Program 2

Development of predictive animal nutritional models of cardiovascular complications of type 2 diabetes .

Diabetic patients have a two- to four-fold-higher risk of cardiovascular events than non diabetic subjects, and cardiovascular events are the most common cause of death among type 2 diabetics. After myocardial infarction, some 80% of diabetic patients may die of cardiac complications ¹. Accurate predictive risk evaluation is urgently needed, as stated by the 2008 FDA Guidance for Industry on Diabetes Mellitus ².
Physiogenex initiated in late 2007 a new research program aimed at using innovative tools for predictive functional non invasive evaluation of cardiovascular outcomes and early cardiac and vascular impairments, as observed in human diabetic populations.
This program includes the development of two complementary animal models reproducing major causes of cardiovascular dysfunction in the human cardiometabolic syndrome:

1. An animal nutritional model displaying direct consequences of insulin resistance on heart function and cardiovascular outcome,
2. An animal nutritional model reproducing the sequence of all “cardiometabolic syndrome” components, from obesity and insulin resistance to hypertension and late cardiomyopathy. This model should be suitable for evaluating drug effects on mortality.

These models, combined with echocardiography and non invasive arterial pressure and heart rate variability measurements (autonomous nervous system activity), and final assessment of cardiac and coronary artery function, should be extremely useful for drug efficacy profiling and predictive safety evaluation in insulin-resistant cardiomyopathy (diastolic dysfunction, cardiac steatosis) and coronary artery disease (coronary artery vasomotricity, arrhythmias and sympathetic activation). We have selected specific animal strains which, in controlled dietary conditions, develop an insulin-resistant phenotype coupled with cardiovascular dysfunctions close to those seen in humans. We are currently in the pathophysiological and pharmacological validation phase. The first validated results are expected in Automne 2008.

Comparative table of rat/mouse model of obesity/insulin resistance/diabetes associated with cardiovascular complications versus human

¹ Jacoby RM, Nesto RW : Acute myocardal infarction in the diabetic patient : pathophysiology, clinical course and prognosis. J Am Coll Cardiol 20:736-744, 1992
² FDA Guidande for industry, Diabetes Meltius : Developping Drugs and Therapeutics Biologics for treatment and prevention, February 2008

“There is a growing recognition that addressing cardiovascular disease risk factors, such as hypertension, smoking and dislipidemia, in patients with diabetes is particularly important, as diabetes is now considered an atherosclerotic heart disease equivalent”,

FDA Guidance for Industry on Diabetes Mellitus: Developing drugs and therapeutic biologics for treatment and prevention, February 2008