS. Serum cytokine/chemokine levels were determined using a multiplex biometric immunoassay. Results Serum levels of eotaxin and interferon (IFN)‐α/γ before DPP‐4i cessation were significantly higher in the remission group (161.6 [standard error 21.9] pg/mL and 14.4 [4.8]/9.2 [4.6] pg/mL, respectively) than in the exacerbation group (51.1 [standard error 9.8] pg/mL and 1.6 [1.6]/1.0 [0.5] pg/mL, respectively, p

Introduction: Nephrotoxicity represents amajor complication of using doxorubicin (DOX) in themanagement of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms. Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20 mg/kg, single I.P. on day 8), DOX + ALO (20 mg/kg/day, P.O. for 10 days), DOX + SEM (12 μg/kg/day, S.C. for 10 days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations. Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO-or SEMtreated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM. Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy. [ABSTRACT FROM AUTHOR]

Linagliptin is a selective dipeptidyl peptidase-4 (DPP-4) inhibitor that indirectly elevates the glucagon-like peptide-1 (GLP-1) level. The aim of the present study was to check whether linagliptin has an influence on neurotransmission in rat brain. Rats were acutely and chronically exposed to linagliptin (10 and 20 mg/kg, intraperitoneally (i.p.)). Twenty-four hours later, the striatum and hippocampus were selected for further studies. In neurochemical experiments, using high-performance liquid chromatography with electrochemical detection (HPLC-ED), the concentrations of three major neurotransmitters—dopamine, serotonin and noradrenaline—and their metabolites were measured. The analysis of mRNA expression of dopamine (D1 and D2), serotonin (5-HT-1 and 5-HT-2) and noradrenaline (α1 and α2a) receptors was also investigated using real-time quantitative reverse transcription polymerase chain reaction (RQ-PCR) in the same brain areas. Linagliptin has the ability to influence the dopaminergic system. In the striatum, the elevation of dopamine and its metabolites was observed after repeated administration of that linagliptin, and in the hippocampus, a reduction in dopamine metabolism was demonstrated. Acute linagliptin exposure increases the serotonin level in both areas, while after chronic linagliptin administration a tendency for the mRNA expression of serotoninergic receptors (5-HT1A and 5-HT2A) to increase was observed. A single instance of exposure to linagliptin significantly modified the noradrenaline level in the striatum and intensified noradrenaline turnover in the hippocampus. The recognition of the interactions in the brain between DPP-4 inhibitors and neurotransmitters and/or receptors is a crucial step for finding novel discoveries in the pharmacology of DPP-4 inhibitors and raises hope for further applications of DPP-4 inhibitors in clinical practices. [ABSTRACT FROM AUTHOR]

DPP-4 inhibitors are frequently used as first-line agents for the treatment of type 2 diabetes in Japan. This study aimed to examine the effects of vildagliptin on glucose metabolism and arterial stiffness. Twenty treatment-naïve patients with type 2 diabetes (8 males and 12 females) received vildagliptin 50 mg twice daily for 6 months. Self-monitored blood glucose measurements and a 75 g OGTT were performed. Arterial stiffness was assessed using the CAVI. After the vildagliptin treatment, a significant decrease in the median HbA1c (from 8.3 to 6.4%) and fasting HOMA-β (from 26.1 to 34.5%), and a marginally significant decrease in the CAVI (from 8.9 to 8.4, p = 0.087) were observed. The glycemic variability parameters also improved, whereas the insulin sensitivity and oxidative stress remained unchanged. Participants with a lower glycemic variability on the 75 g OGTT after vildagliptin treatment showed a significant decrease in their CAVI. The baseline BMI was significantly higher for the participants with a decreased CAVI than in those with no change in their CAVI (24.5 vs. 20.8 kg/m2). After vildagliptin treatment, a decrease in the CAVI was observed, especially in the individuals with improved glycemic variability on the 75 g OGTT. Vildagliptin may be suitable for vascular protection in individuals with high glycemic variability and/or an elevated BMI. [ABSTRACT FROM AUTHOR]

Objectives: Diabetic cardiomyopathy is a known complication of diabetes mellitus. Herein, we aimed to determine whether glycemic control mediated by sitagliptin, a dipeptidyl peptidase-4 inhibitor, can ameliorate diabetic myocardial abnormalities by modulating TGF-β signaling via the SMAD and integrin-linked kinase (ILK) pathways. Methods: Four groups of male Wistar albino rats were used, with six rats in each group. Two nondiabetic and two diabetic (produced by a single intraperitoneal dose of streptozotocin (55 mg/kg)) groups were administered either normal saline or sitagliptin (100 mg/kg) orally for 6 weeks. Subsequently, HW/BW ratios and cardiac enzymes were assessed, along with a histological examination of cardiac tissues. Levels of TGF-β, collagen I, p-SMAD2/3, TNF-α, MMP-9, and ILK were detected. Results: Compared with the diabetic control group, sitagliptin-treated diabetic rats exhibited considerably reduced HW/BW ratios and troponin I and creatine kinase-MB levels, with improvements in histopathological changes in cardiac tissues. TGF-β, collagen I, p-SMAD2/3, TNF-α, and MMP-9 levels were significantly decreased in the sitagliptin-treated diabetic group, whereas ILK was elevated following sitagliptin treatment. Conclusion: Sitagliptin could afford cardioprotective effects for the first time by altering ILK-associated TGF-β/SMAD signaling pathways. Thus, sitagliptin may be a promising therapeutic target for the prevention of diabetic cardiomyopathy. [ABSTRACT FROM AUTHOR]

