Ciprofibrate and Pre-diabetes

Phase 3

Completed

• Conditions: Myocardial Insulin Sensitivity; Impaired Glucose Metabolism; Diastolic Dysfunction
• Interventions: Drug: Ciprofibrate 100Mg Tablet; Drug: Placebo Oral Tablet

• Registration Number: NCT03662984
• Lead Sponsor: Maastricht University Medical Center

Brief 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.

Study Timeline

• Study First Submitted: 2018-08-29
• Study First Submitted QC: 2018-09-05
• Study First Posted: 2018-09-10
• Study Start: 2018-11-01
• Primary Completion: 2020-11-06
• Study Completion: 2020-11-13
• Status Verified: 2021-01
• Last Update Submitted: 2021-01-07
• Last Update Posted: 2021-01-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 11

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Ciprofibrate	Ciprofibrate 100Mg Tablet	1dd100mg at breakfast
Placebo	Placebo Oral Tablet	1dd0mg at breakfast

Primary Outcome Measures

Name	Time	Method
Myocardial insulin sensitivity	1hour, day 35	measured by the insulin-stimulated myocardial glucose uptake by FDG-PET

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Nutrition and Movement Sciences; 🇳🇱 Maastricht, Limburg, Netherlands