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Objective: To explore persistence and adherence with once-daily, twice-daily, or once-weekly DPP-4 inhibitors (DPP-4i) in Japanese patients with type 2 diabetes.Methods: This retrospective, longitudinal, observational cohort study used data from the Japanese nationwide hospital-based Medical Data Vision (MDV) administrative claims database. Data were collected for patients given a new DPP-4i prescription between May 2015 and June 2017 with 1-year follow-up until May 2018. Treatment persistence was defined as the total duration of continuous prescription. Adherence to treatment was measured as the proportion of days covered (PDC).Results: A total of 598,419 patients with a prescription for DPP-4i treatment were identified in the MDV database. Of the 39,826 patients who met the inclusion criteria, 82.4% were receiving once-daily DPP-4i, 15.6% twice-daily DPP-4i, and 2.0% once-weekly DPP-4i. Twelve-month persistence rates with once-daily regimens were 66.3% versus 64.7% with twice-daily (p = .1187), and versus 38.8% with once-weekly, regimens (p < .0001) in the overall population (including untreated [UT] and previously treated [PT] patients); 62.8% with once-daily versus 58.3% with twice-daily (p = .0309), and versus 12.3% with once-weekly regimens (p < .0001) in the UT cohort; and 68.6% with once-daily versus 67.9% with twice-daily (p = .5471), and versus 49.1% with once-weekly regimens (p < .0001) in the PT cohort. In the overall population, 97.8% of patients had a mean PDC of 0.97 with once- and twice-daily, and 65.8% of patients had a mean PDC of 0.74 with once-weekly, DPP-4i regimens.Conclusions: Overall, persistence at 12 months was highest in patients receiving once-daily DPP-4i regimens. [ABSTRACT FROM AUTHOR]

Aims and Objectives: Dipeptidyl peptidase‐4 inhibitor (DPP4i) is widely used for the treatment of type 2 diabetes (T2DM) in several countries such as Japan, whereas biguanide (BG; mostly metformin) is recommended as a first‐line antidiabetic medication in many countries according to evidence mainly from Western countries. Although previous studies reported that DPP4i may be more efficacious for East Asians, direct comparisons of effectiveness and cost between DPP4i and BG have never been conducted in East Asia. Methods: We extracted claims and medical check‐up data (observation period from January 2010 to March 2016) of adult patients under 70 years old with T2DM who received DPP4i or BG as first‐line antidiabetic drugs. Changes in HbA1c and BMI before and 2 years after the first prescription and annual cost of antidiabetic medication during the second year were compared between the DPP4i and BG groups. Results: We extracted 1034 patients who received DPP4i and 365 patients who received BG as the first antidiabetic medication (male sex, 83.0% and 84.9%; HbA1c (mean [SD]), 7.7 [1.4]% and 7.9 [1.4]%; BMI, 26.6 [4.5] kg/m2 and 28.1 [4.3] kg/m2). After propensity score matching, changes in HbA1c and BMI were not significantly different between the groups (HbA1c, −0.67% vs −0.80% [P =.28]; BMI, −0.3 kg/m2 vs −0.4 kg/m2 [P =.42]). Annual cost of antidiabetic drugs was significantly higher in the DPP4i group (US $458.7 vs 273.3 [P <.001]). Many patients continued each medication at the follow‐up visit (78.3% of the DPP4i group and 73.7% of the BG groups). Conclusions: The first antidiabetic prescription for the patient was mostly continued thereafter. BG may be recommendable as the first‐line medication for patients with T2DM, especially for middle‐aged, male population with greater BMI. It is worth addressing the discrepancy between practice in Japan and that recommended in international guidelines. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]. Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies in patients with HF. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP), is a chronic pain resulting from nerve injury, with limited treatment options. Teneligliptin (TEN) is a dipeptidyl peptidase-4 inhibitor (DPP-4i) approved to treat type 2 diabetes. DPP-4is prevent the degradation of the incretin hormone glucagon-like peptide 1 (GLP-1) and prolong its circulation. Apart from glycemic control, GLP-1 is known to have antinociceptive and anti-inflammatory effects. Herein, we investigated the antinociceptive properties of TEN on acute pain, and partial sciatic nerve transection (PSNT)-induced NP in Wistar rats. Seven days post PSNT, allodynia and hyperalgesia were confirmed as NP, and intrathecal (i.t) catheters were implanted and connected to an osmotic pump for the vehicle (1 μL/h) or TEN (5 μg/1 μL/h) or TEN (5 μg) + GLP-1R antagonist Exendin-3 (9–39) amide (EXE) 0.1 μg/1 μL/h infusion. The tail-flick response, mechanical allodynia, and thermal hyperalgesia were measured for 7 more days. On day 14, the dorsal horn was harvested and used for Western blotting and immunofluorescence assays. The results showed that TEN had mild antinociceptive effects against acute pain but remarkable analgesic effects against NP. Furthermore, co-infusion of GLP-1R antagonist EXE with TEN partially reversed allodynia but not tail-flick latency. Immunofluorescence examination of the spinal cord revealed that TEN decreased the immunoreactivity of glial fibrillary acidic protein (GFAP). Taken together, our findings suggest that TEN is efficient in attenuation of PSNT-induced NP. Hence, the pleiotropic effects of TEN open a new avenue for NP management.

Abstract Background Whether dipeptidyl peptidase-4 inhibitor (DPP4i) is associated with a lower risk of new-onset atrial fibrillation (AF) in patients with diabetes remains unclear. This study aimed to evaluate the risk of AF associated with use of DPP4i among a longitudinal cohort of patients with diabetes. Methods Over a 3-year period, 480,000 patients with diabetes were analyzed utilizing Taiwan’s National Health Insurance Research Database and 90,880 patients taking metformin as first-line therapy were enrolled. Patients were further divided into two groups: (1) DPP4i users: those taking DPP4i and (2) non-DPP4i users: those prescribed other hypoglycemic agents (HAs) as second-line drug. Study end point was defined by diagnosis of AF, addition of any third-line HA, or the end of the study period (December 31, 2013), whichever came first. Results A total of 16,017 DPP4i users and 74,863 non-DPP4i users were eligible for the study. For the DPP4i group, most patients were prescribed sitagliptin (n = 12,180; 76%). Among the non-DPP4i group, most patients took sulfonylurea (n = 60,606; 81%) as their second-line medication. DPP4i users were associated with a lower risk of new-onset AF compared with non-DPP4i users after propensity-score weighting (hazard ratio 0.65; P 65 years, presence of hypertension, and ischemic heart disease were independent risk factors for new-onset AF. Conclusions Among patients with diabetes prescribed with metformin, the patients with DPP4i as second HA were associated with a lower risk of AF compared with the patients with other drugs as second HAs in real-world practice.

Saxagliptin, a potent and selective DPP-4 inhibitor, exhibits a slow dissociation from DPP-4. We investigated the sustained effects of saxagliptin on renal DPP-4 activity in a washout study using renal tubular (HK-2) cells, and in a pharmacodynamic study using normal rats. In HK-2 cells, the inhibitory potency of saxagliptin on DPP-4 activity persisted after washout, while that of sitagliptin was clearly reduced. In normal rats, a single treatment of saxagliptin or sitagliptin inhibited the plasma DPP-4 activity to similar levels. The inhibitory action of saxagliptin on the renal DPP-4 activity was retained, even when its inhibitory effect on the plasma DPP-4 activity disappeared. However, the inhibitory action of sitagliptin on the renal DPP-4 activity was abolished in correlation with the inhibition of the plasma DPP-4 activity. In situ staining showed that saxagliptin suppressed the DPP-4 activity in both glomerular and tubular cells and its inhibitory effects were significantly higher than those of sitagliptin. Saxagliptin exerted a sustained inhibitory effect on the renal DPP-4 activity in vitro and in vivo. The long binding action of saxagliptin in renal tubular cells might involve the sustained inhibition of renal DPP-4.

