Ciprofibrate and Pre-diabetes (FIT)

• ClinicalTrials.gov Identifier: NCT03662984
• Recruitment Status: Completed
• First Posted: September 10, 2018
• Last Update Posted: January 8, 2021
• Sponsor: Maastricht University Medical Center
• Collaborator: Maastricht University
• Information provided by (Responsible Party): Maastricht University Medical Center

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Myocardial Insulin Sensitivity; Impaired Glucose Metabolism; Diastolic Dysfunction	Drug: Ciprofibrate 100Mg Tablet; Drug: Placebo Oral Tablet	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 11 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Effects of Ciprofibrate on Myocardial Insulin Sensitivity in Pre-diabetes
• Actual Study Start Date: November 1, 2018
• Actual Primary Completion Date: November 6, 2020
• Actual Study Completion Date: November 13, 2020

Arms and Interventions

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 Name: PPARa agonist
Placebo Comparator: Placebo; 1dd0mg at breakfast	Drug: Placebo Oral Tablet; To compare ciprofibrate

Outcome Measures

Primary Outcome Measures :

1. Myocardial insulin sensitivity [ Time Frame: 1hour, day 35 ]
   measured by the insulin-stimulated myocardial glucose uptake by FDG-PET

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: Male
• Gender Based Eligibility: Yes
• Gender Eligibility Description: Females have a oestrogen receptor which interferes with the PPARa receptor
• Accepts Healthy Volunteers: Yes

Criteria

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

Contacts and Locations

Locations

Netherlands

Nutrition and Movement Sciences

Maastricht, Limburg, Netherlands, 6200MD

Sponsors and Collaborators

Maastricht University Medical Center

Maastricht University

Investigators

• Principal Investigator: Patrick Schrauwen, Professor; Maastricht University

More Information

• Responsible Party: Maastricht University Medical Center
• ClinicalTrials.gov Identifier: NCT03662984
• Other Study ID Numbers: NL.ABR.65583
• First Posted: September 10, 2018
• Last Update Posted: January 8, 2021
• Last Verified: January 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• 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

Additional relevant MeSH terms:

Insulin Resistance; Prediabetic State; Hypersensitivity; Immune System Diseases; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Diabetes Mellitus; Endocrine System Diseases; Ciprofibrate; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents