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DPP4-Inhibition and Coronary Artery Disease

DPP4-Inhibition and Coronary Artery Disease. Mary Anne Lim-Abrahan, MD, FPCP, FPSEM Professor, Endocrinology, Diabetes & Metabolism Dept. of Medicine, UP College of Medicine . DPP-4 Inhibition and CAD. The Heart in Diabetes -- Epidemiology -- Energy needs of the Heart

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DPP4-Inhibition and Coronary Artery Disease

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  1. DPP4-Inhibition and Coronary Artery Disease Mary Anne Lim-Abrahan, MD, FPCP, FPSEM Professor, Endocrinology, Diabetes & Metabolism Dept. of Medicine, UP College of Medicine

  2. DPP-4 Inhibition and CAD • The Heart in Diabetes -- Epidemiology -- Energy needs of the Heart • The Role of Incretins in the Cardiovascular Continuum - Effects on risk factors, LVH ischemia, AMI, remodeling, CHF and survival • Mechanisms for GLP-1 Cardioprotection

  3. Admission Glucose and Mortality N=141,680 Medicare patients discharged 1/94 – 12/96 M Kosiborod et al. Circulation 2005;111;3078-3086.

  4. 1-Year Mortality in Diabetic and Nondiabetic Subjects after a First MI % Mortality Men Women Miettinen H et al. Diabetes Care 1998;21:69-75

  5. Diabetes Doubles Early MI Mortality; Despite in Advances in Cardiac Care Defribillation Hemodynamic monitoring “LYTIC” Reperfusion Beta-blockade Aspirin (2000-present) (1984-1999) (before 1962) (1962-1984) Braunwald NEJM 1997;337:1360-69

  6. Diabetes and IGT are present in AMI Consecutive patients with AMI- n=181. OGTT done in all. The 80% after OGTT 25% DM by OGTT 35% IGT by OGTT 40% normal by OGTT If all patients are tested= 2/3 of non diabetics- we are not doing anything about it Diabetics excluded No diabetes by history Norhammar A Lancet 2002; 357: 2140-44

  7. DIABETIC HEART DISEASE Mechanisms 3. Structural – Myocardial fibrosis and ECM changes 2. Metabolic Effects due to FFA, Insulin resistance Diabetic Heart Disease 1. Abn load due to arterial disease 5. Autonomic dysfunction due to reduced HR 4. Reduced perfusion due to small vessel disease Assuming subclinical CAD and LVH excluded Fang et al. Endocr Rev2004

  8. Diabetes, Insulin Resistance and the Risk of Developing Heart Failure • Type 2 diabetes independently confers ~2- fold ↑ risk in men and 3-5-fold ↑ risk in women1234 • Insulin resistance independently confers ~1.5 increase in risk5 • Both diabetes and IR have a synergistic interaction with other risk factors, especially HTN and CAD 1Kannel et al, Am J Cardiol 1974; 2Levy et al, JAMA 1996; 3Gottdiener et al, J Am Coll Cardiol 2000; 4Nichols et al, Diabetes Care 2001; 5Ingelsson et al, JAMA 2005

  9. Diastolic Dysfunction in DM • DD is most frequently identified in diabetic patients with normal systolic function as an incidental finding at echocardiography • Complaints include dyspnea, limited exercise capacity often ascribed to obesity or deconditioning and not recognized as a symptom. • Delayed or impaired relaxation is earliest and most common change .

  10. Kaplan-Meier Analysis of DiastolicDysfunction and Subsequent HF in Diabetic Patients Aron, M JACC 55, No. 4, 2010

  11. Kaplan-Meier Analysis of DiastolicDysfunction and Death in Diabetic Patients Aron, M JACC 55, No. 4, 2010

  12. Energy Needs of the Heart • Continuous need for largeamounts of ATP • Heart turns over 5 kg/day of • ATP(!) – completely turns over ATP supply every 13 seconds(!) • Potential fuels – “Metabolic omnivore” • Free fatty acids (FFA) • 70% in normal hearts • Glucose • Used in stressed/injured heart • Lactate • Up to 60% of fetal energy production