Abstract Background Dipeptidyl peptidase-4 (DPP-4) inhibitors may have protective effects in the early stage of atherosclerosis in patients with type 2 diabetes, although similar effects in advanced atherosclerosis were not shown in recent randomized placebo-controlled studies. Therefore, we investigated the efficacy of DPP-4 inhibitor on endothelial function and glycemic metabolism compared with high-dose metformin. Methods In this multicenter, open-labeled, prospective, randomized, parallel-group comparison study, patients with type 2 diabetes treated with low-dose metformin (500–750 mg/day) were enrolled and randomly assigned to a vildagliptin, a DPP-4 inhibitor, add-on group (Vilda) or a double dose of metformin group (high Met) for 12 weeks. Flow-mediated dilation (FMD) and serum metabolic markers were assessed before and after treatment. In addition, glycemic control and metabolic parameters were also assessed. Results Ninety-seven subjects (aged 58.7 ± 11.0 years; body mass index, 25.9 ± 4.4 kg/m2; HbA1c, 7.3 ± 0.5%; FMD, 5.8 ± 2.6%) were enrolled. Eight subjects dropped out by the end of the study. There were no significant differences between the two groups in baseline characteristics. After 12 weeks, HbA1c was significantly improved in the Vilda group compared with the high Met group (− 0.80 ± 0.38% vs. − 0.40 ± 0.47%, respectively; p

Abstract Background Achieving control of glycated hemoglobin (HbA1c), blood pressure (BP), and body weight (BW) remains a challenge for most patients with type 2 diabetes mellitus (T2DM). In clinical trials, canagliflozin (CANA), an inhibitor of sodium-glucose co-transporter 2, has shown significant improvement compared to some dipeptidyl peptidase-4 (DPP-4) inhibitors in the achievement of such quality measures. This study used recent electronic medical records (EMR) data to assess quality measure achievement of HbA1C, BP, and BW loss in patients treated with CANA versus DPP-4 inhibitors. Methods Adult patients with ≥1 T2DM diagnosis and ≥12 months of clinical activity (baseline) before first CANA or DPP-4 prescription (index) were identified in the QuintilesIMS Health Real-World Data EMRs–US database (03/29/2012–10/30/2015). Patients were observed from the index to last encounter. Inverse probability of treatment weighting (IPTW) was used to adjust for observed baseline confounders between groups. Kaplan-Meier (KM) rates and Cox proportional hazard models were used to compare achievement of HbA1c

Context: Diabetes mellitus is a recognized risk factor for heart failure. Dipeptidyl peptidase-4 inhibitors (DPP4i) are used in patients with diabetes largely due to its efficacy in glycated hemoglobin (HbA1c) reduction, neutral weight effect, and lower hypoglycemic events. New antidiabetic medications such as the glitazones have been linked with increasing mortality and heart failure exacerbations. The effect of DPP4i in heart failure has not been shown in a heterogenous Asian population. Aims: The aim of this study was to assess incidence of heart failure and cardiovascular (CV) events in patients with diabetes with known coronary artery disease (CAD) treated with DPP4i. Subjects and Methods: This was a single-center, retrospective analysis of patients with diabetes mellitus attending various specialist clinics in Universiti Teknologi MARA treated with available DPP4i agents from January 2013 to July 2015. Medical records were reviewed and data collected for demographic, anthropometric, laboratory, and treatment modalities. Endpoints include changes in body weight, body mass index, lipid, renal profile, and CV events during follow-up. Results: Three hundred and twenty-three patients with diabetes were screened and 307 fulfilled the inclusion criteria. Fifty-four were on linagliptin, 115 were on vildagliptin, and 154 were on saxagliptin. Majority of patients (87.6%) had uncontrolled diabetes at baseline (HbA1c, %) (8.9 ± 2.07). There was a significant reduction in HbA1c from baseline to visit 1 at 3 months (P = 0.000). Similarly, significant improvement in HbA1c seen from baseline to visit 1 (P = 0.000). A higher CV event rate was found between 20 and 30 weeks of therapy with DPP4i. The cumulative survival was 99.5% at 20 weeks and reduced to 98.75% at 30 weeks (P = 0.033). There were seven reported events (0.98%) due to heart failure or acute coronary syndrome. These participants had higher baseline HbA1c and creatinine compared to the overall cohort. Conclusions: Higher CV events were seen in diabetic patients with known CAD treated with DPP4i between 20 and 30 weeks of therapy and occurred earlier in patients with chronic kidney disease. This is later than published data and raises the need to monitor this group of patients for symptoms of heart failure beyond conventional monitoring.

Background: Sitagliptin, a dipeptidyl peptidase-4 inhibitor, is widely used in patients with type 2 diabetes. However, the pleiotropic effects of sitagliptin is not well understood. Objective: To assess the clinical efficacy and safety of sitagliptin on atherosclerosis, β-cell function, and glycemic control in Japanese patients with type 2 diabetes. Methods: A prospective observational study of 270 patients with type 2 diabetes mellitus was carried out. Patients (aged 64.3 [12.4] years, body mas index 25.2 [4.3]) with glycated hemoglobin >6.9% (52 mmol/mol) or fasting plasma glucose >130 mg/dL were treated with sitagliptin for 12 months. The primary end point was glycated hemoglobin level changes from baseline to 3 months. The secondary end points included changes in several biomarkers related to inflammation and β-cell function from baseline to 3 months, as well as changes in glycated hemoglobin level from baseline to 12 months. Results: Glycated hemoglobin levels were significantly lower in patients treated with sitagliptin for 3 months than at baseline (8.1% [1.4%]–7.3% [1.2%]) (65 [16.9]–56 [13.1] mmol/mol]) (P < 0.0001), which continued after 12 months (7.4% [1.3%]) (56 [15.2] mmol/mol) (P < 0.0001). In addition, a marker of vascular-specific inflammation, pentraxin-3, and a marker of β-cell function (proinsulin/insulin ratio), respectively, were lower after treatment with sitagliptin for 3 months than at baseline (1.88 [0.78]–1.65 [0.63] ng/mL [P = 0.0038] and 0.20 [0.14]–0.17 [0.11] [P = 0.01], respectively). On the other hand, a biomarker reflecting whole body inflammation; that is, high-sensitivity C-reactive protein level, was unchanged. Adverse events occurred in 14 patients (5.18%). Conclusions: Sitagliptin may have beneficial effects on vascular inflammation and β-cell function in Japanese patients with type 2 diabetes. Pentraxin-3 may be an early predictive marker for detecting the antiatherosclerotic effects of dipeptidyl peptidase-4.

