Sitagliptin Treatment Research Articles

Impact of sitagliptin on endometrial mesenchymal stem-like progenitor cells: A randomised, double-blind placebo-controlled feasibility trial.

BackgroundRecurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial.MethodsA double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more miscarriages, regular menstrual cycles, and no contraindications to sitagliptin. Thirty-eight subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. Colony forming unit (CFU) assays were used to quantify eMSC in midluteal endometrial biopsies. The primary outcome measure was CFU counts. Secondary outcome measures were endometrial thickness, study acceptability, and first pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations.FindingsCFU counts following sitagliptin were higher compared to placebo only when adjusted for baseline CFU counts and age (RR: 1.52, 95% CI: 1.32–1.75, P<0.01). The change in CFU count was 1.68 in the sitagliptin group and 1.08 in the placebo group. Trial recruitment, acceptability, and drug compliance were high. There were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells.InterpretationSitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted.FundingTommy's Baby Charity.Clinical trial registrationEU Clinical Trials Register no. 2016-001120-54.

Factors associated with the glucose-lowering efficacy of sitagliptin in Japanese patients with type2 diabetes mellitus: Pooled analysis of Japanese clinical trials.

Aims/IntroductionTo explore the factors associated with the glucose‐lowering efficacy of sitagliptin treatment in Japanese patients with type 2 diabetes mellitus.Materials and MethodsThis was a post‐hoc analysis of pooled data from seven sitagliptin phase II and III clinical studies carried out in Japan. All studies were double‐blind, randomized, placebo‐controlled, parallel‐group and of 12‐week duration. The analysis population consisted of 1,075 type 2 diabetes mellitus patients. In two of the trials, sitagliptin 50 mg and/or 100 mg daily were used as monotherapy; in five others, sitagliptin 50 mg daily was used as add‐on treatment to ongoing pioglitazone, glimepiride, metformin, voglibose or glinides. Efficacy (reduction in hemoglobin A1c [HbA1c]) was evaluated in 12 sets of subgroups defined by demographic, glycemic, pancreatic β‐cell function and insulin resistance parameters. An analysis of covariance model was used to evaluate the interaction between each parameter and efficacy.ResultsSitagliptin consistently provided a clinically meaningful reduction in HbA1c relative to placebo across all subgroups. Within subgroups, a greater absolute HbA1c reduction was associated with higher baseline HbA1c, fasting plasma glucose and 2‐h post‐meal glucose. Lower β‐cell function, represented by homeostatic model assessment of β‐cell function and insulinogenic index, was also associated with greater HbA1c reduction. In contrast, age, sex, body mass index, duration of type 2 diabetes mellitus and insulin resistance‐related parameters did not interact with HbA1c changes.ConclusionsSitagliptin treatment was associated with clinically meaningful improvement in glycemic control in all subgroups of Japanese patients with type 2 diabetes mellitus that were evaluated. Higher baseline glycemic status and lower baseline β‐cell function were identified as factors associated with greater HbA1c reduction after sitagliptin treatment.

Differences in lipid metabolism between anagliptin and sitagliptin in patients with type 2 diabetes on statin therapy: a secondary analysis of the REASON trial

BackgroundAnagliptin, a dipeptidyl peptidase-4 inhibitor, is reported to reduce the level of low-density lipoprotein cholesterol (LDL-C). The underlying mechanism of this effect and effect on lipid metabolism however remains uncertain.Aim and methodsWe therefore evaluate the effects of anagliptin on lipid metabolism-related markers compared with those of sitagliptin. The study was a secondary analysis using data obtained from the Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes (REASON) trial. This trial in patients with type 2 diabetes at a high risk of cardiovascular events and on statin therapy showed that anagliptin reduced LDL-C levels to a greater extent than sitagliptin. Cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol) markers were measured at baseline and 52 weeks in the study cohort (n = 353).ResultsThere was no significant difference in the changes of campesterol or sitosterol between the two treatment groups (p = 0.85 and 0.55, respectively). Lathosterol concentration was increased significantly at 52 weeks with sitagliptin treatment (baseline, 1.2 ± 0.7 μg/mL vs. 52 weeks, 1.4 ± 1.0 μg/mL, p = 0.02), whereas it did not change in the anagliptin group (baseline, 1.3 ± 0.8 μg/mL vs. 52 weeks, 1.3 ± 0.7 μg/mL, p = 0.99). The difference in absolute change between the two groups showed a borderline significance (p = 0.06).ConclusionThese findings suggest that anagliptin reduces LDL-C level by suppressing excess cholesterol synthesis, even in combination with statin therapy.Trial registration ClinicalTrials.gov number NCT02330406. https://clinicaltrials.gov/ct2/show/NCT02330406; registered January 5, 2015.

