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Aims: The aim of this study was to investigate the putative link between dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use and the risk of fracture in patients with type 2 diabetes. Methods: This propensity‐score‐matched population‐based cohort study was performed between 2009 and 2013 on patients with type 2 diabetes who were stable metformin users. A total of 3996 patients with type 2 diabetes used DPP‐4i as a second‐line antidiabetic drug. The same number of matched non‐DPP‐4i users were followed up until fracture occurrence, health insurance policy termination, or the end of 2013. The incidence rates of overall and cause‐specific fractures were estimated based on the Poisson assumption. A multiple Cox proportional hazard model was used to estimate the covariate‐adjusted hazard ratio (HR) and 95% confidence interval (CI) to determine the association between DPP‐4i use and overall and cause‐specific fractures stratified by age and sex. Results: Over a maximum follow‐up period of 5 years, 340 DPP‐4i users and 419 non‐DPP‐4i users were newly diagnosed with fractures, yielding incidence rates of 28.03 and 32.04 per 1000 people per year, respectively. The Cox proportional hazard model revealed that DPP‐4i use significantly reduced the risk of all‐cause fractures and upper extremity fractures, with adjusted HRs of 0.86 (95% CI: 0.74–0.99) and 0.75 (95% CI: 0.59–0.95), respectively. The aforementioned associations of DDP‐4i use with fracture were sustained across sex and age stratifications. Conclusions: The results of this study supported the premise that DPP‐4i usage is associated with a reduced risk of all‐cause fractures and upper extremity fractures in patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effects of blood glucose control with antihyperglycaemic agents with minimal hypoglycaemia risk on cardiovascular outcomes in patients with type 2 diabetes (T2D). Materials and methods: Randomized controlled trials (RCTs) comparing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk were comprehensively researched in MEDLINE, Embase and the Cochrane Library up to January 27, 2018. Mixed‐effects meta‐regression analysis was conducted to explore the relationship between haemoglobin A1c (HbA1c) reduction and the risk of major adverse cardiovascular events (MACE), myocardial infarction, stroke, cardiovascular death, all‐cause death, and hospitalization for heart failure. Results: Ten RCTs comprising 92 400 participants with T2D were included and provided information on 9773 MACE during a median follow‐up of 2.6 years. The mean HbA1c concentration was 0.42% lower (range, 0.27%‐0.86%) for participants given antihyperglycaemic agents than those given placebo. The meta‐regression analysis demonstrated that HbA1c reduction was significantly associated with a decreased risk of MACE (β value, −0.39 to −0.55; P < 0.02) even after adjusting for possible confounding factors including age, sex, baseline HbA1c, duration of follow‐up, difference in achieved systolic blood pressure, difference in achieved body weight, and risk difference in hypoglycaemia. Lowering HbA1c by 1% conferred a significant risk reduction of 30% (95% confidence interval, 17%‐40%) for MACE. By contrast, the meta‐regression analysis for trials using conventional agents failed to demonstrate a significant relationship between achieved HbA1c difference and MACE risk (P > 0.74). Conclusions: Compared with placebo, newer T2D agents with less hypoglycaemic hazard significantly reduced the risk of MACE. The MACE reduction appears to be associated with HbA1c reduction in a linear relationship. [ABSTRACT FROM AUTHOR]