Abstract Type 2 diabetes mellitus (T2DM) is a risk factor for depression. Since brain insulin resistance plays a potential role in depression, the future risk of depression in patients with T2DM may be altered depending on the class of oral hypoglycemic agent (OHA) used for T2DM therapy. The aim of the present study was to determine if specific classes of OHAs are associated with a risk for comorbid depression in T2DM. Japanese adult patients with T2DM (n = 40 214) were divided into a case group (with depression; n = 1979) and control group (without depression; n = 38 235). After adjustment for age [adjusted odds ratio (AOR) for 10 years: 1.03; 95% confidence interval (CI): 0.99‐1.07; P = .1211], sex [AOR for female: 1.39; 95% CI: 1.26‐1.53; P

Introduction: In order to prevent the specific diabetes mellitus related macrovascular and microvascular complications, guidelines by American Diabetes Association recommend a reasonable glycosylated haemoglobin goal for non-pregnant adults to be less than 7% (53 mmol/mol). The common practice recently is to use a sulfonylurea like glimepiride or selective Dipeptidyl Peptidase-4 (DPP-4) inhibitor like vildagliptin as addon therapy to metformin when the latter alone fails to achieve the target level of sugar control. Many randomised clinical trials have demonstrated the comparative efficacy of glimepiride and vildagliptin as add-on therapy to metformin. But their results might not always reflect what actually could be expected in clinical practice. Aim: To compare the efficacy and safety of glimepiride and vildagliptin as add-on therapy to metformin in achieving glycaemic control and also to compare the common adverse effects observed. Materials and Methods: This prospective observational study was conducted among adult type 2 diabetes mellitus patients who did not achieve adequate glycaemic control with metformin monotherapy. Patients were purposively selected in a way so that 30 patients received 2 mg of glimepiride once daily and 30 received 50 mg of vildagliptin twice daily as add-on therapy to metformin 1.5 to 2 gm in single or divided doses. Fasting, post-prandial sugar and glycosylated hemoglobin levels were re-examined after 4 to 6 months. Data were analysed using SPSS version 20.0. Paired and unpaired T-tests were applied to compare the parametric data and z-test was used to compare the difference between two proportions at 5% significance level. Results: In both the groups there was a significant reduction in mean FBS, PPBS levels and HbA1c% from the baseline (p0.05). However, glimepiride plus metformin reduced mean HbA1c% significantly more than vildagliptin plus metformin (p

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease in the United States and worldwide. Proteinuria is a major marker of the severity of injury. Dipeptidyl peptidase-4 inhibitor (DPP-4I) increases incretin-related insulin production and is, therefore, used to treat diabetes. We investigated whether DPP4I could have direct effect on kidney independent of its hypoglycemic activity. We, therefore, tested the effects of DPP4I with or without angiotensin-converting enzyme inhibitor (ACEI) on the progression of diabetic nephropathy and albuminuria in a murine model of DKD. eNOS -/- db/db mice were randomized to the following groups at age 10 weeks and treated until sacrifice: baseline (sacrificed at week 10), untreated control, ACEI, DPP4I, and combination of DPP4I and ACEI (Combo, sacrificed at week 18). Systemic parameters and urine albumin-creatinine ratio were assessed at baseline, weeks 14, and 18. Kidney morphology, glomerular filtration rate (GFR), WT-1, a marker for differentiated podocytes, podoplanin, a marker of foot process integrity, glomerular collagen IV, and alpha-smooth muscle actin were assessed at the end of the study. All mice had hyperglycemia and proteinuria at study entry at week 10. Untreated control mice had increased albuminuria, progression of glomerular injury, and reduced GFR at week 18 compared with baseline. DPP4I alone reduced blood glucose and kidney DPP-4 activity but failed to protect against kidney injury compared with untreated control. ACEI alone and combination groups showed significantly reduced albuminuria and glomerular injury, and maintained GFR and WT-1 + cells. Only the combination group had significantly less glomerular collagen IV deposition and more podoplanin preservation than the untreated control. DPP-4I alone does not decrease the progression of kidney injury in the eNOS -/- db/db mouse model, suggesting that targeting only hyperglycemia is not an optimal treatment strategy for DKD. Combined DPP-4I with ACEI added more benefit to reducing the glomerular matrix., (Copyright © 2023 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)

Aim: Recent studies demonstrate that sodium-glucose cotransporter 2 inhibitors (SGLT2i) and dipeptidyl peptidase-4 inhibitors (DPP4i), two classes of antidiabetic drugs, are cardioprotective. However, the mechanisms of these benefits and their comparative efficacy remain unclear. We aimed to compare the effects of these antidiabetic agents on cardiac function, perfusion, and microvascular density using a swine model of chronic myocardial ischemia., Methods: Chronic myocardial ischemia was induced in Yorkshire swine by ameroid constrictor placement to the left circumflex artery. Two weeks later, pigs were administered vehicle ("CON", 8 pigs), 300 mg SGLT2i canagliflozin, ("CANA", 8 pigs), or 100 mg DPP4i sitagliptin ("SIT", 5 pigs) daily. Five weeks later, pigs were euthanized. Cardiac function, perfusion, collateralization, and protein expression were determined by pressure-volume catheter, microsphere analysis, immunofluorescence, and immunoblotting, respectively., Results: Compared with SIT, CANA was associated with improved stroke volume and cardiac output, with a trend towards reduced left ventricular stiffness. Both CANA and SIT trended towards improved perfusion compared to CON, but there were no differences between the two treatment groups. SIT was associated with improved capillary density with a trend towards improved arteriolar density compared to CANA. Both CANA and SIT were associated with increased expression of vascular endothelial cadherin compared to CON, without differences in treatment groups. SIT pigs had decreased 5' adenosine monophosphate-activated protein kinase activation compared to CON and CANA. There was a trend towards increased endothelial nitric oxide synthase activation in the SIT group compared to CON. There were no differences in activation of extracellular signal-regulated kinase 1/2 across groups., Conclusions: In the setting of chronic myocardial ischemia, canagliflozin is associated with improved cardiac function compared to sitagliptin, with similar effects on perfusion despite differences in microvascular collateralization., Competing Interests: DECLARATIONS Conflicts of interest All authors declared that there are no conflicts of interest.

New drugs were recently developed to treat hyperglycemia in patients with type 2 diabetes mellitus (T2D). However, metformin remains the first-line anti-diabetic agent because of its cost-effectiveness. It has pleiotropic action that produces cardiovascular benefits, and it can be useful in diabetic nephropathy, although metformin-associated lactic acidosis is a hindrance to its use in patients with kidney failure. New anti-diabetic agents, including glucagon-like peptide-1 receptor (GLP-1R) agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose transporter-2 (SGLT-2) inhibitors, also produce cardiovascular or renal benefits in T2D patients. Their glucose-independent beneficial actions can lead to cardiorenal protection via hemodynamic stabilization and inflammatory modulation. Systemic hypertension is relieved by natriuresis and improved vascular dysfunction. Enhanced tubuloglomerular feedback can be restored by SGLT-2 inhibition, reducing glomerular hypertension. Patients with non-diabetic kidney disease might also benefit from those drugs because hypertension, proteinuria, oxidative stress, and inflammation are common factors in the progression of kidney disease, irrespective of the presence of diabetes. In various animal models of non-diabetic kidney disease, metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors were favorable to kidney morphology and function. They strikingly attenuated biomarkers of oxidative stress and inflammatory responses in diseased kidneys. However, whether those animal results translate to patients with non-diabetic kidney disease has yet to be evaluated. Considering the paucity of new agents to treat kidney disease and the minimal adverse effects of metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors, these anti-diabetic agents could be used in patients with non-diabetic kidney disease. This paper provides a rationale for clinical trials that apply metformin, GLP-1R agonists, DPP-4 inhibitors, and SGLT-2 inhibitors to non-diabetic kidney disease.

