Acetyl-L-Carnitine in Type 2 Diabetes

BACKGROUND Arterial hypertension, in particular systolic hypertension, is a common component of the metabolic syndrome, a syndrome of hypertension, abdominal obesity, dyslipidemia, impaired glucose tolerance and increased urinary albumin excretion sustained by decreased tissue sensitivity to insulin (insulin resistance). It affects 80 to 90% of people with type 2 diabetes and is the strongest risk factor for macrovascular and microvascular complications of diabetes, such as myocardial infarction, stroke, peripheral artery disease, nephropathy and retinopathy. Despite multi-drug therapy, reduction of systolic blood pressure to normal range is seldom achievable in people with type 2 diabetes. Moreover, due to increased vascular stiffness, reducing systolic blood pressure may decrease diastolic blood pressure to the extent that diastolic myocardial perfusion is impaired and the risk of ischemic event increased. Thus, availability of drugs that may help controlling systolic hypertension without appreciably affecting diastolic blood pressure would have major clinical implications. In addition to arterial hypertension, dyslipidemia is also a component of the metabolic syndrome that is almost invariably observed in people with type 2 diabetes and remarkably contributes to the excess cardiovascular risk in this population. HMGCoA inhibition by statin therapy, significantly ameliorates hypercholesterolemia, but only marginally affects the concomitant hypertriglyceridemia (probably the most typical feature of increased insulin resistance) and fails to significantly reduce the circulating levels of serum lipoprotein(a), one of the strongest predictors of coronary and cerebrovascular events in type 2 diabetics. Thus, availability of drugs that may help achieving a more effective amelioration of dyslipidemia in this population might also have important clinical implications . In an ongoing study in healthy subjects with decreased insulin sensitivity, we found that 6-month treatment with acetylcarnitine - an ester of l-carnitine - improved the glucose disposal rate, taken as a marker of insulin sensitivity. Amelioration of insulin sensitivity was associated with a significant and clinically relevant reduction in systolic blood pressure without appreciable changes in diastolic blood pressure. Whether blood pressure reduction reflected the amelioration of insulin sensitivity or, rather, a direct, specific effect of acetylcarnitine is still unknown. Previous studies also found that L-carnitine added on background simvastatin therapy, marginally affected serum cholesterol, but remarkably reduced serum triglyceride and lipoprotein (a) levels. Whether amelioration of insulin resistance may explain at least in part this effect is unclear. Finally, all available clinical studies consistently showed that acetyl carnitine is a well tolerated drug that can be safely used in humans. Experimental evidence is also available that l-carnitine may improve statin-associated myotoxicity. AIMS Primary To asses the effect of 6-month therapy with acetylcarnitine compared to placebo on systolic blood pressure in 228 patients with type 2 diabetes, arterial hypertension and dyslipidemia on stable background antihypertensive, hypoglycemic, and lipid lowering therapy. Secondary A.To asses the effect of treatment on: * diastolic and pulse pressure * serum triglycerides and apolipoprotein(a) * HOMA index (calculated during data analyses), serum insulin, leptin, adiponectin (pending on the findings on the other efficacy variables) * blood glucose, serum cholesterol (total, HDL and LDL), non-esterified fatty acids (NEFA), lipoproteins A and and uric acid * 2-hours post oral load blood glucose profile * high density C-reactive protein (hsCRP) * urinary albumin excretion and estimated creatinine clearance (calculated during data analyses) * cardiac output, peripheral resistances or large artery compliance (as assessed by echocardiography in a representative subgroup) * 24 hour sodium excretion and sodium fractional clearance, in a representative subgroup * need for concomitant therapy with antihypertensive, hypoglycemic, and lipid lowering agents B.To assess whether the observed changes in systolic, diastolic or pulse pressures and in lipid or metabolic profile correlate with the concomitant changes in markers of insulin sensitivity. C.To monitor systolic/diastolic blood pressure and other clinical/laboratory parameters evaluated during the study two months after Acetyl-L-Carnitine therapy or Placebo withdrawal in patients completing the study and maintained on the same background medications. DESIGN The study will be a prospective, randomized, double-blind, placebo-controlled, multicenter trial.