Abstract Several studies have reported an association between dipeptidyl peptidase 4 inhibitor (DPP4i), a commonly prescribed second‐line oral antihyperglycemic drug, and bullous pemphigoid (BP). However, the benefits of DPP4i withdrawal in patients with BP remain controversial. This study primarily aimed to evaluate the clinical severity of DPP4i‐associated BP by comparing it to those without Type 2 diabetes mellitus (DM). The secondary objective was to determine whether cessation of DPP4i is necessary for all patients with BP. This retrospective case–control study included 83 patients. The participants were divided into three groups according to their diabetic status and the status of discontinuance or continuance of DPP4i. The 12‐month follow‐up of the monthly dosage of systemic steroids per body weight (kg) and the percentage of systemic steroid off‐therapy in these participants were recorded since the diagnosis of BP. Compared to patients with BP without DM, the 1st, 3rd, and 12th systemic prednisolone doses were significantly lower in the DPP4i group (p = 0.01684, 0.02559, and 0.009336, respectively). The 12th systemic prednisolone dose was significantly lower in patients who discontinued DPP4i (p = 0.0338). Nevertheless, several spontaneous remissions with systemic steroid off‐therapy were also noted in the DPP4i‐continuance group within 12 months of follow‐up. This article supports the favorable impact of DPP4i withdrawal in patients with BP and shows that DPP4i may incite or aggravate BP, resulting in a milder disease course.

Abstract Background Many reports have described the development of bullous pemphigoid (BP) following COVID‐19 vaccination. In dipeptidyl peptidase‐4 inhibitor‐associated BP (DPP‐4i‐BP), cessation of DPP‐4i appears to have a paradoxical effect on the clinical course of the BP. Interestingly, similar paradoxical reactions have been shown to develop after antibody‐based therapies that inhibit pro‐inflammatory cytokine signalling. These heterogenous outcomes could be explained by assuming that DPP‐4i‐BP is a manifestation of immune reconstitution inflammatory syndrome (IRIS). Onset of IRIS could be triggered by a variety of stimuli, including initiation of immune checkpoint blockade and vaccination. Objectives To examine whether the onset of postvaccine BP, although rarely reported, is preferentially observed in DPP‐4i‐BP and whether severe outcomes of IRIS can be predicted by specific cytokine profiles. Methods This single‐centre retrospective study was based on the medical records of 63 consecutive outpatients with BP. Results Exacerbation or new onset BP following COVID‐19 vaccination was observed in 6 of 11 patients with BP who were receiving DPP‐4i. One patient who developed dramatic exacerbation of DPP‐4i‐BP and cytomegalovirus (CMV) disease following COVID‐19 vaccination showed high concentrations of granulocyte‐colony‐stimulating factor and interleukin‐10 after vaccination, both of which have been associated with CMV‐IRIS in other settings. Conclusions COVID‐19 vaccine‐induced BP was more frequently associated with DPP‐4i‐BP than with ‘classic’ BP. COVID‐19 vaccination may trigger the shift to infectious IRIS. When infectious IRIS is suspected from the cytokine profile after COVID‐19 vaccination, thorough clinical evaluation for reactivation of CMV should be performed immediately with prompt initiation of anti‐CMV medication if necessary.

Introduction: Nephrotoxicity represents a major complication of using doxorubicin (DOX) in the management of several types of cancers. Increased oxidative stress and the activation of inflammatory mediators play outstanding roles in the development of DOX-induced kidney damage. This study aimed to investigate whether the two pathways of incretin-based therapy, glucagon-like peptide-1 receptor agonist (presented as semaglutide, SEM) and dipeptidyl peptidase-4 inhibitor (presented as alogliptin, ALO), differentially protect against DOX-induced nephrotoxicity in rats and to clarify the underlying molecular mechanisms.Methods: Adult male rats were divided into six groups: control (received the vehicle), DOX (20 mg/kg, single I.P. on day 8), DOX + ALO (20 mg/kg/day, P.O. for 10 days), DOX + SEM (12 μg/kg/day, S.C. for 10 days), ALO-alone, and SEM-alone groups. At the end of the study, the animals were sacrificed and their kidney functions, oxidative stress, and inflammatory markers were assessed. Kidney sections were also subjected to histopathological examinations.Results: The co-treatment with either ALO or SEM manifested an improvement in the kidney functions, as evidenced by lower serum concentrations of creatinine, urea, and cystatin C compared to the DOX group. Lower levels of MDA, higher levels of GSH, and increased SOD activity were observed in either ALO- or SEM-treated groups than those observed in the DOX group. DOX administration resulted in decreased renal expressions of sirtuin 1 (SIRT1) and Nrf2 with increased NF-κB and TNF-α expressions, and these effects were ameliorated by treatment with either ALO or SEM.Discussion: Co-treatment with either ALO or SEM showed a renoprotective effect that was mediated by their antioxidant and anti-inflammatory effects via the SIRT1/Nrf2/NF-κB/TNF-α pathway. The fact that both pathways of the incretin-based therapy demonstrate an equally positive effect in alleviating DOX-induced renal damage is equally noteworthy.