  13. Responses to Injury andInsulin Resistance RM Witteles and MB Fowler. J Am CollCardiol 2008; 51: 93-102

  14. Impact of Insulin Resistance on Myocardial Metabolism: Importance of FF Acid Generation CV stress Coronaryocclusion Catechols, Cortisol  Lipolysis  Insulin TG FFA Acyl CoAAcylcarnitine Phospholipids  Plasma FFA Glucose Lysophospholipids Membrane damage  Glycolysis Glucose oxidation Ca2+ overload Enzyme loss FFA=Free fatty acids. Adapted from Oliver MF et al. Lancet. 1994;343:155-158. Arrhythmias

  15. Diabetic Hearts Rely Almost Completely on FFA Belke et al. Am J PhysiolEndocrinolMetab 2000; 279: E1104-E1113.

  16. Substrate Shifts in the Failing Heart • Glucose metabolism: increased • FFA metabolism: decreased • Result: More efficient energy utilization • Fundamental point: • These shifts are inhibited in the settingof insulin resistance! • Therefore... • Insulin is important for the healthy heartfor transport and utilization of glucose • Insulin is even more important for the failing heart which is more dependent on glucose metabolism. • Insulin resistance is particularly bad in the failing heart.

  17. Diabetic hearts are less powerful... can be overcome with GLUT-4 overexpression Belke et al. Am J PhysiolEndocrinolMetab 2000; 279: E1104-E1113

  18. General features of insulin signal transduction pathways INSULIN SENSITIVE INSULIN RESISTANCE R Muniyappa et al. Endocrine Reviews 2007; 28(5): 463-491.

  19. The concept of metabolic modulation to induce a shift towards glucose utilization may be a particularly useful strategy for these patients.

  20. AMI Pain-Related Burst of Catecholamine 1. Acts on adipose tissue to mobilize FFAs 2. Acutely inhibits the release of insulin from the pancreas 3. AMI is diabetogenic . Causes hyperglycemia. Vetter NJ. Lancet.1974;1:284-288. 4. Elevated FFAs are preferentially oxidized by skeletal and cardiac muscle, hence inhibiting the uptake and oxidation of glucose ( Breham A. Diabetes.2006; 55:136-40) and directly contributing to insulin resistance hyperglycemia (Whitteles RM. J Am Coll Cardiol.2008;51:93-102)

  21. Pain-Related Burst of Catecholamine • Catecholamines increased glucose by promoting hepatic glycogenolysis • Sustained β-adrenergic stimulation directly promotes insulin resistance by inhibition of insulin signaling at the level of protective kinases. MoriscoC.Cardiovasc Res. 2007; 76:453-464. • Early β-blockade can reduce FFA uptake by the failing myocardium Walhaus TR. Circ 2001;103:2441-2446 and lessen FFA accumulation in the ischemic-reperfused heart. Igarashi N. Circ J 006;70:1509-1514. • β-blockade may have adverse hemodynamic consequences including cardiogenic shock and hypotension. Chen ZM.Lancet.2005;366:1622-1632. Giving β-blockade after 3 hours not of much benefit. Gersh BJ. JAMA 2005;293:979-986.

  22. Adverse Effects of FFAs in AMI • Mechanisms: • Membrane-damaging detergent properties of FFAs . Oliver MF. Lancet.1994;343:155-158. • Increased oxygen demand. How OJ. Diabetes2006;55: 466-473. • The metabolic inefficiency leads to contractile abnormalities and adverse left ventricular remodeling. How OJ. Diabetes. 2006;55: 466-473.

