sitagliptin-phosphate and Myocardial-Ischemia

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

Dipeptidyl peptidase 4 inhibitors (DPP4i) may be cardioprotective based on several small animal and clinical studies, though randomized control trials have demonstrated limited benefit. Given these discrepant findings, the role of these agents in chronic myocardial disease, particularly in the absence of diabetes, is still poorly understood. The purpose of this study was to determine the effects of sitagliptin, a DPP4i, on myocardial perfusion and microvessel density in a clinically relevant large animal model of chronic myocardial ischemia. Normoglycemic Yorkshire swine underwent ameroid constrictor placement to the left circumflex artery to induce chronic myocardial ischemia. Two weeks later, pigs received either no drug (CON, n = 8) or 100 mg oral sitagliptin (SIT) daily (n = 5). Treatment continued for 5 weeks, followed by hemodynamic measurements, euthanasia, and tissue harvest of ischemic myocardium. There were no significant differences in myocardial function between CON and SIT as measured by stroke work (p > 0.5), cardiac output (p = 0.22), and end-systolic elastance (p = 0.17). SIT was associated with increased absolute blood flow at rest (17% increase, IQR 12-62, p = 0.045) and during pacing (89% increase, IQR 83-105, p = 0.002). SIT was also associated with improved arteriolar density (p = 0.045) compared with CON, without changes in capillary density (p = 0.72). SIT was associated with increased expression of pro-arteriogenic markers MCP-1 (p = 0.003), TGFß (p = 0.03), FGFR1 (p = 0.002), and ICAM-1 (p = 0.03), with a trend toward an increase in the ratio of phosphorylated/active PLCγ1 to total PLCγ1 (p = 0.11) compared with CON. In conclusion, in chronically ischemic myocardium, sitagliptin improves myocardial perfusion and arteriolar collateralization via the activation of pro-arteriogenic signaling pathways.

Topics: Animals; Coronary Circulation; Dipeptidyl-Peptidase IV Inhibitors; Disease Models, Animal; Myocardial Ischemia; Myocardium; Neovascularization, Physiologic; Perfusion; Pilot Projects; Sitagliptin Phosphate; Swine

Obese-insulin resistance and type 2 diabetes mellitus (T2DM) have become global health problems, and they are both associated with a higher risk of ischemic heart disease. Although reperfusion therapy is the treatment to increase blood supply to the ischemic myocardium, this intervention potentially causes cardiac tissue damage and instigates arrhythmias, processes known as reperfusion injury. Dipeptidyl peptidase 4 (DPP-4) inhibitors are glycemic control drugs commonly used in T2DM patients. Growing evidence from basic and clinical studies demonstrates that a DPP-4 inhibitor could exert cardioprotection and improve left ventricular function by reducing oxidative stress, apoptosis, and increasing reperfusion injury salvage kinase (RISK) activity. However, recent reports also showed potentially adverse cardiac events due to the use of a DPP-4 inhibitor. To investigate this disparity, future large clinical trials are essential in verifying whether DPP-4 inhibitors are beneficial beyond their glycemic control particularly for the ischemic heart in obese-insulin resistant subjects and T2DM patients.

Topics: Adamantane; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Humans; Hypoglycemic Agents; Insulin Resistance; Myocardial Ischemia; Nitriles; Obesity; Oxidative Stress; Pyrrolidines; Rats; Sitagliptin Phosphate; Ventricular Function, Left; Vildagliptin