DPP4 Inhibitor Attenuates Severe Acute Pancreatitis-Associated Intestinal Inflammation via Nrf2 Signaling.

Severe acute pancreatitis (SAP) is a challenging disease with high morbidity and mortality, often complicated by multiple organ dysfunction syndrome (MODS). The intestine, a major organ involved in MODS, correlates strongly with the evolution of the disease. In this study, we demonstrated that the DPP4 inhibitor, sitagliptin, protects SAP-associated intestinal injury both in vitro and in vivo. These beneficial effects were achieved by suppressing oxidative stress and inflammatory responses. Moreover, in sitagliptin-treated SAP mice, expression of Nrf2 was induced and that of NF-κB was reduced, compared to the control SAP mice. In addition, we used Nrf2−/− mice to test the protective effect of Nrf2 during sitagliptin treatment of SAP; our results indicated that Nrf2−/− mice had greater pancreatic and intestinal injury than wild-type mice. Taken together, high levels of ROS induced by SAP may be inhibited by sitagliptin, possibly by inactivating the Nrf2-NF-κB pathway.

Sitagliptin Versus Ipragliflozin for Type 2 Diabetes in Clinical Practice

Background: Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors are frequently used to treat type 2 diabetes. However, there have been no direct comparisons of these antidiabetic drugs in Japanese patients with type 2 diabetes. Methods: We retrospectively assessed the effects of treatment with sitagliptin (a dipeptidyl peptidase-4 inhibitor) for 24 weeks in the ASSET-K study or treatment with ipragliflozin (a sodium-glucose cotransporter-2 inhibitor) for 24 weeks in the ASSIGN-K study. In both studies, patients with poor glycemic control received the study drug in addition to standard care with/without other antidiabetic medications or were switched to the study drug. The effects of each drug on metabolic risk factors (body weight, blood glucose, and lipids), blood pressure, and renal function were compared. Results: After 4 weeks of treatment, hemoglobin A1c was significantly lower in patients receiving ipragliflozin than in those receiving sitagliptin, but the difference was not significant at 12 or 24 weeks. Body mass index showed a significantly larger decrease with ipragliflozin treatment than sitagliptin treatment throughout most of the study period (P < 0.001 at 24 weeks). The mean blood pressure also showed a significantly larger decrease with ipragliflozin treatment than sitagliptin treatment throughout most of the study period (P = 0.007 at 24 weeks). In contrast, the decrease of the estimated glomerular filtration rate after 24 weeks was significantly larger in patients treated with sitagliptin than those receiving ipragliflozin (P = 0.012). Conclusions: Ipragliflozin may be more effective than sitagliptin for Japanese patients with type 2 diabetes who have hypertension, obesity, and/or renal dysfunction. J Endocrinol Metab. 2019;9(5):151-158 doi: https://doi.org/10.14740/jem604

Impact of Sitagliptin on Endometrial Mesenchymal Stem-Like Progenitor Cells: A Randomised, Double-Blind Placebo-Controlled Feasibility Trial

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury by preventing inactivation of stromal cell-derived factor-1α, a potent chemoattractant. Aims: To assess the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, to evaluate the impact on endometrial decidualization, and to assess the feasibility of a full-scale clinical trial. Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more consecutive pregnancy losses, regular ovulatory menstrual cycles, and no contraindications to sitagliptin. Thirty-eighty subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. The primary outcome measure was the posttreatment eMSC count, assessed by colony forming unit (CFU) assays, in midluteal biopsies. Secondary outcome measures were change in CFU count before and after placebo or sitagliptin treatment, endometrial thickness, study acceptability, and subsequent pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations. Findings: CFU counts following sitagliptin were higher compared to placebo when adjusted for baseline CFU counts and age (RR:1.52, 95%CI:1.32-1.75, P<0.01). The CFU count increased 1.68-fold in the sitagliptin group and 1.08-fold in the placebo group. The trial was acceptable and drug compliance high. were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells. Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted. Trial Registration: EU Clinical Trials Register no. 2016-001120-54. Funding Statement: The study was sponsored by UHCW NHS Trust and funded by Tommy’s baby charity (registered charity 1060508/ SC039280, Great Britain). R.F. received funding from Juntendo University, Japan. Declaration of Interests: The authors stated: There are no conflicts of interests. Ethics Approval Statement: The SIMPLANT study was approved by the Medicines and Healthcare Regulatory Authority (MHRA), the National Health Service Research Ethics Committee South Central-Hampshire B (16/SC/0229) and Research, Development and Innovation (RD&I) office at University Hospitals Coventry and Warwickshire (UHCW) National Health Service (NHS) Trust.