Background: Metformin is recommended as a first-line drug in the guidelines of the treatment for type 2 diabetes mellitus. However, high-quality evidence from clinical trials directly comparing the degree of hypoglycemic effect of combination therapy of metformin and a hypoglycemic agent with a different mechanism of action with that of monotherapy of a hypoglycemic drug is lacking. We aimed to examine whether combination therapy of hypoglycemic agents with metformin showed antagonism, addition, or synergism compared to monotherapy with hypoglycemic agents other than metformin regarding hemoglobin A1c levels. Methods: This retrospective cohort study used a medical information database in Japan. Non-insulin anti-hyperglycemic agents with different mechanisms of action were classified into eight drug classes. A monotherapy cohort and a combination therapy added to the metformin cohort were defined. The change in hemoglobin A1c levels was evaluated to compare the treatment effect between the cohorts. Results: A total of 13,359 patients with type 2 diabetes mellitus in the monotherapy cohort and 1,064 in the metformin combination therapy cohort were identified. A comparison of the change from baseline HbA1c level by drug class between the two cohorts showed a similar trend. Among those treated with dipeptidyl peptidase-4 inhibitor and sodium-glucose co-transporter-2 inhibitor, no clinically significant difference was observed between the two cohorts (0.00% and -0.07% for unadjusted, 0.15% and -0.03% for propensity score matching-adjusted, and 0.09% and -0.01% for inverse probability treatment weighting-adjusted analysis). Conclusions: According to the results of this study, the effect of dipeptidyl peptidase-4 inhibitor or sodium-glucose co-transporter-2 inhibitor added to metformin seems to be additive with respect to the reduction in hemoglobin A1c. [ABSTRACT FROM AUTHOR]

Aim: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. Methods: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once‐daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24‐week double‐blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open‐label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all‐patients‐treated population using an analysis of co‐variance. Results: After 24 weeks, both add‐on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were −1.17 ± 0.794%, −1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment β‐function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated. Conclusions: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy and safety of the dipeptidyl peptidase‐4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control. Materials and Methods: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double‐blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open‐label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24. Results: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (−1.08%) and cetagliptin 100 mg (−1.07%) compared with placebo (−0.35%). The placebo‐subtracted HbA1c reduction was −0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2‐hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug‐related hypoglycaemia was reported. Conclusions: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet. [ABSTRACT FROM AUTHOR]

Diabetes is a ubiquitous disease that causes several complications. It is associated with insulin resistance, which affects the metabolism of proteins, carbohydrates, and fats and triggers liver diseases such as fatty liver disease, steatohepatitis, fibrosis, and cirrhosis. Despite the effectiveness of Sitagliptin (ST) as an antidiabetic drug, its role in diabetes-induced liver injury is yet to be fully investigated. Therefore, this study aims to investigate the effect of ST on hepatic oxidative injury, inflammation, apoptosis, and the mTOR/NF-κB/NLRP3 signaling pathway in streptozotocin (STZ)-induced liver injury. Rats were allocated into four groups: two nondiabetic groups, control rats and ST rats (100 mg/kg), and two diabetic groups induced by STZ, and they received either normal saline or ST for 90 days. Diabetic rats showed significant hyperglycemia, hyperlipidemia, and elevation in liver enzymes. After STZ induction, the results revealed remarkable increases in hepatic oxidative stress, inflammation, and hepatocyte degeneration. In addition, STZ upregulated the immunoreactivity of NF-κB/p65, NLRP3, and mTOR but downregulated IKB-α in liver tissue. The use of ST mitigated metabolic and hepatic changes induced by STZ; it also reduced oxidative stress, inflammation, and hepatocyte degeneration. The normal expression of NF-κB/p65, NLRP3, mTOR, and IKB-α were restored with ST treatment. Based on that, our study revealed for the first time the hepatoprotective effect of ST that is mediated by controlling inflammation, oxidative stress, and mTOR/NF-κB/NLRP3 signaling. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes. Methods: We conducted post hoc analyses of a randomized, open‐label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin‐creatinine ratio ≥30 and ≤500 mg/g assigned to 4‐week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4‐week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR‐reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated‐measures linear mixed‐effects models were employed. Results: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best‐performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best‐performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best‐performing drug and the other three was −19.7% (95% CI −23.1, −16.3; P < 0.001). Conclusions: We demonstrated no overall effect of 4‐week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels. [ABSTRACT FROM AUTHOR]

Background: We evaluated the effect of a dipeptidyl peptidase‐4 inhibitor (DPP‐4i) on the progression of obstructive coronary artery disease (OCAD) in patients with type 2 diabetes mellitus (T2DM) receiving insulin therapy. Methods: Using a multicenter clinical data warehouse, we analyzed the patients receiving insulin therapy for T2DM who underwent coronary computed tomography angiography (CCTA) for ≥2 times. The patients were divided into two groups according to the presence of DPP‐4i prescription between the two CCTA examinations. The prevalence of OCAD (>50% stenosis on CCTA), new revascularization rates, and changes in the coronary calcium score (CCS) were analyzed. Results: A total of 623 patients were included, and a DPP‐4i was prescribed to 380 (60.9%) patients. The median time difference between the two CCTAs was 39.0 (17.0–61.4) months. Newly developed OCAD at the follow‐up CCTA was detected in 62 (16.3%) patients in the DPP‐4i group and 76 (31.3%) patients in the no DPP‐4i group (p < 0.001). The risk of new OCAD or new revascularization was lower in the DPP‐4i group (19.7% vs. 38.7%; p < 0.001). After propensity score matching, the prevalence of new OCAD (15.9% vs. 29.5%; p = 0.001) and the composite rate of new OCAD or new revascularization (18.7% vs. 37.3%; p < 0.001) were lower in the DPP‐4i group. The change in CCS per year did not differ significantly between the two groups (9.1 [0.1–56.8] vs. 13.5 [0.0–78.6]; p = 0.715). Conclusions: Add‐on DPP‐4i therapy would be beneficial in preventing coronary artery disease progression in patients with T2DM receiving insulin therapy. [ABSTRACT FROM AUTHOR]

