Transcript Effect of Glucagon-Like Peptide-I (GLP

Effect of Glucagon-Like Peptide-I (GLPI) 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, Lcells 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 Lcells of the gut.
Pre-pro glucagon
(179 amino acid)
GUT
•GLP-1
•GLP-2
•GLP-1
•GLP-1 (7-36)
(Bio. Active)
BRAIN
PANCREAS
•Glucagon
•MPGF
Dipetidyl peptidase-IV (DPP-IV)
GLP-1 (9-36)
Agonis/antagonist
Function?
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
1.–
AHA,
Heart disease and Stroke staistics:2005;2003;
Transcriptional
mechanism2. 4Taegtmeyer 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 40:9:972977,1991.
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 InsulinResistant 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%
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
No. Of
patients
Screened
Site “A”
Site “B”
Site”C”
350
240
120
No. Of
patients
Qualified
45
16
2
Patients
Agreed
6
3
1
Total patients
Enrolled
10
Patients
Withdrawn
From study
3 patients
Total Patients
Analyzed
•2 Irregular rhythm
•1 difficult venous
access
7 patients
Baseline Assessment
•LVEF
Assessment
Multi gated Acquisition
(MUGA) Scan
•Standard Protocol
•Blood
Sugar
•Portable OneTouch
Ultra Glucometer
•Heart Rate
•Systolic BP
•Diastolic BP
•Non-Invasive
•Automatic DynaMax
•Mean Arterial BP
Exenatide (Byetta)
5 mcg
Subcutaneous
administered.
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
•Non-Invasive
•Automatic DynaMax
•Mean Arterial BP
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
•Computer out put was manually analyzed
•Reader was blinded
Calculated:
• Primary End Point
•Secondary End Points
•Patients acted there own controls
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 Demographic
No. 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)
ACE/ARB, N (%)
Beta-Blockers, N (%)
Loop-diuretics, N (%)
Spironolactone, N(%)
121.29  10.59
6(85)*
6 (85)1
4 (57)
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* (2tailed)
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
LVEF (%)
Blood sugar
(mg/dL)
1
121.29  10.58 82.43 7.521
0.021
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)
Heart Rate 71.86  5.378
(beats/min)
60 minutes
P-value* (2Post Exenatide tailed)
(mean  SEM)
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
0.207
93.  2.7092
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
Mean change in LVEF%, 7 patients
Increase in LVEF %, 7 patients
60
36.5
55
36
50
35.5
45
35
LVEF %
LVEF %
p- value = 0.013
40
35
30
34.5
34
33.5
25
33
20
32.5
Baseline
Time
60 minutes
Baseline
Time
60 minutes
LVEF %, Diabetic vs Non-Diabetic
50
p- value = 0.37
40
40
30
30
LVEF %
LVEF %
50
20
20
10
10
0
0
Diabetic
Non- diabetic
Mean LVEF %, Base line
p- value = 0.4
Diabetic
Non-diabetics
Mean LVEF%, 60 minutes
Hemodynamic Changes (Mean, n=7)
140
Heart rate
(beats/min.)
120
Systolic BP (mmHg)
100
Diastolic BP( mmHg)
80
MAP (mmHg)
60
40
20
0
0 min. 30 min. 60 min. 90 min.
Time
Change in Blood Sugar ( Mean, n=7)
160
Blood Sugar, mg/dL)
140
120
100
Blood sugar
(mg/dL)
80
60
40
20
0
0 min.
30 min.
Time
60 min.
90 min.
MUGA Scan Time vs. Change in LVEF %
Scan Time
20
18
16
14
12
10
8
6
4
2
0
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;
• Speakers Bureau;
• Speakers Bureau;
Amylin Pharmaceuticals
Eli Lilly Co.,
Novo Nordisk,
Acknowledgement
Special 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!