Ciprofibrate and Pre-diabetes

Study Overview
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Brief Summary
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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
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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.

Official Title
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Effects of Ciprofibrate on Myocardial Insulin Sensitivity in Pre-diabetes

Conditions
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Myocardial Insulin Sensitivity, Diastolic Dysfunction, Impaired Glucose Metabolism

Intervention / Treatment
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* Drug: Ciprofibrate 100Mg Tablet
* Drug: Placebo Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Race: caucasian Sex: male Age: 40-70 years BMI: 27-35 kg/m2 Stable dietary habits: no weight gain or loss > 5kg in the last three months Insulin resistant: glucose clearance rate below < 360 ml/kg/min, as determined using OGIS120 Exclusion Criteria: Patients with a cardiac disease or with instable angina Patients with hepatic or renal failure Haemoglobin <7.8 mmol/l In case of an abnormal ECG in rest: this will be discussed with the responsible medical doctor HbA1c > 6.5% Diagnosed with type 1 or type 2 diabetes mellitus Patients with alcohol abuse Use of a fibrate Medication use known to interfere with glucose homeostasis/metabolism Use of anti-coagulants, excluding platelet aggregation inhibitors Subjects who do not want to be informed about unexpected medical findings during the screening /study, or do not wish that their physician is informed, cannot participate in the study. Subjects who intend to donate blood during the intervention or subjects who have donated blood less than three months before the start of the intervention. Participation in another biomedical study within 1 month before the first screening visit Any condition, disease or abnormal laboratory test result that, in the opinion of the Investigator, would interfere with the study outcome, affect trial participation or put the subject at undue risk Any contra-indication to MRI scanning. These contra-indications include patients with following devices: Electronic implants such as pacemakers or defibrillator or neurostimulator Central nervous system aneurysm clip Some hearing aids (such as cochlear implant) and artificial (heart) valves which are contraindicated for MRS Iron containing corpora aliena in the eye or brains Claustrophobia Participation in earlier research or medical examinations in the past 3 months that included PET/MRI scanning

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ciprofibrate<br>1dd100mg at breakfast | Drug: Ciprofibrate 100Mg Tablet<br>* 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.<br>* Other names: PPARa agonist;|
| Placebo Comparator: Placebo<br>1dd0mg at breakfast | Drug: Placebo Oral Tablet<br>* To compare ciprofibrate<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial insulin sensitivity | measured by the insulin-stimulated myocardial glucose uptake by FDG-PET | 1hour, day 35 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hepatic glucose uptake | measured by the insulin-stimulated myocardial glucose uptake by FDG-PET | 1hour, day 35 | 
| Skeletal muscle glucose uptake | measured by the insulin-stimulated myocardial glucose uptake by FDG-PET | 1hour, day 35 | 
| Brown adipose tissue (BAT) glucose uptake | measured by the insulin-stimulated myocardial glucose uptake by FDG-PET | 1hour, day 35 | 
| Insulin sensitivity | Glucose infusion rate (GIR) from the hyperinsulinemic euglycemic clamp | 4hours, day 35 | 
| Intracardiomyocellular lipid content | Cardiac 1H-MRS: fasted & insulin-stimulated | 1hour, day 35 | 
| Cardiac systolic function | Functional cardiac MRI: fasted & insulin-stimulated | 1hour, day 35 | 
| In vivo myocardial mitochondrial function (PCr/ATP ratio) | Cardiac 31P-MRS: fasted | 1hour, day 28 | 
| Cardiac diastolic function | Cardiac ultrasound | 1hour, day 34 | 
| Intrahepatic lipid content and hepatic lipid composition | Hepatic 1H-MRS: fasted | 1hour, day 28 | 
| Blood pressure | 24-hour blood pressure monitor | 24hours, day 27 | 
| Whole body (sleeping) energy metabolism (sleeping energy expenditure and substrate oxidation) | Respiration chamber: overnight | 12 hours, day 34 | 
| Whole body maximum aerobic capacity | VO2 max test | 1hour, day 28 | 
| Total body mass and fat mass | Body composition | 0.5 hour, day 35 | 
| Ex vivo PPARalpha expression and downstream targets | Skeletal muscle biopsy | 0.5 hour, day 35 | 
| Postprandial lipid response | Meal test | 5hour, day 34 | 
| Anti-inflammatory effects (in the long term on the immune cells; acute effect on postprandial response), circadian rhythm | PBMC | 6hour, day 0-34-35 | 
| Cholesterol profile | Blood after venapunction | 5hours, day 0,7,14,21,28,35 |