sitagliptin-phosphate and Ventricular-Dysfunction--Left

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

Left ventricular (LV) diastolic dysfunction is frequently observed in patients with type 2 diabetes. Dipeptidyl peptidase-4 inhibitor (DPP-4i) attenuates postprandial hyperglycemia (PPH) and may have cardio-protective effects. It remains unclear whether DPP-4i improves LV diastolic function in patients with type 2 diabetes, and, if so, it is attributable to the attenuation of PPH or to a direct cardiac effect of DPP-4i. We compared the effects of the DPP-4i, sitagliptin, and the alpha-glucosidase inhibitor, voglibose, on LV diastolic function in patients with type 2 diabetes.. We conducted a prospective, randomized, open-label, multicenter study of 100 diabetic patients with LV diastolic dysfunction. Patients received sitagliptin (50 mg/day) or voglibose (0.6 mg/day). The primary endpoints were changes in the e' velocity and E/e' ratio from baseline to 24 weeks later. The secondary efficacy measures included HbA1c, GLP-1, lipid profiles, oxidative stress markers and inflammatory markers.. The study was completed with 40 patients in the sitagliptin group and 40 patients in the voglibose group. There were no significant changes in the e' velocity and E/e' ratio from baseline to 24 weeks later in both groups. However, analysis of covariance demonstrated that pioglitazone use is an independent factor associated with changes in the e' and E/e' ratio. Among patients not using pioglitazone, e' increased and the E/e' ratio decreased in both the sitagliptin and voglibose groups. GLP-1 level increased from baseline to 24 weeks later only in the sitagliptin group (4.8 ± 4.7 vs. 7.3 ± 5.5 pmol/L, p < 0.05). The reductions in HbA1c and body weight were significantly greater in the sitagliptin group than in the voglibose group (-0.7 ± 0.6 % vs. -0.3 ± 0.4, p < 0.005; -1.3 ± 3.2 kg vs. 0.4 ± 2.8 kg, p < 0.05, respectively). There were no changes in lipid profiles and inflammatory markers in both groups.. Our trial showed that sitagliptin reduces HbA1c levels more greatly than voglibose does, but that neither was associated with improvement in the echocardiographic parameters of LV diastolic function in patients with diabetes.. Registered at http://www.umin.ac.jp under UMIN000003784.

Topics: Aged; Diabetes Mellitus, Type 2; Diastole; Dipeptidyl-Peptidase IV Inhibitors; Echocardiography; Female; Glucagon-Like Peptide 1; Glycated Hemoglobin; Glycoside Hydrolase Inhibitors; Humans; Inositol; Male; Middle Aged; Sitagliptin Phosphate; Treatment Outcome; Ventricular Dysfunction, Left

The incretin hormone, glucagon-like peptide-1, promotes myocardial glucose uptake and may improve myocardial tolerance to ischemia. Endogenous glucagon-like peptide-1 (7-36) is augmented by pharmacological inhibition of dipeptidyl peptidase-4. We investigated whether chronic dipeptidyl peptidase-4 inhibition by sitagliptin protected against ischemic left ventricular dysfunction during dobutamine stress in patients with type 2 diabetes mellitus and coronary artery disease.. A total of 19 patients with type 2 diabetes mellitus underwent dobutamine stress echocardiography with tissue Doppler imaging on 2 separate occasions: the first (control) while receiving oral hypoglycemic agents, and the second after the addition of sitagliptin (100 mg once daily) for ≈4 weeks. Sitagliptin increased plasma glucagon-like peptide-1 (7-36) levels and, at peak stress, enhanced both global (ejection fraction, 70.5±7.0 versus 65.7±8.0%; P<0.0001; mitral annular systolic velocity, 11.7±2.6 versus 10.9±2.3 cm/s; P=0.01) and regional left ventricular function, assessed by peak systolic velocity and strain rate in 12 paired, nonapical segments. This was predominantly because of a cardioprotective effect on ischemic segments (strain rate in ischemic segments, -2.27±0.65 versus -1.98±0.58 s(-1); P=0.001), whereas no effect was seen in nonischemic segments (-2.19±0.48 versus -2.18±0.54 s(-1); P=0.87). At 30 minutes recovery, dipeptidyl peptidase-4 inhibition mitigated the postischemic stunning seen in the control scan.. The addition of dipeptidyl peptidase-4 inhibitor therapy with sitagliptin to the treatment regime of patients with type 2 diabetes mellitus and coronary artery disease is associated with a sustained improvement in myocardial performance during dobutamine stress and a reduction in postischemic stunning.. URL: http://www.isrctn.org. Unique identifier ISRCTN61646154.