Aims: TECOS, a cardiovascular safety trial ( ClinicalTrials.gov identifier: NCT00790205) involving 14 671 patients with type 2 diabetes and cardiovascular disease, demonstrated that sitagliptin was non‐inferior to placebo for the primary composite cardiovascular outcome when added to best usual care. This study tested hypotheses that medical resource use and costs differed between these 2 treatment strategies. Materials and methods: Information concerning medical resource use was collected on case report forms throughout the trial and was valued using US costs for: Medicare payments for hospitalizations, medical procedures and outpatient visits, and wholesale acquisition costs (WAC) for diabetes‐related medications. Hierarchical generalized linear models were used to compare resource use and US costs, accounting for variable intercountry practice patterns. Sensitivity analyses included resource valuation using English costs for a UK perspective. Results: There were no significant differences in hospitalizations, inpatient days, medical procedures, or outpatient visits during follow‐up (mean and median 3.0 years in both groups). Hospitalization rates appeared to diverge after 2 years, with lower rates among sitagliptin‐treated vs placebo patients after 2.5 years (relative rate, 0.90 [95% CI, 0.83‐0.97]; P = .01). Mean medical costs, exclusive of study medication, were 11 937 USD in the sitagliptin arm and 12 409 USD in the placebo arm (P = .06). Mean sitagliptin costs based on undiscounted WAC were 9978 USD per patient. Differential UK total costs including study drug costs were smaller (911 GBP), primarily because of lower mean costs for sitagliptin (1072 GBP). Conclusions: Lower hospitalization rates across time with sitagliptin slightly offset sitagliptin treatment costs over 3 years in type 2 diabetes patients at high risk for cardiovascular events. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: To evaluate the efficacy and safety of combining insulin therapy with dipeptidyl peptidase‐4 (DPP‐4) inhibitors compared with combining insulin therapy with a placebo or other antihyperglycemic agents. Materials and Methods: A literature search was carried out via electronic databases. The inclusion criteria were randomized controlled trials comparing the addition of DPP‐4 inhibitors to insulin with the addition of a placebo or other active hypoglycemic agents to insulin therapy, study duration of no less than 12 weeks carried out in type 2 diabetes patients and the availability of outcome data to evaluate a change in the glycated hemoglobin. Results: The glycated hemoglobin‐lowering efficacy was significantly greater with DPP‐4 inhibitor/insulin (DPP‐4i/INS) than with placebo/insulin (weighted mean difference −0.53%, 95% confidence interval −0.63, −0.43, P < 0.01). The postprandial plasma glucose‐lowering efficacies was also significantly greater with DPP‐4i/INS than with placebo/insulin (weighted mean difference −1.65 mmol/L, 95% CI: −2.34, −0.96, P < 0.05). The risk of hypoglycemia or severe hypoglycemia was similar for DPP4i/INS and placebo/insulin treatments. There was no significant difference in the glycemia‐lowering efficacy between DPP‐4i/INS and alpha‐glucosidase inhibitors/insulin, thiazolidinedione/insulin and glucagon‐like peptide‐1 receptor agonist/insulin. Sodium–glucose cotransporter 2 inhibitor/insulin treatment achieved better placebo‐corrected efficacy in lowering postprandial plasma glucose, with less weight gain and no higher risk of hypoglycemia. Conclusions: Treatment with DPP‐4 inhibitors combined with insulin improved glycemic control without an increased risk of hypoglycemia or weight gain compared with insulin treatment alone. [ABSTRACT FROM AUTHOR]

Abstract: Aims/Introduction: The combination of dipeptidyl peptidase‐4 (DPP4) inhibitors and α‐glucosidase inhibitors (AGIs) might provide an additive or synergistic glucose‐lowering effect, as they have a complementary mode of action. In the present study, we examined the efficacy and safety of the addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI. Materials and Methods: We carried out an electronic search of MEDLINE, EMBASE, the Cochrane Library and Clinicaltrials.gov through October 2016. Randomized controlled trials written in English that compared DPP4 inhibitors plus AGI (DPP4i/AGI) and placebo plus AGI (PCB/AGI) in patients with type 2 diabetes were selected. Data on the study characteristics, efficacy and safety outcomes were extracted, and the risk of potential biases was assessed. The efficacy and safety of DPP4i/AGI and PCB/AGI were compared. Results: Of 756 potentially relevant published articles and 40 registered trials, five studies including 845 patients randomized to DPP4i/AGI and 832 patients randomized to PCB/AGI were included for meta‐analysis. Compared with PCB/AGI, DPP4i/AGI showed a greater reduction in glycated hemoglobin (weighted mean difference −1.2%, 95% confidence interval −1.6 to −0.8), fasting plasma glucose and 2‐h postprandial plasma glucose levels, with no increase in bodyweight. The risks of hypoglycemia and gastrointestinal adverse events were similar between DPP4i/AGI and PCB/AGI. Conclusions: The addition of a DPP4 inhibitor to patients with type 2 diabetes inadequately controlled with an AGI achieved better glycemic control without further increasing the risk of weight gain and hypoglycemia. [ABSTRACT FROM AUTHOR]

