Download File - Josephine Carlos

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
• The Role of Incretins in the Cardiovascular
Continuum
- Effects on risk factors, LVH ischemia,
AMI, remodeling, CHF and survival
• Mechanisms for GLP-1 Cardioprotection
Admission Glucose and Mortality
N=141,680 Medicare patients discharged 1/94 – 12/96
M Kosiborod et al. Circulation 2005;111;3078-3086.
% Mortality
1-Year Mortality in Diabetic and Nondiabetic
Subjects after a First MI
Men
Women
Miettinen H et al. Diabetes Care 1998;21:69-75
Diabetes Doubles Early MI Mortality; Despite
in Advances in Cardiac Care
Defribillation
Hemodynamic
monitoring
“LYTIC”
Reperfusion
Beta-blockade
Aspirin
(2000-present)
(before 1962) (1962-1984)
(1984-1999)
Braunwald NEJM 1997;337:1360-69
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
Diabetics excluded
• If all patients are tested=
2/3 of non diabetics- we
are not doing anything
about it
No diabetes by history
Norhammar A Lancet 2002; 357: 2140-44
DIABETIC HEART DISEASE
Mechanisms
2. Metabolic Effects due to
FFA, Insulin resistance
1. Abn load due
to arterial disease
3. Structural – Myocardial
fibrosis and ECM changes
Diabetic Heart
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
Diabetes, Insulin Resistance and the Risk
of Developing Heart Failure
• Type 2 diabetes independently confers ~2fold ↑ 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
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 .
Kaplan-Meier Analysis of Diastolic
Dysfunction and Subsequent HF in Diabetic Patients
Aron, M JACC 55, No. 4, 2010
Kaplan-Meier Analysis of Diastolic
Dysfunction and Death in Diabetic Patients
Aron, M JACC 55, No. 4, 2010
Energy Needs of the Heart
 Continuous need for large
amounts 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
Responses to Injury and Insulin Resistance
RM Witteles and MB Fowler. J Am Coll Cardiol 2008; 51: 93-102
Impact of Insulin Resistance on Myocardial Metabolism:
Importance of FF Acid Generation
CV stress
Coronary
occlusion
Catechols, Cortisol
 Lipolysis
 Insulin
 Plasma FFA
Glucose
TG
Phospholipids
FFA
Acyl CoA
Acylcarnitine
Membrane
damage
 Glycolysis
 Glucose oxidation
FFA=Free fatty acids.
Lysophospholipids
Ca2+ overload
Adapted from Oliver MF et al. Lancet. 1994;343:155-158.
Enzyme loss
Arrhythmias
Diabetic Hearts Rely Almost Completely on FFA
Belke et al. Am J Physiol Endocrinol Metab 2000; 279: E1104-E1113.
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 setting
of insulin resistance!
• Therefore...
– Insulin is important for the healthy heart
for 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.
Diabetic hearts are less powerful... can be overcome
with GLUT-4 overexpression
Belke et al. Am J Physiol Endocrinol Metab 2000; 279: E1104-E1113
General features of insulin signal transduction pathways
INSULIN
SENSITIVE
INSULIN RESISTANCE
R Muniyappa et al. Endocrine Reviews 2007; 28(5): 463-491.
The concept of metabolic
modulation to induce a shift
towards glucose utilization may
be a particularly useful strategy
for these patients.
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)
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. Morisco C.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 ischemicreperfused 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.
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.
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;25:1765-1768 which underlies the FFAinduced increased in myocardial oxygen
consumption Mjos OD. J Clin Invest,1971;50:1869-1873
and local heat production (Mjos OD. Scan J Clin Lab
Invest. 1971;28:389-393)
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
GLP-1R expression in mouse cardiac and
vascular tissues
GLP-1R expression
on cardiomyocytes
GLP-1R expression
on endocardium
GLP-1R expression on
vascular endothelium,
and SMCs
Ban K Circulation. 2008;117:2340-2350
The Cardiovascular Disease Continuum
VJ Dzau et al. Circulation 2006; 114: 2850-2870
The Cardiovascular Disease Continuum
VJ Dzau et al. Circulation 2006; 114: 2850-2870
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 Obes Metab 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
Liraglutide
• Associated with weight loss
• Associated with decrease in systolic blood
pressure
• Decreases visceral fat
• Favorable effect on CRP, etc
LEAD Programme, 2009
GLP-1 Improves Endothelial
Dysfunction Type 2 DM Patients with CAD
*P 0.05
Nystrom T. Am J Physiol Endocrinol Metab 287: E1209–E1215, 2004
The Cardiovascular Disease Continuum
VJ Dzau et al. Circulation 2006; 114: 2850-2870
GLP-1 Therapy vs GIK
• These effects are predicated on ambient
glucose concentration and are mitigated at
plasma glucose concentrations <70 mg/dL,
minimizing risks of hypoglycemia and the
need for glucose infusion.