Background: Evogliptin (EVO) is a potent and selective dipeptidyl peptidase-4 inhibitor (DPP4i) developed for the treatment of type 2 diabetes mellitus (T2DM). DPP4is are known to exhibit a better glucose-lowering effect in Asians compared to other ethnic groups. Once EVO's clinical development program was conducted in Asian patients, this bridging study was designed to validate for the Brazilian population the efficacy and safety of the approved dose regimen (once-daily 5.0 mg). Methods: In this randomized, double-blind, double-dummy, parallel trial, 146 patients with T2DM with inadequate glycemic control on diet and exercise (7.5% ≤ HbA1c ≤ 10.5%) were randomly assigned to a 12-week once-daily treatment with EVO 2.5 mg (N = 35), EVO 5 mg (N = 36), EVO 10 mg (N = 36), or sitagliptin (SITA) 100 mg (N = 39). Absolute changes (Week 12—baseline) in HbA1c, fasting plasma glucose (FPG) and body weight (BW) were obtained. One-sided one sample t test was used to determine if mean HbA1c reduction in each group was < − 0.5% (beneficial metabolic response). An analysis of covariance estimated the change in HbA1c and FPG adjusted by baseline HbA1c, FPG, body mass index (BMI) and study site. Response rates to treatment were also established. No between-group statistical comparisons were planned. Results: HbA1c mean reductions were − 1.26% (90% CI − 1.7%, − 0.8%), − 1.12% (90% CI − 1.4%, − 0.8%), − 1.29% (90% CI − 1.6%, − 1.0%), and − 1.15% (90% CI − 1.5%, − 0.8%) in groups EVO 2.5 mg, EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. FPG levels showed a mean increase of 10.89 mg/dL in group EVO 2.5 mg, with significant mean reductions of − 18.94 mg/dL, − 21.17 mg/dL, and − 39.90 mg/dL in those treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg, respectively. BW showed significant reductions of approximately 1 kg in patients treated with EVO 5 mg, EVO 10 mg, and SITA 100 mg. Mean adjusted reductions of HbA1c and FPG levels confirmed the significant clinical benefit of all study treatments. The clinical benefit of EVO's "target" dose (5 mg) was confirmed. No safety concerns were identified. Conclusions: These results validate for the Brazilian population the approved dose regimen of EVO (once-daily 5 mg). Trial registration ClinicalTrials.gov Identifier: NCT02689362 (first posted on 02/23/2016). [ABSTRACT FROM AUTHOR]

Aims: To characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of the once‐weekly dipeptidyl peptidase‐4 (DPP‐4) inhibitor omarigliptin in healthy subjects and patients with type 2 diabetes mellitus, and use these models to support the dosing recommendation for patient labelling including patients with renal impairment. Methods: PK and PD were assessed from a total of 9827 omarigliptin concentrations collected from 1387 healthy subjects and patients participating in Phase 1, 2 and 3 studies examining single‐ or multiple‐dose weekly administration of omarigliptin at doses ranging from 0.25 to 400 mg. Population PK and PD analyses were performed using nonlinear mixed effect modelling. Results: A semi‐mechanistic 2‐compartment model with linear unbound clearance and concentration‐dependent binding of omarigliptin to the DPP‐4 enzyme in both the central and peripheral compartments adequately described omarigliptin PK. Key covariates on omarigliptin PK included reduced unbound clearance with renal impairment. A direct effect sigmoid maximum inhibitory efficacy model adequately described the relationship between omarigliptin plasma concentrations and DPP‐4 inhibition. These models supported the current Japan label instructions that the approved omarigliptin 25‐mg once‐weekly dose be halved in patients with severe renal impairment and in those with end‐stage renal disease. Also, if patients missed a dose, the next dose of omarigliptin should be taken as soon as remembered up to and including the day before the next scheduled dose. No other clinically important covariates were identified. Conclusion: The models in the present analysis adequately described PK and PD characteristics of omarigliptin and supported the dosing and administration section of the omarigliptin label. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to investigate the metabolic benefits of saxagliptin and its effects on serum bile acids (BAs) in normal weight and overweight/obese drug‐naïve type 2 diabetes (T2D) patients. Methods: In all, 282 drug‐naïve T2D patients (123 normal weight [NW], with body mass index [BMI] between 19.0 and <25.0 kg/m2; 159 overweight/obese [OW/OB], with BMI ≥25.0 kg/m2) were enrolled in the study and treated with saxagliptin 5 mg daily for 24 weeks. Serum BAs were assayed by liquid chromatography with tandem mass spectrometry. Results: At 24 weeks, HbA1c was significantly reduced in both groups, but the HbA1c levels were lower in the OW/OB than NW group. Moreover, significant decreases were seen at 24 weeks in C‐reactive protein (CRP), aspartate aminotransferase, alanine aminotransferase, waist circumference, and systolic blood pressure in the OW/OB group. Interestingly, cholic acid, glycocholic acid, glycochenodeoxycholic acid, glycodeoxycholic acid (GDCA), and glycoursodeoxycholic acid (GUDCA) were increased in both groups after treatment, whereas chenodeoxycholic acid and deoxycholic acid (DCA) were specifically increased in the OW/OB group. Increased DCA and GDCA concentrations were significantly associated with decreased HbA1c or fasting blood glucose and CRP levels, whereas increased GDCA and GUDCA concentrations were associated with decreased waist circumference in the OW/OB group during treatment. In the NW group, increased GUDCA concentrations were significantly associated with a decrease in HbA1c. Conclusions: Type 2 diabetes patients with OW/OB exhibited greater improvement in glycemic control and additional metabolic benefits after saxagliptin treatment. Saxagliptin significantly increased the BA pool, and DCA and GDCA were associated with metabolic improvements in OW/OB T2D patients. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase (DPP)-4 inhibitors, or gliptins, are a class of oral hypoglycemic drugs that have been widely used as a second-line treatment for type 2 diabetes. Gliptins, which were introduced for clinical use a decade ago, have been shown to be beneficial against nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) in animals and humans. Cenicriviroc (CVC), a dual antagonist of C-C chemokine receptor type 2 and 5, is currently under investigation against NASH and fibrosis. It was previously discovered that evogliptin (EVO) reduces hepatic steatosis in diet-induced obese animals but the effectiveness of EVO on NASH remains unexplored. Here, we compared the effectiveness of EVO and CVC against NASH and fibrosis in mice fed a high-fat and high-fructose diet (HFHF). Biochemical and histological analyses showed that mice fed a HFHF for 20 weeks developed severe hepatic steatosis and inflammation with mild fibrosis. Administration of EVO (0.2% wt/wt) for the last 8 weeks of HFHF feeding significantly reduced hepatic triglyceride accumulation, inflammation, and fibrosis as well as restored insulin sensitivity, as evidenced by lowered plasma insulin levels and the improvement in insulin tolerance test curves. Treatment of mice with CVC (0.1% wt/wt) inhibited hepatic inflammation and fibrogenesis with similar efficacy to that of EVO, without affecting hepatic steatosis. CVC treatment also reduced plasma insulin concentrations, despite no improvement in insulin tolerance. In conclusion, EVO administration efficiently ameliorated the development of NASH and fibrosis in HFHF-fed mice, corroborating its therapeutic potential. [ABSTRACT FROM AUTHOR]