Bullous pemphigoid (BP) is an autoimmune blistering disease caused by autoantibodies against hemidesmosomal proteins BP180 and BP230. Recently, several case reports have demonstrated the association of BP with dipeptidyl peptidase-4 inhibitors (DPP-4i), also known as gliptins, which are drugs used to treat type 2 diabetes mellitus. Here, we report a case of BP associated with DPP-4i presenting with skin and oral mucosal lesions. An a-80-year-old woman with type 2 diabetes mellitus was treated with DPP-4i. The clinical diagnosis of DPP-4i-associated BP was confirmed by histological findings of subepidermal blisters, positive direct immunofluorescence testing, and the presence of autoantibodies directing full-length BP180. The symptoms resolved within 5 months after DPP-4i withdrawal. This report suggests that DPP-4i-associated BP may present with oral mucosal lesions. Thus, clinicians should pay close attention to the medical history and medication records of patients with oral blistering diseases. Furthermore, conducting treatment in cooperation with medical departments is necessary. [ABSTRACT FROM AUTHOR]

Introduction: Preference for quality of life is important in deciding the treatment strategy for patients with type 2 diabetes mellitus. This study aimed to assess the effect of omarigliptin on patients' psychological attitudes and responses compared with daily dipeptidyl peptidase-4 inhibitors (DPP4is) by measuring the burden of pharmacotherapy using the Diabetic Treatment Burden Questionnaire (DTBQ). Methods: Patients with type 2 diabetes mellitus who were taking daily DPP-4is were enrolled and randomized to a group that switched to omarigliptin or a group that continued daily DPP4is and were monitored for 12 weeks. The primary endpoint was the change in the DTBQ score from baseline to week 12. The secondary endpoints included changes in blood test results, medication preferences and medication adherence. Results: The DTBQ total score significantly decreased from baseline to week 12 in both groups; however, no significant intergroup differences were observed. The DTBQ subscale, implementation and flexibility burden scores significantly decreased in the group that switched to omarigliptin, although no significant intergroup difference in the change was observed. DTBQ scores and medication preferences were associated with improvements in the DTBQ scores. Conclusion: Although this study failed to demonstrate the improvement of DTBQ total score by switching from daily DPP4is to omarigliptin compared with continuing the daily DPP4is, the DTBQ subscale score implementation and flexibility burden score were significantly improved only in the group that switched to omarigliptin, suggesting the possibility of switching from daily DPP4is to omarigliptin to decrease the patients' medication burden. Trial Registration: jRCTs031200437. [ABSTRACT FROM AUTHOR]

Several studies have reported an association between dipeptidyl peptidase 4 inhibitor (DPP4i), a commonly prescribed second‐line oral antihyperglycemic drug, and bullous pemphigoid (BP). However, the benefits of DPP4i withdrawal in patients with BP remain controversial. This study primarily aimed to evaluate the clinical severity of DPP4i‐associated BP by comparing it to those without Type 2 diabetes mellitus (DM). The secondary objective was to determine whether cessation of DPP4i is necessary for all patients with BP. This retrospective case–control study included 83 patients. The participants were divided into three groups according to their diabetic status and the status of discontinuance or continuance of DPP4i. The 12‐month follow‐up of the monthly dosage of systemic steroids per body weight (kg) and the percentage of systemic steroid off‐therapy in these participants were recorded since the diagnosis of BP. Compared to patients with BP without DM, the 1st, 3rd, and 12th systemic prednisolone doses were significantly lower in the DPP4i group (p = 0.01684, 0.02559, and 0.009336, respectively). The 12th systemic prednisolone dose was significantly lower in patients who discontinued DPP4i (p = 0.0338). Nevertheless, several spontaneous remissions with systemic steroid off‐therapy were also noted in the DPP4i‐continuance group within 12 months of follow‐up. This article supports the favorable impact of DPP4i withdrawal in patients with BP and shows that DPP4i may incite or aggravate BP, resulting in a milder disease course. [ABSTRACT FROM AUTHOR]

Purpose: To report a rare Ocular Cicatricial Pemphigoid (OCP) case in a patient taking a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), a medication used for the management of type 2 diabetes, for at least six years. Observations: A 64-year-old male presented with refractory bilateral conjunctival inflammation and ocular discharge that had persisted for two months, despite multiple prior therapies for presumed bacterial conjunctivitis. Upon initial examination, clinical findings strongly suggested OCP, and he had elevated levels of anti-BP180 antibodies. Despite receiving systemic treatments such as steroid pulse therapy and therapeutic plasma exchange after discontinuing DPP-4 inhibitors, his condition progressively worsened, with manifestations such as forniceal shortening in his left eye. Consequently, the patient required keratoepithelioplasty, amniotic membrane transplantation in his left eye, and bilateral eyelid entropion surgery. His condition initially worsened for a time after discontinuing the DPP-4 inhibitor, but it gradually improved over time, and ocular surface surgical intervention was not required in the right eye. Conclusions and Importance: The findings in this study demonstrate that severe refractory OCP may occur while taking the DPP-4 inhibitor, thus indicating that a detailed interview regarding medications is essential for patients with ocular pemphigoid, especially those with type 2 diabetes.

