New perspectives in cardio protection:

Focus on PPAR activation

Principal mechanisms of action for oral diabetic agents

Adapted from Krentz AJ, Bailey CJ. Drugs. 2005;65:385-411

Biguanides

α-Glucosidase inhibitors

Intestine: ↓glucose absorption

Liver: ↓hepatic glucose output

↑glucose uptake

Blood glucose

Sulfonylureas and repaglinide

Pancreas: ↑insulin secretion

Muscle and adipose tissue: ↓insulin resistance

↑glucose uptake

Thiazolidinediones

Site and mode of action of oral antidiabetic medications

DeFronzo RA. Ann Intern Med 1999;131:281-303

MoA AgentsInsulin

secretionSulphonylureas

Other insulinsecretagogues

Glucoseproduction

BiguanidesThiazolidinediones

Slow carbohydratedigestion

--glucosidaseinhibitors

Peripheral insulinsensitivity

Thiazolidinediones(biguanides)

Site of action

Peroxisome proliferator-activator receptors (PPARs)

PPAR , , and belong to the nuclear hormone receptor superfamily

PPAR agonists appear to play a critical role in regulating

inflammation, lipoprotein metabolism, and glucose homeostasis

Studies suggest that PPAR agonists exert antiatherogenic effects by inhibiting proinflammatory gene expression and enhancing cholesterol efflux

PPAR agonists have potential in the treatment of obesity, diabetes, and atherosclerosis

Li AC et al. J Clin Invest. 2004;114:1564-76. Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40.

PPARs: OverviewPPAR

receptor Main tissue location Regulates

Alpha

Liver, skeletal muscle, heart, kidney

Lipid metabolism (dyslipidemia)Inflammation/atherosclerosis

Gamma

Fat cells, macrophages

Insulin sensitivity/glucose metabolismInflammation/atherosclerosisAdipocyte differentiation

Delta

Widespread, includingskeletal muscle andfat cells

Fatty acid oxidationInflammation

Blaschke F et al. Arterioscler Thromb Vasc Biol. 2006;26:28-40Semple RK et al. J Clin Invest. 2006;116:581-9

Focus on PPAR activation

• Reduces insulin resistance

• Preserves pancreatic -cell function

• Improves CV risk profile

Improves dyslipidemia ( HDL, LDL density, or TG)

Renal microalbumin excretion

Blood pressure

VSMC proliferation/migration in arterial wall

PAI-1 levels

C-reactive protein levels

TNF-α production

Adiponectin

Free fatty acids

Inzucchi SE. JAMA. 2002;287:360-72

Beyond fat and glucose: Potential for CV benefits with PPAR agonists

PPAR is expressed incell types associated with CV disease:

– Vascular endothelial cells (EC)

– Vascular smooth muscle cells (VSMC)

– T-lymphocytes

– Monocyte/macrophages

– Cardiac myocytes

– Renal tubule cells Monocytes

Necrotic core

Lumen

VSMC

Adapted from Marx N et al. Arterioscler Thromb Vasc Biol. 1999;19:546-51

Lumen

EC

PPAR activation and atherosclerosis: A hypothesis

Plutzky J. Science. 2003;302:406-7.

Blunts atherosclerosis

IndirectFat, liver, skeletal muscle cells

Ligand:Endogenousor synthetic

Activated PPAR

Reducesinflammation

DirectVascular and inflammatory cells

FFA Glucose Insulin sensitivity Triglycerides HDL Atherogenic LDL

Cytokines Chemokines Cholesterol efflux Adhesion molecules

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