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Effect of Glucagon-Like Peptide-I (GLP-I) Analogue in Patients with Stable Coronary Artery Disease With Left Ventricular

Effect of Glucagon-Like Peptide-I (GLP-I) Analogue in Patients with Stable Coronary Artery Disease With Left Ventricular Ejection Fraction ≤ 40 %. Principal Investigator: Wamiq Y Banday. M.B.B.S Sub Investigators: Howard Lippes, MD. Benjamin G. Rueda, MD. Aravind Herle, MD.

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Effect of Glucagon-Like Peptide-I (GLP-I) Analogue in Patients with Stable Coronary Artery Disease With Left Ventricular

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  1. Effect of Glucagon-Like Peptide-I (GLP-I) Analogue in Patients with Stable Coronary Artery Disease With Left Ventricular Ejection Fraction ≤ 40 %. Principal Investigator: Wamiq Y Banday. M.B.B.S Sub Investigators: Howard Lippes, MD. Benjamin G. Rueda, MD. Aravind Herle, MD. Internal Medicine Training Program. Catholic Health System. SUNY at Buffalo. 2157 Main Street. Buffalo, NY 14214

  2. Our Study • Prospective • Single site • Non-randomized • Pilot study

  3. Glucagon Like Peptide-1 • GLP-1 in a gut-derived incretin hormone that is secreted in response to nutrients. • It is a degradation product of pre-proglucagon molecule, a 179 amino acid residue, a product of single Glucagon gene. • Gene is expressed in the Alpha-cells of pancreas, L-cells of Gut & neurons of the brainstem. • GLP-1(7-36) is one of the 5 separately processed domains of pre-proglucagon. This is processed in the L-cells of the gut.

  4. Pre-pro glucagon (179 amino acid) GUT PANCREAS BRAIN • GLP-1 • GLP-2 • Glucagon • MPGF • GLP-1 • GLP-1 (7-36) • (Bio. Active) Dipetidyl peptidase-IV (DPP-IV) GLP-1 (9-36) Agonis/antagonist Function?

  5. GLP-1 Receptors & its effect. Adapted from: T. Nystrom: Hormone Metabolism 2008:40

  6. GLP-1 receptor • G-protein coupled receptor.

  7. Figure 1.

  8. FIG. 2.

  9. GLP-1 contd • GLP-1 (7-36) is biologically active having both insulinomimetic and insulinotropic activity. • GLP-1 has glucoregulatory effects including • Augmentation of glucose-stimulated insulin secretion • Suppression of postprandial glucagon secretion • Delayed gastric emptying • Hypothalmic-mediated satiety of apetite. • Primarily implicated in the control of appetite and satiety.

  10. GLP-1 and Exenatide • Exenatide is a synthetic analogue of exendin-4 found in salivary secretion of Gila Monster, Heloderma suspectum- “Lizard spit” • Exenatide, GLP-1 analogue, is a 39-residue reptilian peptide. • It shares 53% of its amino acid sequence with mammilian GLP-1 • It is functionally similar to mammalian GLP-1. • Half life of exenatide is 2.4 hrs vs. 1 -4 minute for GLP-1

  11. Mean (SEM) Serum Insulin and Plasma glucose Concentration Following a One-time Injection of BYETTA or Placebo in Fasting Type-2 Diabetic patient Adapted from http://www.BYETTA.com

  12. Bench to Bedside • Pancreatic type GLP-1 receptors are found in lung, brain, kidney, stomach and Heart. • T. Nystrom Hor Metabolism Res. 2008 • GLP-1 in myocardium • Increases glucose uptake • Cardioprotection (pro-survival factors)- • Akt1,PI-3K & p44/p42 MAPK • Endothelial protection (nitric oxide pathway) • Pressor effect

  13. “Bench to Bedside” contd. • Bose et al, Diabetes 2005.GLP-1 infusion reduced the infarct size in isolated rat heart. • Nikolaidis L A et al, J. Pharmacol Exp Ther, 2005. Limits the Myocardial stunning canines. • Nikolaidis L A et al, Circulation 2004. LV function Improved in dogs with pacing induced DCM.