Neuropeptide Y system mRNA expression changes in the hippocampus of a type I diabetes rat model

BackgroundNeuropeptide Y (NPY) plays a crucial role in many neurobiological functions, such as cognition and memory. Cognitive and memory impairment have been described in diabetic patients. The metabolism of NPY is determined by the activity of proteases, primarily dipeptidyl-peptidase-IV (DPP-IV). Therefore, DPP-IV inhibitors, such as sitagliptin, may modulate the function of NPY. In this study, we investigated the effect of type 1 diabetes and sitagliptin treatment on the regulation of the mRNA encoding for NPY and its receptors (Y1, Y2, and Y5 receptors) in the hippocampus. MethodsType 1 diabetes was induced in male Wistar rats by i.p. injection of streptozotocin. Starting two weeks after diabetes onset, animals were treated orally with sitagliptin (5mg/kg, daily) for two weeks. The mRNA expression of Npy and its receptors (Npy1r, Npy2r, and Npy5r) in the hippocampus was evaluated using in situ hybridization with 33P-labeled oligonucleotides. ResultsThe mRNA expression of Npy, Npy1r and Npy5r was higher in the dentate gyrus, whereas Npy2r highest level was observed in the CA3 subregion. The mRNA expression of Npy, Npy1r and Npy5r in dentate gyrus, CA1 and CA3 was not affected by diabetes and/or by sitagliptin treatment. Type 1 diabetes increased the mRNA expression of Npy2r in the CA3 subregion, which was prevented by sitagliptin treatment. ConclusionsOur results show that type 1 diabetes, at early stages, induces mild changes in the NPY system in the hippocampus that were counteracted by sitagliptin treatment.

Effect of sitagliptin on tubulointerstitial Wnt/β-catenin signalling in diabetic nephropathy.

To investigate the effect of sitagliptin on Wnt/β-catenin signalling in the tubulointerstitium of diabetic nephropathy. Forty male Wistar rats were divided into normal control (NC), diabetic model (DM), low and high-dose sitagliptin intervention groups (ST1 and ST2, respectively). Changes in the biochemical parameters and tubulointerstitial fibrosis index were observed. The levels of protein and gene expression of different indicators were detected via immunohistochemistry and real-time polymerase chain reaction. NRK-52E cells were divided into the normal control group, mannitol control group, high glucose group (HG), high glucose plus sitagliptin intervention group (HG + ST) and high glucose plus Wnt/β-catenin inhibitor group (HG + XAV939). The relevant indicators were examined by Western blot or enzyme-linked immunosorbent assay. Compared with the NC group, the blood glucose, glycosylated haemoglobin, 24 h urinary albumin, creatinine clearance and tubulointerstitial fibrosis index were significantly increased in the DM group. These parameters were decreased in the ST1 and ST2 groups compared to the DM group. Compared with the NC group, the levels of Wnt4, β-catenin, dipeptidyl peptidase-4 and α-smooth muscle actin were higher and E-cadherin was lower in the DM group. Sitagliptin treatment reversed these changes. In the high glucose-stimulated NRK-52E cells, sitagliptin and XAV939 inhibited the elevated expression of Wnt4, β-catenin, dipeptidyl peptidase-4, α-smooth muscle actin, transforming growth factor-β and fibronectin and restored E-cadherin activity. Sitagliptin may inhibit the tubulointerstitial Wnt/β-catenin signalling pathway in diabetic nephropathy and provide renal protection by alleviatinge renal tubulointerstitial transdifferentiation and fibrosis.

The dipeptidyl peptidase 4 inhibitor sitagliptin improves oxidative stress and ameliorates glomerular lesions in a rat model of type 1 diabetes

AimsOxidative stress has been linked to the development and progression of diabetic nephropathy (DN). The present study evaluated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates glomerular lesions and oxidative stress evoked by chronic hyperglycemia, by a mechanism independent of insulin secretion and glycemia normalization. Main methodsA rat model of DN caused by streptozotocin injection was established and the effects of sitagliptin (5 mg/kg/day) were evaluated after two weeks of treatment. Key findingsSitagliptin treatment did not change body weight, glycemic and lipid profiles. However, histopathological observation revealed that sitagliptin attenuates diabetes-induced glomerular lesions on diabetic rats. Sitagliptin also ameliorated the increase in DPP-4 content and promoted the stabilization of GLP-1 in the diabetic kidney. Furthermore, sitagliptin treatment significantly attenuated the increase of free-radical formation and the decrease of antioxidant defenses, attenuating therefore the oxidative stress in the kidneys of diabetic animals. SignificanceThe results suggest that sitagliptin treatment alleviates kidney oxidative stress in type 1 diabetic rats, which could play a key role in reducing the progression of DN.

