A Study Comparing the Mechanisms of Action of Lifibrol and Pravastatin
Condition: Hypercholesterolemia; Hyperlipoproteinemia
MeSH terms: Hypercholesterolemia; Hyperlipoproteinemias; Hyperlipidemias
Study type: Interventional
Phase: Phase 3

Summary: 
      Lifibrol is a new lipid-lowering drug which lowers cholesterol to an extent in the order of
      magnitude of the statins. The mechanism of action of this compound is different from the one
      of statins but remains unknown. The current study will investigate the mechanism of action
      using stable-isotope turnover methods. The study will be done in healthy male volunteers.
    

Detailed description: 
      Elevated lipoprotein concentrations are a major risk factor for the development of
      atherosclerotic cardiovascular disease. Effective reduction of low density lipoprotein
      (LDL)-cholesterol concentrations has been shown to greatly reduce this risk. The most widely
      used lipid-lowering agents are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase
      inhibitors (statins), which have been shown to reduce morbidity and mortality from coronary
      heart disease (CHD) in large prospective clinical trials. However, despite significant LDL-C
      reduction approximately 70% of the events are still not avoided and the search for improved
      or alternative lipid-modifying drug therapies continuous. HDL-C has been addressed as a
      potential modifiable target for decreasing this residual risk, since a low HDL-C
      concentration is an acknowledged independent risk factor for CHD. However, recent studies
      showed that an increase in HDL-C concentrations was surprisingly not associated with a
      decrease in atherosclerosis, but with a possible increase. Therefore it seems that not the
      concentrations of HDL-C should be targeted but HDL function in reverse cholesterol transport.

      Lifibrol is a lipid-modifying drug which has been shown to improve HDL particle flux via
      increased apoA-I production, while not having HDL-raising properties. Furthermore, it
      decreases dose-dependently LDL-C by up to 40%. It is of major interest to clarify the,
      apparently unique, mechanisms of action of a compound, whose LDL-lowering effects are
      comparable in magnitude to the ones of statins.

      The mechanisms of lifibrol's LDL-lowering effects are not completely clarified. There is
      evidence suggesting that it increases hepatic LDL receptor expression by a sterol-independent
      mechanism, i.e. not through a reduction in cholesterol synthesis, the mechanism of action of
      statins. ApoB turnover studies have indicated that increased catabolism of LDL rather than a
      decrease in hepatic apoB production may be responsible for its cholesterol-lowering effects.
      Since apoB metabolism and cholesterol synthesis are closely related, we designed a study to
      investigate the effects of lifibrol on the metabolism of apoB-100-containing lipoproteins and
      on endogenous sterol synthesis in parallel, using stable isotope methods. In addition, since
      lifibrol may inhibit cholesterol synthesis at steps earlier than HMG-CoA reductase, we
      investigated [13C]acetate catabolism analyzing 13CO2 appearance in breath. The
      HMG-CoA-reductase inhibitor pravastatin was used as comparator, since its mode of action is
      well characterized. The principle questions addressed were (i) whether lifibrol exerts its
      cholesterol-lowering effects through decreased synthesis/enhanced catabolism of
      apoB-100-containing lipoproteins or through inhibition of sterol de novo synthesis and (ii)
      whether these effects are interrelated.
    

Intervention name(s): Pravastatin; Lifibrol
Intervention type(s): Drug; Drug
Intervention description(s): Pravastatin 40 mg; Lifibrol (K12.148; 4-(4'-tert. butylphenyl)-1-(4'-carboxyphenoxy)-2-butanol) given as a 600 mg film-coated tablet
Intervention MeSH terms: Pravastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: Cholesterol