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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]

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]

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]

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]

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]

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]

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]

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]

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.

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]

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.

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 Aims/Introduction The union of dipeptidyl peptidase‐4 inhibitors and insulin in patients with type 2 diabetes and chronic kidney disease provides satisfactory glucose management without increasing adverse events (AEs). This research appraised the therapeutic effect and safety of combination therapy in patients with type 2 diabetes and chronic kidney disease. Materials and Methods We carried out a meta‐analysis of randomized controlled trials to analyze AEs, hypoglycemia, serious AEs, severe hypoglycemia, estimated glomerular filtration rate, fasting plasma glucose, glycated hemoglobin, insulin dose, low‐density lipoprotein cholesterol, uric acid and weight between combination treatment groups and control groups by searching the Cochrane Library, Excerpta Medica Database (Embase), PubMed and Web of Science databanks until October 2020. Results Five studies (6 trials, 1,278 participants) met the inclusion criteria. The evidence quality ranged from moderate to high. Glycated hemoglobin (standardized mean difference −0.29, 95% confidence interval −0.44 to −0.14) and insulin dose (standardized mean difference −0.16, 95% confidence interval −0.29 to −0.02) were obviously smaller in the combination cure patients than in the control patients. Compared with the control groups, combination treatment did not increase AEs, hypoglycemia, serious AEs or severe hypoglycemia. Conclusions This study showed the effectiveness and safety of dipeptidyl peptidase‐4 inhibitors bonded with insulin in patients with type 2 diabetes and chronic kidney disease, but the protective actions of this cure on kidney and cardiovascular outcomes, as well as the functions of other dipeptidyl peptidase‐4 inhibitors, need to be affirmed by more good‐quality randomized controlled trials.

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. [ABSTRACT FROM AUTHOR]

Aims: Hyperglucagonemia occurs in the pathogenesis of type 2 diabetes mellitus (T2DM). In this meta-analysis, we summarized the effects of DPP4 inhibitors on glucagon levels in patients with T2DM. Materials and methods: Randomized controlled trials (RCTs) comparing the influence of DPP4 inhibitors on circulating glucagon levels with placebo or other oral antidiabetic drugs (OADs) in patients with T2DM were identified by searches of Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library). Only studies reporting changes in glucagon level presented as total area under the curve (AUCglucagon) using a meal or oral glucose tolerance test were included. Results were combined using a random-effects model that incorporated potential heterogeneity among the included studies. Results: A total of 36 RCTs with moderate to high quality were included. Overall, the numbers of T2DM patients included for the meta-analyses comparing DPP4 inhibitors with placebo and other OADs were 4266 and 1652, respectively. Compared to placebo, DPP4 inhibitors significantly reduced circulating glucagon levels (standard mean difference [SMD]: -0.32, 95% CI: -0.40 to -0.24, P<0.001; I2 = 28%). Analysis of subgroups revealed that study characteristics had no significant effect on results, such as study design (parallel group or crossover), number of patients, mean patient age, proportion of men, baseline HbA1c, duration of diabetes, background therapy, treatment duration, or methods for glucagon measurement (all P for subgroup differences >0.05). Moreover, DPP4 inhibitors significantly reduced glucagon levels compared to other OADs (SMD: -0.35, 95% CI: -0.53 to -0.16, P<0.001; I2 = 66%), and the reduction in glucagon was greater in comparison with insulin secretagogues than in comparison with non-insulin secretagogues (P for subgroup difference =0.03). Conclusions: DPP4 inhibitors are effective at reducing the circulating postprandial glucagon level in T2DM patients. [ABSTRACT FROM AUTHOR]