Efficacy and safety of oral semaglutide with flexible dose adjustment versus sitagliptin in type 2 diabetes (PIONEER 7): a multicentre, open-label, randomised, phase 3a trial

Oral semaglutide is the first oral formulation of a glucagon-like peptide-1 (GLP-1) receptor agonist developed for the treatment of type 2 diabetes. We aimed to compare the efficacy and safety of flexible dose adjustments of oral semaglutide with sitagliptin 100 mg. In this 52-week, multicentre, randomised, open-label, phase 3a trial, we recruited patients with type 2 diabetes from 81 sites in ten countries. Patients were eligible if they were aged 18 years or older (19 years or older in South Korea), had type 2 diabetes (diagnosed ≥90 days before screening), HbA1c of 7·5-9·5% (58-80 mmol/mol), and were inadequately controlled on stable daily doses of one or two oral glucose-lowering drugs (for 90 days or more before screening). Participants were randomly assigned (1:1) by use of an interactive web-response system, stratified by background glucose-lowering medication at screening, to oral semaglutide with flexible dose adjustments to 3, 7, or 14 mg once daily or sitagliptin 100 mg once daily. To approximate treatment individualisation in clinical practice, oral semaglutide dose could be adjusted on the basis of prespecified HbA1c and tolerability criteria. Two efficacy-related estimands were prespecified: treatment policy (regardless of treatment discontinuation or use of rescue medication) and trial product (on treatment and without use of rescue medication) for participants randomly assigned to treatment. The primary endpoint was achievement of HbA1c of less than 7% (53 mmol/mol) at week 52 and the confirmatory secondary efficacy endpoint was change in bodyweight from baseline to week 52. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02849080, and European Clinical Trials Database, EudraCT number 2015-005593-38, and an open-label extension is ongoing. Between Sept 20, 2016, and Feb 7, 2017, of 804 patients assessed for eligibility, 504 were eligible and randomly assigned to oral semaglutide (n=253) or sitagliptin (n=251). Most participants were male (285 [57%] of 504) with a mean age of 57·4 years (SD 9·9). All participants were given at least one dose of their allocated study drug except for one participant in the sitagliptin group. From a mean baseline HbA1c of 8·3% (SD 0·6%; 67 mmol/mol [SD 6·4]), a greater proportion of participants achieved an HbA1c of less than 7% with oral semaglutide than did with sitagliptin (treatment policy estimand: 58% [134 of 230] vs 25% [60 of 238]; and trial product estimand: 63% [123 of 196] vs 28% [52 of 184]). The odds of achieving an HbA1c of less than 7% was significantly better with oral semaglutide than sitagliptin (treatment policy estimand: odds ratio [OR] 4·40, 95% CI 2·89-6·70, p<0·0001; and trial product estimand: 5·54, 3·54-8·68, p<0·0001). The odds of decreasing mean bodyweight from baseline to week 52 were higher with oral semaglutide than with sitagliptin (estimated mean change in bodyweight, treatment policy estimand: -2·6 kg [SE 0·3] vs -0·7 kg [SE 0·2], estimated treatment difference [ETD] -1·9 kg, 95% CI -2·6 to -1·2; p<0·0001; and trial product estimand: -2·9 kg [SE 0·3] vs -0·8 kg [SE 0·3], ETD -2·2 kg, -2·9 to -1·5; p<0·0001). Adverse events occurred in 197 (78%) of 253 participants in the oral semaglutide group versus 172 (69%) of 250 in the sitagliptin group, and nausea was the most common adverse event with oral semaglutide (53 [21%]). Two deaths occurred in the sitagliptin group during the trial. Oral semaglutide, with flexible dose adjustment, based on efficacy and tolerability, provided superior glycaemic control and weight loss compared with sitagliptin, and with a safety profile consistent with subcutaneous GLP-1 receptor agonists. Novo Nordisk A/S.

112-LB: Melatonin and DPP-IV Inhibitor: A Novel Combinatorial Approach for ß-Cell Regeneration