Introduction: Two 52-week Phase III studies evaluated the efficacy and safety of once-daily combinations of empagliflozin/linagliptin as monotherapy or add-on to metformin in patients with type 2 diabetes (T2DM). The aim of this analysis was to further assess the safety and tolerability of empagliflozin/linagliptin compared with their individual components in patients with T2DM, using pooled data from these trials.Methods: A total of 1363 patients were treated with empagliflozin 25 mg/linagliptin 5 mg (n = 273), empagliflozin 10 mg/linagliptin 5 mg (n = 272), empagliflozin 25 mg (n = 276), empagliflozin 10 mg (n = 275), or linagliptin 5 mg (n = 267). Adverse events (AEs) were assessed descriptively in patients who took ≥ 1 dose of study drug.Results: Total exposure was 251, 255, 256, 249, and 243 patient-years in the empagliflozin 25 mg/linagliptin 5 mg, empagliflozin 10 mg/linagliptin 5 mg, empagliflozin 25 mg, empagliflozin 10 mg, and linagliptin 5 mg groups, respectively. The proportion of patients with ≥ 1 AE was similar across groups (70.4-74.9%). The percentage of patients with confirmed hypoglycemic AEs (plasma glucose ≤ 70 mg/dL and/or requiring assistance) was low in all groups (1.1-2.2%); none required assistance. Events consistent with urinary tract infection were reported in similar percentages of patients in all groups (11.4-13.8%), and in a greater proportion of female than male patients. Events consistent with genital infection were reported in higher percentages of patients on empagliflozin/linagliptin or empagliflozin (4.0-6.5%) than linagliptin 5 mg (2.6%), and in a greater proportion of females than males. The risks of hypersensitivity reactions and events consistent with volume depletion were low across treatment groups.Conclusion: Empagliflozin/linagliptin as monotherapy or add-on to metformin for 52 weeks was well tolerated in patients with T2DM, with safety profiles similar to individual components, including a low risk of hypoglycemia.Funding: The Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.Trial Registration: ClinicalTrials.gov identifiers, NCT01422876 & NCT01422876. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a prevalent but underestimated complication of diabetes, which can cause spatial memory and learning deficits. In the present study, a streptozotocin- induced type 2 diabetic rat model was employed to investigate the effects of vildagliptin, a new oral hypoglycemic agent that acts by inhibiting dipeptidyl peptidase-4, on diabetes-associated cognitive impairments, as well as the molecular mechanisms involved. The present findings demonstrated that vildagliptin treatment prevented memory impairment and decreased the apoptosis of hippocampal neurons. It also attenuated the abnormal expression of caspase-3, B cell lymphoma-2 (Bcl-2) and Bcl-2 associated X protein in the diabetic model. Vildagliptin treatment also reversed diabetes-induced decreases in phosphorylated (p)-protein kinase B (Akt) and p-glycogen synthase kinase 3β (GSK3β), brain-derived neurotrophic factor and nerve growth factor expression levels. The results indicated that the administration of vildagliptin exerts a protective effect against cognitive deficits by decreasing the expression of apoptosis-related proteins in the hippocampus and that this protective effect was mediated via the Akt/GSK3β signaling pathway. [ABSTRACT FROM AUTHOR]

Introduction: The Japanese guidelines for type 2 diabetes mellitus (T2DM) emphasize individualization of treatment based on patient need and encourage physicians to select an appropriate oral antidiabetes drug (OAD). However, limited evidence is available on the factors influencing the selection by physicians (diabetes specialists and nonspecialists) of the first-line OAD to treat drug-naive patients with T2DM. A survey was designed to explore the treatment factors and patient characteristics that influence physicians when they choose an initial OAD to prescribe to a drug-naive patient with T2DM in a real-world setting in Japan.Methods: The 25-min web-based online survey consisted of simple and focused multiple-choice questions, and was circulated to physicians across eight selected regions in Japan. The primary endpoints were the proportions of physicians who considered particular treatment factors and patient characteristics when selecting the appropriate treatment for drug-naive T2DM patients.Results: A total of 491 physicians participated in the survey. Dipeptidyl peptidase-4 inhibitors (DPP-4is) were the most-preferred first-line OADs, followed by metformin, of both specialists (69% vs. 60%) and nonspecialists (73% vs. 47%). The most influential factors when a DPP-4i was selected were found to be glycated hemoglobin (HbA1c), postprandial glucose (PPG)-lowering effect, and a low risk of hypoglycemia, which were considered by > 80% of physicians, whereas the key factors when metformin was selected were improvement in insulin resistance, low cost, low risk of hypoglycemia, and PPG- and HbA1c-lowering effects, which were considered by > 85% of physicians. Regression analysis revealed that the dominant reason for choosing DPP-4is over metformin was their ease of use in patients with renal impairment, whereas the dominant reasons for choosing metformin over DPP-4is were improvement in insulin resistance and low cost. The key patient characteristics driving the choice of DPP-4is or metformin as the first-line OAD by physicians were similar to those that influenced the treatment intensification decision (DPP-4is: PPG and renal function; metformin: age, BMI, insulin resistance, and renal function).Conclusion: In Japan, DPP-4is are the preferred first-line OADs, followed by metformin. The key treatment factors and patient characteristics considered when selecting DPP-4is or metformin are similar for both specialists and nonspecialists. These results may prompt further discussion of the differences in T2DM treatment between Japan and other counties.Funding: Novartis. [ABSTRACT FROM AUTHOR]