Aims: Glucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients. Methods:Medline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUCGIP) using a meal or oral glucose tolerance test were included. A random-effectsmodel was used for data pooling after incorporating heterogeneity. Results: Overall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference [SMD]: 0.77, 95% confidence interval [CI]: 0.48-1.05, P<0.001; I² = 52%) and postprandial AUCGIP (SMD: 1.33, 95% CI: 1.02-1.64, P<0.001; I² = 65%). Influence analysis by excluding one dataset at a time showed consistent results. Sensitivity analyses only including studies with radioimmunoassay showed also consistent results (fasting GIP: SMD: 0.75, 95% CI: 0.51-1.00, P<0.001; I² = 0%; and postprandial AUCGIP: SMD: 1.48, 95% CI: 1.18-1.78, P<0.001; I² = 54%). Further subgroup analyses demonstrated that the influence of DPP4 inhibitors on fasting and postprandial GIP levels in T2DM patients was not significantly changed by study characteristics such as study design, patient mean age, baseline glycated hemoglobin (HbA1c) concentration, body mass index (BMI), background treatment, treatment duration, or method for postprandial GIP measurement (all P for subgroup effects <0.05). Conclusion: The use of DPP4 inhibitors effectively increases the fasting and postprandial GIP concentrations in T2DM patients. [ABSTRACT FROM AUTHOR]

OBJECTIVES: The benefit of sodium-glucose cotransporter 2 (SGLT2) inhibitors in reducing the occurrence rate of adverse cardiac and renal outcomes in patients with type 2 diabetes has been well described in randomized trials. Whether this benefit extends to patients at the most severe end of the disease spectrum requiring admission to the ICU remains to be examined. DESIGN: Retrospective observational study. SETTING: Data were obtained from a territory-wide clinical registry in Hong Kong (Clinical Data Analysis and Reporting System). PATIENTS: All adult patients (age ≥ 18 yr) with type 2 diabetes and newly prescribed SGLT2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors between January 1, 2015, and December 31, 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After 1:2 propensity score matching, a total of 27,972 patients (10,308 SGLT2 inhibitors vs 17,664 DPP-4 inhibitors) were included in the final analysis. The mean age was 59 ± 11 years, and 17,416 (62.3%) were male. The median follow-up period was 2.9 years. The use of SGLT2 inhibitors was associated with decreased ICU admission (286 [2.8%] vs 645 [3.7%]; hazard ratio [HR], 0.79; 95% CI, 0.69–0.91; p = 0.001) and lower risks of all-cause mortality (315 [3.1%] vs 1,327 [7.5%]; HR, 0.44; 95% CI, 0.38–0.49; p < 0.001), compared with DPP-4 inhibitors. The severity of illness upon ICU admission by Acute Physiology and Chronic Health Evaluation IV-predicted risk of death was also lower in SGLT2 inhibitors users. Admissions and mortality due to sepsis were lower in SGLT2 inhibitor users compared with DPP-4 inhibitor users (admissions for sepsis: 45 [0.4%] vs 134 [0.8%]; p = 0.001 and mortality: 59 [0.6%] vs 414 [2.3%]; p < 0.001, respectively). CONCLUSIONS: In patients with type 2 diabetes, SGLT2 inhibitors were independently associated with lower rates of ICU admission and all-cause mortality across various disease categories. [ABSTRACT FROM AUTHOR]

Morphine (MOR) is a commonly prescribed drug for the treatment of moderate to severe diabetic neuropathic pain (DNP). However, long-term MOR treatment is limited by morphine analgesic tolerance (MAT). The activation of microglial cells and the release of glia-derived proinflammatory cytokines are known to play an important role in the development of MAT. In this study, we aimed to investigate the effects of the dipeptidyl peptidase-4 inhibitor (DPP-4i) teneligliptin (TEN) on MOR-induced microglial cell activation and MAT in DNP rats. DNP was induced in four groups of male Wistar rats through a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg, freshly dissolved in 5 mmol/L citrate buffer, pH 4.5). Sham rats were administered with the vehicle. Seven days after STZ injection, all rats were implanted with an intrathecal (i.t) catheter connected to a mini-osmotic pump, divided into five groups, and infused with the following combinations: sham + saline (1 µL/h, i.t), DNP + saline (1 µL/h, i.t), DNP + MOR (15 µg/h, i.t), DNP + TEN (2 µg/h, i.t), and DNP + MOR (15 µg/h, i.t) + TEN (2 µg/h, i.t) for 7 days at a rate of 1 μL/h. The MAT was confirmed through the measurement of mechanical paw withdrawal threshold and tail-flick tests. The mRNA expression of neuroprotective proteins nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase-1 (HO-1) in the dorsal horn was evaluated by quantitative PCR (qPCR). Microglial cell activation and mononucleate cell infiltration in the spinal cord dorsal horn were assessed by immunofluorescence assay (IFA) and Western blotting (WB). The results showed that co-infusion of TEN with MOR significantly attenuated MAT in DNP rats through the restoration of neuroprotective proteins Nrf2 and HO-1 and suppression of microglial cell activation in the dorsal horn. Though TEN at a dose of 2 μg has mild antinociceptive effects, it is highly effective in limiting MAT. [ABSTRACT FROM AUTHOR]