Background: Type 2 diabetes mellitus (T2DM) is a common health issue, with heart failure (HF) being a common and lethal long-term complication. Although insulin is widely used for the treatment of T2DM, evidence regarding the efficacy of insulin compared to noninsulin therapies on incident HF risk is missing among randomized controlled trials. Real-world evidence on insulin's effect on long-term HF risk may supplement existing guidelines on the management of T2DM., Objective: This study aimed to compare insulin therapy against other medications on HF risk among patients with T2DM using real-world data extracted from insurance claims., Methods: A retrospective, observational study was conducted based on insurance claims data from a single health care network. The study period was from January 1, 2016, to August 11, 2021. The cohort was defined as patients having a T2DM diagnosis code. The inclusion criteria were patients who had at least 1 record of a glycated hemoglobin laboratory test result; full insurance for at least 1 year (either commercial or Medicare Part D); and received glucose-lowering therapy belonging to 1 of the following groups: insulin, glucagon-like peptide 1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 inhibitors (DPP-4Is), or sodium-glucose cotransporter-2 inhibitors (SGLT2Is). The main outcome was the 5-year incident HF rate. Baseline covariates, including demographic characteristics, comorbidities, and laboratory test results, were adjusted to correct for confounding., Results: After adjusting for a broad list of confounders, patients receiving insulin were found to be associated with an 11.8% (95% CI 11.0%-12.7%), 12.0% (95% CI 11.5%-12.4%), and 15.1% (95% CI 14.3%-16.0%) higher 5-year HF rate compared to those using GLP-1 RAs, DPP-4Is, and SGLT2Is, respectively. Subgroup analysis showed that insulin's effect of a higher HF rate was significant in the subgroup with high HF risk but not significant in the subgroup with low HF risk., Conclusions: This study generated real-world evidence on the association of insulin therapy with a higher 5-year HF rate compared to GLP-1 RAs, DPP-4Is, and SGLT2Is based on insurance claims data. These findings also demonstrated the value of real-world data for comparative effectiveness studies to complement established guidelines. On the other hand, the study shares the common limitations of observational studies. Even though high-dimensional confounders are adjusted, remaining confounding may exist and induce bias in the analysis., (© Xuan Wang, Anna M Plantinga, Xin Xiong, Sara J Cromer, Clara-Lea Bonzel, Vidul Panickan, Rui Duan, Jue Hou, Tianxi Cai. Originally published in JMIR Diabetes (https://diabetes.jmir.org).)

Abstract Aims/Introduction This study investigated the impact of the dipeptidyl peptidase‐4 inhibitor, anagliptin, on hepatic insulin clearance (HIC) in Japanese type 2 diabetes patients and explored its relationship to glycemic status. Materials and Methods Data on 765 participants in anagliptin phase 2 and 3 studies were analyzed. Adjusted changes in variables during 12 weeks of anagliptin therapy were compared with a placebo. HIC was calculated as the ratio, C‐peptide area under the curve 0–120 min to insulin area under the curve 0–120 min, after a meal tolerance test. To explore the effects of baseline HIC levels on variables, participants receiving anagliptin were divided according to quartiles of baseline HIC. Furthermore, multivariate analysis investigated the association between baseline HIC levels and glycemic status. Results Anagliptin significantly reduced glycosylated hemoglobin levels (P

ObjectivesInvestigating whether dipeptidyl peptidase-4 inhibitors (DPP4i) could influence the progression of type B intramural hematoma (IMHB) in patients with diabetes mellitus (DM).Materials and methodsUncomplicated IMHB patients were matched by age, sex, and body mass index. Cox proportional hazard models were constructed to identify risk factors. A Kaplan–Meier survival analysis was used to estimate all-cause and aorta-related mortality.ResultsNinety-six matched IMHB patients were divided into Group A (n = 32, IMHB patients without DM), Group B (n = 32, IMHB patients with DMreceiving oral antidiabetic drugs [without DPP4i]) and Group C (n = 32, IMHB patients with DM receiving oral antidiabetic drugs [with DPP4i]). Group C had the lowest rate of aorta-related adverse events (3.1%), aorta-related mortality (0.0%) and reintervention (3.1%). Cox proportional hazard models revealed that a lower eosinophil count (per 0.1, HR, 0.48; 95% CI, 0.29–0.79, P = 0.004) and a higher neutrophil to lymphocyte ratio (NLR) (HR, 1.13; 95% CI, 1.05–1.21, P = 0.001) were associated with higher occurrences of aorta-related adverse events. A lower eosinophil count (per 0.1, HR, 0.40; 95% CI, 0.18–0.89, P = 0.025) and a higher NLR (HR, 1.19; 95% CI, 1.08–1.32, P = 0.001) were also associated with increased aorta-related mortality.ConclusionDPP4i administration in DM patients with IMHB was associated with lower aorta-related mortality and more benign progression than in those who did not receive DPP4i or those without DM. Furthermore, a higher eosinophil count and a lower NLR ratio are potential protective factors that may explain the potential therapeutic benefit of DPP4i.

