sitagliptin-phosphate and Diabetic-Cardiomyopathies

Diabetes is associated closely with an increased risk of cardiovascular events, including diastolic dysfunction and heart failure that leads to a shortening of life expectancy. It is therefore extremely valuable to evaluate the impact of antidiabetic agents on cardiac function. However, the influence of dipeptidyl peptidase 4 inhibitors on cardiac function is controversial and a major matter of clinical concern. We therefore evaluated the effect of sitagliptin on echocardiographic parameters of diastolic function in patients with type 2 diabetes as a sub-analysis of the PROLOGUE study.. Patients in the PROLOGUE study were assigned randomly to either add-on sitagliptin treatment or conventional antidiabetic treatment. Of the 463 patients in the overall study, 115 patients (55 in the sitagliptin group and 60 in the conventional group) who had complete echocardiographic data of the ratio of peak early diastolic transmitral flow velocity (E) to peak early diastolic mitral annular velocity (e') at baseline and after 12 and 24 months were included in this study. The primary endpoint of this post hoc sub-analysis was a comparison of the changes in the ratio of E to e' (E/e') between the two groups from baseline to 24 months.. The baseline-adjusted change in E/e' during 24 months was significantly lower in the sitagliptin group than in the conventional group (-0.18 ± 0.55 vs. 1.91 ± 0.53, p = 0.008), irrespective of a higher E/e' value at baseline in the sitagliptin group. In analysis of covariance, sitagliptin treatment was significantly associated with change in E/e' over 24 months (β = -9.959, p = 0.001), independent of other clinical variables at baseline such as blood pressure, HbA1c, and medications for diabetes. Changes in other clinical variables including blood pressure and glycemic parameters, and echocardiographic parameters, such as cardiac structure and systolic function, were comparable between the two groups. There was also no significant difference in the serum levels of N-terminal-pro brain natriuretic peptide and high-sensitive C-reactive protein between the two groups during the study period.. Adding sitagliptin to conventional antidiabetic regimens in patients with T2DM for 24 months attenuated the annual exacerbation in the echocardiographic parameter of diastolic dysfunction (E/e') independent of other clinical variables such as blood pressure and glycemic control. Trial registration UMIN000004490 (University Hospital Medical Information Network Clinical Trials). https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000005356 ; registered November 1, 2010.

Topics: Adult; Aged; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Diastole; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Echocardiography, Doppler; Female; Humans; Japan; Male; Middle Aged; Mitral Valve; Predictive Value of Tests; Prospective Studies; Recovery of Function; Sitagliptin Phosphate; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors treat type 2 diabetes through incretin-signaling pathways. This study compared the efficacy and safety of the glucagon-like peptide-1 receptor agonist exenatide once-weekly (Miglyol) suspension for autoinjection (QWS-AI) with the dipeptidyl peptidase-4 inhibitor sitagliptin or placebo.. In this open-label, multicentre study of patients with type 2 diabetes who had suboptimal glycaemic control on metformin monotherapy, 365 patients were randomized to receive exenatide 2.0 mg QWS-AI, sitagliptin 100 mg once daily or oral placebo (3:2:1 ratio). The primary endpoint was change in glycated hemoglobin (HbA1c) from baseline to 28 weeks.. At 28 weeks, exenatide QWS-AI significantly reduced HbA1c from baseline compared to sitagliptin (-1.13% vs -0.75% [baseline values, 8.42% and 8.50%, respectively]; P  = .02) and placebo (-0.40% [baseline value, 8.50%]; P = .001). More exenatide QWS-AI-treated patients achieved HbA1c <7.0% than did sitagliptin- or placebo-treated patients (43.1% vs 32.0% and 24.6%; both P  < .05). Exenatide QWS-AI and sitagliptin reduced fasting plasma glucose from baseline to 28 weeks (-21.3 and -11.3 mg/dL) vs placebo (+9.6 mg/dL), with no significant difference between the 2 active treatments. Body weight decreased with both active treatments (-1.12 and -1.19 kg), but not with placebo (+0.15 kg). No improvement in blood pressure was observed in any group. The most common adverse events with exenatide QWS-AI were gastrointestinal events and injection-site reactions.. This study demonstrated that exenatide QWS-AI reduced HbA1c more than sitagliptin or placebo and was well tolerated.

