Search

Introduction: The association between sodium-glucose cotransporter-2 (SGLT2) inhibitors and the risk of urogenital infections remains controversial. This study aimed to investigate the association between SGLT2 inhibitors and the incidence of perineal soft tissue infections, including Fournier's gangrene (FG), genital bacterial infections, and urinary tract infections (UTIs), using administrative claims data in Japan. Methods: In this retrospective cohort study, we utilized the JMDC Claims Database. The study included patients aged 18 years or older diagnosed with type 2 diabetes mellitus, identified by a diagnostic code, who received new prescriptions for SGLT2 inhibitors or dipeptidyl peptidase 4 (DPP-4) inhibitors between April 2014 and August 2020. Using one-to-one propensity score (PS) matching, we compared the incidence of perineal soft tissue infections, including FG, genital bacterial infection, and UTIs between groups treated with SGLT2 and DPP-4 inhibitors. Hazard ratios (HR) and their 95% confidence intervals (CI) were estimated using the Cox proportional hazards model. Results: We identified 34,897 patients in the SGLT2 inhibitor group and 135,311 patients in the DPP-4 inhibitor group. After one-to-one PS matching, 31,665 pairs were generated. The mean age of the patients was 51 years, with approximately 70% being male. The use of SGLT2 inhibitors was associated with a decreased risk of UTI (HR 0.90, 95% CI 0.83–0.98) and an increased risk of genital bacterial infection (HR 1.23, 95% CI 1.03–1.46) compared to DPP-4 inhibitors. However, no significant association was observed with perineal soft tissue infection (HR 1.05, 95% CI 0.61–1.81). Conclusions: SGLT2 inhibitors were associated with a reduced risk of UTI and an increased risk of genital bacterial infection. They showed no significant association with perineal soft tissue infection when compared to DPP-4 inhibitors. Future research should explore broader demographics, focusing on the elderly and achieving gender balance, to gain a comprehensive understanding of infection risks. [ABSTRACT FROM AUTHOR]

Introduction: Long-term effectiveness and durability of glucose-lowering medications are important considerations in managing type 2 diabetes (T2D). This study aimed to compare durability of treatment efficacy of once-weekly (OW) semaglutide for T2D with that of the dipeptidyl peptidase 4 inhibitor (DPP–4i) class. Methods: This observational cohort study used 2017–2022 data from the Optum® Clinformatics® Data Mart to compare long-term clinical outcomes associated with semaglutide or DPP–4i in US adults with T2D. The primary outcomes were HbA1c at 2-year follow-up, change in HbA1c from baseline, and the odds of achieving HbA1c targets. BMI at 2-year follow-up, change in BMI from baseline, odds of reducing BMI category, and the need for treatment augmentation were exploratory outcomes. Bivariate and multivariate analyses were conducted using inverse probability of treatment weighting (IPTW) weighted descriptive statistics. Results: Weighted HbA1c and BMI cohorts included 865 and 642 semaglutide users and 779 and 537 DPP–4i users, respectively. In the weighted HbA1c cohort, semaglutide and DPP–4i users had an average age of 60 years and similar baseline characteristics including HbA1c level and comorbidity status. Two-year follow-up HbA1c with semaglutide was 0.56% lower than with DPP–4i; reduction in HbA1c from baseline was 0.61% greater. Odds of achieving HbA1c level < 7% were 2.16 times greater after covariate adjustment (all, p < 0.001). Semaglutide was associated with 1.03 kg/m2 greater reduction in BMI and 2.27 times greater odds of reducing BMI category vs DPP–4i (p < 0.001). Semaglutide users were less likely to add new glucose-lowering treatment (hazard ratio [HR] 0.57; p < 0.001) or initiate insulin (HR 0.49; p < 0.001) vs DPP–4i users. Conclusion: Compared with DPP–4i, semaglutide was associated with lower follow-up HbA1c and BMI, greater reduction in HbA1c and BMI from baseline, and reduced likelihood of requiring treatment augmentation or insulin initiation to manage T2D in US adults, suggesting better durability of semaglutide vs DPP–4i. Infographic: Plain language summary: Type 2 diabetes (T2D) is a progressive disease. Over time, many patients with T2D will need multiple drugs to manage their disease. Long-term efficacy is important for achieving treatment goals, such as blood sugar control and weight loss. The amount of time that different types of diabetes drugs remain effective varies. This study used real-world data to compare two distinct types of diabetes drugs, semaglutide and dipeptidyl peptidase 4 inhibitors (DPP–4is). We looked at how blood sugar control and body weight changed with each drug after 2 years of use. We also compared how many patients needed to start using new drugs to meet their treatment goals and the odds that a patient would need to start using new drugs. Semaglutide was better than DPP–4i in reducing both blood sugar levels and body weight. Patients had over two times the odds of meeting target blood sugar levels with semaglutide. Fewer patients needed to start using new drugs with semaglutide, and patients were 43% less likely to start using new drugs to lower blood sugar than patients taking DPP–4is. [ABSTRACT FROM AUTHOR]

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008–2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer’s disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p

Background: Antihyperglycemic drug utilization studies are conducted frequently and describe the uptake of new drug therapies across may jurisdictions. An increasingly important, yet often absent, aspect of these studies is the impact of rurality on drug utilization. Objective(s): The objective of this study was to explore the association between place of residence (rural, urban, metropolitan) and the use of dipeptidyl peptidase 4 inhibitors (DPP-4i) for first treatment intensification of type 2 diabetes. Methods: A retrospective cohort study was conducted from April 1, 2008 to March 31, 2019 of new metformin users. A multivariable logistic regression analysis was performed to determine the association between place of residence (using postal codes) and likelihood of DPP-4i dispensing. Results: After adjusting for confounders, analysis revealed that rural-dwellers are less likely to have a DPP-4i dispensed, compared with metropolitan-dwellers (aOR:0.64; 95%CI:0.61–0.67) and over-time, the uptake in rural areas was slower. Conclusions: This study demonstrates that rurality can have an impact on drug therapy decisions at first treatment intensification, with respect to the utilization of new therapies.

Abstract Background Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. Methods Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression‐free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune‐related adverse events (irAEs). Results Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second‐line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all‐grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). Conclusions Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC.

Introduction: Although not definitive, there is small increased risk of acute pancreatitis with the use of dipeptidyl peptidase 4 inhibitors (DPP4i). Hence, there is an interest in the elevation of pancreatic enzymes among type 2 diabetes mellitus (T2DM) patients using DPP4i. However, the studies regarding their association are limited and provide conflicting results. Moreover, there are no such studies among South Indian T2DM patients. Hence, we evaluated the prevalence of hyperamylasemia among South Indian T2DM patients and its association with DPP4i use. Methods: This cross-sectional study was conducted at a tertiary health care center from South India. Adult T2DM patients on stable doses of antidiabetic medications for at least previous 3 months were included in the study. Patients with other types of diabetes mellitus, gall stones, diabetic ketoacidosis, acute illness, chronic kidney disease and untreated hypothyroidism were excluded from the study. All participants were evaluated with glycemic parameters, serum creatinine and serum amylase. Hyperamylasemia was defined as serum amylase ≥220 U/L. Results: A total of 200 participants were included in the study among whom 93 patients were not on DPP4i whereas 107 were on DPP4i including 41 (38.32%) each on teneligliptin and sitagliptin. Baseline characteristics including glycemic measures were comparable between DPP4i users and nonusers. A total of 14 patients (7%) had hyperamylasemia but the prevalence of hyperamylasemia did not differ between DPP4i users and nonuser (6/107 vs. 8/93, P = 0.42). Conclusions: Asymptomatic hyperamylasemia is not uncommon in South Indian T2DM patients but is not associated with the use of DPP4i. [ABSTRACT FROM AUTHOR]

Background/Aims We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD). Methods An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy. Results DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels. Conclusions The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.