Background Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleotropic anti-inflammatory and immune regulatory effects in addition to glucoregulation. We evaluated inflammation and immune markers in suppressed human immunodeficiency virus (HIV) infection during treatment with the DPP-4 inhibitor sitagliptin. Methods Virologically suppressed adults with HIV without diabetes on stable antiretroviral therapy (ART) with ≥100/μL CD4 cells were randomized to 16 weeks of sitagliptin 100 mg/day vs placebo in a multicenter trial. The primary endpoint was the change in plasma soluble CD14 (sCD14) from baseline to week 15–16. Results Ninety participants were randomized, and 42 from each arm were included in per-protocol analyses. Participants were 45% non-Hispanic white, 38% non-Hispanic black, and 15% Hispanic, with a median age of 51 years; 83% were male; and the median CD4 count was 602 cells/μL. At week 15–16, there was no difference in sCD14 change between the 2 arms (P =.69). Relative to placebo, the sitagliptin arm had 47% greater decline in CXCL10 (95% confidence interval, –57% to –35%) at week 15 (P <.001). There were no significant between-arm differences in other soluble biomarkers, total CD4 and CD8 counts, or markers of lymphocyte or monocyte activation. Sitagliptin was well tolerated. Conclusions Sixteen weeks of sitagliptin had no effect on sCD14 levels in virologically suppressed participants with HIV. CXCL10, a chemokine involved in atherogenesis that predicts non-AIDS events during ART, declined markedly with sitagliptin. This suggests that DPP-4 inhibition has the potential to reduce cardiovascular morbidity in treated HIV infection. Clinical Trials Registration NCT01426438. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Exercise for type 2 diabetes patients treated with insulin therapy involves the risk of hypoglycaemia. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors can be effective in combination with exercise because they reduce the incidence of hypoglycaemia. We evaluated the effect of this combination of treatments on hepatic lipid metabolism in diabetic KK/Ta mice.What is the main finding and its importance?The combination of a DPP‐4 inhibitor and exercise, which lowers the risk of hypoglycaemia, is useful for improving insulin resistance by inhibiting excess insulin secretion and decreasing hepatic lipid accumulation, validated by downregulated CD36. The role of exercise training in prevention of diabetes and/or dyslipidaemia has been firmly established. Dipeptidyl peptidase‐4 (DPP‐4) inhibitors improve insulin sensitivity and have attracted attention as therapeutics for hepatic lipid accumulation. The effect of a combination of DPP‐4 inhibitor and exercise training on the prevention and treatment of hepatic lipid accumulation is unclear. Here, we investigated whether alogliptin, a DPP‐4 inhibitor, enhances the preventive effect of exercise‐induced hepatic lipid accumulation in diabetic mice. Balb/c and KK/Ta mice were fed a high‐fat diet. Mice were divided into the following five groups: B, Balb/c mice; K, KK/Ta mice; K‐A, KK/Ta mice with alogliptin (0.01%); K‐Ex, KK/Ta mice with exercise training (3 days week−1, 15–20 m min−1 for 30 min); and K‐Ex+A, KK/Ta mice with alogliptin and exercise training (n = 8 or 9 mice per group). After 8 weeks, glucose, insulin and triglyceride concentrations in the blood and triglyceride levels in the liver were significantly lower in the K‐Ex+A group than in the K group. The liver expression level of PPAR‐γ in the K group was significantly higher than that in the other groups. Additionally, the liver CD36 expression level was significantly lower in the K‐Ex+A and B groups than in the K group. Thus, combined therapy of a DPP‐4 inhibitor with exercise training was effective against high‐fat diet‐induced hepatic lipid accumulation in KK/Ta mice. The results of this study provide useful support for the practice of safe exercise therapy even in diabetic patients who require treatment with a DPP‐4 inhibitor. [ABSTRACT FROM AUTHOR]

Aims/Introduction: The present study investigated the effect of high‐dose metformin or low‐dose metformin/linagliptin combination therapy on glycemic variability (GV) in type 2 diabetes patients with insufficient glycemic control despite low‐dose metformin monotherapy in a cross‐over study using continuous glucose monitoring. Materials and Methods: The present study was carried out with 11 type 2 diabetes outpatients (7% < glycated hemoglobin < 10%) receiving low‐dose metformin monotherapy (500–1,000 mg). All patients were assigned to either metformin 1,500 mg monotherapy (HMET) or combination therapy of low‐dose (750 mg) metformin and linagliptin 5 mg (LMET + dipeptidyl peptidase‐4 [DPP4]). GV was evaluated by continuous glucose monitoring after >4 weeks of the initial treatment and again after cross‐over to the other treatment. GV metrics were compared between the treatments using the Wilcoxon signed‐rank test. Results: Of the continuous glucose monitoring‐derived GV metrics for the HMET versus LMET + DPP4, mean glucose levels, standard deviations and mean amplitude of glucose excursions were not significantly different. Although the pre‐breakfast glucose levels were not significantly different among the treatments (P = 0.248), the 3‐h postprandial glucose area under the curve (>160 mg/dL) after breakfast was significantly larger with HMET versus LMET + DPP4 (9,550 [2,075–11,395] vs 4,065 [1,950–8,895]; P = 0.041). Conclusions: A comparison of GV with HMET versus LMET + DPP4 suggested that LMET + DPP4 might reduce post‐breakfast GV to a greater degree than HMET in type 2 diabetes patients receiving low‐dose metformin monotherapy. [ABSTRACT FROM AUTHOR]

Abstract Objective Perivascular adipose tissue (PVAT) regulates vascular function in a paracrine manner and the vasodilatory effect of PVAT on vessels is completely abolished in obesity. In addition, autophagy is required for maintaining biological function of PVAT and has been shown to be inhibited in obesity. The aim of this study was to explore whether alogliptin improves endothelial function by promoting autophagy in PVAT in obese mice. Methods C57BL/6 mice were maintained on high fat diet with or without alogliptin intervention for 3 months. Vasorelaxation function of thoracic aorta with or without PVAT was determined. Autophagy related protein level of p62 and LC3B, along with phosphorylated mTOR (p-mTOR) were evaluated. In addition, the effects of alogliptin on autophagy were also investigated in cultured adipocytes. Results The presence of PVAT significantly impaired endothelium-dependent vasodilation in obese mice and alogliptin intervention corrected this defect. Autophagy in PVAT was decreased in obese mice and alogliptin intervention activated autophagy. Activating autophagy in PVAT improved endothelium-dependent vasodilation while blocking it in PVAT impaired vasodilation function. Further, addition of glucagon-like peptide-1 (GLP-1) but not alogliptin alone activated autophagy. Moreover, GLP-1 and alogliptin co-treatment did not show additive effect on activating autophagy. Conclusions These results revealed that promoting autophagy in PVAT improved endothelial function in response to alogliptin intervention. Additionally, the beneficial effect of alogliptin intervention on PVAT was GLP-1 dependent. Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