Chun-Feng Huang,1– 3 Tso-Yen Mao,3 Shinn-Jang Hwang1,2 1Division of Family Medicine, En Chu Kong Hospital, New Taipei City, Taiwan, Republic of China; 2Faculty of Medicine, School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, Republic of China; 3Department of Leisure Services Management, Chaoyang University of Technology, Taichung, Taiwan, Republic of ChinaCorrespondence: Tso-Yen Mao, Department of Leisure Services Management, Chaoyang University of Technology, 168, Jifeng E. Road, Wufeng District, 413, Taichung, Taiwan, Republic of China, Tel +886 4 23323000 #7453, Fax +886 4 23742363, Email tymao.research@gmail.com Shinn-Jang Hwang, En Chu Kong Hospital, 399, Fuxing Road, Sanxia District, 237, New Taipei City, Taiwan, Republic of China, Tel +886 2 26723456, Fax +886 2 2671-9537, Email sjhwang@vghtpe.gov.twPurpose: Diabetes increases the risk of fragility fractures. As a result, when choosing a diabetes treatment, whether the drug affects bone density should be taken into account. The goal of this study was to determine how switching from dipeptidyl peptidase-4 inhibitors (DPP-4i) to glucagon-like peptide-1 receptor agonists (GLP-1RA) influenced bone mineral density (BMD) in diabetic patients.Patients and Methods: In this retrospective cohort study, diabetic patients with osteoporosis or osteopenia who used DPP-4i but not anti-osteoporosis medications were divided into two groups: those who switched to GLP-1RA (n = 132) and those who did not (control group, n = 133). We compared changes in glycemic control and BMD with and without conversion from DPP-4i to GLP-1RA.Results: Prior to switching, there was no difference between the groups in terms of age, gender, glycosylated hemoglobin (HbA1c), or BMD. HbA1c was 8.7% in the participants (mean age 62.7 years, 17.4% female). Despite the fact that there was no difference in femoral neck BMD, the GLP-1RA group had a greater decrease in lumbar spine BMD (− 0.028 g/cm2 versus − 0.019 g/cm2, p = 0.041) than the control group. Furthermore, HbA1c levels in the GLP-1RA-treated group were considerably lower than in the control group (7.5% versus 8.0%, p = 0.027).Conclusion: While switching to GLP-1RA improves glycemic control, it appears to have a less favorable effect on bone density than continuing DPP-4i. More research is needed, however, to determine whether diabetic patients with low bone density should be switched from DPP-4i to GLP-1RA.Keywords: bone mineral density, diabetes, dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, osteoporosis

ABSTRACT Aims/Introduction This study was designed and carried out to investigate the association of dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. Materials and Methods The JMDC Claims Database, which contains the medical and prescription information of Japanese employment‐based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP‐4is or other oral glucose‐lowering agents (GLAs). Results Individuals with diabetes who received DPP‐4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow‐up periods (median [interquartile range]) were 17 months (8–33) for DPP‐4is and 14 months (7–28) for other oral GLAs. Kaplan–Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log‐rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP‐4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8–1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8–1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. Conclusion This database study shows that there is not a significant PC risk due to DPP‐4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings.

Aim: The CAROLINA trial established non‐inferiority of linagliptin versus glimepiride for major adverse cardiovascular events in patients with relatively early type 2 diabetes at increased cardiovascular risk. In pre‐specified and post‐hoc analyses, we investigated treatment effects on total hypoglycaemic burden in CAROLINA. Materials and methods: Patients were randomized and treated with 5 mg linagliptin (n = 3014) or 1‐4 mg glimepiride (n = 3000) once daily added to standard care. Hypoglycaemia captured from investigator‐reported adverse events was analysed with Poisson and negative binomial regressions for the first and total (first plus recurrent) events, respectively. The influence of insulin initiation and glycated haemoglobin (HbA1c) change on the treatment effect for hypoglycaemia was also explored. Results: Over 6.3 years median follow‐up, average HbA1c over time did not differ between linagliptin versus glimepiride (weighted mean difference [95% confidence interval]: 0.00%, [−0.05, 0.05]), nor did insulin initiation (18.6% vs. 19.2% of patients, respectively), whereas body weight was lower with linagliptin (−1.54 kg, [−1.80, −1.28]). Hypoglycaemia frequency was lower with linagliptin across all hypoglycaemia categories, including severe episodes. Rate ratios (95% confidence interval) for first and total events for investigator‐reported hypoglycaemia were 0.21 (0.19‐0.24) and 0.12 (0.10‐0.14), respectively, with 8.7 first and 60.8 total estimated events prevented/100 patient‐years with linagliptin versus glimepiride. These differences occurred during night‐time and daytime, and in subgroup analyses of total events. Treatment differences in hypoglycaemia were neither impacted by HbA1c changes nor insulin initiation. Conclusions: Across the severity spectrum, linagliptin substantially reduced the hypoglycaemic burden versus glimepiride in patients with relatively early type 2 diabetes at increased cardiovascular risk. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-4 inhibitors (DPP4is) and metformin are the most frequently prescribed first-line drugs for Japanese patients with type 2 diabetes (T2D). We investigated the risk of cardiovascular events by second-line treatment type in these patients. Patients with T2D, prescribed either metformin or DPP4i as a first-line drug, were identified in claims data from Japanese acute care hospitals. The primary and secondary outcomes were cumulative risks of MI or stroke and of death, respectively, from second-line treatment initiation. Patients prescribed first-line metformin or DPP4i was 16,736 and 74,464, respectively. In patients receiving first-line DPP4i, the death incidence was lower in those receiving second-line metformin than in those receiving second-line sulfonylurea (p < 0.001), whereas the primary outcome was not significantly different. No significant differences were observed for either outcome when DPP4is and metformin were used as first- and second-line drugs or vice versa. Metformin was suggested to have larger effect to reduce death than sulfonylurea in patients receiving first-line DPP4i. The order of first- and second-line for the DPP4i and metformin combination did not affect the outcomes. Given the nature of the study design, certain limitations, including potential under-adjustment for confounders, should be considered. [ABSTRACT FROM AUTHOR]