Topics: Aged; Coronary Angiography; Coronary Artery Disease; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Echocardiography, Doppler; Echocardiography, Stress; Electrocardiography; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Heart Ventricles; Humans; Male; Myocardial Ischemia; Pilot Projects; Pyrazines; Sitagliptin Phosphate; Stroke Volume; Treatment Outcome; Triazoles; Ventricular Dysfunction, Left

Increased mortality due to type 2 diabetes mellitus (T2DM) has been associated with renal and/or cardiovascular dysfunction. Dipeptidyl dipeptidase-4 inhibitors (iDPP-4s) may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms. In this study, the pharmacological profile of a new iDPP-4 (LASSBio-2124) was investigated in rats with cardiac and renal dysfunction induced by T2DM.. T2DM was induced in rats by 2 weeks of a high-fat diet followed by intravenous injection of streptozotocin. Metabolic disturbance and cardiac, vascular, and renal dysfunction were analyzed in the experimental groups.. Sitagliptin and LASSBio-2124 administration after T2DM induction reduced elevated glucose levels to 319.8 ± 13.2 and 279.7 ± 17.8 mg/dL, respectively (p < 0.05). LASSBio-2124 also lowered the cholesterol and triglyceride levels from 76.8 ± 8.0 to 42.7 ± 3.2 mg/dL and from 229.7 ± 25.4 to 100.7 ± 17.1 mg/dL, in diabetic rats. Sitagliptin and LASSBio-2124 reversed the reduction of the plasma insulin level. LASSBio-2124 recovered the increased urinary flow in diabetic animals and reduced 24-h proteinuria from 23.7 ± 1.5 to 13.3 ± 2.8 mg (p < 0.05). It also reduced systolic and diastolic left-ventricular dysfunction in hearts from diabetic rats.. The effects of LASSBio-2124 were superior to those of sitagliptin in the cardiovascular systems of T2DM rats. This new prototype showed promise for the avoidance of comorbidities in a T2DM experimental model, and thus may constitute an innovative therapeutic agent for the treatment of these conditions in the clinical field in future.

Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Heart; Kidney Diseases; Male; Rats; Rats, Wistar; Sitagliptin Phosphate; Streptozocin; Ventricular Dysfunction, Left

Sitagliptin, a dipeptidyl peptidase IV (DPP-Ⅳ) inhibitor, has a biological role in improving the serum levels of glucagon-like peptide 1 (GLP-1). Hence, we sought to determine the effect of sitagliptin on myocardial inflammation, collagen metabolism, lipid content and myocardial apoptosis in diabetic rats.. The type 2 diabetic rat model was induced by low-dose streptozotocin and a high-fat diet. Characteristics of diabetic rats were evaluated by electrocardiography, echocardiography and blood analysis. Cardiac inflammation, fibrosis, cardiomyocyte density, lipid accumulation, and receptor-interacting protein kinase 3 (RIP3) level, related to apoptosis, were detected by histopathologic analysis, RT-PCR and western blot analysis to evaluate the effects of sitagliptin on myocardial remodeling of the left ventricle.. Diabetic rats showed myocardial hypertrophy or apoptosis, inflammation, lipid accumulation, myocardial fibrosis, elevated collagen content, RIP3 overexpression, and left-ventricular dysfunction. Sitagliptin could reverse the overexpression of RIP3 and alleviate cellular apoptosis in myocardial tissues. It could significantly improve left-ventricular systolic pressure and +dp/dt max, reduce the E/E' ratio, left ventricular end diastolic pressure, -dp/dt max and Tau in diabetic rats.. Sitagliptin might have a myocardial protective effect by inhibiting apoptosis, inflammation, lipid accumulation and myocardial fibrosis in diabetic rats, for a potential role in improving left-ventricular function in diabetes.