Preclinical data suggested that dipeptidyl peptidase‐4 (DPP‐4) inhibitors may promote metastatic progression of preexisting cancer via nuclear factor erythroid 2‐related factor 2 (NRF2) activation. We aimed to investigate the association between different glucose‐lowering treatments, including DPP‐4 inhibitors and metformin, both with potential NRF2 modulating effects, and new‐onset metastatic cancer among type 2 diabetes patients with comorbid incident cancer. This population‐based cohort study included 223,530 diabetic patients newly diagnosed with primary cancer during 2009–2011 in Korea. The patients were categorized into five study cohorts in accordance with treatment modalities during the follow‐up until the end of 2016: no‐antidiabetic drugs (no‐AD), metformin, DPP‐4 inhibitors, metformin+DPP‐4 inhibitors, and insulin treatment. After propensity score (PS) matching in a 1:1 ratio against the no‐AD group, 18,805 patients in metformin, 1,865 in DPP‐4 inhibitors, 31,074 in metformin+DPP‐4 inhibitors, and 1,895 patients in insulin groups were identified for cohort entry and analyzed against the corresponding number of no‐AD patients in each PS‐matched comparison pair. Metastatic risk was lower with metformin plus or minus DPP‐4 inhibitors (HR 0.84, 95% CI 0.79–0.90 and 0.87, 0.80–0.95, respectively), not significantly associated with DPP‐4 inhibitors (0.99, 0.77–1.29) except after thyroid cancer (3.89, 1.01–9.64), and higher with insulin therapy (1.81, 1.46–2.24) compared to no‐AD use for all cancers combined. In conclusion, DPP‐4 inhibitor therapy was not associated with significant risk of cancer metastasis relative to no‐AD therapy, irrespective of patient age and sex, except after thyroid cancer, while metastatic risk was decreased with metformin treatment among type 2 diabetes patients with preexisting cancer. What's new? Dipeptidyl peptidase‐4 (DPP‐4) inhibitors have been suggested to accelerate metastatic progression of preexisting cancer by upregulating the NRF2‐driven antioxidant response in cancer cells. DPP‐4 inhibitors and other potential NRF2 modulators like metformin are widely used as antidiabetic drugs. However, little is known on how the prognosis of diabetic patients with comorbid cancer differs in terms of metastatic progression across commonly‐used glucose‐lowering therapies. This population‐based clinical study found no significant metastatic risk with DPP‐4 inhibitors after most types of primary cancer compared with no antidiabetic therapy among diabetic cancer patients, except after thyroid cancer, while metastatic risk was decreased with metformin. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Dipeptidyl peptidase‐4 inhibitor has been proven to improve glycemic control and β‐cell function in latent autoimmune diabetes in adults (LADA). The potential immune modulation mechanism is still unknown. Thus, we tested T‐lymphocyte subsets and expression of relevant transcription factors in LADA patients with sitagliptin intervention for up to 1‐year. Materials and Methods: A total of 40 LADA patients were randomly assigned to sitagliptin and/or insulin treatment (SITA group; n = 20) or insulin alone treatment (CONT group; n = 20). Peripheral blood mononuclear cells were isolated at baseline, 6 months and 12 months. The percentage of T‐lymphocyte subsets (T helper 1, T helper 2, T helper 17 and regulatory T cells) tested by flow cytometry, and the messenger ribonucleic acid expression (T box expressed in T cells [T‐BET], GATA binding protein 3 [GATA3], forkhead box protein 3 [FOXP3] and related orphan receptor C [RORC]) tested by real‐time polymerase chain reaction were determined at baseline, 6 months and 12 months. Results: The percentage of regulatory T cells in the SITA group was significantly lower than that of the CONT group at baseline. The percentage of T helper 2 cells was higher than that of the CONT group at 6 months and 12 months. At 12 months, the percentage of T helper 17 cells was lower in the SITA group than that of the CONT group. After a 1‐year visit, the messenger ribonucleic acid expression levels of T‐BET expressed in T cells and RORC in the SITA group were significantly lower than at baseline. Whereas that of RORC in the CONT group were significantly lower than that at baseline. Conclusions: The data confirmed that sitagliptin altered the phenotype of T cells and downregulated the expression of T‐BET and RORC in LADA patients, and ameliorated glycemic control in LADA patients. Th2 was higher and Th17 was lower in SITA group than that in CONT group at 12M. Meanwhile, the mRNA expression levels of both T‐BET and RORC in SITA group were significantly lower than its baseline. We first implicated that sitagliptin, a DPP4 inhibitor, could alter the frequency of CD4+ T cell subsets on both cellular and mRNA level in LADA patients. [ABSTRACT FROM AUTHOR]

Aim: To elucidate the mechanisms involved in the sequential use of SGLT2 and DPP4 inhibitors (SGLT2i and DPP‐4i). Methods: Twenty‐six type‐2 diabetes mellitus patients were recruited into a stepped regimen of 100 mg of canagliflozin daily from day 1, supplemented with 20 mg of teneligliptin daily from day 4. Glucose (Glu), insulin and glucagon were measured at fasting and after ingesting a mixed meal on days 1, 4 and 6. Results: Canagliflozin decreased fasting plasma glucose to an extent inversely proportional to the change in the glucagon‐to‐insulin (G/I) ratio. This correlation at fasting was maintained when adding teneligliptin, while the change in the area under the curve of Glu (GluAUC) correlated closely with that in the G/I ratio at fasting and 60 min with canagliflozin. Moreover, these correlations persisted at 60 and 120 min postprandially, but not at fasting on day 6 when teneligliptin was added. Conclusion: The result suggested that the dominant mechanism responsible for the glucose metabolism reflected in the G/I ratio was attributable to SGLT2i and that its active mechanism persisted, despite adding a DPP‐4i. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase‐4 (DPP‐4) cleaves N‐terminal dipeptides, with Pro, Ala or Ser at the penultimate position, and, in that way, modulates biological activity of certain polypeptides. Due to its ubiquitous distribution, many pathological processes are associated with altered DPP‐4 expression and activity. Besides the regulation of glucose metabolism, DPP‐4 also exhibits many other systemic effects, and the inhibition of its activity might lead to cardiovascular and renal protection. Mechanisms underlying these protective effects of DPP‐4 inhibition are ascribed to elevated bioavailability of its substrates, to impacts on mediators and signaling pathways that ameliorate cardiovascular and renal function through the suppression of oxidative stress, inflammation, fibrosis and apoptosis, improved endothelial function and tissue reparation. Inflammation contributes to and promotes progression of cardiovascular and renal disorders. Herein, we discuss cellular and molecular mechanisms mediating the anti‐inflammatory activity of clinically used DPP‐4 inhibitors in cardiovascular and renal protection. [ABSTRACT FROM AUTHOR]

Context Accurate glucagon level measurements are necessary for investigation of mechanisms for postprandial hyperglycemia in type 2 diabetes. Objective To evaluate the accuracy of postprandial glucagon level measurements using a sandwich ELISA vs a recently established liquid chromatography-high resolution mass spectrometry (LC-HRMS) method in type 2 diabetes mellitus. Design and Participants Twenty patients with type 2 diabetes treated with insulin underwent a meal test before and after administration of the dipeptidyl peptidase-4 inhibitor anagliptin for 4 weeks. Blood samples were taken serially after the meal, and glucagon levels were measured using both ELISA and LC-HRMS. We compared the change from baseline to 4 weeks (Δ 0–4W) using the area under the curve for plasma glucagon during the meal test [area under the curve (AUC)0–3h] measured using ELISA and LC-HRMS. Results ELISA-based glucagon AUC0–3h was higher than LC-HRMS–based AUC0–3h at baseline and 4 weeks. However, differences in Δ 0–4W-AUC0–3h measured using ELISA and LC-HRMS were not statistically significant. Additionally, Δ 0–4W-AUC0–3h measured using ELISA and LC-HRMS were strongly correlated (r = 0.87, P < 0.001). Conclusions Plasma glucagon levels during a meal test in patients with type 2 diabetes measured using ELISA were consistently higher than those measured using LC-HRMS. However, given that the changes in glucagon levels measured using ELISA before and after dipeptidyl peptidase-4 inhibitor therapy were similar to those based on LC-HRMS, this ELISA seems to be useful for evaluating the effect of the drug interventions on postprandial glucagon levels. [ABSTRACT FROM AUTHOR]