Acute kidney injury (AKI) is a prevalent medical condition accompanied by mutual affection of other organs, including the liver resulting in complicated multiorgan malfunction. Macrophages play a vital role during tissue injury and healing; they are categorized into "classically activated macrophages" (M1) and "alternatively activated macrophages" (M2). The present study investigated and compared the conventional fluid therapy vs Dipeptidyl peptidase 4 inhibitor (DPP-4i) vildagliptin on the liver injury induced by AKI and evaluated the possible molecular mechanisms. Thirty rats comprised five groups (n = 6 rats/group): control, AKI, AKI+saline (received 1.5 mL of normal saline subcutaneous injection), AKI+vildagliptin (treated with oral vildagliptin 10 mg/kg), AKI+saline+vildagliptin. AKI was induced by intramuscular (i.m) injection of 50% glycerol (5 ml/kg). At the end of the work, we collected serum and liver samples for measurements of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrotic factor-a (TNF-a), and interleukin-10 (IL-10). Liver samples were processed for assessment of inducible nitric oxide synthase (iNOS) as a marker for M1, arginase 1 (Arg-1) as an M2 marker, c-fos, c-Jun, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and high-mobility-group-box1 (HMGB1) protein. The difference was insignificant regarding the relative expression of AP-1, c-Jun, c-fos, MAPK, and HMGB between the AKI+saline group and the AKI +Vildagliptin group. The difference between the same two groups concerning the hepatic content of the M1 marker (iNOS) and the M2 marker Arg-1 was insignificant. However, combined therapy produced more pronounced changes in these markers, as the difference in their relative expression between the AKI+saline +Vildagliptin group and both the AKI+saline group and the AKI+Vildagliptin group was significant. Accordingly, we suggest that the combined saline and vildagliptin hepatoprotective effect involves the downregulation of the MAPK/AP-1 signaling pathway. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM® MarketScan® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2, which are responsible for the pathophysiology of BP in monocytes/ macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitorassociated BP. [ABSTRACT FROM AUTHOR]

Background: Preclinical data have shown the immunomodulatory effects of metformin and dipeptidyl peptidase 4 (DPP4) inhibitors in patients with diabetes. However, its clinical impact remains unclear in lung cancer. Methods: Between 2017 and 2021, 466 patients received ICI monotherapy. Patients were categorized into concurrent (MET; metformin or combination of metformin and DPP4 inhibitor) and without concomitant (NMET; nonmetformin/DPP4 inhibitors) administration of metformin and DPP4 inhibitors groups at least 8 weeks before and during ICI therapy. The primary objectives were the objective response rate (ORR) and progression‐free survival (PFS). The second objective was to evaluate the overall survival (OS) and the occurrence of immune‐related adverse events (irAEs). Results: Among 466 patients, 89 (19.0%) and 377 (81%) were categorized into the MET and NMET groups, respectively. MET group had a significantly higher ORR (MET group: 24.7% vs. NMET group: 14.8%, p = 0.025) and longer PFS than those in the NMET group (MET group 5.1 month vs. NMET group 2.8 months, p = 0.018). After patients were stratified based on the prior line of therapy and PD L1 expression status, the PFS of the second‐line therapy and PD L1 ≥50 was significantly higher in the MET than in the NMET group. The proportion of patients experiencing all‐grade irAEs was numerically higher in the MET group (19.1%) than in the NMET group (14.3%), without statistical significance (p = 0.382). Conclusions: Concurrent use of metformin and DPP4 inhibitors with ICIs significantly improved the clinical outcomes without increasing the incidence of irAEs in NSCLC. [ABSTRACT FROM AUTHOR]

Abstract Background Dipeptidyl peptidase 4 inhibitor (DPP4i) is an effective medicine for type 2 diabetes mellitus (T2DM). Some articles reported DPP4i improves insulin secretion and insulin resistance. However, these effects are not well established by glucose clamp test and test meal in Japanese. We investigated the effect of DPP4i on insulin resistance and insulin secretion by using the glucose clamp test and meal tolerance test (MTT). Methods We performed a MTT, and the hyperinsulinemic-euglycemic clamp in 8 Japanese patients with T2DM. This study was a single-arm study. We measured fasting and postprandial glucose, insulin, incretins, and glucagon levels. We also measured serum adiponectin levels. Results HbA1c was significantly decreased after 3 months. The fasting and postprandial glucose levels were significantly decreased. Fasting and postprandial insulin levels were not changed. The insulin resistance derived from the glucose clamp test was significantly improved. HOMA-IR was not significantly changed. GLP-1 and GIP were significantly increased but glucagon did not change. Adiponectin was not significantly changed. Conclusions Although the number of patients was very small, these results suggested that DPP4i treatment might improve insulin resistance without changing insulin secretion.

Acute kidney injury (AKI) is a prevalent medical condition accompanied by mutual affection of other organs, including the liver resulting in complicated multiorgan malfunction. Macrophages play a vital role during tissue injury and healing; they are categorized into “classically activated macrophages” (M1) and “alternatively activated macrophages” (M2). The present study investigated and compared the conventional fluid therapy vs Dipeptidyl peptidase 4 inhibitor (DPP-4i) vildagliptin on the liver injury induced by AKI and evaluated the possible molecular mechanisms. Thirty rats comprised five groups (n = 6 rats/group): control, AKI, AKI+saline (received 1.5 mL of normal saline subcutaneous injection), AKI+vildagliptin (treated with oral vildagliptin 10 mg/kg), AKI+saline+vildagliptin. AKI was induced by intramuscular (i.m) injection of 50% glycerol (5 ml/kg). At the end of the work, we collected serum and liver samples for measurements of serum creatinine, blood urea nitrogen (BUN), alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrotic factor-α (TNF-α), and interleukin-10 (IL-10). Liver samples were processed for assessment of inducible nitric oxide synthase (iNOS) as a marker for M1, arginase 1 (Arg-1) as an M2 marker, c-fos, c-Jun, mitogen-activated protein kinase (MAPK), activator protein 1 (AP-1), and high-mobility-group-box1 (HMGB1) protein. The difference was insignificant regarding the relative expression of AP-1, c-Jun, c-fos, MAPK, and HMGB between the AKI+saline group and the AKI+Vildagliptin group. The difference between the same two groups concerning the hepatic content of the M1 marker (iNOS) and the M2 marker Arg-1 was insignificant. However, combined therapy produced more pronounced changes in these markers, as the difference in their relative expression between the AKI+saline+Vildagliptin group and both the AKI+saline group and the AKI+Vildagliptin group was significant. Accordingly, we suggest that the combined saline and vildagliptin hepatoprotective effect involves the downregulation of the MAPK/AP-1 signaling pathway.

