Ciprofibrate and Pre-diabetes (FIT)

Effects of Ciprofibrate on Myocardial Insulin Sensitivity in Pre-diabetes

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.

Study Overview

• Status: Completed
• Conditions: Diastolic Dysfunction; Impaired Glucose Metabolism; Myocardial Insulin Sensitivity
• Intervention / Treatment: Drug: Ciprofibrate 100Mg Tablet; Drug: Placebo Oral Tablet

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 Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 3

Contacts and Locations

Study Locations

• Netherlands
  • Limburg
    • Maastricht, Limburg, Netherlands, 6200MD
      • Nutrition and Movement Sciences

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: BASIC_SCIENCE
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Ciprofibrate; 1dd100mg at breakfast	Drug: Ciprofibrate 100Mg Tablet; 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.; Other Names: PPARa agonist
PLACEBO_COMPARATOR: Placebo; 1dd0mg at breakfast	Drug: Placebo Oral Tablet; To compare ciprofibrate

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Maastricht University Medical Center
• Collaborators: Maastricht University
• Investigators: Principal Investigator: Patrick Schrauwen, Professor, Maastricht University

Study record dates

Study Major Dates

• Study Start (ACTUAL): November 1, 2018
• Primary Completion (ACTUAL): November 6, 2020
• Study Completion (ACTUAL): November 13, 2020

Study Registration Dates

• First Submitted: August 29, 2018
• First Submitted That Met QC Criteria: September 5, 2018
• First Posted (ACTUAL): September 10, 2018

Study Record Updates

• Last Update Posted (ACTUAL): January 8, 2021
• Last Update Submitted That Met QC Criteria: January 7, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperinsulinism; Hypersensitivity; Prediabetic State; Insulin Resistance; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Hypolipidemic Agents; Lipid Regulating Agents; Ciprofibrate
• Other Study ID Numbers: NL.ABR.65583

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No