Introduction: Teneligliptin is a novel oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM). Safety and efficacy of teneligliptin have been demonstrated in clinical studies; however, data supporting its use in patients with moderate or severe renal impairment are limited. This interim analysis of a post-marketing surveillance of teneligliptin, exploRing the long-term efficacy and safety included cardiovascUlar events in patients with type 2 diaBetes treated bY teneligliptin in the real-world (RUBY), aims to verify the long-term safety and efficacy of teneligliptin in Japanese patients with T2DM and impaired renal function.Methods: For this analysis, we used the data from case report forms of the RUBY surveillance between May 2013 and June 2017. The patients were classified into G1-G5 stages of chronic kidney disease according to estimated glomerular filtration rate (eGFR) at initiation of teneligliptin treatment. Safety and efficacy were evaluated in these subgroups. Patients on dialysis were also assessed. Safety was assessed from adverse drug reactions (ADRs). Glycemic control was evaluated up to 2 years after teneligliptin initiation.Results: A total of 11,677 patients were enrolled in the surveillance and 11,425 patient case-report forms were collected for the interim analysis. The incidence of ADRs in each subgroup was 2.98-6.98% of patients, with no differences in the ADR profile (including hypoglycemia and renal function ADRs) between subgroups. At 1 and 2 years after starting teneligliptin, the least-squares mean change in HbA1c adjusted to the baseline was − 0.68 to − 0.85% and − 0.71 to − 0.85% across the eGFR groups, respectively. Treatment with teneligliptin in patients on dialysis reduced or tended to reduce glycated albumin levels [− 2.29%, (p < 0.001) after 1 year; − 1.64%, (p = 0.064) after 2 years].Conclusions: During long-term treatment, teneligliptin was generally well tolerated in patients with any stage of renal impairment from normal to end-stage renal disease, including those on dialysis, and improved glycemic control.Trial Registration Number: Japic CTI-153047.Funding: Mitsubishi Tanabe Pharma Corporation and Daiichi Sankyo Co, Ltd. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Dipeptidyl peptidase- 4 (DPP-4) inhibitors are a new class of oral antidiabetic agents for type 2 diabetes mellitus (T2DM) patients. However, the effects and safety of DPP-4 inhibitors in T2DM patients with renal impairment (RI) remain controversial. Therefore, we conducted this meta-analysis to assess the efficacy and safety of DPP-4 inhibitors in T2DM patients with moderate to severe RI. MATERIALS AND METHODS: The PubMed, Embase, and Web of Science database were searched for published randomized controlled trials (RCTs), which compared DPP-4 inhibitors with placebo or a control regimen. A fixed-model effect or random-effect model was used to assess the effects of DPP-4 inhibitors on T2DM patients with RI. Subgroup analysis or meta-regression analysis were performed to explore the potential sources of heterogeneity among the included studies. RESULTS: 13 RCTs with a total of 2,940 patients were included in this meta-analysis. Compared with other treatments, DPP-4 inhibitors were associated with a greater change in HbA1c level (weight mean difference (WMD)=-0.50, 95%CI: -0.61, -0.39; p<0.001), and a higher response rate of patients achieving the HbA1c goal of <7% (risk ratio (RR)=1.38, 95%CI: 1.12, 1.70; p=0.002). Subgroup analysis suggested that the reduced HbA1c was observed in all types of DPP-4 inhibitors, and in patients with moderate or severe RI, but not in those with end-stage renal disease. DPP-4 inhibitors did not significantly lower the FPG level (WMD=-0.36, 95%CI: -0.92, 0.20; p=0.204), and this was seen in all types of DPP-4 inhibitors except gemigliptin, which showed a significant reduction in FPG level. The prevalence of adverse events (RR=0.98, 95%CI: 0.94, 1.02; p=0.256) in the two groups was not significantly different, and DPP-4 inhibitors did not induce a higher rate of hypoglycemia (RR=1.31, 95%CI: 0.97, 1.77; p=0.075). CONCLUSIONS: DPP-4 inhibitors significantly lowered HbA1c levels in T2DM patients with moderate to severe RI. And the treatment of DPP-4 inhibitors did not increase the risk of hypoglycemia and adverse events. Considering the potential limitations in this meta-analysis, more large-scale, well-conducted RCTs are needed to identify our findings. [ABSTRACT FROM AUTHOR]

Background: Case reports have suggested an association between dipeptidyl peptidase-4 inhibitors (DPP4is) and development of bullous pemphigoid (BP).Objective: To evaluate the association between DPP4i treatment and development of BP.Methods: We conducted a retrospective 1:2 case-control study, comparing case patients with diabetes and BP with age- and sex-matched control patients with diabetes issued from Swiss (Bern) and French (Marseille) dermatologic departments from January 1, 2014, to July 31, 2016.Results: We collected 61 case patients with diabetes and BP and 122 controls. DPP4is were associated with an increased risk for development of BP (adjusted odds ratio, 2.64; 95% confidence interval, 1.19-5.85; P = .02), with vildagliptin showing the highest adjusted odds ratio (3.57 [95% confidence interval, 1.07-11.84; P = .04]). Stratified analysis showed a stronger association in males and patients age 80 years or older. DPP4i withdrawal and the initiation of first-line treatments led to clinical remission in 95% of cases.Limitations: This was a retrospective study in tertiary referral hospitals. We focused the analysis on DPP4i intake, without analyzing the potential isolated effect of metformin.Conclusions: DPP4is, especially vildagliptin, are associated with an increased risk for development of BP. Their use needs to be carefully evaluated, particularly in high-risk patients, such as males and those age 80 years or older. [ABSTRACT FROM AUTHOR]