Background: Dipeptidyl peptidase 4 inhibitor (DPP4i) is an effective medicine for type 2 diabetes mellitus (T2DM). Some articles reported DPP4i improves insulin secretion and insulin resistance. However, these effects are not well established by glucose clamp test and test meal in Japanese. We investigated the effect of DPP4i on insulin resistance and insulin secretion by using the glucose clamp test and meal tolerance test (MTT). Methods: We performed a MTT, and the hyperinsulinemic-euglycemic clamp in 8 Japanese patients with T2DM. This study was a single-arm study. We measured fasting and postprandial glucose, insulin, incretins, and glucagon levels. We also measured serum adiponectin levels. Results: HbA1c was significantly decreased after 3 months. The fasting and postprandial glucose levels were significantly decreased. Fasting and postprandial insulin levels were not changed. The insulin resistance derived from the glucose clamp test was significantly improved. HOMA-IR was not significantly changed. GLP-1 and GIP were significantly increased but glucagon did not change. Adiponectin was not significantly changed. Conclusions: Although the number of patients was very small, these results suggested that DPP4i treatment might improve insulin resistance without changing insulin secretion. [ABSTRACT FROM AUTHOR]

Introduction: Vildagliptin and metformin are two well-established oral antidiabetics with a complementary mechanism of action. Two new generic products, vildagliptin and its fixed-drug combination (FDC) with metformin, were tested for bioequivalence versus the approved originator reference products (Galvus® and Eucreas®). Methods: Three randomized studies with two-treatment, two-period, two-sequence crossover design were conducted in healthy adults. One study evaluated vildagliptin 50 mg tablets as single dose under fasting conditions. Vildagliptin–metformin FDC tablet strengths of 50/850 mg and 50/1000 mg were evaluated in separate studies as single dose under fed conditions, given 30 min after a standardized high-fat, high-calorie breakfast following 10 h overnight fasting. Blood samples for analysis were collected until 24 h after dosing in each study period. Bioequivalence between test (T) and reference (R) products required 90% confidence interval (CIs) for the geometric least square (LS) mean T/R ratio to be within 80–125% for the pharmacokinetic parameters, maximum plasma concentration (Cmax), and area under the curve (AUC0–t). Results: The 90% CIs of geometric LS means of T/R ratio for Cmax and AUC0–t with vildagliptin tablets of 50 mg were 92.22–103.94% and 99.00–102.66%, respectively; corresponding results with FDC tablets for 50/850 mg tablets were 94.81–115.41% and 95.28–106.00% for vildagliptin and 90.87–101.18% and 90.56–100.09% for metformin; for 50/1000 mg tablets Cmax and AUC0–t were 105.56–122.30% and 98.30–107.55%, respectively, for vildagliptin and 92.14–103.73% and 94.60–101.81%, respectively, for metformin. Other parameters such as AUC0–∞, time to maximum concentration (Tmax), and terminal half-life (t1/2) were comparable between test and reference products. Adverse events (AEs), mainly vomiting, were reported without relevant difference between test and reference products in each study. AEs were generally mild and transient. No severe or serious AEs occurred. Conclusions: The new generic drug products of vildagliptin and the FDCs of vildagliptin and metformin demonstrated bioequivalence to the approved originator products and are therefore expected to provide similar therapeutic effects. [ABSTRACT FROM AUTHOR]

Eugene Han,1 Minyoung Lee,2 Yong-ho Lee,2– 4 Hye Soon Kim,1 Byung-wan Lee,2– 4 Bong-Soo Cha,2– 4 Eun Seok Kang2– 4 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Keimyung University School of Medicine, Daegu, Republic of Korea; 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; 3Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea; 4Severance Hospital Diabetes Center, Yonsei University College of Medicine, Seoul, Republic of KoreaCorrespondence: Eun Seok KangDivision of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of KoreaTel +82 2 2228 1938Fax +82 2 393 6884Email edgo@yuhs.acIntroduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely prescribed for type 2 diabetes (T2D) and their glycemic control effects are well studied. However, information regarding the effects of switching DPP-4 inhibitors is limited, especially in older patients.Research Design and Methods: We investigated whether switching from linagliptin to teneligliptin decreases blood glucose in older (≥ 65 years) T2D patients. In total, 164 patients with T2D who switched from linagliptin to teneligliptin for > 12 weeks were included and the primary outcome was glycemic changes.Results: Switching from linagliptin to teneligliptin ameliorated fasting blood glucose (148.1 ± 47.1 to 139.6 ± 43.4 mg/dL), glycated hemoglobin (HbA1c; 7.9 ± 1.3 to 7.5 ± 1.2%), and postprandial blood glucose (224.8 ± 77.4 to 205.8 ± 70.8 mg/dL) levels (all P < 0.05). Low-density lipoprotein cholesterol concentration was reduced while liver and kidney functions were maintained. Subgroup analysis showed that glucose control improved more in patients with uncontrolled hyperglycemia (HbA1c > 8.0%) and chronic kidney disease (estimated glomerular filtration rate < 90 mL/min/1.73m2). Multiple logistic analysis indicated higher baseline HbA1c was the strongest predictor of teneligliptin switching response.Conclusion: Switching from linagliptin to teneligliptin helps maintain kidney function and reduce blood glucose safely in older patients with T2D.Keywords: dipeptidyl peptidase 4 inhibitor, linagliptin, teneligliptin, type 2 diabetes mellitus, older patients, chronic kidney disease

Lin Chen,1,* Xiujuan Zhang,2,* Li Zhang,3 Dongmei Zheng2 1Department of Breast and Thyroid Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, People’s Republic of China; 2Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, People’s Republic of China; 3Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Dongmei ZhengDepartment of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong University, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province 250021, People’s Republic of ChinaTel + 86 531 68776375Email zhengdongmei1971@163.comBackground and Aim: Non-alcoholic fatty liver disease (NAFLD) represents a broad spectrum of chronic liver disease characterized by aberrant accumulation of triglycerides (TG) in hepatocytes without excessive alcohol consumption. Hepatic lipotoxicity derived from overaccumulation of free fatty acids is considered as one of the typical hallmarks of NAFLD. Insulin resistance (IR) and chronic inflammation are widely recognized as the key etiological factors associated with NAFLD. Dipeptidyl peptidase 4 inhibitor (DPP4i) is a novel pharmacological agent extensively applied in the treatment of Type 2 Diabetes Mellitus (T2DM) for decades which also have a liver protective effect.Methods: In order to invest the therapeutic efficiency and underlying mechanism of DPP4i saxagliptin, we used high-fat diet (HFD) and streptozotocin-induced NAFLD treated with saxagliptin. Biochemical, histomorphological, genetic and protein expression of related pathways were investigated.Results: Fasting blood glucose (FBG), TG, total cholesterol (TC), and low-density lipoprotein cholesterin significantly increased in NAFLD group, which also exhibited severe steatosis. Other remarkable findings were hyperinsulinemia, increased DPP4, PTP-1B and TNF-α level and decreased GLP-1, ACOX-1, CPT-1A expression, concomitant with liver DPP4 expression enhancement and serum DPP4 elevation. These undesirable consequences were alleviated by saxagliptin to a certain degree.Conclusion: DPP4i saxagliptin improves NAFLD by ameliorating IR, inflammation, downregulation of hepatic DPP4 and sDPP4, as well as subsequent steatosis. The elevation of hepatic DPP4 and sDPP4 and succedent post-treatment decrease suggested that DPP4 may involve in the development of NAFLD. The anti-lipotoxic effect of DPP4i may involve the activation of CPT1A and ACOX1 related β-oxidation signaling pathway suppression of TNF-α mediated inflammatory and PTP-1B. The results covered in this article showed that saxagliptin affects many aspects of the pathological characteristics of NAFLD, suggesting that DPP4i saxagliptin may offer a novel therapeutic option for NAFLD.Keywords: dipeptidyl peptidase 4 inhibitor DPP4i, non-alcoholic fatty liver disease NAFLD, inflammation, insulin resistance IR