Progressive deterioration of β-cell function and mass is a central parameter to the development of type-1/2 diabetes (T1/2D). Over the last decade, many studies have explored the potential benefits of incretin-based therapies on β-cell preservation and/or regeneration. In this context, DPP-IV inhibitor is known to improve GLP-1 and GIP longevity besides increasing β-cell mass. Melatonin, a pineal hormone is shown to ameliorate oxidative stress and bring about insulin secretion via MT1 receptor activation. Our aim was to evaluate the additive therapeutic effect of melatonin and DPP-IV inhibitor (sitagliptin) on β-cell regeneration in chemically (streptozotocin) induced T1D young and old mouse models, and on insulin resistance in high-fat diet (HFD)-induced T2D mouse model. Our results on pancreatic β-cell regeneration in T1D young and old mice suggest that the combinatorial treatment significantly increased insulin levels thereby lowering FBG levels and increasing glucose tolerance. In young diabetic mice, sitagliptin and melatonin work in an additive manner by increasing β-cell mass (replication and neogenesis) and decreasing apoptosis thus, ameliorating TID manifestations. However, in old diabetic mice, melatonin treatment alone was not as effective as sitagliptin treatment but a significant additive effect was observed in S+M group on β-cell regeneration. In HFD-induced T2D mice the combination therapy was superior to monotherapies in reducing FBG levels, and increasing glucose tolerance. Further, the combination treatment showed increased glucose metabolism, glycogen synthesis, and insulin sensitivity. There was no significant change in β-cell mass in HFD-induced T2D mice. In conclusion, combinatorial therapy is able to ameliorate T1D and T2D in mouse models by β-cell regeneration and increasing insulin sensitivity. Melatonin promotes β-cell proliferation whereas sitagliptin promotes β-cell neogenesis and in concert, they enhance β-cell regeneration. Disclosure R. Patel: None. S. Pramanik: None. N.N. Rathwa: None. N.R. Parmar: None. H. Dhimmar: None. D.A. Pancholi: None. R. A.v.: None. R. Begum: None. Funding Department of Biotechnology, New Delhi, India (BT/PR12584/MED/31/289/2014)

1119-P: Efficacy and Safety of Sitagliptin (SITA) Compared with Dapagliflozin (DAPA) in People ≥65 Years Old with T2D

In the U.S., ~45% of patients with T2D are ≥65 years old, of whom ~50% have mild renal insufficiency (eGFR ≥60 and &amp;lt;90 mL/min/1.73 m2). Older people may respond to AHA treatment differently from younger people, and assessments focused on the older population are desirable. We conducted a post hoc analysis of the cohort of patients ≥65 years who participated in a 24-week randomized, double-blind clinical trial (NCT02532855) of the efficacy and safety of SITA 100 mg qd vs. DAPA 10 mg qd in people with mild renal insufficiency while on MET ± SU; the primary efficacy endpoint was change in A1C at Week 24, analyzed with an LDA model. Treatment groups were well-balanced at baseline (mean A1C [%] = 7.7/7.7, mean eGFR [mL/min/1.73 m2] = 79/76 for SITA/DAPA). At Week 24, LS mean reduction from baseline A1C was greater with SITA compared with DAPA (Table). With SITA treatment, 41% of participants were at A1C goal of &amp;lt;7.0% compared to 28% with DAPA (Table). The SITA group had greater reductions in post-prandial glucose endpoints, and the DAPA group had greater reductions in FPG (Table). Treatments were generally well tolerated; there were significantly fewer drug-related AEs with SITA than with DAPA, but AE profiles were otherwise similar. Disclosure A. Raji: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. Z. Xu: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. R.L. Lam: Employee; Self; Merck &amp; Co., Inc. K.D. Kaufman: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. S.S. Engel: Employee; Self; Merck &amp; Co., Inc. Stock/Shareholder; Self; Merck &amp; Co., Inc. Funding Merck &amp; Co., Inc.

1011-P: Therapeutic Potential of Novel Combination of a Long-Acting Glucagon Analog (HM15136) and Antidiabetic Drugs for the Treatment of Obesity

The obesity epidemic represents a major challenge for public health. However, existing anti-obesity drugs have limited efficacy because they only suppress appetite, emphasizing the development of next generation therapeutic option. Recently, we showed that prolonged glucagon (GCG) receptor activation with HM15136, a long-acting GCG analog, could provide potent body weight loss (BWL) in obese animal models. Considering the stimulatory effect of GCG on glucose production, transient blood glucose (BG) elevation might be important when utilizing HM15136 as a novel anti-obesity drug. Antidiabetic drugs such as metformin, and DPP-4 inhibitor have been widely used for T2DM patients. Considering their safety profile and treatment adherence in addition to BG lowering nature, we hypothesized that combination of antidiabetic drugs might minimize the transient BG elevation by HM15136 and confer additional BWL. To investigate this hypothesis, the present study evaluated the combination effect of HM15136 and antidiabetic medication on BG and BW in vivo. In normal mice, HM15136-induced BG increase was effectively reversed by concomitant treatment of metformin, sitagliptin, or empagliflozin. To further confirm, DIO mice were chronically administered with HM15136 and/or antidiabetic drugs, and normal BG control was continuously maintained in COMBO groups. These results indicate that when combined, antidiabetic drugs could effectively counteract the transient BG elevation by HM15136. As to the BWL efficacy, combination of HM15136 either with metformin, sitagliptin, or empagliflozin provided additional BWL (-18% to -31% by metformin COMBO; -35% to -47% by sitagliptin COMBO; -35% to -40% by empagliflozin COMBO), highlighting the therapeutic benefit of this novel combination. In conclusion, our results demonstrate the prolonged GCG receptor stimulation with antidiabetic medication as a novel therapeutic option for obesity treatment. Disclosure Y. Park: None. J. Lee: None. J. Kim: None. D. Kim: None. Y. Kim: None. I. Choi: Employee; Self; Hanmi Pharm. Co., Ltd.