Topics: Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Drug Therapy, Combination; Excipients; Exenatide; Female; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemic Agents; Incidence; Incretins; Injections, Jet; Male; Metformin; Middle Aged; Peptides; Sitagliptin Phosphate; Triglycerides; United States; Venoms

To report baseline characteristics and cardiovascular (CV) risk management by region, age, sex and CV event type for 14 724 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a randomized, double-blind, placebo-controlled trial exploring whether sitagliptin added to usual type 2 diabetes (T2DM) care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization.. TECOS enrolled patients aged ≥50 years, with T2DM and CV disease from 38 countries in five regions: North America, Eastern Europe, Western Europe, Asia Pacific and Latin America. Participants had a glycated haemoglobin concentration of 6.5-8.0% (48-64 mmol/mol) and were receiving oral and/or insulin-based antihyperglycaemic therapy. Analysis of variance or logistic regression was used to compare regional CV risk factors and treatments, referenced to North America.. Patients had a mean [1 standard deviation (SD)] age of 66 (8) years, a median (interquartile range) diabetes duration of 9.4 (4.9, 15.3) years, and a mean (SD) body mass index 30.2 (5.7) kg/m² . Compared with North America, blood pressure and lipids were higher in all regions. Statin use was lowest in Latin America (68%) and Eastern Europe (70%) and aspirin use was lower compared with North America in all regions except Asia Pacific. Achievement of treatment targets did not differ by age group or insulin usage, but men and participants with previous MI were more likely than women or those with previous stroke or peripheral arterial disease to reach most treatment goals.. The CV risk factors of participants in TECOS are reasonably controlled, but differences in CV risk management according to region, sex and history of disease exist. This diversity will enhance the generalizability of the trial results.

Topics: Age Factors; Aged; Asia; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Europe; Female; Hospitalization; Humans; Hypoglycemic Agents; Latin America; Male; Middle Aged; Mortality; North America; Risk Factors; Sex Characteristics; Sitagliptin Phosphate

The aim of this paper was to study sitagliptin in improving the endothelial-mesenchymal transition (EndMT) of human aortic endothelial cells (HAECs) and cardiac function of rats with diabetes mellitus (DM) and its possible pathway.. Sprague Dawley (SD) rats were divided into control group, DM group and sitagliptin group. The myocardial contraction and relaxation functions of rats in each group were observed via echocardiography. The changes in cardiac structure and fiber were observed via hematoxylin-eosin (HE) staining, Masson staining and Sirius red staining. The immunohistochemical assay was performed to observe the expressions of α-smooth muscle actin (α-SMA) and VE-cadherin in HAECs; the expression of reactive oxygen species (ROS) in HAECs was detected using the fluorescence probe. Moreover, the expressions of transforming growth factor-β1 (TGF-β1), phosphorylated-protein kinase A (p-PKA), PKA and extracellular signal-regulated kinase (ERK) were observed via Western blotting.. Sitagliptin could improve the myocardial contraction and relaxation functions in diabetic rats and EndMT and ROS production in HAECs. In the DM group, the expression of Glucagon-like peptide-1 (GLP-1) was decreased, while the expression of stromal-derived factor-1α (SDF-1α) was decreased and the expressions of downstream PKA/ERK pathway and TGF-β1 were increased. The above changes could be reversed by sitagliptin.. Sitagliptin can reverse the EndMT in HAECs as well as the cardiac function in diabetic rats through the SDF-1α/PKA pathway.

Topics: Actins; Animals; Aorta; Chemokine CXCL12; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Endothelial Cells; Endothelium, Vascular; Epithelial-Mesenchymal Transition; Humans; Hypoglycemic Agents; Male; Myocardial Contraction; Myocardium; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction; Sitagliptin Phosphate; Streptozocin

The distribution of glucose and fatty-acid transporters in the heart is crucial for energy consecution and myocardial function. In this sense, the glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, improves glucose homeostasis but it could also trigger direct cardioprotective actions, including regulation of energy substrate utilization.. Type-II diabetic GK (Goto-Kakizaki), sitagliptin-treated GK (10 mg/kg/day) and wistar rats (n = 10, each) underwent echocardiographic evaluation, and positron emission tomography scanning for [. Besides of its anti-hyperglycemic effect, sitagliptin-enhanced GLP-1 may ameliorate diastolic dysfunction in type-II diabetes by shifting fatty acid to glucose utilization in the cardiomyocyte, and thus, improving cardiac efficiency and reducing lipolysis.

