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

•Prospective•Single site•Non-randomized•Pilot study

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.

Pre-pro glucagon(179 amino acid)

BRAINPANCREAS

•Glucagon•MPGF

GUT

•GLP-1•GLP-2

•GLP-1 •GLP-1 (7-36)(Bio. Active) GLP-1 (9-36)

Agonis/antagonistFunction?

Dipetidyl peptidase-IV (DPP-IV)

GLP-1 Receptors & its effect.

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

GLP-1 receptor • G-protein coupled receptor.

Figure 1.

FIG. 2.

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• 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

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• 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.• 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” 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”

• 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 mechanism41. 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”

• Loss of metabolic flexibility exhibits-– Early metabolic dysregulation in failing heart1

– Features of insulin resistance 2,3

• 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

• 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

“Metabolic Kick” to Chronically Insulin-Resistant Myocardium

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%

•IRB proposal & Approval

•Protocol and • SITE

Material & Methods

SITE “A”ICD-9 Code,

MUGA

SITE “B”ICD-9 Code,

CHF

SITE “C”Manual

chart review

Site “A”350

Site “B”240

Site”C”120

45 16 2

No. Of patients Screened

No. Of patients Qualified

6 3 1PatientsAgreed

Total patients Enrolled 10

3 patients•2 Irregular rhythm•1 difficult venous

access

Total Patients Analyzed

Patients WithdrawnFrom study

7 patients

Baseline Assessment

•LVEF Assessment

•Blood Sugar

•Heart Rate•Systolic BP•Diastolic BP

•Mean Arterial BP

Multi gated Acquisition (MUGA) Scan

•Standard Protocol

•Portable OneTouch Ultra Glucometer

•Non-Invasive•Automatic DynaMax

Exenatide (Byetta) 5 mcg

Subcutaneous administered.

60 Minutes post Exenatide.

•LVEF Assessment

•Blood Sugar

•Heart Rate•Systolic BP•Diastolic BP

•Mean Arterial BP

Multi gated Acquisition (MUGA) Scan

•Standard Protocol

•Portable OneTouch Ultra Glucometer

•Non-Invasive•Automatic DynaMax

Monitoring•Heart Rate

•Blood Pressure( SBP,DBP & MAP)

•Blood Sugar

•30 minutes•60 minutes•90 minutes

Analysis of Ejection fraction of Pre & post Exenatide•Automatic, computerized

•Compared pre and post Exenatide

Calculated:• Primary End Point

•Secondary End Points•Patients acted there own controls

•Computer out put was manually analyzed•Reader was blinded

Compliance with HIPAA

Statistical analysis

• SPSS software• Paired t-test• Independent t-test• Mean ± SEM• P-value(2-tailed) and <0.05 was

statistically significant.

Table: Patient DemographicNo. Of patients 7

Age (yrs) 70 3

Male, N (%) 5 (71.4)

Female 2 (28.5)

Weight (kgs) 94 9.2

BMI (kg/m2) 30.5 3.2

SBP (mmHg) 125 4

DBP (mmHg) 73.4 4.26

MAP (mmHg) 88.2 4.182

Heart rate (beats/min.) 73 5.34

Regular rhythm, N (%) 7 (100)

Diabetes , N (%) 4 (57)

Hypertension, N (%) 3 (43)

Coronary artery disease, N (%) 7(100)

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

Table: Patient Demographic (contd)Dyslipidemia 6 (85)

Serum Creat. (mg/dL) 1.29 0.107

BUN (mg/dL) 22.7 3.23

HbAIC (%) 6.4 0.252

Baseline BGT (mg/dL) 121.29 10.59

ACE/ARB, N (%) 6(85)*

Beta-Blockers, N (%) 6 (85)1

Loop-diuretics, N (%) 4 (57)

Spironolactone, N(%) 1 (14.3)

Aspirin, N(%) 6 (85)2

Plavix, N(%) 1 (14.3)

Statin, (N%) 6 (85)

AICD, N (%) 2 (28.5)

Pacemaker, N (%) 1 (14.3)

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

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• 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

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.

Results.

Table 4: Pre Exenatide (mean SEM)

60 minutes Post Exenatide (mean SEM)

P-value* (2-tailed)

LVEF (%) 33.86 3.051 35.86 2.915

0.013

EDVI (ml/m 2)1 63.2 4.7 70.4 3.5 0.212

ESVI (ml/m 2) 2 41 3.9 44.2 3.85 0.381

Blood sugar (mg/dL)

121.29 10.58 82.43 7.521 0.0211

EDV 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;

Table 4: Contd.

Pre Exenatide (mean SEM)

60 minutes Post Exenatide (mean SEM)

P-value* (2-tailed)

Heart Rate (beats/min)

71.86 5.378 71.29 3.414

0.888

SBP (mmHg)1

124.86 4.334 128.6 2.836

0.528

DBP (mmHg)2

73.43 4.264 76.71 1.985

0.276

MAP (mmHg)3

88.2 4.182 93. 2.7092 0.207

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

20

25

30

35

40

45

50

55

60

Baseline 60 minutes

32.5

33

33.5

34

34.5

35

35.5

36

36.5

Baseline 60 minutes

p- value = 0.013

Increase in LVEF %, 7 patients Mean change in LVEF%, 7 patients

LV

EF

%

LV

EF

%

Time Time

LVEF %, Diabetic vs Non-Diabetic

0

10

20

30

40

50

Diabetic Non-diabetics0

10

20

30

40

50

Diabetic Non- diabetic

p- value = 0.4

Mean LVEF %, Base line Mean LVEF%, 60 minutesMean LVEF%, 60 minutes

LV

EF

%

LV

EF

%

p- value = 0.37

Hemodynamic Changes (Mean, n=7)

0

20

40

60

80

100

120

140

0 min. 30 min. 60 min. 90 min.

Heart rate(beats/min.)

Systolic BP (mmHg)

Diastolic BP( mmHg)

MAP (mmHg)

Time

Change in Blood Sugar ( Mean, n=7)

0

20

40

60

80

100

120

140

160

0 min. 30 min. 60 min. 90 min.

Blood sugar(mg/dL)

Blo

od S

ugar

, mg/

dL)

Time

MUGA Scan Time vs. Change in LVEF %

0

2

4

6

8

10

12

14

16

18

20

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

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.• No significant change in-

–End diastolic volume index (EDVI)–End systolic volume index (ESVI)–Heart rate (HR) and –Mean arterial pressure (MAP).

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

• Non-randomized.• Small number of subjects.• Short-Term effect.

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,

AcknowledgementSpecial Thanks!

All Patients who participated in the Study

Acknowledgement• Mentor

– Dr. Howard Lippes.– Benjamin G. Rueda.– Dr Aravind Herle.

• 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.

Question?

Thank you!