21-LB: The Study of Dapagliflozin vs. Sitagliptin Treatment Efficacy on Prevention of Cardiovascular Risk Factors in Type 2 Diabetes Patients: The DIVERSITYCVR Study

Background: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have attracted attention by the recently reported improved cardiovascular (CV) outcomes in patients with T2DM. In contrast, dipeptidyl peptidase 4 inhibitors (DPP-4i) were reported neutral on CV outcomes. However, there are few prospective studies that have compared the efficacy of SGLT2i and DPP-4i on the prevention of CV disease risks. Therefore, we planned this prospective, randomized, parallel-group trial aimed to compare the therapeutic benefits of dapagliflozin (Dapa) and sitagliptin (Sita) on CV disease risks, with special focus on HbA1c, body weight (BW), and hypoglycemia. Methods: A total of 340 T2DM patients treated with metformin alone or with no glucose-lowering agents (20-80 years of age, HbA1c ≥ 7.1% and &amp;lt; 10.0%) were equally randomized to Dapa 5 mg/day or Sita 50 mg/day add-on group, and treated for 24 weeks. After the 8 weeks, if HbA1c is 7.0% or higher, Dapa and Sita were increased to 10 mg/day and 100 mg/day, respectively. The primary endpoint was the ratio of achieving composite endpoints of the following all 3 items; 1) HbA1c below 7.0%; 2) 3.0% BW loss from baseline; 3) avoidance of hypoglycemia {&amp;lt; 3.0 mmol/L (&amp;lt; 54 mg/dL)}. Hypoglycemia was monitored by flash glucose monitoring system. Results: The achievement ratio of HbA1c below 7.0% was comparable between the groups (49.4 vs. 50.0%, p=1.00, Dapa vs. Sita, respectively). However, 3.0% BW loss was preferably achieved in Dapa group (54.4 vs. 19.6%, p&amp;lt;0.001). There was no significant difference regarding the avoidance of hypoglycemia between the groups (88.7 vs. 92.3%, p=0.27). Thus, the ratio of achieving composite endpoints was superior in Dapa group compared to Sita group (24.4% vs. 13.8%, p&amp;lt;0.05). In summary, Dapa treatment for 24 weeks improved CV risk factors in patients with inadequately controlled T2DM. This study provides the evidence on ideal therapeutic choice for preventing CV events in T2DM. Disclosure A. Fuchigami: None. F. Shigiyama: None. T. Kitazawa: Speaker’s Bureau; Self; AstraZeneca, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kowa Pharmaceutical Europe Co. Ltd., Kyowa Hakko Kirin Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Y. Okada: None. T. Ichijo: None. M. Higa: None. T. Hiyoshi: Other Relationship; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly Japan K.K., Merck Sharp &amp; Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sanwa Kagaku Kenkyusho, Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. I. Inoue: None. K. Iso: Research Support; Spouse/Partner; AstraZeneca. H. Yoshii: None. T. Hirose: None. N. Kumashiro: Speaker’s Bureau; Self; Novo Nordisk Inc., Sanofi, Takeda Pharmaceutical Company Limited. Funding AstraZeneca K.K.

Cardioprotection Conferred by Sitagliptin Is Associated with Reduced Cardiac Angiotensin II/Angiotensin-(1-7) Balance in Experimental Chronic Kidney Disease.

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.