Topics: Animals; Blood Glucose; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Energy Metabolism; Fatty Acids; Glucagon-Like Peptide 1; Glucose Transporter Type 4; Incretins; Male; Mice; Myocytes, Cardiac; Protein Transport; Rats, Wistar; Signal Transduction; Sitagliptin Phosphate

The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 β (GSK-3β) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3β and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3β and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3β and p38MAPK.

Topics: AMP-Activated Protein Kinase Kinases; AMP-Activated Protein Kinases; Animals; Apoptosis; Biomarkers; Blood Glucose; Body Weight; Collagen; Diabetes Mellitus, Experimental; Diabetic Cardiomyopathies; Disease Models, Animal; Fatty Acids; Glucagon-Like Peptide 1; Glycogen Synthase Kinase 3 beta; Male; Metformin; Mitogen-Activated Protein Kinase 14; Myocardium; Organ Size; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats, Wistar; RNA, Messenger; Signal Transduction; Sitagliptin Phosphate

The purpose of the study is to identify potential mechanisms involved in the cardiac protective effects of sitagliptin in Zucker diabetic fatty (ZDF) rats.. Male non-diabetic lean Zucker rats (Lean) and ZDF rats treated with saline (ZDF) or sitagliptin (ZDF + sita) were used in this study. The blood pressure and lipid profiles were increased significantly in ZDF rats compared with Lean rats. ZDF + sitagliptin rats had decreased systolic blood pressure compared with ZDF rats. Sitagliptin treatment decreased total cholesterol (TC), triglycerides (TGs), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) levels. Ejection fraction (EF) and fractional shortening (FS) were decreased in ZDF rats, which improved with sitagliptin from 59.8% ± 3.0 and 34.5% ± 3.1 to 66.9% ± 3.4 and 40.9% ± 4.2, respectively. Moreover, the nitroxidative stress level was increased while autophagy levels were decreased in ZDF rats, which was reversed by the administration of sitagliptin. Treatment with sitagliptin or FeTMPyP improved the autophagy level in high-glucose cultured H9c2 cells by increasing autolysosome numbers from 15 ± 4 to 21 ± 3 and 22 ± 3, respectively. We detected a positive correlation between DPP-4 activity and 3-nitrotyrosine levels (r = 0.3903; P < 0.01), a negative correlation between Beclin-1 levels and DPP-4 activity (r = - 0.3335; P < 0.01), and a negative correlation between 3-nitrotyrosine and Beclin-1 levels (r = - 0.3794; P < 0.01) in coronary heart disease patients.. Sitagliptin alleviates diabetes-induced cardiac injury by reducing nitroxidative stress and promoting autophagy. This study indicates a novel target pathway for the treatment of cardiovascular complications in type 2 diabetes mellitus.

Topics: Animals; Autophagy; Beclin-1; Blood Glucose; Cell Line; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Humans; Lipids; Male; Myocytes, Cardiac; Nitrosative Stress; Obesity; Rats, Zucker; Sitagliptin Phosphate; Stroke Volume; Tyrosine; Ventricular Function, Left

To examine whether patients using sitagliptin at the time of an acute coronary syndrome event are at increased risk of incident heart failure compared with those not exposed.. Using US claims data, people with diabetes without a history of heart failure in the 3 years before hospitalization for acute coronary syndrome were identified for the period 2004 to 2010. We used a nested case-control design, whereby cases were patients who developed incident heart failure <30 days after admission to hospital for acute coronary syndrome and were matched by age and sex with up to 10 controls with no heart failure. Subjects exposed or not exposed to sitagliptin in the 90 days before acute coronary syndrome admission were compared using conditional logistic regression after adjustment for clinical and laboratory data, healthcare utilization and propensity scores.. In total, 457 cases of heart failure developing de novo after diagnosis of acute coronary syndrome were matched to 4570 controls. The average age of the subjects was 55 years and 65% were male. Overall, 11 of 147 (7%) people exposed to sitagliptin developed heart failure compared with 446 of the 4880 people not exposed (9%, adjusted odds ratio 0.75, 95% CI 0.38-1.46; P=0.40). Sitagliptin exposure before acute coronary syndrome was not associated with an increased risk of death or heart failure combined (7% vs 9%, adjusted odds ratio 0.66, 95% CI 0.34-1.28).. In our sample of patients who are at high risk of heart failure after acute coronary syndrome, sitagliptin exposure was not associated with an increased risk of de novo heart failure.

