Ezetimibe and Simvastatin in Dyslipidemia of Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2

Summary: 
      Diabetes mellitus is becoming a global epidemic burden. Its chronic cardiovascular
      complications, myocardial infarction and stroke, are the main causes of death in diabetic
      patients. It was found that low density lipoprotein (LDL) cholesterol concentration is
      related to the increased coronary disease risk that could be successfully reduced by
      cholesterol-lowering therapy. Furthermore, preliminary evidence suggests that ameliorating
      dyslipidemia may be renoprotective in diabetic patients with proteinuria.

      Ezetimibe is the first selective inhibitor of cholesterol absorption and it has demonstrated
      a high efficacy in lowering cholesterol concentration and an excellent safety profile.
      Preliminary data suggest that ezetimibe, combined with a drug that blocks the cholesterol
      synthesis (statins), could be even more effective in decreasing cholesterol concentration.
      The aim of this study is to evaluate whether ezetimibe-simvastatin combined therapy is
      superior to simvastatin monotherapy in ameliorating the lipid profile and albuminuria in type
      2 diabetic patients.
    

Detailed description: 
      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.
    

Intervention name(s): Ezetimibe; Simvastatin
Intervention type(s): Drug; Drug
Intervention MeSH terms: Simvastatin; Ezetimibe
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Diagnostic