OR05-6 The Effect of the GLP1R Variant rs6923761 on Post-Prandial Glucose Levels during Treatment with Sitagliptin

BACKGROUND: Glucagon-like peptide-1 (GLP-1) functions to increase insulin production in a glucose-dependent manner. Endogenous GLP-1 is rapidly degraded by the enzyme dipeptidyl peptidase 4 (DPP4), and GLP-1 receptor agonists and DPP4 inhibitors (DPP4Is) are now used in the treatment of diabetes. The GLP-1 receptor (GLP-1R) is a G-protein coupled receptor that is expressed widely, encoded for by GLP1R. The GLP1R variant rs6923761 (Gly168Ser) has been associated with increased weight loss in response to GLP-1 agonist therapy in some studies. This study tested the hypothesis that this variant would be associated with responsiveness to endogenous GLP-1 during DPP4I therapy. METHODS: Forty-seven subjects with hypertension and type 2 diabetes mellitus were assigned to one-week crossover therapy with placebo and the DPP4I sitagliptin (100 mg/d), and underwent a mixed meal study. Subjects were excluded for type 1 diabetes, poorly controlled diabetes with Hgb A1c ≥8.7%, use of an anti-diabetic medication other than metformin for last 12 months, or presence of secondary hypertension. RESULTS: Post-prandial GLP-1 levels were increased during sitagliptin (AUC 11413, 95% CI [7113, 15712]) as compared with placebo treatment (AUC 5101, 95% CI [2254, 7949], p<0.05), and did not significantly differ by genotype. Peak post-prandial glucose was significantly higher in placebo as compared with sitagliptin treatment (146.6 +/- 35.8 mg/dL versus 133.0 +/- 26.5 mg/dL, respectively; t=90 minutes, p<0.01). Subjects with one or two copies of the wild-type allele (Gly/Gly or Gly/Ser) had increased post-prandial glucose excursion as compared with Ser/Ser subjects, in both the placebo and sitagliptin treatments (plasma glucose at 90 minutes: placebo Gly/- 150.1 +/- 38.0 mg/dL vs Ser/Ser 132.6 +/- 13.7 mg/dL, p<0.05; sitagliptin Gly/- 135.8 +/- 27.3 mg/dL vs Ser/Ser 117.4 +/- 14.7 mg/dL, p<0.05). Post-prandial insulin levels were not different in the placebo versus sitagliptin treatments (AUC 13264, 95% CI [9296,17232] vs 11996, 95% CI [8278, 15714], respectively), but there was a genotype by drug treatment interaction (p<0.05) such that Ser/Ser subjects had higher post-prandial insulin in the placebo treatment as compared with other genotypes. This difference was eliminated with sitagliptin therapy. CONCLUSIONS: Homozygosity for the Ser variant of GLP1R is associated with decreased glucose after a mixed meal without altering the effect of sitagliptin on post prandial GLP-1 concentrations. Further studies are needed to assess whether this variant confers increased sensitivity at the GLP-1R and whether it affects the long-term response to DPP4I.

The dipeptidyl peptidase-4 inhibitor sitagliptin ameliorates renal injury in type 1 diabetic mice via inhibiting the TGF-β/Smad signal pathway.

Diabetic nephropathy (DN) is a common cause of end-stage kidney disease (ESKD) all over the world. Sitagliptin, an inhibitor of DPP-IV plays a beneficial role in type 2 diabetic nephropathy. The purpose of this study was to explore the effect and mechanism of sitagliptin on renal injury in type 1 diabetic mice. Streptozotocin (STZ) induced type 1 diabetic mice were treated with oral administration of sitagliptin (15 mg/kg/ day) for 4 weeks. The results showed that sitagliptin treatment did not change the levels of blood glucose in STZ induced type 1 diabetic mice. Sitagliptin attenuates diabetic nephropathy by significantly inhibiting 24 h proteinuria, renal injury and fibrosis. Sitagliptin can inhibit the expression level of TGF-β1 and the other related fibrosis factors in renal tissue of type 1 diabetic mice while delaying the progression of type 1 diabetic nephropathy. These results indicated that sitagliptin treatment is potentially a new strategy for treating type 1 diabetic nephropathy.

Anti-Inflammatory Effect of Combined Sitagliptin and Vitamin D3 on Cytokines Profile in Patients with Type 2 Diabetes Mellitus.

Studies indicated that imbalance of proinflammatory and anti-inflammatory cytokines may contribute to development of type 2 diabetes mellitus (T2DM). We hypothesized that sitagliptin and VitD3 may exert more anti-inflammatory effects on the regulation of cytokine balance in T2DM. Nonnephropathic and nephropathic T2DM patients were divided into the subgroups, based on treatments. The effect of 8 months sitagliptin, alone or together with 2 months of VitD3, on serum IFN-γ, IL-4, IL-17, IL-6, IL-21, TGF-β, and IL-37 levels was determined using enzyme-linked immunosorbent assay. Increased levels of interferon (IFN)-γ and IL-17 in untreated (without sitagliptin and VitD3) nephropathic and nonnephropathic patients and decreased levels of IL-37 in untreated nephropathic patients were observed compared with healthy controls. Treatment with sitagliptin plus VitD3 reduced the levels of IFN-γ and IL-17 in both nonnephropathic and nephropathic patients compared with untreated patients. The level of IL-37 was enhanced in patients treated with sitagliptin or sitagliptin plus VitD3, compared with untreated patients. Sitagliptin plus VitD3 treatment increased the levels of IL-4 in nonnephropathic patients. These findings indicated that the sitagliptin plus VitD3 was more effective to reduce the increased proinflammatory IFN-γ and IL-17 cytokines in T2DM patients.

