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Effect of Glucagon-Like Peptide-I (GLP-I) Analogue in Patients with Stable Coronary Artery Disease With Left Ventricular PowerPoint Presentation
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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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slide1

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

our study
Our Study
  • Prospective
  • Single site
  • Non-randomized
  • Pilot study
glucagon like peptide 1
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.
slide4

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?

glp 1 receptors its effect
GLP-1 Receptors & its effect.

Adapted from: T. Nystrom: Hormone Metabolism 2008:40

glp 1 receptor
GLP-1 receptor
  • G-protein coupled receptor.
glp 1 contd
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.
glp 1 and exenatide
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
slide11

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

bench to bedside
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
bench to bedside contd
“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.
bench to bedside contd14
“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
myocardium metabolic omnivore
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

congestive heart failure an insulin resistant state
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.

over come insulin resistance and improve glucose utilization
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

hypothesis
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%

material methods
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

slide21

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

slide22

Total patients Enrolled

10

Patients Withdrawn

From study

  • 3 patients
  • 2 Irregular rhythm
  • 1 difficult venous access

Total Patients

Analyzed

7 patients

slide23

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
slide25

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
slide26

Monitoring

  • Heart Rate
  • Blood Pressure( SBP,DBP & MAP)
  • Blood Sugar
  • 30 minutes
  • 60 minutes
  • 90 minutes
slide27

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
statistical analysis
Statistical analysis
  • SPSS software
  • Paired t-test
  • Independent t-test
  • Mean ± SEM
  • P-value(2-tailed) and <0.05 was statistically significant.
table patient demographic
Table: Patient Demographic

BMI, Body mass index; SBP, Systolic blood pressure; DBP, diastolic blood pressure; MAP, Mean arterial pressure;

table patient demographic contd
Table: Patient Demographic (contd)

* Patient was Allergic to ACE/ARB; 1 Patient developed bradycardia and Mobitz Type I- 20 Heart Block.

inclusion criteria
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
exclusion criteria
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*)
end points
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.
slide36

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;

slide37

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

change in lvef 60 min post exenatide
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

lvef diabetic vs non diabetic
LVEF %, Diabetic vs Non-Diabetic

p- value = 0.4

p- value = 0.37

LVEF %

LVEF %

Mean LVEF%, 60 minutes

Mean LVEF %, Base line

change in blood sugar mean n 7
Change in Blood Sugar ( Mean, n=7)

Blood Sugar, mg/dL)

Time

muga scan time vs change in lvef
MUGA Scan Time vs. Change in LVEF %
  • No linear relation was seen between “Duration of MUGA scan” and “Change in LVEF %”.
conclusion
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.
conclusion contd
Conclusion contd.
  • No significant change in-
    • End diastolic volume index (EDVI)
    • End systolic volume index (ESVI)
    • Heart rate (HR) and
    • Mean arterial pressure (MAP).
further recommendations
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
limitation of our study
Limitation of Our Study
  • Non-randomized.
  • Small number of subjects.
  • Short-Term effect.
disclosure
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,
acknowledgement
Acknowledgement

Special Thanks!

All Patients who participated

in the Study

acknowledgement49
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.