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.

Objective: The influence of dipeptidyl peptidase-4 (DPP4) inhibitors on glycemic variability compared to other oral antidiabetic drugs (OADs), measured based on the mean amplitude of glycemic excursions (MAGE), has not been comprehensively analyzed. The aim of the study was to perform a meta-analysis to compare the effects of DPP4 inhibitors on MAGE with other OADs in type 2 diabetes mellitus (T2DM) patients without concurrent insulin treatments. Methods: The Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library) databases were searched for relevant randomized controlled trials (RCTs). Study characteristics and outcome data were independently extracted by two authors. A random-effect model was used to combine the results. Results: Fourteen studies with 855 patients were included. Compared to other OADs, DPP4 inhibitors significantly reduced MAGE (mean difference [MD]: -0.69 mmol/L, 95% confidence interval [CI]: -0.95 to -0.43, P<0.001) with mild heterogeneity (I² = 28%). Predefined subgroup analyses suggested that DPP4 inhibitors were more effective in reducing MAGE compared to insulin secretagogues (MD: -0.92 mmol/L, P<0.001) and non-secretagogues (MD: -0.43 mmol/L, P=0.02), as well as compared to sulfonylureas (MD: -0.91 mmol/L, P<0.001) and sodium glucose cotransporter 2 inhibitors (MD: -0.67 mmol/L, P=0.03). Conclusions: DPP4 inhibitors may significantly reduce glycemic variability compared to other oral anti-diabetic drugs, as evidenced by MAGE in T2DM patients with no concurrent insulin treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Sodium–glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of a deterioration in heart failure (HF) and mortality in patients with a broad range of cardiovascular risks. Recent guidelines recommend considering the use of SGLT2 inhibitors in patients with type 2 diabetes (T2D) and HF, irrespective of their glycemic control status and background use of other glucose-lowering agents including metformin. However, only a small number of studies have investigated whether the effects of SGLT2 inhibitor in these patients differ by the concomitant use of other glucose-lowering agents. Methods This was a post-hoc analysis of the CANDLE trial (UMIN000017669), an investigator-initiated, multicenter, open-label, randomized, controlled trial. The primary aim of the analysis was to assess the effect of 24 weeks of treatment with canagliflozin, relative to glimepiride, on N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration in patients with T2D and clinically stable chronic HF. In the present analysis, the effect of canagliflozin on NT-proBNP concentration was assessed in the patients according to their baseline use of other glucose-lowering agents. Results Almost all patients in the CANDLE trial presented as clinically stable (New York Heart Association class I to II), with about 70% of participants having HF with a preserved ejection fraction phenotype (defined as a left ventricular ejection fraction ≥ 50%) at baseline. Of the 233 patients randomized to either canagliflozin (100 mg daily) or glimepiride (starting dose 0.5 mg daily), 85 (36.5%) had not been taking any glucose-lowering agents at baseline (naïve). Of the 148 patients who had been taking at least one glucose-lowering agent at baseline (non-naïve), 44 (29.7%) and 127 (85.8%) had received metformin or a dipeptidyl dipeptidase-4 (DPP-4) inhibitor, respectively. The group ratio (canagliflozin vs. glimepiride) of proportional changes in the geometric means of NT-proBNP concentration was 0.95 (95% confidence interval [CI] 0.76 to 1.18, p = 0.618) for the naïve subgroup, 0.92 (95% CI 0.79 to1.07, p = 0.288) for the non-naïve subgroup, 0.90 (95% CI 0.68 to 1.20, p = 0.473) for the metformin-user subgroup, and 0.91 (95% CI 0.77 to 1.08, p = 0.271) for the DPP-4 inhibitor-user subgroup. No heterogeneity in the effect of canagliflozin, relative to glimepiride, on NT-proBNP concentration was observed in the non-naïve subgroups compared to that in the naïve subgroup. Conclusion The impact of canagliflozin treatment on NT-proBNP concentration appears to be independent of the background use of diabetes therapy in the patient population examined. Trial registration University Medical Information Network Clinical Trial Registry, number 000017669. Registered on May 25, 2015