AimsGlucose-dependent insulinotropic polypeptide (GIP) confers a variety of metabolic benefits in type 2 diabetes mellitus (T2DM). This meta-analysis was conducted to investigate the impact of dipeptidyl peptidase 4 (DPP4) inhibitors on GIP levels in T2DM patients.MethodsMedline (PubMed), CENTER (Cochrane Library), and Embase (Ovid) were searched and randomized controlled trials (RCTs) evaluating the impact of DPP4 inhibitors on fasting and postprandial GIP levels were obtained. For postprandial GIP, only studies with the data of GIP changes reported as the total area under the curve (AUCGIP) using a meal or oral glucose tolerance test were included. A random-effects model was used for data pooling after incorporating heterogeneity.ResultsOverall, 14 RCTs with 541 T2DM patients were included. Compared to placebo/no treatment, the use of DPP4 inhibitors significantly increased the fasting GIP level (standard mean difference [SMD]: 0.77, 95% confidence interval [CI]: 0.48–1.05, P

Introduction: Three studies compared the bioequivalence (BE) of new generic tablet formulations of sitagliptin (100 mg; fasting) and the fixed-dose combination (FDC) of sitagliptin/metformin (50/850 mg, 50/1000 mg; both fed) in healthy volunteers with the same tablet strengths of the reference products Januvia and Janumet. Methods: The study design was open-label, single-dose, randomized with two-way crossover periods. Blood sampling was performed for 72/48 h in the sitagliptin/FDC studies, respectively. Primary pharmacokinetic (PK) parameters for sitagliptin and metformin were area under the plasma concentration–time curve from time 0 to last timepoint of measurable concentration (AUC0–t) and maximum plasma concentration (Cmax). Test (T) and reference (R) formulations proved bioequivalent if 90% confidence interval (CI) of geometric least-squares mean ratio for AUC0–t and Cmax were within BE acceptance range of 80.00–125.00%. Safety evaluations included vital signs, clinical laboratory tests, and adverse events (AEs). Results: Treated/evaluable volunteers for BE per study were: 30/28 (sitagliptin 100 mg), 26/25 (FDC 50/850 mg), and 26/24 (FDC 50/1000 mg). The 90% CI of the geometric means of T/R ratios for primary PK parameters were within predefined BE limits: CI for AUC0–t and Cmax were 95.83–100.37% and 91.85–109.56% (sitagliptin 100 mg); 100.84–103.69% and 93.44–105.10% (FDC 50/850 mg), and 101.26–105.20% and 98.71–112.89% (FDC 50/1000 mg); respective values for metformin were 94.23–101.89% and 91.66–99.38% (FDC 50/850 mg) and 98.45–104.89% and 96.79–105.62% (FDC 50/1000 mg). All AEs were nonserious, transient, and mostly mild. Safety evaluations did not reveal any relevant difference between T and R formulations. Conclusions: The new generic tablet formulations of sitagliptin 100 mg and the FDCs sitagliptin/metformin 50/850 mg and 50/1000 mg demonstrated bioequivalence to originator reference products. Therefore, the new products are expected to provide efficacy and tolerability similar to those of the reference products in the treatment of patients with type 2 diabetes (T2D). Trial registration: EudraCT EU Clinical Trials Registry (2014-005437-31); ClinicalTrials.gov Registry (NCT05549570 and NCT05549583, both retrospectively registered on 20 September 2022). [ABSTRACT FROM AUTHOR]

Bullous systemic lupus erythematosus (BSLE) is a rare blistering disease in patients with SLE. BSLE is a heterogenous disease caused by autoantibodies to the basement membrane, mainly type VII collagen. The pathogenesis of the development of autoantibodies in BSLE remains unknown. We report a case of SLE taking dipeptidyl peptidase 4 inhibitors (DPP4i) who developed tense blister lesions after administration of SARS‐CoV‐2 vaccine. Initial erythematous lesion before administration of SARS‐CoV‐2 vaccine had not shown IgG deposition at basement membrane both direct and indirect immunofluorescence (IIF). However, the result of those examinations became positive after the administration of SARS‐CoV‐2 vaccine. Furthermore, IIF test results using NaCl split skin had shown positive against epidermal side. These observations suggest that SARS‐CoV‐2 vaccination triggered production of autoantibodies that cause bullous SLE. The present case fulfills the diagnostic criteria for both BSLE and DPP4i‐associated bullous pemphigoid. Skin lesions were cleared after withdrawal of DPP4i. Therefore, physicians should ask patients who develop blisters after the vaccination whether they are taking DPP4i. [ABSTRACT FROM AUTHOR]

Aims/Introduction: This study was designed and carried out to investigate the association of dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use with pancreatic cancer (PC) in individuals with diabetes in Japan. Materials and Methods: The JMDC Claims Database, which contains the medical and prescription information of Japanese employment‐based health insurance programs, was used. The primary outcome was duration to the first occurrence of PC (International Classification of Diseases 10th Revision code C25), both all and hospitalized, from prescription of DPP‐4is or other oral glucose‐lowering agents (GLAs). Results: Individuals with diabetes who received DPP‐4is (n = 61,430) or other oral GLAs (n = 83,304) were analyzed. Follow‐up periods (median [interquartile range]) were 17 months (8–33) for DPP‐4is and 14 months (7–28) for other oral GLAs. Kaplan–Meier curve analysis to determine the duration of first use of DPP4i or other oral GLA to diagnosis of PC disclosed no differences between the two groups in duration to all or hospitalized PC (log‐rank test: all, P = 0.7140; hospitalized, P = 0.3446). Cox proportional hazards models showed that use of DPP‐4is did not affect the PC risk adjusted for medications, age, sex and risk comorbidities (all, hazard ratio 1.1, 95% confidence interval 0.8–1.3, P = 0.6518; hospitalized, hazard ratio 1.1, 95% confidence interval 0.8–1.4, P = 0.6662). Similar results were obtained when individuals with ≥2 years oral GLA treatment and those with medical checkup data (e.g., smoking or drinking habit) available were analyzed. Conclusion: This database study shows that there is not a significant PC risk due to DPP‐4i treatment in individuals with diabetes in Japan, but larger studies with longer follow up are required to confirm these findings. [ABSTRACT FROM AUTHOR]

