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

Diabetes Mellitus, Type 2 Clinical Trial

— ACP  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00943059
• Other study ID #: MEC 09-3-033
• Secondary ID: CTMM2008172EFSD1
• Status: Completed
• Phase: N/A
• First received: July 20, 2009
• Last updated: May 13, 2013
• Start date: March 2010
• Est. completion date: December 2012

Study information

• Verified date: May 2013
• Source: Maastricht University Medical Center
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 31
• Est. completion date: December 2012
• Est. primary completion date: December 2012
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 40 Years to 70 Years

Eligibility

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.

Study Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Acipimox
A capsula is given with 250mg Acipimox, 3dd; 1 after each meal. This will be done during 14 days.
• Cellulosum Mycrocryst
Capsule with cellulosum powder; this has to be taken 3 dd; 1 after each meal during 14 days.

Locations

Country	Name	City	State
Netherlands	Maastricht University Medical Centre	Maastricht

Sponsors (2)

Lead Sponsor	Collaborator
Maastricht University Medical Center	Center for Translational Molecular Medicine

Country where clinical trial is conducted

Netherlands, 

References & Publications (4)

De Feyter HM, Lenaers E, Houten SM, Schrauwen P, Hesselink MK, Wanders RJ, Nicolay K, Prompers JJ. Increased intramyocellular lipid content but normal skeletal muscle mitochondrial oxidative capacity throughout the pathogenesis of type 2 diabetes. FASEB J. 2008 Nov;22(11):3947-55. doi: 10.1096/fj.08-112318. Epub 2008 Jul 24. — View Citation

Phielix E, Schrauwen-Hinderling VB, Mensink M, Lenaers E, Meex R, Hoeks J, Kooi ME, Moonen-Kornips E, Sels JP, Hesselink MK, Schrauwen P. Lower intrinsic ADP-stimulated mitochondrial respiration underlies in vivo mitochondrial dysfunction in muscle of male type 2 diabetic patients. Diabetes. 2008 Nov;57(11):2943-9. doi: 10.2337/db08-0391. Epub 2008 Aug 4. — View Citation

Schrauwen-Hinderling VB, Kooi ME, Hesselink MK, Jeneson JA, Backes WH, van Echteld CJ, van Engelshoven JM, Mensink M, Schrauwen P. Impaired in vivo mitochondrial function but similar intramyocellular lipid content in patients with type 2 diabetes mellitus and BMI-matched control subjects. Diabetologia. 2007 Jan;50(1):113-20. Epub 2006 Nov 9. — View Citation

Schrauwen-Hinderling VB, Roden M, Kooi ME, Hesselink MK, Schrauwen P. Muscular mitochondrial dysfunction and type 2 diabetes mellitus. Curr Opin Clin Nutr Metab Care. 2007 Nov;10(6):698-703. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	changes in mitochondrial function		2 weeks	No
Primary	changes in cardiac function		2 weeks	No
Primary	lipid accumulation in ectopic tissue (cardiac and skeletal muscle)		2 weeks	No
Secondary	insulin sensitivity		2 weeks	No
Secondary	oxidative stress markers		2 weeks	Yes

External Links

•   Website of location of trail.