Sitaglitpin phosphate treatment in patients with reactive hypoglycemia secondary to dysinsulinism. Controlled, randomized, double-blind study.

We evaluated the effect of sitagliptin in correction of symptomatic reactive hypoglycemia. Randomized, double blind, placebo-controlled clinical trial. Thirteen patients treated with sitagliptin and 15 with placebo, with mean age of 34.3 ± 10.6 years and body mass index of 24.6 ± 5.1 kg/m2, mostly women (n = 24, 85.7%), were evaluated. Basal glycemia was similar in placebo versus sitagliptin (92.3 ± 18.9 vs. 93.4 ± 17.3 mg/dl; p = 0.41) as was median and interquartile range of insulin (15.2 [8.8-43.7] vs. 14.7 µU/ml [7.0-39.0]; p = 0.44). Patients with sitagliptin recovered the first phase insulin secretion (FISP). This was related with higher glucose level at the end of the oral glucose tolerance test (79.5 [74.2-83.0] vs. 83.5 [81.2-89.7]; p = 0.003) with a similar insulin median level (13.0 [5.0-34.4] vs. 13.8 [4.8-30.6]; p = 0.32). Symptomatology was significantly lower under sitagliptin treatment (p < 0.0001). Sitagliptin improved FISP and reduced post-prandial symptomatology. These results suggest a novel therapeutic option for patients with reactive hypoglycemia related with FISP.

Sitagliptin Ameliorates Renal Tubular Injury in Diabetic Kidney Disease &lt;i&gt;via&lt;/i&gt; STAT3-Dependent Mitochondrial Homeostasis Through SDF-1α/CXCR4 Pathway

Background: Mitochondrial abnormalities play critical roles in diabetic tubular injury progression. Dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycaemic agents that exert renal protective and positive effects against mitochondrial dysfunction in diabetic kidney disease (DKD). Methods: We examined whether DPP4 inhibitor sitagliptin ameliorate mitochondrial altered fusion-fission processes and fragmentation in the tubules of diabetic mice and albumin-overloaded tubular cells. The possible role of sitagliptin-mediated SDF-1α/CXCR4 signalling and mitochondrial STAT3 in protecting against mitochondrial abnormalities was also studied. Findings: DPP4 upregulation, accompanied by mitochondrial fragmentation and altered mitochondrial dynamic protein expressions, were observed in the tubules of DBA2/J (D2) diabetic mice with unilateral nephrectomy and in albumin-stimulated tubular cells. Sitagliptin ameliorated these mitochondrial perturbations both in vivo and in vitro, whereas DPP4 overexpression aggravated mitochondrial fusion-fission disorder and tubular cell injury in albumin-treated HK-2 cells. DPP4 downstream SDF-1α/CXCR4 pathway was significantly suppressed in diabetic tubules, which was restored after sitagliptin treatment. Furthermore, a direct interaction between STAT3 and OPA1 was found in mitochondria in tubular cells, and this effect was weakened by overloaded albumin and CXCR4 siRNA, suggesting a possible link between DPP4-mediated SDF-1α/CXCR4/STAT3 signalling and mitochondrial dysfunction in diabetic tubular cells. Interpretation: The results suggest a novel mechanism linking the DPP4 enzyme to impaired mitochondrial dynamics homeostasis during tubular injury in DKD and highlight that the SDF-1α/CXCR4/STAT3 signalling pathway could become a potential target for managing DKD. Funding Statement: This study was supported by National Nature Science Foundation of China (81670657,81870504,81870468,81400735), National “Twelfth Five-Year” Plan for Science & Technology Support (2013BAI02B01-01), Medical and Engineering Cross funding of Shanghai Jiao Tong University (YG2017MS10), Shanghai Municipal Commission of Science and Technology (Grant No.18DZ2260200), Open Project of Shanghai Key Laboratory of Sleep Disordered Breathing (SHKSDB-KF-19-04), Science and Technology Commission of Shanghai Municipality (14DZ2260200, the project of Shanghai Key Laboratory of Kidney and Blood Purification). Declaration of Interests: No potential conflicts of interest relevant to this article are reported. Ethics Approval Statement: All animal procedures used in this study were approved by the Animal Care and Use Committee of Shanghai Jiao Tong University.