Introduction: Healthy eating is a critical aspect of the prevention and management of type 2 diabetes (T2DM). Disrupted eating patterns can result in poor glucose control and increase the likelihood of diabetic complications. Teneligliptin inhibits dipeptidyl peptidase-4 activity for 24 h and suppresses postprandial hyperglycemia after all three daily meals. This interim analysis of data from the large-scale post-marketing surveillance of teneligliptin (RUBY) in Japan examined eating patterns and their relationship with metabolic parameters and diabetic complications. We also examined whether eating patterns affected safety and efficacy of teneligliptin.Methods: We analyzed baseline data from survey forms collected in RUBY between May 2013 and June 2017, including patient characteristics, metabolic parameters, and eating patterns (eating three meals per day or not; timing of evening meal) before teneligliptin treatment was initiated. Safety and efficacy of 12 months' teneligliptin (20-40 mg/day) treatment was assessed.Results: Data from 10,532 patients were available for analysis. Most patients who did not eat three meals per day (n  =757) or who ate their evening meal after 10 PM (n  =206) were 64 years old or younger. At baseline, glycated hemoglobin (HbA1c), fasting blood glucose, triglycerides, total and low-density lipoprotein cholesterol, body mass index, alanine aminotransferase, and aspartate aminotransferase levels were higher in those patients who did not eat three meals per day (p < 0.05) or who ate their evening meal late (p < 0.05). Diabetic complications were more common in patients who did not eat three meals per day. Treatment with teneligliptin reduced HbA1c over 6 or 12 months across all eating patterns, with a low incidence of adverse drug reactions.Conclusions: Eating patterns may be associated with altered metabolic parameters and diabetic complications among Japanese patients with T2DM. Teneligliptin may be well tolerated and improve hyperglycemia in patients with T2DM irrespective of eating patterns.Funding: Mitsubishi Tanabe Pharma Corporation and Daiichi Sankyo Co. Ltd.Trial Registration Number: Japic CTI-153047. [ABSTRACT FROM AUTHOR]

Introduction: We aimed to evaluate the effectiveness and safety of canagliflozin as compared to sitagliptin in a real-world setting among multiethnic patients with Type 2 diabetes mellitus (T2DM) in Singapore.Methods: This was a new-user, active-comparator, single-centre retrospective cohort study. Patients aged 18-69 years with T2DM and estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 were eligible for inclusion if they were initiated and maintained on a steady daily dose of canagliflozin 300 mg or sitagliptin 100 mg between 1 May and 31 December 2014, and followed up for 24 weeks.Results: In total, 57 patients (canagliflozin 300 mg, n = 22; sitagliptin 100 mg, n = 35) were included. The baseline patient characteristics in the two groups were similar, with overall mean glycated haemoglobin (HbA1c) of 9.4% ± 1.4%. The use of canagliflozin 300 mg was associated with greater reductions in HbA1c (least squares [LS] mean change -1.6% vs. -0.4%; p < 0.001), body weight (LS mean change -3.0 kg vs. 0.2 kg; p < 0.001) and systolic blood pressure (LS mean change: -9.7 mmHg vs. 0.4 mmHg; p < 0.001), as compared with sitagliptin 100 mg. About half of the patients on canagliflozin 300 mg reported mild osmotic diuresis-related side effects that did not lead to drug discontinuation.Conclusion: Our findings suggest that canagliflozin was more effective than sitagliptin in reducing HbA1c, body weight and systolic blood pressure in patients with T2DM, although its use was associated with an increased incidence of mild osmotic diuresis-related side effects. [ABSTRACT FROM AUTHOR]