Alogliptin, a dipeptidylpeptidase-4 inhibitor, is an oral hypoglycemic agent approved in many countries for the treatment of patients with type 2 diabetes, including the United States, Europe, and Japan. The drug is effective both as a monotherapy, and as an additional or combined treatment of type 2 diabetes. Alogliptin is well tolerated by patients, including the elderly, as well as those suffering from kidney and / or liver failure or having a high risk of cardiovascular events. The low risk of hypoglycemia, weight gain, acute pancreatitis, and side gastrointestinal events. During treatment with alogliptin has been demonstrated in both long-term (up to 4.5 years) studies and in actual clinical practice. Alogliptin increases postprandial levels of the glucagon-like peptide-1, which leads to insulin secretion and normalization of glucose homeostasis. Treatment with alogliptin is associated not only with improved glucose metabolism, but also with a decrease in blood pressure and arterial rigidity in patients with arterial hypertension and diabetes, as well as normalizing the lipid profile. In patients with diabetes mellitus who have recently undergone acute coronary syndrome and received alogliptin, the frequency of serious adverse cardiovascular events does not increase. Experimental data show that alogliptin reduces ventricular hypertrophy, interstitial fibrosis, and diastolic dysfunction. Alogliptin has a number of unique properties. It is assumed that it can increase the number of circulating endothelial progenitor cells that play an important role in endothelial repair and neovascularization. Alogliptin preserves the functionality and structure of the mitochondria of cardiomyocytes. The drug may be a potential treatment for patients with MODY1 diabetes at an early stage of the disease, when residual insulin secretion is preserved. Treatment with a fixed combination of Alogliptin + Metformin results in better glycemic control than monotherapy and is well tolerated. There is evidence that treatment with alogliptin is not associated with an increased risk of pancreatitis or pancreatic cancer.

Introduction: No study has compared the effects of sodium–glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP4is) on patients' quality-of-life (QOL). Methods: We enrolled 253 drug-naïve Japanese patients with type 2 diabetes mellitus (T2DM), randomly assigned them into a dapagliflozin (SGLT2i) group or DPP4i group in approximately 1:1 ratio, and monitored them for 24 weeks. The primary endpoint was the proportion of subjects indicating improvement in the "overall quality of life" domain of SHIELD-WQ-9 at week 24. Secondary endpoints included other domains of SHIELD-WQ-9, DTR-QOL, EQ-5D-5L, medication preference, medication adherence, diet therapy adherence, body weight, body mass index (BMI), abdominal circumference, HbA1c, and frequency of adverse events. Results: The proportion of subjects indicating improvement in the "overall quality of life" domain of SHIELD-WQ-9 at week 24 was higher in the dapagliflozin group (28.4%) than in the DPP4i group (18.6%) (p = 0.08). The proportion of subjects indicating improvement in the "physical health" domain of SHIELD-WQ-9 at week 24 was significantly higher in the dapagliflozin group (42.2%) than in the DPP4i group (23.7%) (p = 0.004). Total scores and domain 1 scores of DTR-QOL showed greater improvement in the dapagliflozin group (14.3 ± 15.6 and 15.5 ± 20.8, respectively) than in the DPP4i group (10.2 ± 15.6 and 10.3 ± 19.5, respectively) (both p = 0.05). EQ-5D-5L scores had significantly improved in the DPP4i group (0.023 ± 0.088) (p = 0.005); the intergroup difference was not significant (p = 0.14). Body weight (p < 0.001), BMI (p < 0.001), and abdominal circumference (p = 0.019) had significantly decreased in the dapagliflozin group compared with the corresponding values in the DPP4i group. Conclusion: Dapagliflozin showed a comparable or more favorable benefit on Japanese patients' QOL compared with DPP4is. Dapagliflozin was well tolerated. It significantly reduced body weight, which was significantly correlated with improvement in the patients' QOL. This study demonstrates that dapagliflozin can be used as a first-line drug for T2DM in Japan with a beneficial impact on patients' QOL. Trial Registration: University Hospital Medical Information Network Clinical Trial Registry (UMIN000030514); Japan Registry of Clinical Trials (jRCTs051180165). [ABSTRACT FROM AUTHOR]

Introduction: To evaluate the efficacy and safety of dipeptidyl peptidase 4 inhibitors (DPP4i) used in combination with insulin in patients with type 2 diabetes mellitus (T2DM). Methods: We searched the MEDLINE, Embase, and Cochrane library databases for randomized controlled trials (RCTs) published through June 2018. Studies with at least a 12-week treatment period were included to compare the addition of DPP4i to insulin with insulin control therapy. Meanwhile, groups on a stable insulin dosage (insulin-stable subgroup) or titrating insulin dosage (insulin-flexible subgroup) were analyzed separately. Results: Twenty-one RCTs with 3697 patients randomized to a DPP4i/insulin treatment arm and 3538 to an insulin control arm were included. DPP4i, when added to insulin therapy, led to a significantly greater reduction in HbA1c (− 0.57%, 95% CI − 0.66, − 0.48) and provided significantly greater odds of achieving the HbA1c target < 7% (OR 3.45; 95% CI 2.58, 4.63). These effects were achieved in the context of a decrease in the daily insulin requirement, without increases in hypoglycemia risk and body weight, compared with the control treatment. Subgroup analysis showed control-adjusted reductions in HbA1c from baseline in the insulin-stable subgroup (− 0.64%; 95% CI − 0.74, − 0.53) and the insulin-flexible subgroup (− 0.43%; 95% CI − 0.56, − 0.30). Other results occurred similarly in both subgroups. Conclusions: The addition of DPP4i to insulin is associated with a statistically significant reduction in glycemic control as measured by HbA1c, fasting plasma glucose, and 2-h postprandial glucose, without increasing the risk of hypoglycemia and weight gain. These conclusions were also observed in both stable-dose and flexible-dose insulin subgroups. [ABSTRACT FROM AUTHOR]

Introduction: Metformin is the recommended initial treatment in type 2 diabetes mellitus (T2DM), but when this does not give adequate glucose control the choice of which second-line drug to use is uncertain as none have been found to have a better overall glycaemic response. In this real-world study dipeptidyl peptidase 4 inhibitors (DPP4i), sulphonylureas (SU), thiazolidinediones (TZD) and sodium glucose co-transporter 2 inhibitors (SGLT2i) were compared for their effectiveness in lowering glycated haemoglobin (HbA1c) levels for a particular individual based on their clinical characteristics. Methods: A retrospective analysis was undertaken of electronic health records of people with T2DM prescribed metformin alongside a DPP4i, SU, TZD or SGLT2i at second-line. Regression modelling was used to model the changes in HbA1c from baseline at month 6 and month 12 for the individual therapies, adjusting for demographic and clinical characteristics. Results: There were 7170 people included in the study. Treatment at second-line with SUs, DPP4i, TZDs and SGLT2i resulted in similar percentages of people achieving the recommended HbA1c target of < 7.5% (58 mmol/mol) at both 6 and 12 months. For those receiving SGLT2i and SUs, the greatest improvement in HbA1c was observed in relatively younger and older people, respectively. Trends were detected between other baseline characteristics and HbA1c improvement by drug class, but they were not statistically significant. Non-adherence rates were low for all drug classes. People with a higher medication possession ratio (≥ 80%) also had greater improvements in HbA1c at 12 months. Conclusion: This study identified patients' phenotypic characteristics that may have the potential to influence individual treatment response. Accounting for these characteristics in clinical treatment decisions may facilitate individualised prescribing by being able to select the right drug for the right patient. [ABSTRACT FROM AUTHOR]