Background: Both sodium glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular protective effects in patients with type 2 diabetes mellitus. However, the comparative risk of GLP-1RA versus SGLT-2i for major adverse limb events remains unknown.Materials and methods: We studied a nationwide cohort involving 123,048 diabetes patients 20–100 years of age who initiated a SGLT-2i or GLP-1RA during 2012 and 2017. The patients in the two groups were matched by propensity score (PS), and incidence rates for hospitalization for major adverse limb events, critical limb ischemia (CLI) and lower extremity amputation (LEA), were assessed. Cox proportional hazards regression was applied to estimate hazard ratios (HRs) between patients receiving SGLT-2i as compared with GLP-1RA. The modification effects of age, a history of established cardiovascular disease, and chronic kidney disease were examined. In addition, use of dipeptidyl peptidase-4 inhibitor (DPP-4i) was chosen as a second active comparator.Results: After PS-matching, a total of 13,378 SGLT-2i and 13,378 GLP-1RA initiators were identified. Use of SGLT-2i was not associated with an increased risk for hospitalization for CLI and LEA, either compared with GLP-1RA (HR, 1.13; 95% CI, 0.77–1.65 and 1.27; 95% CI, 0.63–2.55, respectively) or compared with DPP-4i use (HR, 1.06; 95% CI, 0.75–1.50 and HR, 0.80; 95% CI, 0.42–1.53, respectively). Although the study was underpowered to explore potential effect modification, a trend of higher risks for LEA was noted among SGLT-2i users with cardiovascular disease as compared with either GLP-1RA or DPP-4i.Conclusion: Use of SGLT-2i was not associated with higher risks for hospitalization for CLI and LEA as compared with reference drugs. Further large-scale studies are needed for a precise risk estimation.

IntroductionThe dipeptidyl peptidase-4 inhibitor (DPP-4i) drugs, such as evogliptin, as the second-line drugs for type 2 diabetes mellitus (T2DM) treatment have been reported to facilitate insulin secretion by reducing glucagon and inhibiting glucagon like peptides. With a vague consensus, the advantageous and non-inferior effects of evogliptin relative to other DPP-4i drugs were recently demonstrated on hemoglobin A1c (HbA1c) levels and overall adverse events in T2DM patients. Thus, the aim was to evaluate the overall influence of evogliptin on HbA1c levels and the adverse events in T2DM patients compared to sitagliptin and linagliptin.MethodsComplying with PRISMA guidelines, we conducted a systematic literature search in databases and a meta-analysis. Data about HbA1c levels and the adverse events of T2DM patients were collected and analyzed.ResultsFrom 1,397 studies, we found five matched studies involving 845 subjects (mean age: 54.7 ± 3 years). The meta-analysis revealed that evogliptin was non-inferior to sitagliptin/linagliptin with a mean difference of 0.062 (95% CI: -0.092 to 0.215. I2: 0%. P = 0.431) regarding the HbA1c level reduction, and the risk ratio was -0.006 (95% CI: -0.272 to 0.260. I2: 1.7%. P = 0.966) regarding the adverse effects, indicating no significant difference between evogliptin and linagliptin or sitagliptin in affecting the HbA1c level and adverse effects.ConclusionThe study provides preliminary evidence regarding the similarity in the efficacy of evogliptin compared to other DPP-4i drugs, including sitagliptin and linagliptin, for managing HbA1c levels and adverse events.