The efficacy and safety of medications can be affected by alterations in gut microbiota in human beings. Among antidiabetic medications, incretin-based therapy such as dipeptidyl peptidase 4 inhibitors might affect gut microbiomes, which are related to glucose metabolism. This was a randomized, controlled, active-competitor study that aimed to compare the effects of combinations of gemigliptin–metformin vs. glimepiride–metformin as initial therapies on gut microbiota and glucose homeostasis in drug-naïve patients with type 2 diabetes. Seventy drug-naïve patients with type 2 diabetes (mean age, 52.2 years) with a glycated hemoglobin (HbA1c) level ≥7.5% were assigned to either gemigliptin–metformin or glimepiride–metformin combination therapies for 24 weeks. Changes in gut microbiota, biomarkers linked to glucose regulation, body composition, and amino acid blood levels were investigated. Although both treatments decreased the HbA1c levels significantly, the gemigliptin–metformin group achieved HbA1c ≤ 7.0% without hypoglycemia or weight gain more effectively than did the glimepiride–metformin group (59% vs. 24%; p < 0.05). At the phylum level, the Firmicutes/Bacteroidetes ratio tended to decrease after gemigliptin–metformin therapy (p = 0.065), with a notable depletion of taxa belonging to Firmicutes, including Lactobacillus, Ruminococcus torques, and Streptococcus (all p < 0.05). However, regardless of the treatment modality, a distinct difference in the overall gut microbiome composition was noted between patients who reached the HbA1c target goal and those who did not (p < 0.001). Treatment with gemigliptin–metformin resulted in a higher achievement of the glycemic target without hypoglycemia or weight gain, better than with glimepiride–metformin; these improvements might be related to beneficial changes in gut microbiota. [ABSTRACT FROM AUTHOR]

Abstract Background Although a few meta-analyses were conducted to compare the risk of incident atrial fibrillation (AF) between sodium-glucose cotransporter-2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and other anti-hyperglycemic agents using indirect or direct comparison, the above analyses showed conflicting results with each other. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i, GLP-1RA, and dipeptidyl peptidase-4 inhibitor (DPP4i) among a large longitudinal cohort of diabetic patients. Methods In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, a total of 344,893, 44,370, and 393,100 consecutive patients with type 2 diabetes without preexisting AF receiving GLP-1RA, SGLT2i, and DPP4i, respectively, were enrolled from May 1, 2016, to December 31, 2019. We used 1:1 propensity score matching (PSM) to balance covariates across paired study groups. Patients were followed from the drug index date until the occurrence of AF, death, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. Results After PSM, there were 245,442, 43,682, and 39,190 paired cohorts of SGLT2i-DPP4i, SGLT2i-GLP-1RA, and GLP-1RA-DPP4i, respectively. SGLT2i treatment was associated with lower risk of new-onset AF in participants with type 2 diabetes compared with either DPP4i [hazard ratio (HR):0.90; 95% confidential interval (CI) 0.84–0.96; P = 0.0028] or GLP-1RA [HR 0.74; 95% CI 0.63–0.88; P = 0.0007] treatment after PSM. There was no difference in the risk of incident AF between GLP-1RA and DPP4i users [HR 1.01; 95% CI 0.86–1.19; P = 0.8980]. The above findings persisted among several important subgroups. Dapagliflozin was specifically associated with a lower risk of new-onset AF compared with DPP4i (P interaction = 0.02). Conclusions Compared with DPP4i, SGLT2i but not GLP-1RA was associated with a lower risk of incident AF in patients with type 2 diabetes.

Non-HIV immune reconstitution inflammatory syndrome (non-HIV IRIS) is associated with the recovery from an immunocompromised condition. It is defined as inflammatory disorders caused by antigens, including drugs or pathogenic microorganisms present prior to immune recovery, or by the exacerbation of an inflammatory disorder that was already present. Drug-induced hypersensitivity syndrome is a prototype of IRIS, and the pathophysiology of non-HIV IRIS can be recognized in several disorders treated with corticosteroids, immunosuppressants, molecular-targeted drugs, TNF-α antibody drugs, immune checkpoint inhibitors, and dipeptidyl peptidase-4 inhibitors. This review focuses on the relationship between the immune mechanism of non-HIV IRIS and drug allergies, especially severe drug eruption. The antigen recognition mechanism in drug allergy varies depending on the clinical type and the causative drug. The p-i concept is the main mechanism in severe drug eruption such as Stevens-Johnson syndrome/toxic epidermal necrolysis, and drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms. Lymphocytes activated by an antigen other than a drug, such as a virus, can also develop drug allergy by the loose binding of drugs with immune receptors of T cells or human leukocyte antigen. Therefore, fluctuations in the immune environment affect the onset of severe drug eruption. Novel agents that cause major changes in immunity have been marketed mainly for autoimmune diseases and malignant tumors; therefore, it is necessary to consider their effects when treating severe drug eruptions. Moreover, although a list of diagnostic criteria for this syndrome has been drafted, predictive and diagnostic biomarkers for this syndrome needs to be urgently developed.