New Concepts in Dyslipidemia in the Metabolic Syndrome and Diabetes

Abstract

Trials have revealed that cardiovascular risk is not uniform in the population, but is distributed in a "risk pyramid." Diabetic patients with prior cardiovascular disease (CVD) are at greatest risk. Nondiabetic patients with CVD, diabetic patients without CVD, and subjects with the metabolic syndrome form the next three risk categories. The presence of insulin resistance-related metabolic abnormalities is a common denominator in this risk pyramid. Insulin resistance is a core defect in type 2 diabetes and the metabolic syndrome. Because insulin resistance may cause the atherogenic dyslipidemia that is commonly associated with these conditions, therapeutic strategies that combat insulin resistance could substantially reduce cardiovascular risk. Evidence suggests that defects in mitochondrial oxidative phosphorylation(which may be inherited, age related, or lifestyle acquired) may play a critical role in the pathogenesis of insulin resistance. Reduced mitochondrial oxidative phosphorylation can be partially reversed by improved diet, increased exercise, and administration of peroxisome proliferator-activated receptor-α agonists (ω-3 fatty acids and fibrates). Statin therapy has demonstrated clinical benefits in insulin-resistant patients but residual cardiovascular risk remains elevated. Fibrates also improve the lipid profile and reduce cardiovascular risk in a variety of insulin-resistant populations. Affected individuals should be targeted for therapeutic lifestyle intervention. Patients with atherogenic dyslipidemia who have developed insulin resistance, the metabolic syndrome, or type 2 diabetes should receive more intensive interventions including, where appropriate, statin–fibrate combination therapy, to comprehensively modify the lipid profile together with aggressive control of blood pressure and glucose to minimize risk in this very high-risk population.