Ciprofibrate and Pre-diabetes

Diastolic Dysfunction Clinical Trial

— FIT  

Official title:

Effects of Ciprofibrate on Myocardial Insulin Sensitivity in Pre-diabetes

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03662984
• Other study ID #: NL.ABR.65583
• Status: Completed
• Phase: Phase 3
• Start date: November 1, 2018
• Est. completion date: November 13, 2020

Study information

• Verified date: January 2021
• Source: Maastricht University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 11
• Est. completion date: November 13, 2020
• Est. primary completion date: November 6, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 40 Years to 70 Years

Eligibility

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

Related Conditions & MeSH terms

• Diastolic Dysfunction
• Hypersensitivity
• Impaired Glucose Metabolism
• Insulin Resistance
• Myocardial Insulin Sensitivity
• Prediabetic State

Intervention

Drug:
• Ciprofibrate 100Mg Tablet
Ciprofibrate is a PPARa ligand and is considered to be a major regulator of the lipid metabolism. PPARa 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 PPARa in the heart may have beneficial effects on mitochondrial function and fat oxidative capacity.
• Placebo Oral Tablet
To compare ciprofibrate

Locations

Country	Name	City	State
Netherlands	Nutrition and Movement Sciences	Maastricht	Limburg

Sponsors (2)

Lead Sponsor	Collaborator
Maastricht University Medical Center	Maastricht University

Country where clinical trial is conducted

Netherlands, 

Outcome

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