ObjectiveThe influence of dipeptidyl peptidase-4 (DPP4) inhibitors on glycemic variability compared to other oral antidiabetic drugs (OADs), measured based on the mean amplitude of glycemic excursions (MAGE), has not been comprehensively analyzed. The aim of the study was to perform a meta-analysis to compare the effects of DPP4 inhibitors on MAGE with other OADs in type 2 diabetes mellitus (T2DM) patients without concurrent insulin treatments.MethodsThe Medline (PubMed), Embase (Ovid), and CENTER (Cochrane Library) databases were searched for relevant randomized controlled trials (RCTs). Study characteristics and outcome data were independently extracted by two authors. A random-effect model was used to combine the results.ResultsFourteen studies with 855 patients were included. Compared to other OADs, DPP4 inhibitors significantly reduced MAGE (mean difference [MD]: -0.69 mmol/L, 95% confidence interval [CI]: -0.95 to -0.43, P

Introduction: Dipeptidyl peptidase-4 (DPP-4) has been hypothesized to improve responsiveness to erythropoiesis-stimulating agent (ESA). We aimed to describe the trend in DPP-4 inhibitor prescription patterns and assess the association between DPP-4 inhibitor prescription and ESA hyporesponsiveness (eHypo) in Japanese hemodialysis (HD) patients with diabetes mellitus (DM). Methods: We analyzed data from the Japan Dialysis Outcomes and Practice Patterns Study phase 4–6 (2009–2017) on patients with DM who underwent HD thrice per week for at least 4 months. The primary exposure of interest was having a DPP-4 inhibitor prescription. The primary analysis outcomes were a binary indicator of eHypo (mean hemoglobin 6,000 units/week over 4 months) and the natural log-transformed ESA resistance index (ERI). We used conditional logistic regression to compare within-patient changes in eHypo before and after initial DPP-4 inhibitor prescription. We used linear generalized estimating equation models to compare continuous ERI outcomes while accounting for within-patient repeated measurements with an exchangeable correlation structure. Results: There was a monotonic increase in DPP-4 inhibitor prescription according to study year up to 20% in 2017. Moreover, 12.8% of patients with a DPP-4 inhibitor prescription were ESA hyporesponsive before the initial DPP-4 inhibitor prescription. After DPP-4 inhibitor prescription, the odds of eHypo and mean log-ERI remained unchanged in the whole cohort of our study. The interaction analysis of DPP-4 inhibitor and sideropenia showed that DPP-4 inhibitors attenuated eHypo in the patients without iron deficiency. Conclusion: Our findings indicate a recent increase in DPP-4 inhibitor prescription among Japanese HD patients with DM. DPP-4 inhibitors could improve ERI in patients undergoing HD without iron deficiency.

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. [ABSTRACT FROM AUTHOR]

Our study aimed to evaluate the exposure–response relationship between incretin-based medications and the risk of major adverse cardiovascular events (MACE) using cardiovascular outcome trials (CVOTs). Eleven CVOTs with incretin-based medications were included. The median follow-up time, percentage of time exposure, and hazard ratio (HR) of MACE were obtained from each CVOT. The pharmacokinetic parameters of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitor (DPP-4) were obtained from published studies. Regression analysis was performed to assess the relationship between drug exposure and MACE HR. Cutoff values were determined from the ROC curves. The linear regression results indicated that log Cmax, log AUC0–24h, and log AUCCVOT are negatively correlated with MACE HR (R2 = 0.8494, R2 = 0.8728, and R2 = 0.8372, respectively; all p < 0.0001). The relationship between drug exposure (log Cmax, log AUC0–24h, and log AUCCVOT) and MACE HR strongly corresponded with the log (inhibitor) vs. response curve (R2 = 0.8383, R2 = 0.8430, and R2 = 0.8229, respectively). The cutoff values in the ROC curves for log Cmax, log AUC0–24h, and log AUCCVOT, were 2.556, 3.868, and 6.947, respectively (all p = 0.007). A Fisher’s exact test revealed that these cutoff values were significantly related to cardiovascular benefits (all p < 0.05). Our study revealed a linear exposure–response relationship between drug exposure and MACE HR. We conclude that the cardiovascular benefits of incretin-based therapies may occur with higher doses of GLP-1 RAs and with increased exposure. [ABSTRACT FROM AUTHOR]