Background: Antihyperglycemic drug utilization studies are conducted frequently and describe the uptake of new drug therapies across may jurisdictions. An increasingly important, yet often absent, aspect of these studies is the impact of rurality on drug utilization., Objectives: The objective of this study was to explore the association between place of residence (rural, urban, metropolitan) and the use of dipeptidyl peptidase 4 inhibitors (DPP-4i) for first treatment intensification of type 2 diabetes., Methods: A retrospective cohort study was conducted from April 1, 2008 to March 31, 2019 of new metformin users. A multivariable logistic regression analysis was performed to determine the association between place of residence (using postal codes) and likelihood of DPP-4i dispensing., Results: After adjusting for confounders, analysis revealed that rural-dwellers are less likely to have a DPP-4i dispensed, compared with metropolitan-dwellers (aOR:0.64; 95%CI:0.61-0.67) and over-time, the uptake in rural areas was slower., Conclusions: This study demonstrates that rurality can have an impact on drug therapy decisions at first treatment intensification, with respect to the utilization of new therapies., Competing Interests: No potential conflicts of interest relevant to this article were reported. S.H.S. is supported as the Chair in Patient Health Management, jointly held by the Faculty of Pharmacy and Pharmaceutical Sciences and Faculty of Medicine and Dentistry, University of Alberta. This study is based in part on data provided by Alberta Health. The interpretation and conclusions contained herein are those of the researchers and do not necessarily represent the views of the Government of Alberta. Neither the Government of Alberta nor Alberta Health express any opinion in relation to this study., (© 2024 The Authors.)

Diabetes mellitus relates a metabolic disorder of collective aetiology which is characterized by chronic hyperglycaemia caused due to disturbances of carbohydrate, lipid and protein metabolism due to impaired β cell function of pancreas or insulin resistance or both. Dipeptidyl peptidase-4 (DPP-4) inhibitors have recently emerged as a new class of antidiabetic that show favorable results in improving glycemic control with a minimal risk of hypoglycemia and weight gain. Teneligliptin is a recently developed oral dipeptidyl peptidase 4 inhibitor indicated for the management of type 2 diabetes mellitus. Teneligliptin, characterized by a "J-shaped" structure formed by five consecutive rings which give unique binding characteristics, reflect in higher potency than other dipeptidyl peptidase 4 inhibitor. Teneligliptin is a novel antihyperglycemic agent with a preferable profile in terms of long-term efficacy and safety in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Surendra Kumar Sharma,1 A Panneerselvam,2 KP Singh,3 Girish Parmar,4 Pradeep Gadge,5 Onkar C Swami6 1Diabetes, Thyroid and Endocrine Centre, Galaxy Speciality Centre, Jaipur, 2Aruna Diabetes Centre, Chennai, 3Fortis Hospital, Sector 62, Phase VIII, Mohali, 4Kokilaben Dhirubhai Ambani Hospital, Andheri (W), Mumbai, 5Dr Gadge’s Diabetes Care Centre, Mumbai, 6Unichem Laboratories Ltd, Jogeshwari (W), Mumbai, India Abstract: Teneligliptin is a recently developed oral dipeptidyl peptidase 4 inhibitor indicated for the management of type 2 diabetes mellitus (T2DM) in adults along with diet and exercise. Teneligliptin has been recently available in Japan (Teneria®), Argentina (Teneglucon®), and India (Tenepure; Teneza) at relatively affordable price. This is a positive step toward the management of T2DM in developing countries, where the cost of medicine is out-of-pocket expenditure and is a limiting factor for health care. This review evaluates the efficacy and safety of teneligliptin in the management of T2DM. Teneligliptin has been systematically evaluated in T2DM as monotherapy with diet and exercise and in combination with metformin, glimepiride, pioglitazone, and insulin in short-term (12 weeks) and long-term (52 weeks) studies. These studies have reported a reduction in HbA1c of 0.8%–0.9% within 12 weeks of therapy. Two 52-week studies reported sustained improvement in glycemic control with teneligliptin. Teneligliptin has been found to be well tolerated, and the safety profile is similar to other dipeptidyl peptidase 4 inhibitors. Hypoglycemia and constipation are the main adverse events. Teneligliptin can be administered safely to patients with mild, moderate, or severe renal impairment or end-stage renal disease without dose adjustment. Similarly, it can be used in patients with mild-to-moderate hepatic impairment. Teneligliptin is effective and well tolerated and may have an important role in the management of T2DM. Keywords: diabetes mellitus, dipeptidyl peptidase 4 inhibitor, newer DPP-4 inhibitor, teneligliptin, India

BackgroundWe compared the efficacies of vildagliptin (50 mg twice daily) relative to pioglitazone (15 mg once daily) as an add-on treatment to metformin for reducing glycosylated hemoglobin (HbA1c) levels in Korean patients with type 2 diabetes.MethodsThe present study was a multicenter, randomized, active-controlled investigation comparing the effects of vildagliptin and pioglitazone in Korean patients receiving a stable dose of metformin but exhibiting inadequate glycemic control. Each patient underwent a 16-week treatment period with either vildagliptin or pioglitazone as an add-on treatment to metformin.ResultsThe mean changes in HbA1c levels from baseline were –0.94% in the vildagliptin group and –0.6% in the pioglitazone group and the difference between the treatments was below the non-inferiority margin of 0.3%. The mean changes in postprandial plasma glucose (PPG) levels were –60.2 mg/dL in the vildagliptin group and –38.2 mg/dL in the pioglitazone group and these values significantly differed (P=0.040). There were significant decreases in the levels of total, low density lipoprotein, high density lipoprotein (HDL), and non-HDL cholesterol in the vildagliptin group but increases in the pioglitazone group. The mean change in body weight was –0.07 kg in the vildagliptin group and 0.69 kg in the pioglitazone group, which were also significantly different (P=0.002).ConclusionAs an add-on to metformin, the efficacy of vildagliptin for the improvement of glycemic control is not inferior to that of pioglitazone in Korean patients with type 2 diabetes. In addition, add-on treatment with vildagliptin had beneficial effects on PPG levels, lipid profiles, and body weight compared to pioglitazone.