  23. Changes in Oxygen Demand on Switching from Carbohydrate to Fatty Acid Metabolism • Normal Heart- 11% increased in oxygen demand. Ashrafian H. Circulation. 2007;116:434-448. • Diabetic Hearts perfused with FFAs- 85% increase with “pronounced oxygen wastage” coupled with decreased cardiac efficiency. How OJ. Diabetes2006;55: 466-473. • This is due to mitochondrial uncoupling Essop F.Eur Heart J.2004;25:1765-1768which underlies the FFA-induced increased in myocardial oxygen consumption Mjos OD. J Clin Invest,1971;50:1869-1873and local heat production (Mjos OD. Scan J Clin Lab Invest. 1971;28:389-393)

  24. DPP-4 Inhibition and CAD • The Heart in Diabetes -- Epidemiology -- Energy needs of the Heart • The Role of Incretins in the Cardiovascular Continuum - Effects on risk factors, LVH ischemia, AMI, remodeling, CHF and survival • Mechanisms for GLP-1 Cardioprotection

  25. GLP-1R expression in mouse cardiac and vascular tissues GLP-1R expression on vascular endothelium, and SMCs GLP-1R expression on cardiomyocytes GLP-1R expression on endocardium Ban K Circulation. 2008;117:2340-2350

  26. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

  27. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

  28. GLP-1 and Cardiovascular Effects • Weight loss associated with GPL-1 (exenatide) may have indirect benefit on CV risk including blood pressure, cholesterol levels , inflammatory markers and insulin resistance. Blonde L Diabetes ObesMetab 2006;8:436-447. • In 217 patients from open-label extensions of various exenatide trials, modest benefit on certain CV risk factors. Klonoff DC. Curr Med Res Opin 2008;24:275-286. - trend to decrease SBP; significant decrease DBP - decrease TG (-44.4 mg/dL), TC (-10.8 mg/dL) and LDL-C (-11.8 mg/dL) and increase HDL-C(8.5 mg/d/L) • ↓ CRP from 3.2 mg/L  1.35 mg/L

  29. Liraglutide • Associated with weight loss • Associated with decrease in systolic blood pressure • Decreases visceral fat • Favorable effect on CRP, etc LEAD Programme, 2009

  30. GLP-1 Improves Endothelial Dysfunction Type 2 DM Patients with CAD *P 0.05 Nystrom T. Am J PhysiolEndocrinolMetab 287: E1209–E1215, 2004

  31. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

  32. GLP-1 Therapy vs GIK • These effects are predicated on ambientglucose concentration and are mitigated at plasma glucose concentrations<70 mg/dL, minimizing risks of hypoglycemia and the needfor glucose infusion. • Thus, the pharmacological properties ofGLP-1 are attractive as a means to stimulate myocardial glucoseuptake during post-ischemic contractile dysfunction.

  33. Glucose-Dependent Actions of GLP-1in Patients With Type 2 Diabetes

  34. GLP-1 May Protect Against Infarction • GPL-1 administered prior to ischemia can activated glycolysis and decrease pyruvate and lactate in the myocardium. GLP-1 can protect myocardium by reducing infarct size when given throughout ischemia and reperfusion • This protective effect is in addition to activation of prosurvivalkinases like PI3K /Akt. • The prosurvivalkinases are part of the Reperfusion Injury Salvage Kinase pathway (RISK pathway) associated with both precondtioning protection as well as protection against reperfusion injury. • Thus GLP-1 may protect against infarction when given before ischemia (as a preconditioning mimetic) or at reperfusion Bose AK Cardiovascular Drugs and Therapy 19 9–11 2005

  35. Myocardial infarction in hearts that have been subjected to 35 min of left main coronary artery occlusionfollowed by 120 min of reperfusion AK Bose et al. Diabetes 2005; 54: 146-151.

  36. GLP-1 Decreases Myocardial Infarct Size In vitro myocardial infarct size In vivo myocardial infarct size AK Bose et al. Diabetes 2005; 54: 146-151.

