Ciprofibrate and Pre-diabetes
Condition: Myocardial Insulin Sensitivity; Impaired Glucose Metabolism; Diastolic Dysfunction
MeSH terms: Insulin Resistance; Prediabetic State; Hypersensitivity
Study type: Interventional
Phase: Phase 3

Summary: 
      Free fatty acids (FFA) are the main fuel source in a healthy adult heart, since they are
      responsible for 70-80% of the myocardial ATP production. Plasma FFA and triglycerides (TG)
      levels are elevated in obesity and diabetes, evoking substrate competition in the heart: the
      increased availability of lipids will lead to fat accumulation in the heart, which is
      associated with cardiac insulin resistance and will therefore restrain insulin-stimulated
      cardiac glucose oxidation. It is shown that a lower myocardial glucose uptake correlates with
      decreased diastolic function. The benefits of counterbalancing this lipid overload is proven
      by previous research in pre-diabetes, which showed the reversibility of impaired myocardial
      substrate metabolism and improvement of function and structure after modest weight loss
      induced by lifestyle changes.

      Ciprofibrates are a ligand of the peroxisome proliferator-activated receptor (PPAR) α and are
      considered to be a major regulator of the lipid metabolism and promote fat oxidative
      capacity. They are not only effective in normalizing lipid-lipoprotein levels in patients
      with the metabolic syndrome, but improve also their insulin sensitivity. We therefore
      hypothesize that ciprofibrate administration in subjects with impaired glucose metabolism
      (IGM) influence the myocardial substrate metabolism (via the PPARα pathway) and thereby
      improve myocardial insulin sensivity.
    

Detailed description: 
      Objectives: The main objective of the study is to investigate whether ciprofibrate treatment
      can improve myocardial insulin sensitivity in subjects with IGM. As secondary objectives we
      want to investigate whether ciprofibrate treatment also improves diastolic and myocardial
      mitochondrial function and decreases intracardiomyocellular lipid content. Futhermore, since
      ciprofibrate could also affect cardiac metabolism indirectly, we want to investigate the
      effect of ciprofibrate on skeletal and hepatic glucose uptake, hepatic lipid storage and
      composition.

      Study design: In a randomized, double-blind, cross-over design, the effects of ciprofibrate
      supplementation on myocardial insulin sensitivity will be compared to placebo in humans with
      IGM.

      Study population: Twelve male, overweight (BMI > 27 kg/m2), insulin-resistant subjects, aged
      between 40 and 70 years, without cardiac disease, will participate in this study.

      Intervention: Subjects will be asked to take one pill of ciprofibrate 100mg, or placebo, once
      daily (at dinner), for 35 days.

      Main study parameters/endpoints: The main study endpoint is the difference in myocardial
      insulin sensitivity (measurement of glucose uptake using radio-active labeled 18F-FDG tracer
      in PET-MRI) after ciprofibrate administration compared to the placebo trial.
    

Intervention name(s): Ciprofibrate 100Mg Tablet; Placebo Oral Tablet
Intervention type(s): Drug; Drug
Intervention description(s): Ciprofibrate is a PPARα ligand and is considered to be a major regulator of the lipid metabolism. PPARα regulates the genes involved in mitochondrial function and fat metabolism and is therefore abundantly expressed in tissues that require high rates of FFA oxidation, like for instance in the heart and activation of PPARα in the heart may have beneficial effects on mitochondrial function and fat oxidative capacity.; To compare ciprofibrate
Other intervention name(s): PPARa agonist
Intervention MeSH terms: Ciprofibrate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science