Abstract: Bullous pemphigoid (BP) is an acquired autoimmune blistering disease in which autoantibodies against epitopes in the basement membrane zone of the skin such as BP180 or BP230 are produced. Dipeptidyl peptidase (DPP)‐4 inhibitors have become commonly used to treat diabetes. As DPP‐4 inhibitors are more commonly prescribed for diabetes, BP related to DPP‐4 inhibitors has been reported and has attracted attention. Therefore, we retrospectively investigated patients who were diagnosed with BP in order to examine characteristics of DPP‐4 inhibitor‐related BP (nine patients; median age, 85 years) in comparison with non‐DPP‐4 inhibitor‐related BP (21; median age, 85 years). There was no significant difference in Bullous Pemphigoid Disease Area Index between DPP‐4 inhibitor‐related BP patients and non‐DPP‐4 inhibitor‐related BP patients, except for erosions/blisters score in mucosa. Laboratory tests revealed no significant differences between DPP‐4 inhibitor‐related BP patients and non‐DPP‐4 inhibitor‐related BP patients in total white blood cell count, eosinophil count, neutrophil count and the titer of anti‐BP180 antibody. The number of eosinophils infiltrating into the skin was significantly lower in patients with DPP4 inhibitor‐related BP than in patients with non‐DPP4 inhibitor‐related BP. Our results showed that DPP‐4 inhibitor‐related BP has some distinct pathological characteristics from BP not associated with DPP‐4 inhibitor. [ABSTRACT FROM AUTHOR]

Aim: The aim of the present study was to assess the efficacy and safety of sitagliptin in elderly patients with type 2 diabetes mellitus. Methods: A total of 188 patients were enrolled who had type 2 diabetes mellitus with poor glycemic profiles (hemoglobin A1c [HbA1c] ≥6.2%). Patients were assigned to one of three age groups (<65, 65–74 and ≥75 years) and received 50–100 mg of sitagliptin daily for 12 months. Changes in HbA1c classified by age and body mass index (BMI) were assessed in addition to physiological parameters. Results: Mean HbA1c decreased significantly in all age groups (<65 years 8.01 ± 1.59% to 7.29 ± 1.23%; 65–74 years 7.61 ± 1.11% to 7.05 ± 0.99%; ≥75 years 7.21 ± 0.87% to 6.74 ± 0.96%). Reductions in HbA1c were not significantly different among age groups (P = 0.324). In older patients aged 65–74 years and ≥75 years, HbA1c decreased significantly in lean (BMI <25 kg/m2) patients (7.52 ± 1.10% to 6.99 ± 1.08%; P < 0.001) and in obese (BMI ≥25 kg/m2) patients (7.25% ± 0.90% to 6.86% ± 0.86%; P = 0.015); the changes in HbA1c were not significantly different between the lean and the obese groups (P = 0.943). Adverse events occurred in 12 patients (10.3%) aged ≥65 years, although there was no significant difference among the three age groups. Conclusions: Sitagliptin treatment offers elderly patients aged ≥65 years efficacious and safe reductions in HbA1c values regardless of BMI. Geriatr Gerontol Int 2018; 18: 631–639. [ABSTRACT FROM AUTHOR]

Introduction: Teneligliptin, an antihyperglycemic agent belonging to the dipeptidyl peptidase-4 inhibitor class, is usually prescribed at a dose of 20 mg/day. In Japan, the dose can be increased to 40 mg/day if needed. We examined the treatment response when the teneligliptin dose was increased from 20 to 40 mg in a post hoc pooled analysis of data from two 52-week, open-label, phase III clinical trials of teneligliptin 20-40 mg/day as monotherapy or combination treatment in Japanese patients with type 2 diabetes. Methods: In both studies, patients received teneligliptin 20 mg for at least 28 weeks; thereafter the dose was increased if glycemic control was inadequate. The data set for this post hoc analysis comprised those patients whose teneligliptin dose was increased to 40 mg at week 28 (N = 204). We assessed (i) the proportion of patients achieving HbA1c reduction after teneligliptin dose increase [≤-0.1% change in HbA1c during weeks 28-52 (24 weeks); responders] and (ii) the response to teneligliptin 40 mg according to whether or not patients experienced HbA1c re-elevation (≥ 0.1% increase) during 28 weeks of teneligliptin 20 mg. Results: Of 204 patients, 108 (52.9%) showed a response to teneligliptin 40 mg (HbA1c change ≤-0.1% during weeks 28-52) and had mean (± SD) HbA1c reduction of 0.50 ± 0.44%. Of patients showing re-elevation of HbA1c during treatment with teneligliptin 20 mg, 89/143 (62.2%) achieved HbA1c reduction after dose increase to 40 mg. Logistic regression analyses suggested that change in body weight is one of the parameters linked to HbA1c reduction after dose increase to teneligliptin 40 mg. The incidence of adverse events was not changed after teneligliptin dose increase. Conclusion: Increasing the dosage of teneligliptin from 20 to 40 mg/day has potential as a well-tolerated and effective option for treating type 2 diabetes. [ABSTRACT FROM AUTHOR]

