INTRODUCTION
Diabetes mellitus contributes substantially to the global burden of disease, with an estimated 150 million people affected worldwide and its prevalence is expected to double by 2025. Myocardial infarction and stroke are common causes of major morbidity in people with diabetes, most of whose deaths are attributed to cardiovascular causes. Recent findings provide definitive evidences that cholesterol-lowering therapy can produce substantial reductions in the risk of heart attacks, stroke and revascularizations in diabetic patients even if they do not have high blood cholesterol concentrations.
Also preliminary evidence is available that ameliorating dyslipidemia may be renoprotective in diabetic patients with proteinuria.
Ezetimibe is the first member of a class of highly selective cholesterol absorption inhibitors that effectively and potently prevents the absorption of cholesterol by inhibiting the passage of biliary and dietary cholesterol across the wall of the small intestine, without affecting absorption of other fat-soluble nutrients.
Many pre-clinical models have demonstrated the lipid-lowering and anti-atherosclerotic properties of ezetimibe as a single agent, and showed its synergistic effect in combination with HMGCoA reductase inhibitors (statins).
Phase I/II studies on patients with hypercholesterolemia have explored the safety and efficacy of ezetimibe monotherapy and co-administration with simvastatin. In these studies, combined therapy was safely and invariably more effective than single therapy in ameliorating the lipid profile.
Ezetimibe had an excellent safety profile in standard toxicity studies in pre-clinical models. Clinical studies in patients with primary hyperlipidemia have also indicated that monotherapy with ezetimibe and coadministration with a statin were both well tolerated. Whether ezetimibe-simvastatin combined therapy more effectively than simvastatin monotherapy ameliorates the lipid profile and albuminuria in people with diabetes is worth investigating. Evidence of a superior efficacy of ezetimibe-simvastatin would provide the rationale for a prospective trial aimed to explore the possibility of a superior cardioprotective and renoprotective effect of the combined therapy.
AIM
Primary:
* To compare the effect of ezetimibe-simvastatin combination (10-40mg/day) and simvastatin (40mg/day) alone on LDL-cholesterol concentrations in type 2 diabetic patients with basal total cholesterol \>135mg/dl and/or concomitant lipid lowering therapy with HMGCoA reductase inhibitors.
Secondary:
* To compare the effect of the above treatments on total cholesterol, apolipoprotein A1 and B, lipoprotein (a) and triglyceride concentrations.
* To evaluate the safety profile of these two treatments.
Explorative:
To explore the hypothesis that ameliorating dyslipidemia therapy may also result in a reduction of urinary albumin excretion rate.
DESIGN
This will be a randomized, prospective, double-blind, parallel group study. Following a 4-week wash-out period from previous lipid-lowering therapy (if any) with HMGCoA reductase inhibitors or any other kinds of lipid-lowering drugs, patients will enter a two-month run-in phase with simvastatin 40mg per day. At completion of the run-in period, patients will be randomly allocated into two double-blind treatment arms, ezetimibe 10mg + simvastatin 40mg per day or placebo + simvastatin 40mg per day for a two-month treatment period.