Objective: To examine long-term efficacy/safety of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, added to ongoing insulin therapy in Japanese patients with type 2 diabetes.Methods: We conducted a 36-week, open-label extension of ipragliflozin therapy following a 16-week, randomized, placebo-controlled, double-blind period (treatment periods II and I, respectively). Prior to the open-label period, patients taking insulin with/without a dipeptidyl peptidase-4 (DPP-4) inhibitor were randomized to receive placebo or 50 mg once-daily ipragliflozin. Oral antidiabetic drugs other than DPP-4 inhibitors were discontinued 4 weeks before screening. Following treatment period I, all patients received open-label ipragliflozin 50 mg, with the possibility of a dose increase to 100 mg at week 24 if HbA1c was ≥ 7.0% at week 20. Efficacy endpoints were changes in HbA1c, fasting plasma glucose (FPG), self-monitored blood glucose, bodyweight, and metabolic hormones. Drug-related treatment-emergent adverse events (TEAEs) were monitored for safety.Results: Of 175 patients randomized to ipragliflozin, 168 entered treatment period II, 121 (69%) of whom completed this period. The mean ± standard deviation changes in HbA1c, FPG, and bodyweight from baseline (start of treatment period I) to the end of treatment were − 0.83 ± 0.72%, − 31.5 ± 41.2 mg/dL, and − 1.34 ± 1.80 kg, respectively. Between weeks 8 and 32, HbA1c was lower in patients taking a DPP-4 inhibitor than in those without. The most common drug-related TEAE was hypoglycemia; no drug-related TEAEs not already reported for ipragliflozin were observed.Conclusions: Ipragliflozin was well tolerated, effective, and reduced bodyweight over a period of 52 weeks in patients treated with insulin with/without a DPP-4 inhibitor.Clinicaltrials.gov identifier: NCT02175784 [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2D) share common features, including insulin resistance. Brain insulin resistance has been implicated as a key factor in the pathogenesis of AD. Recent studies have demonstrated that anti-diabetic drugs sodium–glucose cotransporter-2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) improve insulin sensitivity and provide neuroprotection. However, the effects of these two inhibitors on the brain metabolism and insulin resistance remain uninvestigated. We developed a T2D–AD mouse model using a high-fat diet (HFD) for 19 weeks along with a single dose of streptozotocin (100 mg/kg, intraperitoneally) at the fourth week of HFD initiation. Subsequently, the animals were treated with SGLT2-i (empagliflozin, 25 mg/kg/day orally [p.o.]) and DPP4-i (sitagliptin, 100 mg/kg/day p.o.) for 7 weeks. Subsequently, behavioral tests were performed, and the expression of insulin signaling, AD-related, and other signaling pathway proteins in the brain were examined. T2D–AD mice not only showed increased blood glucose levels and body weight but also insulin resistance. SGLT2-i and DPP4-i effectively ameliorated insulin sensitivity and reduced body weight in these mice. Furthermore, SGLT2-i and DPP4-i significantly improved hippocampal-dependent learning, memory, and cognitive functions in the T2D–AD mouse model. Interestingly, SGLT2-i and DPP4-i reduced the hyperphosphorylated tau (pTau) levels and amyloid β (Aβ) accumulation and enhanced brain insulin signaling. SGLT2-i reduced pTau accumulation through the angiotensin converting enzyme-2/angiotensin (1−7)/ mitochondrial assembly receptor axis, whereas DPP4-i reduced Aβ accumulation by increasing insulin-degrading enzyme levels. These findings suggest that SGLT2-i and DPP4-i prevent AD-like pathology and cognitive dysfunction in T2D mice potentially through affecting brain insulin signaling via different mechanisms. • SGLT2-i and DPP4-i improve peripheral and brain insulin signaling in T2D-AD mouse model induced with HFD and STZ. • SGLT2-i and DPP4-i reduce AD-related proteins in the brain and improve cognitive functions. • SGLT2-i reduces pTau by activating ACE2/MasR signaling pathway. • DPP4-i decreases Aβ accumulation by increasing IDE. [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used to treat type 2 diabetes (T2D). Lowering blood glucose is expected also to reduce the progression of diabetic nephropathy. We experienced a patient with T2D who achieved good glycemic control with a DPP-4 inhibitor but experienced rapid deterioration of renal function. Therefore, we performed a retrospective study of similar patients treated at our hospital. Out of 56 patients with biopsy-proven diabetic nephropathy who underwent native kidney biopsy at Toranomon Hospital from January 2018 through December 2022, we selected 22 patients who had been receiving DPP-4 inhibitors for at least 9 months at the time of kidney biopsy. Of these patients, we evaluated 16 diagnosed with class IIa diabetic nephropathy according to Tervaert's pathologic classification. The yearly estimated glomerular filtration rate (eGFR) slope in the 16 patients was arranged from the highest to the lowest slope. Ten patients with a large eGFR slope had thrombotic microangiopathy (TMA)-like lesions characterized by glomerular endothelial cell proliferation and GBM duplication on kidney biopsy (group A), whereas the remaining 6 patients did not have TMA-like lesions (group B). Group A had a median (interquartile range [IQR]) eGFR of 18.2 (16.2, 26.2) and a yearly median (IQR) eGFR slope of −11.2 (−17.6, −9.2) mL/min/1.73 m2 after of DPP-4 administration, whereas group B had a median (IQR) eGFR of 31.5 (21.9, 34.8) mL/min/1.73 m2 and a yearly median (IQR) eGFR slope of −1.6 (−3.1, −0.3). Renal function declined significantly more rapidly in group A than in group B, and proteinuria was higher in group A than in group B (median [IQR], 3.4 [2.6, 4.4] g/day vs 0.8 [0.4, 1.3] g/day, respectively). Five patients in group A progressed to dialysis during follow-up, but none of the patients in group B did. Median (IQR) hemoglobin A1c was 6.2 % (6.0 %, 6.6 %) in group A and 5.8 % (5.7 %, 6.6 %) in group B. DPP-4 inhibitors promote vascular endothelial regeneration, but when this effect occurs in the glomerulus, glomerular endothelial cell proliferation leads to TMA-like lesions, which may cause an increase in proteinuria and rapid decline in renal function. • Dipeptidase-4 inhibitors lead to TMA-like lesions, which may cause an increase in rapid decline in renal function. [ABSTRACT FROM AUTHOR]

Abstract Objectives To evaluate the efficacy and predictive factors of Dipeptidyl peptidase-4 (DPP-4) inhibitors in type 2 diabetes mellitus (T2DM) patients who were not well controlled with other oral antidiabetic drugs or insulin in real clinical practice. Methods From December 2012 to January 2014, retrospective longitudinal observation study was conducted for patients with T2DM who were not reached a glycemic target (glycated hemoglobin [HbA1c] > 6.5%) with other oral antidiabetic drugs or insulins. Type 1 diabetes or other types of diabetes were excluded. Responders were eligible with decreased HbA1c from baseline for more than 5% during follow up period. Results Of total 135 T2DM patients having an average 9.0 months follow-up period, 84 (62.2%) of patients were responder to DPP-4 inhibitors. After concomitant treatment with DPP-4 inhibitors, patients had a mean decrease in HbA1c of 0.69 ± 1.3%, fasting plasma glucose of 13 ± 52 ㎎/㎗, and postprandial plasma glucose of 29 ± 85 ㎎/㎗ from baseline (all P< 0.05). Independent predictive factor for an improvement of glycemic control with DPP-4 inhibitors was higher baseline HbA1c (odds ratio 2.07 with 95% confidence interval 1.15–3.72) compared with non-responders. Conclusions A clinical meaningful improvement in glycemic control was seen when DPP-4 inhibitors were added to other anti-diabetic medications in patients with T2DM regardless of age, duration of T2DM, type of combination treatment regimen. Patients who had higher HbA1c were more easily respond to DPP-4 inhibitors treatment in short-term follow-up period.

Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure.

Type 2 diabetes mellitus (T2DM) is a multifactorial disease with a complex and progressive pathogenesis. The two primary mechanisms of T2DM pathogenesis are pancreatic β-cell dysfunction and insulin resistance. Pancreatic β-cell dysfunction is recognized to be a prerequisite for the development of T2DM. Therapeutic modalities that improve β-cell function are considered critical to T2DM management; however, blood glucose control remains a challenge for many patients due to suboptimal treatment efficacy and the progressive nature of T2DM. Incretin-based therapies are now the most frequently prescribed antidiabetic drugs in Korea. Incretin-based therapies are a favorable class of drugs due to their ability to reduce blood glucose by targeting the incretin hormone system and, most notably, their potential to improve pancreatic β-cell function. This review outlines the current understanding of the incretin hormone system in T2DM and summarizes recent updates on the effect of incretin-based therapies on β-cell function and β-cell mass in animals and humans.