Topics: Acute Coronary Syndrome; Case-Control Studies; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Electronic Health Records; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Incidence; Insurance, Health; Logistic Models; Male; Middle Aged; Patient Readmission; Propensity Score; Risk; Sitagliptin Phosphate; United States

Although dipeptidyl peptidase-4 (DPP-4) inhibitor improves glycemic control, the actual cardiovascular outcomes remain unclear. The objective of this cohort study was to thus evaluate the cardiovascular outcome in diabetic patients who received DPP-4 inhibitors (Sitagliptin).. A total of 104,756 new diabetic patients were identified from the Taiwan National Health Insurance Research Database during the period from March 1, 2003 to December 31, 2011. Patients who received Sitagliptin therapy were included as exposures, and up to four age- and sex-matched controls were selected by risk-set sampling. Outcomes such as major adverse cardiovascular diseases (CVD) and deaths were assessed. Logistic regression models were applied to estimate the hazard ratios and 95 % CIs between DPP-4 inhibitor use and cardiovascular outcome.. Over a mean of 14 months, the rates of total CVD per 1000 person-months were significantly lower in Sitagliptin users (3.41 vs. 5.17, p < 0.001), whereas other different CVDs (hazard ratio [HR] 0.59; 95 % confidence interval [CI] 0.48-0.72 for coronary heart disease; HR 0.75; 95 % CI 0.59-0.96 for ischemic stroke; HR 0.86; 95 % CI 0.45-1.65 for peripheral artery occlusive disease) and all-cause mortality (HR 0.56; 95 % CI 0.41-0.74]) were also fewer after adjustment for covariates.. The results showed a favorable outcome of Sitagliptin as a class on lowering CVD incidence in patients with type 2 diabetes.

Topics: Adult; Aged; Case-Control Studies; Cohort Studies; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Dipeptidyl-Peptidase IV Inhibitors; Female; Humans; Hypoglycemic Agents; Incidence; Male; Middle Aged; Sitagliptin Phosphate; Taiwan; Treatment Outcome

Myocardial fibrosis is a key process in diabetic cardiomyopathy. However, their underlying mechanisms have not been elucidated, leading to a lack of therapy. The glucagon-like peptide-1 (GLP-1) enhancer, sitagliptin, reduces hyperglycemia but may also trigger direct effects on the heart.. Goto-Kakizaki (GK) rats developed type-II diabetes and received sitagliptin, an anti-hyperglycemic drug (metformin) or vehicle (n=10, each). After cardiac structure and function assessment, plasma and left ventricles were isolated for biochemical studies. Cultured cardiomyocytes and fibroblasts were used for in vitro assays.. Untreated GK rats exhibited hyperglycemia, hyperlipidemia, plasma GLP-1 decrease, and cardiac cell-death, hypertrophy, fibrosis and prolonged deceleration time. Moreover, cardiac pro-apoptotic/necrotic, hypertrophic and fibrotic factors were up-regulated. Importantly, both sitagliptin and metformin lessened all these parameters. In cultured cardiomyocytes and cardiac fibroblasts, high-concentration of palmitate or glucose induced cell-death, hypertrophy and fibrosis. Interestingly, GLP-1 and its insulinotropic-inactive metabolite, GLP-1(9-36), alleviated these responses. In addition, despite a specific GLP-1 receptor was only detected in cardiomyocytes, GLP-1 isoforms attenuated the pro-fibrotic expression in cardiomyocytes and fibroblasts. In addition, GLP-1 receptor signalling may be linked to PPARδ activation, and metformin may also exhibit anti-apoptotic/necrotic and anti-fibrotic direct effects in cardiac cells.. Sitagliptin, via GLP-1 stabilization, promoted cardioprotection in type-II diabetic hearts primarily by limiting hyperglycemia e hyperlipidemia. However, GLP-1 and GLP-1(9-36) promoted survival and anti-hypertrophic/fibrotic effects on cultured cardiac cells, suggesting cell-autonomous cardioprotective actions.

Topics: Animals; Apoptosis; Cardiomegaly; Cardiotonic Agents; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Cardiomyopathies; Disease Models, Animal; Drug Evaluation, Preclinical; Fibroblasts; Fibronectins; Fibrosis; Glucagon-Like Peptide 1; Glucose Intolerance; Hypoglycemic Agents; Insulin; Male; Metformin; Myocardium; Myocytes, Cardiac; PPAR delta; Protein Isoforms; Pyrazines; Rats; Sitagliptin Phosphate; Triazoles