dpp4-inhibition and coronary artery disease mary anne lim-abrahan, md, fpcp, fpsem professor,...

DPP4-Inhibition and Coronary Artery Disease

Mary Anne Lim-Abrahan, MD, FPCP, FPSEMProfessor, Endocrinology, Diabetes & MetabolismDept. 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

M Kosiborod et al. Circulation 2005;111;3078-3086.

N=141,680 Medicare patients discharged 1/94 – 12/96

Men Women

% M

ort

alit

y1-Year Mortality in Diabetic and Nondiabetic

Subjects after a First MI

Miettinen H et al. Diabetes Care 1998;21:69-75

Diabetes Doubles Early MI Mortality; Despite in Advances in Cardiac Care

Braunwald NEJM 1997;337:1360-69

Defribillation Hemodynamic

monitoring“LYTIC”

ReperfusionBeta-blockade

Aspirin

(before 1962) (1962-1984) (1984-1999)(2000-present)

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

• If all patients are tested= 2/3 of non diabetics- we are not doing anything about it

Norhammar A Lancet 2002; 357: 2140-44

Diabetics excluded

No diabetes by history

DIABETIC HEART DISEASEMechanisms

Diabetic Heart Disease

1. Abn load dueto arterial disease

2. Metabolic Effects due to FFA, Insulin resistance

3. Structural – Myocardial fibrosis and ECM changes

5. Autonomic dysfunction due to reduced HR

4. Reduced perfusion due to small vessel disease

Assuming subclinical CAD and LVH excludedFang et al. Endocr Rev2004

Diabetes, Insulin Resistance and the Risk of Developing Heart Failure

• Type 2 diabetes independently confers ~2- fold ↑ 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 DiastolicDysfunction and Subsequent HF in Diabetic Patients

Aron, M JACC 55, No. 4, 2010

Kaplan-Meier Analysis of DiastolicDysfunction and Death in Diabetic Patients

Aron, M JACC 55, No. 4, 2010

Energy Needs of the Heart

Continuous need for largeamounts of ATP

Heart turns over 5 kg/day ofATP(!) – completely turns overATP supply every 13 seconds(!)

Potential fuels – “Metabolic omnivore”Free fatty acids (FFA)

• 70% in normal heartsGlucose

• Used in stressed/injured heartLactate

• 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

FFA=Free fatty acids.Adapted from Oliver MF et al. Lancet. 1994;343:155-158.

CV stress

Catechols, Cortisol

Lipolysis

Plasma FFA

Glucose

Insulin

Coronaryocclusion

Lysophospholipids

Ca2+ overload Enzyme loss

Glycolysis Glucose oxidation

Membranedamage

Arrhythmias

PhospholipidsTG

FFA

Acyl CoAAcylcarnitine

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 settingof 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

R Muniyappa et al. Endocrine Reviews 2007; 28(5): 463-491.

INSULIN RESISTANCEINSULINSENSITIVE

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 ischemic-reperfused 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 FFA-induced 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)

GLP-1R expression in mouse cardiac and vascular tissues

GLP-1R expression on cardiomyocytes

GLP-1R expression on endocardium

Ban K Circulation. 2008;117:2340-2350

GLP-1R expression on vascular endothelium, and SMCs

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

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

GLP-1 are attractive as a means to stimulate myocardial glucose uptake during post-ischemic contractile dysfunction.

Glucose-Dependent Actions of GLP-1in 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

AK Bose et al. Diabetes 2005; 54: 146-151.

In vitro myocardialinfarct size

In vivo myocardialinfarct size

Exenatide Reduces Infarct Size in a Porcine Model of Ischemia and Reperfusion Injury

Blue - nonthreatened myocardium, red - noninfarcted area within AAR, white - myocardial infarction. Timmers L. JACC 2009;53(6)501-510

Infa

rct

Siz

e (%

of A

AR

)

Infa

rct

Siz

e (%

of

LV)

A Bp = 0.031

p = 0.047

C

PBS Exenatide

D

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 per-infarct zone after 72 hours of rGLP-1 infusion

LA Nikolaidis et al. Circulation 2004; 109: 962-965.

Results- Mortality/MorbidityrGLP-1 TreatedN=10

Controls N=11

p value

In-Hospital Mortality Rate

1 (10%) 3 (27%)

CV Death 0 2 (18%); VF, Cardiogenic Shock

Length of Hospital Stay (days)

6.1 ± 1.3 9.8 ± 1.5 0.02

CCU Days 3.1 ± 4 5.1 ± 1.0

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.

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

Proof of Concept Clinical Study

• 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 improvesHeart 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.



Survival???

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 inType 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

dpp4-inhibition and coronary artery disease mary anne lim-abrahan, md, fpcp, fpsem professor,...

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