To determine if the use of sitagliptin in newly treated patients with type 2 diabetes is associated with any changes in clinical outcomes.. Retrospective population based cohort study.. Large national commercially insured US claims and integrated laboratory database.. Inception cohort of new users of oral antidiabetic drugs between 2004 and 2009 followed until death, termination of medical insurance, or December 31 2010.. Composite endpoint of all cause hospital admission and all cause mortality, assessed with time varying Cox proportional hazards regression after adjustment for demographics, clinical and laboratory data, pharmacy claims data, healthcare use, and time varying propensity scores.. The cohort included 72,738 new users of oral antidiabetic drugs (8032 (11%) used sitagliptin; 7293 (91%) were taking it in combination with other agents) followed for a total of 182,409 patient years. The mean age was 52 (SD 9) years, 54% (39,573) were men, 11% (8111) had ischemic heart disease, and 9% (6378) had diabetes related complications at the time their first antidiabetic drug was prescribed. 14,215 (20%) patients met the combined endpoint. Sitagliptin users showed similar rates of all cause hospital admission or mortality to patients not using sitagliptin (adjusted hazard ratio 0.98, 95% confidence interval 0.91 to 1.06), including patients with a history of ischemic heart disease (adjusted hazard ratio 1.10, 0.94 to 1.28) and those with estimated glomerular filtration rate below 60 mL/min (1.11, 0.88 to 1.41).. Sitagliptin use was not associated with an excess risk of all cause hospital admission or death compared with other glucose lowering agents among newly treated patients with type 2 diabetes. Most patients prescribed sitagliptin in this cohort were concordant with clinical practice guidelines, in that it was used as add-on treatment.

Topics: Comparative Effectiveness Research; Confounding Factors, Epidemiologic; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Hospitalization; Humans; Hypoglycemic Agents; Insurance, Health; Male; Middle Aged; Myocardial Ischemia; Practice Guidelines as Topic; Propensity Score; Proportional Hazards Models; Pyrazines; Retrospective Studies; Sitagliptin Phosphate; Time Factors; Treatment Outcome; Triazoles; United States

Topics: Cardiomyopathies; Combined Modality Therapy; Dipeptidyl-Peptidase IV Inhibitors; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Myocardial Ischemia; Pyrazines; Severity of Illness Index; Sitagliptin Phosphate; Treatment Outcome; Triazoles

Glucagon-like peptide-1 (7-36)amide (GLP-1) is cleaved by dipeptidyl peptidase-4 (DPP-4) to GLP-1 (9-36)amide. We examined whether chemical inhibition or genetic elimination of DPP-4 activity affects cardiovascular function in normoglycemic and diabetic mice after experimental myocardial infarction.. Cardiac structure and function was assessed by hemodynamic monitoring and echocardiography in DPP-4 knockout (Dpp4(-/-)) mice versus wild-type (Dpp4(+/+)) littermate controls and after left anterior descending (LAD) coronary artery ligation-induced myocardial infarction (MI). Effects of sustained DPP-4 inhibition with sitagliptin versus treatment with metformin were ascertained after experimental MI in a high-fat diet-streptozotocin model of murine diabetes. Functional recovery from ischemia-reperfusion (I/R) injury was measured in isolated hearts from Dpp4(-/-) versus Dpp4(+/+) littermates and from normoglycemic wild-type (WT) mice treated with sitagliptin or metformin. Cardioprotective signaling in the murine heart was examined by RT-PCR and Western blot analyses.. Dpp4(-/-) mice exhibited normal indexes of cardiac structure and function. Survival post-MI was modestly improved in normoglycemic Dpp4(-/-) mice. Increased cardiac expression of phosphorylated AKT (pAKT), pGSK3beta, and atrial natriuretic peptide (ANP) was detected in the nonischemic Dpp4(-/-) heart, and HO-1, ANP, and pGSK3beta proteins were induced in nonischemic hearts from diabetic mice treated with sitagliptin or metformin. Sitagliptin and metformin treatment of wild-type diabetic mice reduced mortality after myocardial infarction. Sitagliptin improved functional recovery after I/R injury ex vivo in WT mice with similar protection from I/R injury also manifest in hearts from Dpp4(-/-) versus Dpp4(+/+) mice.. Genetic disruption or chemical inhibition of DPP-4 does not impair cardiovascular function in the normoglycemic or diabetic mouse heart.

Topics: Animals; Cardiovascular System; Coronary Vessels; Diabetes Mellitus, Experimental; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Gene Deletion; Heart; Hypoglycemic Agents; Male; Metformin; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Ischemia; Pyrazines; Reference Values; Reperfusion; Sitagliptin Phosphate; Survivors; Triazoles