• Thus, the pharmacological properties of GLP1 are attractive as a means to stimulate
myocardial glucose uptake during postischemic contractile dysfunction.
Glucose-Dependent Actions of GLP-1
in Patients With Type 2 Diabetes
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 prosurvival
kinases like PI3K /Akt.
• The prosurvival kinases 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
Myocardial infarction in hearts that have been subjected to 35
min of left main coronary artery occlusion followed by 120
min of reperfusion
AK Bose et al. Diabetes 2005; 54: 146-151.
GLP-1 Decreases Myocardial Infarct Size
In vitro myocardial
In vivo myocardial
infarct size
infarct size
AK Bose et al. Diabetes 2005; 54: 146-151.
Exenatide Reduces Infarct Size in a Porcine
Model of Ischemia and Reperfusion Injury
p = 0.031
B
Infarct Size (% of LV)
Infarct Size (% of AAR)
A
C
p = 0.047
D
PBS
Exenatide
Blue - nonthreatened myocardium, red - noninfarcted area
within AAR, white - myocardial infarction. Timmers L. JACC 2009;53(6)501-510
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
Effects of GLP-1 in Patients with AMI and LV
Dysfunction After Successful Reperfusion
• Primary objective - safety and efficacy of a 72-hour infusion of
GLP-1 (1.5 pmol/kg per minute) added to background therapy
in 10 patients with AMI and LV ejection fraction (EF) <40%
after successful primary angioplasty compared with 11 control
patients.
• Inclusion Critiria - Patients presenting within 6 hrs from
symptom onset, with Killip class II–IV clinical 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 after
reperfusion and after the completion of the GLP-1 infusion.
Nikolaidis LA. Circ 2004:109:962-965
Changes in LVEF and in regional wall motion score at the perinfarct zone after 72 hours of rGLP-1 infusion
LA Nikolaidis et al. Circulation 2004; 109: 962-965.
Results- Mortality/Morbidity
In-Hospital
Mortality
Rate
CV Death
rGLP-1 Treated
N=10
Controls
N=11
1 (10%)
3 (27%)
0
2 (18%); VF,
Cardiogenic
Shock
Length of
6.1 ± 1.3
Hospital Stay
(days)
CCU Days
3.1 ± 4
9.8 ± 1.5
5.1 ± 1.0
p value
0.02
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 contribute to improved outcomes through
non–glucose-dependent mechanisms. These include
reductions in plasma NEFA levels that have been
implicated in arrhythmogenesis. Kavianipour M Peptides
2003:24:560-578.
• rGLP-1 may improve endothelial function and
microcirculatory integrity, as suggested by the higher
peak creatine phosphokinase, consistent with greater
washout, in the rGLP-1–treated patients, despite
comparable baseline regional and global LV dysfunction
in both groups.
The Cardiovascular Disease Continuum
VJ Dzau et al. Circulation 2006; 114: 2850-2870
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.
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
rGLP-1 improves myocardial glucose uptake, oxygen
consumption, and CBF responses at matched levels of
hyperinsulinemia, consistent with insulinomimetic effect
LA Nikolaidis et al. Circulation 2004; 110: 955-961
• 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.
GLP-1 Therapy improves
Heart Failure –Class III-IV
GG Sokos. J Cardiac Fail 2006; 12(9): 694-699.
GLP-1 Therapy Improves Heart Failure
GG Sokos. J Cardiac Fail 2006; 12(9): 694-699.
The Cardiovascular Disease Continuum
Survival???
VJ Dzau et al. Circulation 2006; 114: 2850-2870
SHHF rats randomized to receive intraperintoneal continuous
infusion of GLP-1 had better survival compared with control
I Poornima. Circ Heart Fail 2008; 1: 153-160
GLP-1 treatment was associated with significantly less myocyte
apoptosis. There was no difference in nonmyocyte apoptosis.
I Poornima. Circ Heart Fail 2008; 1: 153-160
Mechanisms for GLP-1 Cardioprotection
• Improvement of risk factors – weight loss, BP
reduction, improved lipids and PPG reduction
• Improved vascular FMD.
• Increases myocardial glucose uptake
• Recruitment of intracellular signaling pathways
involving Akt, Erk1/2, p70S6K and AMPK as well
as the downstream phosphorylation and
inhibition of the pro-apoptotic protein BAD, etc.
• Decreased myocyte apoptosis
• Strongly cardioprotective in multiple preclinical
models
Incretin-based therapies in
Type 2 Diabetes Mellitus
Cardiovascular risk factors and DPP-4
inhibition
• Effective control of PPG
• Reduction of postprandial lipids, especially
chylomicrons and TGs
• Body weight – no effect or slight reduction
• Preclinical data- modest but significant
cardioprotection in vivo
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