  14. “Bench to Bedside” contd. • Nikolaidis L A et al, Circulation 2004. Benefits of GLP-1 Infusion in patients with Severe LV dysfunction following Acute MI and reperfusion. • George G. Sokos et al, Journal of Cardiac Failure . GLP-1 Infusion improves LV function, functional Status and quality of life in Severe heart failure patients

  15. Myocardium, “Metabolic omnivore” • Normal heart utilizes NEFAs (preferably), Glucose and lactate for the production ATP1,2 • Under stress –Myocardial infarction and CHF- it switches to Glucose preferably3 • Energetically more efficient. • Less O2 requirement for ATP production. • Metabolic adaption and flexibility by • Physiological changes and • Transcriptional mechanism4 1. AHA, Heart disease and Stroke staistics:2005;2003; 2. Taegtmeyer et al, Circulation 2002:105;1727-33; 3. Goodwin GW et al; J Biol Chem 1998;273;29530-29539; 4. Taegtmeyer et al, Circulation 2002;106; 2043-5

  16. Congestive Heart Failure -“An Insulin Resistant State” • Loss of metabolic flexibility exhibits- • Early metabolic dysregulation in failing heart1 • Features of insulin resistance2,3 • Left Ventricular dysfunction results in • Myocardial insulin resistance as well as • Whole body insulin resistance • Magnitude and cellular mechanism underlying myocardial insulin resistance demonstrated in concious dogs with DCM3 • Increased glucose utilization can improve Cardiac function. • Giuseppa Paolisso et al demonstrated high norepinephrine levels associated with insulin resistance in in CHF patients4. 1. Taegtmeyer et al, ANN N Y Acad Sci, 2004;1015:1-12; 2. Shah A et al Rev A Cardiovasc Med. 2003 (suppl 6); S50-S57; 3. Nikolaidis L A et al, Cardiovascular Res 2004; 61: 297-306. 4. Metabolism 40:9:972-977,1991.

  17. Over come insulin resistance and improve glucose Utilization • Glucose-insulin-potassium (GIK) infusion has been used as an adjuvant to MI- mixed results. • GIK infusion can’t be used in CHF- volume • GLP-1 has similar effects on glucose metabolism. • GLP-1 has been effective in Acute MI1 1. Nikolaidis L A et al, circulation 200; 109:962-5

  18. “Metabolic Kick” to Chronically Insulin-Resistant Myocardium

  19. Hypothesis We hypothesize that Exenatide, would improve myocardial glucose utilization and will increase the Left ventricular ejection fraction in patients with stable ischemic cardiomyopathy and LVEF </= 40%

  20. Material & Methods • IRB proposal & Approval • Protocol and • SITE SITE “A” ICD-9 Code, MUGA SITE “B” ICD-9 Code, CHF SITE “C” Manual chart review

  21. No. Of patients Screened Site “A” 350 Site “B” 240 Site”C” 120 No. Of patients Qualified 45 16 2 Patients Agreed 6 3 1

  22. Total patients Enrolled 10 Patients Withdrawn From study • 3 patients • 2 Irregular rhythm • 1 difficult venous access Total Patients Analyzed 7 patients

  23. Baseline Assessment • LVEF • Assessment • Multi gated Acquisition (MUGA) Scan • Standard Protocol • Blood Sugar • Portable OneTouch Ultra Glucometer • Heart Rate • Systolic BP • Diastolic BP • Mean Arterial BP • Non-Invasive • Automatic DynaMax

  24. Exenatide (Byetta) 5 mcg Subcutaneous administered.

  25. 60 Minutes post Exenatide. • LVEF • Assessment • Multi gated Acquisition (MUGA) Scan • Standard Protocol • Blood Sugar • Portable OneTouch Ultra Glucometer • Heart Rate • Systolic BP • Diastolic BP • Mean Arterial BP • Non-Invasive • Automatic DynaMax

  26. Monitoring • Heart Rate • Blood Pressure( SBP,DBP & MAP) • Blood Sugar • 30 minutes • 60 minutes • 90 minutes

  27. Analysis of Ejection fraction of Pre & post Exenatide • Automatic, computerized • Compared pre and post Exenatide • Computer out put was manually analyzed • Reader was blinded • Calculated: • Primary End Point • Secondary End Points • Patients acted there own controls

  28. Compliance with HIPAA

  29. Statistical analysis • SPSS software • Paired t-test • Independent t-test • Mean ± SEM • P-value(2-tailed) and <0.05 was statistically significant.