  37. Exenatide Reduces Infarct Size in a Porcine Model of Ischemia and Reperfusion Injury A B p = 0.031 p = 0.047 Infarct Size (% of LV) Infarct Size (% of AAR) C D PBS Exenatide Blue - nonthreatened myocardium, red - noninfarcted area within AAR, white - myocardial infarction. Timmers L. JACC 2009;53(6)501-510

  38. Proof of Concept Clinical Study – AMI • Small trial with GLP-1 in AMI and LV dysfunction after successful reperfusion – GLP-1 started after reperfusion. • 21 patients with ST segment elevation MI and impaired LV systolic function (LVEF<40%) were undergoing primary PCI Nikolaidis LA. Circ 2004:109:962-965

  39. Effects of GLP-1 in Patients with AMI and LV Dysfunction After Successful Reperfusion • Primary objective - safety and efficacyof a 72-hour infusion of GLP-1 (1.5 pmol/kg per minute) addedto background therapy in 10 patients with AMI and LV ejectionfraction (EF) <40% after successful primary angioplasty comparedwith 11 control patients. • Inclusion Critiria - Patients presentingwithin 6 hrs from symptom onset, with Killip class II–IVclinical presentation and LV ejection fraction (EF) <40%,who were treated with primary angioplasty • Patient characteristics - Both groups had severe LV dysfunction at baseline (LVEF=29±2%). • Parameters - Echocardiograms were obtained afterreperfusion and after the completion of the GLP-1 infusion. Nikolaidis LA. Circ 2004:109:962-965

  40. Changes in LVEF and in regional wall motion score at the per-infarct zone after 72 hours ofrGLP-1 infusion LA Nikolaidis et al. Circulation 2004; 109: 962-965.

  41. Results- Mortality/Morbidity

  42. Conclusion • GLP-1 infusion improved regional and global LV function in patients with AMI and severe systolic dysfunction after successful primary angioplasty. • rGLP-1 may contributeto improved outcomes through non–glucose-dependent mechanisms.These include reductions in plasma NEFA levels that have beenimplicated in arrhythmogenesis.Kavianipour M Peptides 2003:24:560-578. • rGLP-1 mayimprove endothelial function and microcirculatory integrity,as suggested by the higher peak creatinephosphokinase, consistentwith greater washout, in the rGLP-1–treated patients,despite comparable baseline regional and global LV dysfunctionin both groups.

  43. The Cardiovascular Disease Continuum VJ Dzau et al. Circulation 2006; 114: 2850-2870

  44. GLP-1 Improves the Failing Heart • In failing myocardium, Shannon’s group reported beneficial effects of LV contractile function. • -- in a canine model of pacing-induced dilated CM, 48 hour infusion of GLP-1 improved myocardial insulin sensitivity and glucose uptake; increased SV and CO, and decreased LVED volume, HR and systemic vascular resistance. Nikolaidis LA. Circulation 2004; 110:955-961. • -- in a canine model of myocardial stunning, GLP-1 improved regional contractile function. Nikolaidis LA. J Pharmacol Exp Ther 2005; 312:303-308.

  45. Hemodynamic Effects of Continuous infusion of rGLP-1 • Failing heart has a preference for glucose as its metabolic substrate • Examine impact rGLP-1 on LV and systemic hemodynamics and myocardial substrate uptake • - 16 conscious dogs with advanced DCM vs 8 controls • May provide a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake. Nikolais LA Circulation 2004;110:955-961

  46. rGLP-1 improves myocardial glucose uptake, oxygen consumption, and CBF responsesat matched levels of hyperinsulinemia,consistent with insulinomimetic effect LA Nikolaidis et al. Circulation 2004; 110: 955-961

  47. Proof of Concept Clinical Study • 12 patients, chronic HF (NYHA III & IV) • 5 weeks of chronic GLP-1 infusion increased LVEF from 21% to 27%, augmented maximum myocardial oxygen consumption and improved the 6-minute walk test and QOL in both diabetic and non-diabetic patients. • No significant changes in any of the parameters in the control patients on standard therapy. • Benefits were seen in both diabetic both diabetic and non-diabetic patients. Sokos GG. J Card Fail 2006;12:694-699.

  48. GLP-1 Therapy improvesHeart Failure –Class III-IV GG Sokos. J Cardiac Fail 2006; 12(9): 694-699.

  49. GLP-1 Therapy ImprovesHeart Failure GG Sokos. J Cardiac Fail 2006; 12(9): 694-699.

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