Background and Objectives: Myocarditis is a potentially fatal disease, but curative treatments have not yet been established. Myocardial inflammation is an important pathogenesis of this disease, and immunosuppressants such as methylprednisolone and immunoglobulin have been used for treatment; however, the effectiveness needs to be improved. Thalidomide and dipeptidyl peptidase (DPP) 4 inhibitors were recently investigated regarding their immunomodulatory properties. This study aimed to test whether thalidomide or a DPP4 inhibitor (evogliptin) can improve the effectiveness of myocarditis treatment using a rat model of experimental autoimmune myocarditis (EAM)., Methods: Rats with or without myocarditis were administered thalidomide at 100 mg/kg/day and DPP4 inhibitor at 10 mg/kg/day orally. Measurement of echocardiography, serum inflammatory cytokines, myocardial histopathological examination, and immunohistochemical staining for leukocytes, macrophages, CD4+ T cells, and cytoskeleton were performed after 3 weeks, and the fibrosis area was measured after 3 and 6 weeks., Results: Thalidomide and DPP4 inhibitor did not reduce the severity of myocarditis compared with the EAM without treatment rats by comparing the echocardiographic data, myocardial CD4 + , macrophages, neutrophil infiltrations, and the heart weight/body weight ratio in 3 weeks. The levels of inflammatory cytokines were not lower in the thalidomide and DPP4 inhibitor-treated group than in the untreated group in 3 weeks. In 6 weeks, thalidomide and DPP4 inhibitors did not reduce the fibrosis area compared to untreated groups., Conclusions: Although thalidomide and the DPP4 inhibitor had an immunomodulatory effect and are used against inflammatory diseases, they did not ameliorate myocardial inflammation and fibrosis in this rat model of EAM., Competing Interests: The authors have no financial conflicts of interest., (Copyright © 2023. The Korean Society of Cardiology.)

Aims/Introduction: Recent data showed that dipeptidyl peptidase 4 (DPP‐4) inhibitors exert a lipid‐lowering effect in diabetes patients. However, the mechanism of action is not yet clearly understood. We investigated the effect of anagliptin on cholesterol metabolism and transport in the small intestine using non‐diabetic hyperlipidemic animals, to clarify the mechanisms underlying the cholesterol‐lowering action. Materials and Methods: Male apolipoprotein E (ApoE)‐deficient mice were orally administered anagliptin in the normal chow. Serum cholesterol levels and lipoprotein profiles were measured, and cholesterol transport was assessed by measuring the radioactivity in the tissues after oral loading of 14C‐labeled cholesterol (14C‐Chol). In additional experiments, effects of exendin‐4 in mice and of anagliptin in DPP‐4‐deficient rats were assessed. Effects on target gene expressions in the intestine were analyzed by quantitative polymerase chain reaction in normal mice. Results: The serum total and non‐high‐density lipoprotein cholesterol concentrations decreased after anagliptin treatment in the ApoE‐deficient mice. The cholesterol‐lowering effect was predominantly observed in the chylomicron fraction. The plasma 14C‐Chol radioactivity was significantly decreased by 26% at 2 h after cholesterol loading, and the fecal 14C‐Chol excretion was significantly increased by 38% at 72 h. The aforementioned effects on cholesterol transport were abrogated in rats lacking DPP‐4 activity, and exendin‐4 had no effect on the 14C‐Chol transport in ApoE‐deficient mice. Furthermore, significant decreases of the intestinal cholesterol transport‐related microsomal triglyceride transfer protein, acyl‐coenzyme A:cholesterol acyltransferase 2, ApoA2 and ApoC2 messenger ribonucleic acid expressions were observed in the mice treated with repeated doses of anagliptin. Conclusions: These findings suggest that anagliptin might exert a cholesterol‐lowering action through DPP‐4‐dependent and glucagon‐like peptide 1‐independent suppression of intestinal cholesterol transport. Anagliptin delayed the lipid transport from intestine to systemic circulation. This effect is DPP‐4‐dependent but GLP‐1R independent manner. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Anagliptin (ANA) improves dyslipidemia in addition to blood glucose levels. However, there are no comparative studies on the effects of ANA and other dipeptidyl peptidase‐4 inhibitors on serum lipid profile. We compared the effects of ANA on serum lipid profile with those of alogliptin (ALO) in type 2 diabetes mellitus outpatients. Materials and Methods: The study participants were 87 type 2 diabetes mellitus patients who had been treated with dipeptidyl peptidase‐4 inhibitors for ≥8 weeks and had a low‐density lipoprotein cholesterol (LDL‐C) level of ≥120 mg/dL. Participants were switched to either 200 mg/day ANA or 25 mg/day ALO for 24 weeks. Results: There was no significant difference in percentage change in LDL‐C level at 24 weeks between the ANA and ALO groups. Treatment with ANA for 12 weeks significantly decreased LDL‐C levels, one of the secondary end‐points. Treatment with ANA for 24 weeks significantly improved apolipoprotein B‐100 levels, and the percentage change in LDL‐C levels at 24 weeks correlated significantly with the percentage change in apolipoprotein B‐100 levels in the ANA group. Conclusions: The LDL‐C‐lowering effects of ANA and ALO at 24 weeks were almost similar in patients with type 2 diabetes mellitus. However, the results showed a tendency for a decrease in LDL‐C level at 24 weeks in the ANA group, and that such improvement was mediated, at least in part, through the suppression of apolipoprotein B‐100 synthesis. [ABSTRACT FROM AUTHOR]

Introduction: Teneligliptin is a recently developed Dipeptidyl Peptidase 4 (DPP4) inhibitor. Teneligliptin is suitable for glycaemic control in Type 2 Diabetes Mellitus (T2DM) patients with renal impairment including end stage renal disease. Aim: To assess the efficacy and safety of teneligliptin in Asian Indian T2DM patients with early Diabetic Kidney Disease (DKD). Materials and Methods: This was a single centre, retrospective analysis of patients with early DKD, who received teneligliptin 20 mg once daily for 24 weeks. Data related to glycaemic parameters, kidney function, lipid levels, retinopathy, neuropathy and safety variables available at 12 and 24 weeks were analysed. Descriptive statistical analysis was carried out. Statistical significance was assessed at a 5% level. Results: Total 37 patients (21 males; 16 females) were analysed. Compared to baseline, significant reduction in Fasting Plasma Glucose (FPG) (mg/dl) (143.89±28.26 vs 125.78±20.52, p=0.001); Postprandial Glucose (PPG) (mg/dl) (200.62±41.88 vs 165.76±26.02, p=0.001); Glycated Haemoglobin (HbA1c) (%) (8.65±0.58 vs 8.17±0.54, p=0.001) was noted at 12 weeks. This trend was further continued for 24 weeks with significant reduction in mean FPG, PPG and HbA1c to 113.73±16.82 mg/dl (p=0.008); 142.95±20.76 mg/dl (p=0.001); and 7.65±0.45% (p=0.001) respectively. Significant improvement in serum creatinine (mg/ dl) (2.45±0.27 vs. 2.26±0.23, p=0.001) and eGFR (CKD-EPI), (ml/ min/1.73 m2 ) (53.35±4.24 vs. 55.08±4.19, p=0.001) was noted at 12 weeks and continued for 24 weeks with reduction in serum creatinine of 0.37±0.18 mg/dl (p=0.001) and increase of eGFR of 4.60±1.59 ml/min/1.73 m2 (p=0.001). At baseline, proteinuria was noted in all patients while at 24 weeks, 40.5% (p=0.001) patients did not report proteinuria. Significant improvements in lipid parameters with no deterioration in retinopathy and subjective improvement in peripheral neuropathy was also noted. No adverse events were noted. Conclusion: Teneligliptin reported significant and sustained improvement in glycaemic control in Asian Indian Patients of T2DM with early DKD and was well tolerated. Additionally, Teneligliptin reported significant improvement in renal function.