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

Background: Sitagliptin, a dipeptidyl peptidase-4 inhibitor possibly affects bone turnover. We conducted this cohort study to determine whether sitagliptin is associated with an increased risk of fracture.Methods: The sitagliptin cohort included 1,578 patients aged 20 years and above. The nonsitagliptin cohort comprised propensity-score matched patients at a ratio of 1:1. The primary outcome was the incidence of fractures, which was evaluated using Kaplan–Meier survival analysis and proportional hazards modeling.Results: The mean age of patients in the sitagliptin and nonsitagliptin cohorts was 63.1 and 63.3 years, respectively. The incidence of fractures in the sitagliptin cohort was 46 per 1,000 person-years and that in the nonsitagliptin cohort was 40.8 per 1,000 person-years. Compared with patients in the nonsitagliptin cohort, those in the sitagliptin cohort who received sitagliptin for ≥250 days had a higher risk of fracture (aHR = 1.32, 95% CI = 1.06–1.64).Conclusion: Using sitaglipin ≥250 days was associated with an increased risk of fracture.

Context and Objectives: The number of people with diabetes is increasing exponentially in India. Owing to a unique "Asian Indian Phenotype," Indians develop diabetes a decade earlier and have an earlier onset of complications than Western populations. Therefore, it is essential to evaluate more effective treatment strategies at an earlier stage of disease progression, such as initial combination therapy, in Indian patients. In this study, we evaluated the efficacy and safety of initial combination therapy with linagliptin plus metformin in comparison to linagliptin or metformin monotherapy in Indian patients with type 2 diabetes mellitus. Methods: This is a subgroup analysis of Indian patients who participated in a Phase III, 24-week, double-blind, placebo-controlled, trial. Overall, 249 Indian patients were randomized to one of six treatment arms (Two free combination therapy arms: Linagliptin 2.5 mg twice daily [bid] + either low [500 mg, n = 36] or high [1000 mg, n = 44] dose metformin bid and four monotherapy arms: Linagliptin 5 mg once daily [qd, n = 40], metformin 500 mg [n = 49] or 1000 mg bid [n = 45], or placebo [n = 23]). Results: The placebo-corrected mean change in glycated hemoglobin from baseline (8.9%) to week 24 was −1.83% for linagliptin + metformin 1000 mg bid; −1.46% for linagliptin + metformin 500 mg bid; −1.30% for metformin 1000 mg bid; −1.00% for metformin 500 mg bid; and −0.77% for linagliptin 5 mg qd. None of the patients in the combination therapy arms had hypoglycemia, whereas there was one event in the metformin 1000 mg bid arm. Rates of adverse event were similar across various treatments. Conclusions: In this subgroup analysis of Indian patients, initial combination therapy with linagliptin + metformin was more efficacious in improving glycemic control than the monotherapy arms, with a comparable tolerability profile. The results were comparable to the overall population.

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.

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 A 1c 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 A 1c 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 A 1c ., (© 2023. The Author(s).)

Aim: This trial was designed to assess the efficacy and safety of cetagliptin added to metformin in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy., Methods: In total, 446 patients with type 2 diabetes on metformin monotherapy were randomized to receive the addition of once-daily cetagliptin 100 mg, cetagliptin 50 mg and placebo in a 2:2:1 ratio for 24-week double-blind treatment. At week 24, patients initially randomized to cetagliptin 50 mg and placebo were switched to cetagliptin 100 mg for 28 weeks open-label treatment. The primary endpoint was the change in haemoglobin A1c (HbA1c) from baseline, and the efficacy analyses were based on an all-patients-treated population using an analysis of co-variance., Results: After 24 weeks, both add-on therapies led to greater glycaemic control. Reductions in HbA1c from baseline were -1.17 ± 0.794%, -1.23 ± 0.896% in cetagliptin 100 mg and 50 mg plus metformin group, respectively. No difference was observed between the cetagliptin 100 mg and 50 mg plus metformin group. Patients with higher baseline HbA1c levels (≥8.5%) experienced greater reductions in HbA1c. A significantly greater proportion of patients achieved an HbA1c <7.0% with cetagliptin 100 mg (49.4%) and cetagliptin 50 mg (51.1%) plus metformin than metformin monotherapy (14.4%). Both combination therapies also improved the homeostasis model assessment β-function index and decreased systolic blood pressure. There was no increased risk of adverse effects with combination therapy, and both combination therapies were generally well tolerated., Conclusions: The addition of cetagliptin once daily to metformin was more efficacious and well tolerated than metformin monotherapy in Chinese patients with type 2 diabetes who had inadequate glycaemic control with metformin monotherapy., (© 2023 John Wiley & Sons Ltd.)

Aim: To assess the efficacy and safety of the dipeptidyl peptidase-4 inhibitor, cetagliptin, as monotherapy in Chinese patients with type 2 diabetes (T2D) and inadequate glycaemic control., Materials and Methods: In total, 504 eligible patients with T2D were enrolled and randomized to cetagliptin 50 mg once daily, cetagliptin 100 mg once daily or placebo at a ratio of 2:2:1 for 24 weeks of double-blind treatment, then all patients received cetagliptin 100 mg once daily for 28 weeks of open-label treatment. The primary efficacy endpoint was the change in HbA1c level from baseline at week 24., Results: After 24 weeks, HbA1c from baseline was significantly reduced with cetagliptin 50 mg (-1.08%) and cetagliptin 100 mg (-1.07%) compared with placebo (-0.35%). The placebo-subtracted HbA1c reduction was -0.72% with cetagliptin 50 mg and 100 mg. Patients with a baseline HbA1c of 8.5% or higher had a greater HbA1c reduction with cetagliptin than those patients with a baseline HbA1c of less than 8.5%. Both doses studied led to a significantly higher proportion of patients (42.3% with 100 mg and 45.0% with 50 mg) achieving an HbA1c of less than 7.0% compared with placebo (12.9%). Cetagliptin also significantly lowered fasting plasma glucose and 2-hour postmeal plasma glucose relative to placebo. The incidence of adverse experiences was similar between cetagliptin and placebo. No drug-related hypoglycaemia was reported., Conclusions: Cetagliptin monotherapy was effective and well tolerated in Chinese patients with T2D who had inadequate glycaemic control on exercise and diet., (© 2023 John Wiley & Sons Ltd.)

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., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Aim: To evaluate the effect of four different drug classes on soluble urokinase plasminogen activator receptor (suPAR), a biomarker active in multiple inflammatory processes and a risk factor for complications, in people with type 1 and type 2 diabetes., Methods: We conducted post hoc analyses of a randomized, open-label, crossover trial including 26 adults with type 1 and 40 with type 2 diabetes with urinary albumin-creatinine ratio ≥30 and ≤500 mg/g assigned to 4-week treatments with telmisartan 80 mg, empagliflozin 10 mg, linagliptin 5 mg and baricitinib 2 mg, separated by 4-week washouts. Plasma suPAR was measured before and after each treatment. SuPAR change after each treatment was calculated and, for each individual, the best suPAR-reducing drug was identified. Subsequently, the effect of the best individual drug was compared against the mean of the other three drugs. Repeated-measures linear mixed-effects models were employed., Results: The baseline median (interquartile range) plasma suPAR was 3.5 (2.9, 4.3) ng/mL. No overall effect on suPAR levels was observed for any one drug. The individual best-performing drug varied, with baricitinib being selected for 20 participants (30%), followed by empagliflozin for 19 (29%), linagliptin for 16 (24%) and telmisartan for 11 (17%). The individual best-performing drug reduced suPAR by 13.3% (95% confidence interval [CI] 3.7, 22.8; P = 0.007). The difference in suPAR response between the individual best-performing drug and the other three was -19.7% (95% CI -23.1, -16.3; P < 0.001)., Conclusions: We demonstrated no overall effect of 4-week treatment with telmisartan, empagliflozin, linagliptin or baricitinib on suPAR. However, individualization of treatment might significantly reduce suPAR levels., (© 2023 John Wiley & Sons Ltd.)