Topics: Animals; Apoptosis; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diastole; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Lipid Metabolism; Male; Myocardium; Rats, Wistar; Receptor-Interacting Protein Serine-Threonine Kinases; Sitagliptin Phosphate; Streptozocin; Ventricular Dysfunction, Left; Ventricular Remodeling

Obesity and Type 2 diabetes mellitus (DM) induce left ventricular (LV) diastolic dysfunction, which contributes to an increasing prevalence of heart failure with a preserved LV ejection fraction. We investigated the effects of sitagliptin (SITA), an inhibitor of dipeptidylpeptidase-4 (DPP-4) and anti-diabetic drug, on LV structure and function of obese mice with Type 2 DM.. Obese Type 2 diabetic mice (Lepr(db/db), BKS.Cg-Dock7(m)+/+ Lepr(db)/J), displaying increased cardiomyocyte and LV stiffness at the age of 16 weeks, were treated with SITA (300 mg/kg/day) or vehicle for 8 weeks. SITA severely impaired serum DPP-4 activity, but had no effect on glycaemia. Invasive haemodynamic recordings showed that SITA reduced LV passive stiffness and increased LV stroke volume; LV end-systolic elastance remained unchanged. In addition, SITA reduced resting tension of isolated single cardiomyocytes and intensified phosphorylation of the sarcomeric protein titin. SITA also increased LV concentrations of cGMP and increased activity of protein kinase G (PKG). In vitro activation of PKG decreased resting tension of cardiomyocytes from vehicle-treated mice, but had no effect on resting tension of cardiomyocytes from SITA-treated mice.. In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus.

Topics: Animals; Atrial Natriuretic Factor; Compliance; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Diabetes Mellitus, Experimental; Diastole; Dipeptidyl-Peptidase IV Inhibitors; Drug Evaluation, Preclinical; Heart; Heart Ventricles; Male; Mice; Myocytes, Cardiac; Pyrazines; Random Allocation; Sitagliptin Phosphate; Triazoles; Ventricular Dysfunction, Left

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted postprandially that promotes myocardial glucose uptake. The active amide GLP-1 (7-36) is degraded by the enzyme DPP-4, and drugs that inhibit this enzyme (such as sitagliptin) have been introduced to treat type 2 diabetes. We assessed the hypothesis that increasing the plasma concentration of GLP-1 by DPP-4 inhibition would protect the heart from ischemic left ventricular (LV) dysfunction during dobutamine stress echocardiography in patients with coronary artery disease.. Fourteen patients with coronary artery disease and preserved LV function awaiting revascularization were studied. After either a single dose of 100 mg sitagliptin or placebo, 75 g of glucose was given orally to promote GLP-1 secretion and dobutamine stress echocardiography was conducted with tissue Doppler imaging at rest, peak stress, and 30 minutes. After sitagliptin, plasma GLP-1 (7-36) was increased at peak stress (16.5+/-10.7 versus 9.7+/-8.7 pg/mL; P=0.003) and in recovery (12.4+/-5.5 versus 9.0+/-5.5 pg/mL; P=0.01), and the LV response to stress was enhanced (ejection fraction, 72.6+/-7.2 versus 63.9+/-7.9%, P=0.0001; mitral annular systolic velocity, 12.54+/-3.18 versus 11.49+/-2.52 cm/s; P=0.0006). DPP-4 inhibition also improved LV regional function in the 12 paired nonapical segments assessed by peak systolic tissue Doppler (velocity, 10.56+/-4.49 versus 9.81+/-4.26 cm/s, P=0.002; strain, -15.9+/-6.3 versus -14.6+/-6.6%, P=0.01; strain rate, -2.04+/-1.04 versus -1.75+/-0.98 s(-1), P=0.0003). This was predominantly due to a cardioprotective effect on ischemic segments (velocity in ischemic segments, 9.77+/-4.18 versus 8.74+/-3.87, P=0.007; velocity in nonischemic segments, 11.51+/-4.70 versus 11.14+/-4.38, P=0.14). In recovery, sitagliptin attenuated the postischemic stunning seen after the control study.. The augmentation of GLP-1 (7-36) by inhibition of DPP-4 improves global and regional LV performance in response to stress and mitigates postischemic stunning in humans with coronary artery disease. Clinical Trial Registration- URL: http://www.isrctn.org. Unique identifier: ISRCTN78649100.

Topics: Coronary Artery Disease; Dipeptidyl-Peptidase IV Inhibitors; Echocardiography, Stress; Female; Glucagon-Like Peptide 1; Humans; Male; Middle Aged; Myocardial Stunning; Pilot Projects; Pyrazines; Reproducibility of Results; Sitagliptin Phosphate; Triazoles; Ventricular Dysfunction, Left