BackgroundThe aims of this study are to investigate the glycemic efficacy and predictive parameters of vildagliptin therapy in Korean subjects with type 2 diabetes.MethodsIn this retrospective study, we retrieved data for subjects who were on twice-daily 50 mg vildagliptin for at least 6 months, and classified the subjects into five treatment groups. In three of the groups, we added vildagliptin to their existing medication regimen; in the other two groups, we replaced one of their existing medications with vildagliptin. We then analyzed the changes in glucose parameters and clinical characteristics.ResultsUltimately, 327 subjects were analyzed in this study. Vildagliptin significantly improved hemoglobin A1c (HbA1c) levels over 6 months. The changes in HbA1c levels (ΔHbA1c) at month 6 were -2.24% (P=0.000), -0.77% (P=0.000), -0.80% (P=0.001), -0.61% (P=0.000), and -0.34% (P=0.025) for groups 1, 2, 3, 4, and 5, respectively, with significance. We also found significant decrements in fasting plasma glucose levels in groups 1, 2, 3, and 4 (P

Background: No conclusive evidence has been obtained yet on the significance of the effects of dipeptidyl peptidase-4 (DPP-4 inhibitor) treatment on the arterial stiffness in clinical settings. In addition, the effects of good glycemic control on the arterial stiffness have also not been clarified yet. As a sub-analysis of the PROLOGUE study, we examined the effect of a DPP-4 inhibitor (sitagliptin) on the 2-year progression of the arterial stiffness and also to determine the effect of good glycemic control on the rate of progression of the arterial stiffness. Methods: In the PROLOGUE study, the study participants were either allocated to add-on sitagliptin treatment or to continued treatment with conventional anti-diabetic agents. Among the 463 participants of the PROLOGUE study, we succeeded in measuring the brachial-ankle pulse wave velocity (baPWV) at least two times during the 2-year study period in 96 subjects. Results: The changes in the baPWV during the study period were similar between the both groups (i.e., with/without staglipitin), overall. On the other hand, when the study subjects were divided into two groups according to the glycemic control status during the study period {good glycemic control group (GC) = hemoglobin (Hb)A1c <7.0 at both 12 and 24 months after the treatment randomization; poor glycemic control group (PC) = HbA1c ≥7.0 at either 12 months, 24 months, or both}, the 2-year increase of the baPWV was marginally significantly larger in the PC group (144 ± 235 cm/s) as compared to that the GC group (-10 ± 282 cm/s) (p = 0.036). Conclusion: While the present study could not confirm the beneficial effect of sitagliptin per se on the arterial stiffness, the results suggested that good glycemic control appears to be beneficial for delaying the annual progression of the arterial stiffness. [ABSTRACT FROM AUTHOR]

Background: As a sub-analysis of the PROLOGUE study, we evaluated the long-term effect of sitagliptin, a dipeptidyl peptidase 4 inhibitor, on endothelial function in the conduit brachial artery in patients with type 2 diabetes. Methods: In the PROLOGUE study, patients were randomly assigned to either add-on sitagliptin treatment (sitagliptin group) or continued conventional antihyperglycemic treatment (conventional group). Among the 463 participants in the PROLOGUE study, FMD was measured in 17 patients in the sitagliptin group and 18 patients in the conventional group at the beginning and after 12 and 24 months of treatment. Results: HbA1c levels were significantly decreased after 12 and 24 months of treatment compared to baseline values in both groups (7.0 ± 0.4 vs. 6.6 ± 0.3 and 6.6 ± 0.4% in the sitagliptin group; 7.0 ± 0.6 vs. 6.6 ± 0.7 and 6.6 ± 0.7% in the conventional group; P < 0.05, respectively). There was no significant difference between FMD values at baseline and after 12 and 24 months in the sitagliptin group (4.3 ± 2.6 vs. 4.4 ± 2.1 and 4.4 ± 2.3%, P = 1.0, respectively). Although FMD had a tendency to increase from 4.3 ± 2.4% at baseline to 5.2 ± 1.9% after 12 months and 5.1 ± 2.2% after 24 months in the conventional group, there was no significant difference between FMD values at baseline and after 12 and 24 months (P = 0.36 and 0.33, respectively). Conclusions: Add-on sitagliptin to conventional antihyperglycemic drugs in patients with type 2 diabetes did not alter endothelial function in the conduit brachial artery measured by FMD during a 2-year study period. Sitagliptin may be used without concern for an adverse effect on endothelial function in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Non-alcoholic fatty liver disease (NAFLD) represents one of the most common causes of chronic liver disease worldwide and is characterized by chronic liver inflammation and fibrosis leading to cirrhosis and increased risk of liver cancer in a proportion of patients. Effective anti- fibrotic agents have yet to be approved for the treatment of NAFLD. The present study aimed to evaluate the efficacy of dipeptidyl peptidase 4 inhibitors (DPP4-I) in the prevention of NAFLD progression in NAFLD patients with type 2 diabetes. The study was a single arm, multi-centre, non-randomised study of NAFLD patients with type 2 diabetes. NAFLD was diagnosed according to ultrasonographic findings. All the patients received 25 mg/day of alogliptin for 12 months. The efficacy of alogliptin in preventing NAFLD progression was assessed using overall NAFIC scores [non-alcoholic steatohepatitis (NASH), ferritin, insulin and type IV collagen 7S] and individual component scores according to baseline haemoglobin A1c (HbA1c) levels. Of the 39 patients enrolled in the study, 16 patients (40.3%) had NAFIC scores >2 points, indicating the presence of NASH. NAFIC scores markedly decreased following 12 months of alogliptin administration, but remained >2 points in 10 patients, indicating that NASH may have persisted in these patients. The relative risks for persistent NASH were 4.92 (95% confidence interval, 0.61-40.0) in the highest HbA1c tertile group compared with those in the lowest group. However, no statistically significant linear trend was observed across all HbA1c categories (P=0.145). DPP4-I may have efficacy against NAFLD progression in patients with type 2 diabetes with relatively lower HbA1c levels. DPP4-I may represent a potential new therapeutic strategy for the prevention of disease progression in NAFLD patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Recent studies have suggested that dipeptidyl peptidase 4 (DPP4) inhibitors increase the risk of development of bullous pemphigoid (BP), which is the most common autoimmune blistering skin disease; however, the associated mechanisms remain unclear, and thus far, no therapeutic targets responsible for drug-induced BP have been identified. Therefore, we used clinical data mining to identify candidate drugs that can suppress DPP4 inhibitor-associated BP, and we experimentally examined the underlying molecular mechanisms using human peripheral blood mononuclear cells (hPBMCs). A search of the US Food and Drug Administration Adverse Event Reporting System and the IBM ® MarketScan ® Research databases indicated that DPP4 inhibitors increased the risk of BP, and that the concomitant use of lisinopril, an angiotensin-converting enzyme inhibitor, significantly decreased the incidence of BP in patients receiving DPP4 inhibitors. Additionally, in vitro experiments with hPBMCs showed that DPP4 inhibitors upregulated mRNA expression of MMP9 and ACE2 , which are responsible for the pathophysiology of BP in monocytes/macrophages. Furthermore, lisinopril and Mas receptor (MasR) inhibitors suppressed DPP4 inhibitor-induced upregulation of MMP9. These findings suggest that the modulation of the renin-angiotensin system, especially the angiotensin1-7/MasR axis, is a therapeutic target in DPP4 inhibitor-associated BP., Competing Interests: KNo is employed by Japan Tobacco Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Nozawa, Suzuki, Kayanuma, Yamamoto, Nagayasu, Shirakawa and Kaneko.)