  30. Table: Patient Demographic BMI, Body mass index; SBP, Systolic blood pressure; DBP, diastolic blood pressure; MAP, Mean arterial pressure;

  31. Table: Patient Demographic (contd) * Patient was Allergic to ACE/ARB; 1 Patient developed bradycardia and Mobitz Type I- 20 Heart Block.

  32. Inclusion criteria • Left ventricular ejection fraction ≤ 40%. • Optimum medical therapy for CHF for 6 weeks: • ACE inhibitors/ARB and • Beta Blockers • Loop diuretics ± Spironolactone • Stable coronary artery disease

  33. Exclusion Criteria • Heart failure due to or associated with • Uncorrected thyroid disease, • Obstructive cardiomyopathy, • Pericardial disease, • Amyloidosis or • Active myocarditis. • Hospitalization for acute decompensation of CHF in the past 60 days. • Type 1 diabetes mellitus. • CABG, LV reduction procedure or cardiomyoplasty within 30 days. • Liver enzyme > 5 times the upper limit of normal, • Prolonged prothrombin time in the absence of systemic anticoagulation therapy at the time of screening. • Serum creatinine > 3.5 mg/dL or long-term dialysis. • Currently on Exenatide ( Byetta*)

  34. END POINTS Primary • Short term change in • Left Ventricular Ejection Fraction, % Secondary • End diastolic volume index (EDVI). • End systolic volume index (ESVI) • Hemodynamic response. • SBP, DBP, MAP, HR. • Short term side effects.

  35. Results.

  36. 1EDV was measured in only 6 out of 7 patients. 2 ESV was measured in only 6 out of 7 patients. * P-values were calculated with paired t-test LVEF, left ventricular ejection fraction; EDV, End diastolic volume; ESV, End systolic volume;

  37. 1. SBP, Systolic blood pressure; 2. DBP, Diastolic blood pressure; 3. MAP, Mean arterial pressure. * P-values were calculated with paired t-test.

  38. Change in LVEF %, 60 min. post Exenatide Mean change in LVEF%, 7 patients Increase in LVEF %, 7 patients p- value = 0.013 LVEF % LVEF % Time Time

  39. LVEF %, Diabetic vs Non-Diabetic p- value = 0.4 p- value = 0.37 LVEF % LVEF % Mean LVEF%, 60 minutes Mean LVEF %, Base line

  40. Hemodynamic Changes (Mean, n=7) Time

  41. Change in Blood Sugar ( Mean, n=7) Blood Sugar, mg/dL) Time

  42. MUGA Scan Time vs. Change in LVEF % • No linear relation was seen between “Duration of MUGA scan” and “Change in LVEF %”.

  43. Conclusion • Left Ventricular Ejection Fraction (LVEF) significantly improved 60 minutes after administration of Exenatide • Improvement in LVEF was seen in both- • Diabetic and • Non-diabetics • There was no increasing tendency of change in LVEF with high average MUGA scan time. • Blood sugar significantly decreased.

  44. Conclusion contd. • No significant change in- • End diastolic volume index (EDVI) • End systolic volume index (ESVI) • Heart rate (HR) and • Mean arterial pressure (MAP).

  45. Further Recommendations • No study has yet been conducted to elucidate the long term effects of GLP-1 in large clinical trials (randomised, blinded and adequately powered) • This paucity appears to be due to technical difficulties with the continuous infusion of GLP-1. • Exenatide used in the standard doses, technically feasible, has providing the promisisng results in our Pilot Study

  46. Limitation of Our Study • Non-randomized. • Small number of subjects. • Short-Term effect.

  47. Disclosure • Exenatide is unlabeled/unapproved drugs for CHF. • This study was not funded by any Pharmaceutical company or any government organization • Wamiq Y Banday MBBS None • Benjamin G. Rueda MD None • Aravind Herle MD None • Howard Lippes MD • Speakers Bureau; Amylin Pharmaceuticals • Speakers Bureau; Eli Lilly Co., • Speakers Bureau; Novo Nordisk,

  48. Acknowledgement Special Thanks! All Patients who participated in the Study

  49. Acknowledgement • Mentor • Dr. Howard Lippes. • Benjamin G. Rueda. • Dr AravindHerle. • Nuclear medicine staff. • Research Nurse coordinator- Rose Ganong • Institutional Review Board • Dr. Mohammad Tahir - For Statistics • Department of Internal Medicine- Sisters hospital. • Program Director. Dr Khalid J Qazi.

  50. Question?

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