Diabetes has been identified to be a risk factor for Alzheimer's disease (AD). Vildagliptin, a novel oral hypoglycemic agent, has been demonstrated to exert protective effects on the pancreas and cardiovascular system. The present study examined the potential protective effects of vildagliptin on neurons in an AD rat model. Treatment with vildagliptin improved memory deficits and decreased neuronal apoptosis in the hippocampus. The expression levels of B cell lymphoma 2 (Bcl‑2) were increased, and the expression levels of caspase‑3, Bcl‑2 associated X protein and AD‑associated proteins were decreased in the hippocampus following treatment with vildagliptin. Additionally, the AD model‑induced decrease in phosphorylated (p) protein kinase B (p‑Akt), p‑glycogen synthase kinase 3β (p‑GSK3β), post‑synaptic density 95 and synaptophysin expression was reversed. These results indicate that vildagliptin administration exerts a protective effect against cognitive deficits by reducing tau phosphorylation and increasing the expression of proteins associated with synaptic plasticity in the hippocampus. Targeting of the Akt/GSK3β signaling pathway may be a key mechanism in preventing the disease progression of AD. [ABSTRACT FROM AUTHOR]

Objective Women with insulin-requiring gestational diabetes mellitus (GDM) are at high risk of developing diabetes within a few years postpartum. We implemented this phase II study to test the hypothesis that vildagliptin, a dipeptidyl peptidase-4 inhibitor, is superior to placebo in terms of reducing the risk of postpartum diabetes. Methods Women with insulin-requiring GDM were randomized to either placebo or 50 mg vildagliptin twice daily for 24 months followed by a 12-month observation period (EudraCT: 2007-000634-39). Both groups received lifestyle counseling. The primary efficacy outcomes were the diagnosis of diabetes (American Diabetes Association (ADA) criteria) or impaired fasting glucose (IFG)/impaired glucose tolerance (IGT). Results Between 2008 and 2015, 113 patients (58 vildagliptin, 55 placebo) were randomized within 2.2–10.4 (median 8.6) months after delivery. At the interim analysis, nine diabetic events and 28 IFG/IGT events had occurred. Fifty-two women withdrew before completing the treatment phase. Because of the low diabetes rate, the study was terminated. Lifestyle adherence was similar in both groups. At 24 months, the cumulative probability of postpartum diabetes was 3% and 5% (hazard ratio: 1.03; 95% confidence interval: 0.15–7.36) and IFG/IGT was 43% and 22% (hazard ratio: 0.55; 95% confidence interval: 0.26–1.19) in the placebo and vildagliptin groups, respectively. Vildagliptin was well tolerated with no unexpected adverse events. Conclusions The study did not show significant superiority of vildagliptin over placebo in terms of reducing the risk of postpartum diabetes. However, treatment was safe and suggested some improvements in glycemic control, insulin resistance, and β-cell function. The study identified critical issues in performing clinical trials in the early postpartum period in women with GDM hampering efficacy assessments. With this knowledge, we have set a basis for which properly powered trials could be performed in women with recent GDM. Trial registration number at ClinicalTrials.gov NCT01018602 . [ABSTRACT FROM AUTHOR]

Dipeptidyl peptidase‐4 (DPP‐4) inhibitors and sodium glucose co‐transporter 2 (SGLT2) inhibitors are frequently used in combination for the treatment of type 2 diabetes mellitus (T2DM). We examined the efficacy and safety of teneligliptin (a DPP‐4 inhibitor) added to canagliflozin (an SGLT2 inhibitor) monotherapy in Japanese patients with poorly controlled T2DM as part of the development of a fixed‐dose combination of teneligliptin and canagliflozin. Japanese patients treated with canagliflozin (100 mg) for ≥12 weeks were randomized to receive add‐on teneligliptin (20 mg; C + T group) or placebo (C + P group) for 24 weeks. The primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 24. The between‐group differences in reductions from baseline to Week 24 were significantly greater in the C + T group for HbA1c (−0.94%; P < .001). The incidence of adverse events was similar in both groups (55.8% and 49.4% in the C + T and C + P groups, respectively). No episodes of hypoglycaemia were reported. Teneligliptin added to ongoing canagliflozin monotherapy improved glycaemic control and was well tolerated in Japanese patients with inadequately controlled T2DM. [ABSTRACT FROM AUTHOR]