Background: There have only been a few reports about use of dipeptidyl peptidase 4 (DPP-4) inhibitors in elderly patients with type 2 diabetes mellitus (T2DM), suggesting that the safety of these agents has not been sufficiently demonstrated. We performed a comparative review of the efficacy and safety of sitagliptin for Japanese patients with T2DM managed in the real-world clinical setting. Methods: An age-stratified analysis was performed of 831 patients who were treated with sitagliptin for 2 years. Parameters assessed included the hemoglobin A1c (HbA1c), body weight, serum creatinine, and adverse events. HbA1c and the incidence of hypoglycemia were also evaluated in patients treated with sitagliptin and a sulfonylurea (SU), who were divided into three age groups (<65 years, 65-74 years, and ≥75 years). Results: Comparison of glycemic control parameters, laboratory values, and adverse events revealed significant improvement of HbA1c, casual postprandial plasma glucose, and fasting plasma glucose in each age group with no change in body weight. Serum creatinine increased significantly in all age groups. Hypoglycemia only occurred in patients who received combined treatment with an SU and sitagliptin, and there was no age-related difference in its incidence. Conclusions: HbA1c was improved by 2 years of sitagliptin therapy in all three age groups, and age did not seem to influence the incidence of hypoglycemic events. These results confirm the efficacy and safety of sitagliptin in patients ≥ 75 years old, suggesting that it is also useful for treating elderly patients with T2DM. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase 4 (DPP4) inhibitors suppress the metabolism of the potent antihyperglycemic hormone glucagon-like peptide-1 (GLP-1). DPP4 was recently shown to provide cardioprotection through a reduction of infarct size, but the mechanism for this remains elusive. Known interactions between DPP4 and adenosine deaminase (ADA) suggest an involvement of adenosine signaling in DPP4 inhibitor-mediated cardioprotection. We tested whether the protective mechanism of the DPP4 inhibitor alogliptin against myocardial ischemia-reperfusion injury involves GLP-1- and/or adenosine-dependent signaling in canine hearts. In anesthetized dogs, the coronary artery was occluded for 90 min followed by reperfusion for 6 h. A 4-day pretreatment with alogliptin reduced the infarct size from 43.1 ± 2.5% to 17.1 ± 5.0% without affecting collateral flow and hemodynamic parameters, indicating a potent antinecrotic effect. Alogliptin also suppressed apoptosis as demonstrated by the following analysis: 1) reduction in the Bax-to-Bcl2 ratio; 2) cytochrome c release, 3) an increase in Bad phosphorylation in the cytosolic fraction; and 4) terminal deoxynucleotidyl transferase dUTP nick end labeling assay. This DPP4 inhibitor did not affect blood ADA activity or adenosine concentrations. In contrast, the nonselective adenosine receptor blocker 8-(p-sulfophenyl) theophylline (8SPT) completely blunted the effect of alogliptin. Alogliptin did not affect Erk1/2 phosphorylation, but it did stimulate phosphorylation of Akt, glycogen synthase kinase-3β, and cAMP response element-binding protein (CREB). Only 8SPT prevented alogliptin-induced CREB phosphorylation. In conclusion, the DPP4 inhibitor alogliptin suppresses ischemia-reperfusion injury via adenosine receptor- and CREB-dependent signaling pathways. [ABSTRACT FROM AUTHOR]

Background Heart failure with left ventricular (LV) hypertrophy is often associated with insulin resistance and inflammation. Recent studies have shown that dipeptidyl peptidase 4 (DPP4) inhibitors improve glucose metabolism and inflammatory status. We therefore evaluated whether vildagliptin, a DPP4 inhibitor, prevents LV hypertrophy and improves diastolic function in isoproterenol-treated rats. Methods Male Wistar rats received vehicle (n = 20), subcutaneous isoproterenol (2.4 mg/kg/day, n = 20) (ISO), subcutaneous isoproterenol (2.4 mg/kg/day + oral vildagliptin (30 mg/kg/day, n = 20) (ISO-VL), or vehicle + oral vildagliptin (30 mg/kg/day, n = 20) (vehicle-VL) for 7 days. Results Blood pressure was similar among the four groups, whereas LV hypertrophy was significantly decreased in the ISO-VL group compared with the ISO group (heart weight/body weight, vehicle: 3.2 ± 0.40, ISO: 4.43 ± 0.39, ISO-VL: 4.14 ± 0.29, vehicle-VL: 3.16 ± 0.16, p < 0.05). Cardiac catheterization revealed that vildagliptin lowered the elevated LV end-diastolic pressure observed in the ISO group, but other parameters regarding LV diastolic function such as the decreased minimum dp/dt were not ameliorated in the ISO-VL group. Histological analysis showed that vildagliptin attenuated the increased cardiomyocyte hypertrophy and perivascular fibrosis, but it did not affect angiogenesis in cardiac tissue. In the ISO-VL group, quantitative PCR showed attenuation of increased mRNA expression of tumor necrosis factor-α, interleukin-6, insulin-like growth factor-l, and restoration of decreased mRNA expression of glucose transporter type 4. Conclusions Vildagliptin may prevent LV hypertrophy caused by continuous exposure to isoproterenol in rats. [ABSTRACT FROM AUTHOR]

A 74-year-old male patient with type 2 diabetes mellitus admitted to the emergency department with the complaints of progressive breathlessness, dry cough, and swollen lower extremities. Our patient had type 2 diabetes mellitus and hypertension for 3 years. His HbA1c was not within the target range so sitagliptin was added to on-going therapy. After 1 week of starting sitagliptin therapy, even though the patient had not heart failure he applied to the emergency department with a complaint of dyspnea. The cardiovascular safety and efficacy of many anti-hyperglycemic agents such as sitagliptin, saxagliptin are unclear. Our case has shown that dipeptidyl peptidase 4 inhibitors may cause pulmonary edema. Hence, it should be used with cautious, especially in patients with heart failure.

Background/aims: We aimed to define an optimal target population and drug-specific biomarkers that may predict dipeptidyl peptidase (DPP)-4 inhibitor responses in non-alcoholic fatty liver disease (NAFLD)., Methods: An exploration study (study I) was performed using three different NAFLD models (basket study design; high-fat diet [HFD], methionine choline-deficient diet [MCD], and high-cholesterol Western diet [WD] models). RNA transcriptome analysis was performed on pre-studied liver tissues to identify biomarkers that could predict the response to DPP-4 inhibitors. In the validation study (study II), the HFD-induced NAFLD model was divided into high and low hepatic insulin-like growth factor binding protein 1 (Igfbp-1) groups based on the pre-study liver biopsy., Results: DPP-4 inhibitor attenuated the NAFLD activity score and fibrosis stage in the HFD model but not in the WD and MCD models. The overall response rate was 19% across the modified basket NAFLD trial and 42%, 25%, and 0% in the HFD, WD, and MCD models. Hepatic Igfbp-1 expression was higher in the responder group than in the non-responder group in pre-study biopsy samples. In contrast, hepatic Igfbp-1 expression was lower in the responder group than in the non-responder group in the end-study biopsy samples. DPP-4 inhibitor response rates were 83% and 17% in the baseline hepatic high Igfbp-1 and low Igfbp-1 groups, respectively. Hepatic messenger RNA Igfbp-1 expression was positively correlated with serum IGFBP-1 levels., Conclusion: The DPP-4 inhibitor response was higher in the HFD phenotype and pre-treatment levels of hepatic or serum IGFBP-1 were high.