Cross-over Study on Effect of Lipid Lowering by Acipimox on Cardiac and Skeletal Muscle Mitochondrial Function

Study Overview
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Brief Summary
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Accumulation of lipid in skeletal and cardiac muscle has been associated with insulin resistance and diabetic cardiomyopathy. In skeletal muscle, lipotoxic damage has been suggested to lead to dysfunction of mitochondria. It remains unknown whether lipotoxicity leads to mitochondrial dysfunction in heart as well, and if so, whether this also leads to cardiomyopathy (failure of the heart). Although it has been shown that lipid lowering agents can improve insulin sensitivity, the effect of lowering free fatty acids on cardiac and skeletal muscle mitochondrial function remains unknown. In this study the investigators want to investigate whether lowering cardiac and muscular lipid content will improve mitochondrial and cellular function in type 2 diabetic patients. To this end, type 2 diabetic patients and body mass index (BMI)-matched controls will be included in a blinded cross-over design, in which subjects will receive a lipid lowering agent (Acipimox) or placebo for 2 weeks in random order. During treatment, diabetes medication will be stopped. Baseline measurements will be performed prior to the study and after each treatment to assess cardiac and muscular lipid accumulation, cardiac function, mitochondrial function and insulin sensitivity.

Official Title
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The Effect of Lipid Lowering by Acipimox on Cardiac and Skeletal Muscle Mitochondrial Function

Conditions
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Diabetes Mellitus, Type 2, Cardiomyopathy, Dilated

Intervention / Treatment
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* Drug: Acipimox
* Drug: Cellulosum Mycrocryst


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or postmenopausal females Age 40-70 years Obese (BMI > 30 kg/m2), non-insulin dependent type 2 diabetic patients and BMI matched control subjects without diabetes. Generally healthy with specifically no known cardiovascular disease, dyslipidemia, or gastric ulcers (contra-ind. of Acipimox), which can affect the study parameters. Must be on sulphonylurea(SU)- derivate or metformin therapy for at least six months with a constant dose for at least two months, or on dietary treatment for at least six months Well-controlled diabetes: HbA1c<8%. Control subjects must have a plasma glucose lower than 6,1 mmol/L. Stable dietary habits (no weight loss/gain > 3 kg in the last 6 months) Exclusion Criteria: Known cardiovascular disease, dyslipidemia, hepatic or renal failure and gastric ulcers. Insulin dependent Diabetic patients. Use of lipid lowering agents, except from Statins, as these do not affect triglycerides levels (with exception to Lipitor). Use of Thiazolidines (glitazone/rosiglitazone/pioglitazone/troglitazone) Use of anti-coagulants (not thrombocyte-aggregation inhibitors) Aberrant ECG (with signs of ischemia or cardiac failure or arrythmia's) Weight gain/loss > 3 kg in the last 6 months. Hb < 7,3 in women, and < 7,8 in men. Contraindications for MRI scans: Electronic implants such as pacemakers or neurostimulator Iron-containing corpora aliena in eyes or brain Some hearing aids and artificial (heart) valves which are contraindicated for MRS Claustrophobia Subjects, who do not want to be informed about unexpected medical findings, or do not wish that their physician is informed, cannot participate in the study.

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

Sexes Eligible for Study
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All

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 |
| --- | --- |
| Experimental: Acipimox<br>Subjects will receive Acipimox or a placebo in random order. Acipimox is a commercially available and registrated drug, that lowers free fatty acids by inhibiting hormone sensitive lipase in the peripheral adipose tissue. No serious side-effects are known other than rare anaphylactic reactions. | Drug: Acipimox<br>* A capsula is given with 250mg Acipimox, 3dd; 1 after each meal. This will be done during 14 days.<br>* Other names: Nedios;|
| Placebo Comparator: Cellulosum mycrocryst capsula<br>Subjects will receive Acipimox or a placebo in random order. Acipimox is a commercially available and registrated drug, that lowers free fatty acids by inhibiting hormone sensitive lipase in the peripheral adipose tissue. No serious side-effects are known other than rare anaphylactic reactions. | Drug: Cellulosum Mycrocryst<br>* Capsule with cellulosum powder; this has to be taken 3 dd; 1 after each meal during 14 days.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| changes in mitochondrial function |  | 2 weeks | 
| changes in cardiac function |  | 2 weeks | 
| lipid accumulation in ectopic tissue (cardiac and skeletal muscle) |  | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| insulin sensitivity |  | 2 weeks | 
| oxidative stress markers |  | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mitochondrial function, Diabetes, Cardiomyopathy, insulin resistance, lipid lowering, triglycerides, Acipimox