We previously reported that inhibition of dipeptidyl peptidase (DPP)-4, the catalytic site of CD26, prevents atherosclerosis in animal models through suppression of inflammation; however, the underlying molecular mechanisms have not been fully elucidated. Caveolin-1 (Cav-1), a major structural protein of caveolae located on the surface of the cellular membrane, has been reported to modulate inflammatory responses by binding to CD26 in T cells. In this study, we investigated the role of Cav-1 in the suppression of inflammation mediated by the DPP-4 inhibitor, teneligliptin, using mouse and human macrophages. Mouse peritoneal macrophages were isolated from Cav-1 +/+ and Cav-1 −/− mice after stimulation with 3% thioglycolate. Inflammation was induced by the toll-like receptor (TLR)4 agonist, lipopolysaccharide (LPS), isolated from Escherichia coli . The expression of pro-inflammatory cytokines was determined using reverse transcription-polymerase chain reaction. Co-expression of Cav-1 and CD26 was detected using immunohistochemistry in both mouse and human macrophages. Teneligliptin treatment (10 nmol/L) suppressed the LPS-induced expression of interleukin (IL)-6 (70%) and tumor necrosis factor-α (37%) in peritoneal macrophages isolated from Cav-1 +/+ mice. However, teneligliptin did not have any effect on the macrophages from Cav-1 −/− mice. In human monocyte/macrophage U937 cells, teneligliptin treatment suppressed LPS-induced expression of pro-inflammatory cytokines in a dose-dependent manner (1–10 nmol/L). These anti-inflammatory effects of teneligliptin were mimicked by gene knockdown of Cav-1 or CD26 using small interfering RNA transfection. Furthermore, neutralization of these molecules using an antibody against CD26 or Cav-1 also showed similar suppression. Teneligliptin treatment specifically inhibited TLR4 and TLR5 agonist-mediated inflammatory responses, and suppressed LPS-induced phosphorylation of IL-1 receptor-associated kinase 4, a downstream molecule of TLR4. Next, we determined whether teneligliptin could directly inhibit the physical interaction between Cav-1 and CD26 using the Biacore system. Binding of CD26 to Cav-1 protein was detected. Unexpectedly, teneligliptin also bound to Cav-1, but did not interfere with CD26-Cav-1 binding, suggesting that teneligliptin competes with CD26 for binding to Cav-1. In conclusion, we demonstrated that Cav-1 is a target molecule for DPP-4 inhibitors in the suppression of TLR4-mediated inflammation in mouse and human macrophages. [ABSTRACT FROM AUTHOR]

BackgroundChronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP‐4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. Methods and ResultsIAs were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP‐1 and IL‐6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. ConclusionsA DPP‐4 inhibitor, anagliptin, prevents the growth of IAs via its anti‐inflammatory effects on macrophages.

Maternal obesity is associated with increased risk of pregnancy complications and greater risk of obesity in offspring, but studies designed to examine preconception weight loss are limited. The objective of this study was to determine if a combined dietary [oligofructose (OFS)] and pharmacological (sitagliptin) preconception intervention could mitigate poor pregnancy outcomes associated with maternal obesity and improve offspring metabolic health and gut microbiota composition. Diet-induced obese female Sprague-Dawley rats were randomized to one of four intervention groups for 8 weeks: (1) Obese-Control (consumed control diet during intervention); (2) Obese-OFS (10% OFS diet); (3) Obese-S (sitagliptin drug); (4) Obese-OFS + S (combination treatment). Two reference groups were also included: (5) Obese-HFS (untreated obese consumed high fat/sucrose diet throughout study); (6) Lean-Control (lean reference group that were never obese and consumed control diet throughout). Offspring consumed control diet until 11 weeks of age followed by HFS diet until 17 weeks of age. The Obese-OFS + S rats lost weight during the intervention phase whereas the OFS and S treatments attenuated weight gain compared with Obese-HFS (p

Diabetes is a global health emergency of this century. Diabetic nephropathy is the most common microvascular complication associated with Type 2 Diabetes Mellitus (T2DM). T2DM has been reported as a major etiological factor in almost 45% of patients undergoing dialysis due to kidney failure. Lifestyle modifications; cessation of smoking, optimum control of blood glucose, blood pressure and lipids are required to reduce the progression of Diabetic Kidney Disease (DKD). Presently, Dipeptidyl peptidase-4 (DPP-4) inhibitors are preferred in the management of T2DM due to their established efficacy; favorable tolerability including, low risk of hypoglycaemia; weight neutrality and convenient once-a-day dosage. Present evidence suggests that linagliptin and teneligliptin can be used safely without dose adjustments in patients with T2DM with renal impairment, including End Stage Renal Disease (ESRD). There is a limited data about teneligliptin particularly in T2DM patients with renal impairment. The objective of this review is to evaluate efficacy and safety of teneligliptin in T2DM patients with renal impairment, in order to assess the current place in therapy and future prospects of teneligliptin. Reported evidence suggests that teneligliptin has consistent pharmacokinetic in mild, moderate, severe or ESRD, without any need for dose adjustments. Limited data from small sample studies of teneligliptin in DKD patients reported significant improvements in glycaemic parameters. Additionally, there is an improvement in kidney parameters like glycated albumin, urinary albumin and eGFR. There is an evidence of reduction in biomarkers of kidney impairment like P-selectin (sP-selectin), Platelet-Derived Microparticles (PDMPs) and Plasminogen Activator Inhibitor 1 (PAI-1). Clinical significance of these will be known in near future. Thus, teneligliptin has an important place of therapy in the management of T2DM with renal impairment.