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

Primary Purpose

Diabetes Mellitus, Type 2, Cardiomyopathy, Dilated

Status
Completed
Phase
Not Applicable
Locations
Netherlands
Study Type
Interventional
Intervention
Acipimox
Cellulosum Mycrocryst
Sponsored by
Maastricht University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Diabetes Mellitus, Type 2 focused on measuring Mitochondrial function, Diabetes, Cardiomyopathy, insulin resistance, lipid lowering, triglycerides, Acipimox

Eligibility Criteria

40 Years - 70 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

  • Maastricht University Medical Centre

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Acipimox

Cellulosum mycrocryst capsula

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

changes in mitochondrial function
changes in cardiac function
lipid accumulation in ectopic tissue (cardiac and skeletal muscle)

Secondary Outcome Measures

insulin sensitivity
oxidative stress markers

Full Information

First Posted
July 20, 2009
Last Updated
May 13, 2013
Sponsor
Maastricht University Medical Center
Collaborators
Center for Translational Molecular Medicine
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1. Study Identification

Unique Protocol Identification Number
NCT00943059
Brief Title
Cross-over Study on Effect of Lipid Lowering by Acipimox on Cardiac and Skeletal Muscle Mitochondrial Function
Acronym
ACP
Official Title
The Effect of Lipid Lowering by Acipimox on Cardiac and Skeletal Muscle Mitochondrial Function
Study Type
Interventional

2. Study Status

Record Verification Date
May 2013
Overall Recruitment Status
Completed
Study Start Date
March 2010 (undefined)
Primary Completion Date
December 2012 (Actual)
Study Completion Date
December 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Maastricht University Medical Center
Collaborators
Center for Translational Molecular Medicine

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diabetes Mellitus, Type 2, Cardiomyopathy, Dilated
Keywords
Mitochondrial function, Diabetes, Cardiomyopathy, insulin resistance, lipid lowering, triglycerides, Acipimox

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Acipimox
Arm Type
Experimental
Arm Description
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.
Arm Title
Cellulosum mycrocryst capsula
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Acipimox
Other Intervention Name(s)
Olbetam, Nedios
Intervention Description
A capsula is given with 250mg Acipimox, 3dd; 1 after each meal. This will be done during 14 days.
Intervention Type
Drug
Intervention Name(s)
Cellulosum Mycrocryst
Other Intervention Name(s)
Placebo
Intervention Description
Capsule with cellulosum powder; this has to be taken 3 dd; 1 after each meal during 14 days.
Primary Outcome Measure Information:
Title
changes in mitochondrial function
Time Frame
2 weeks
Title
changes in cardiac function
Time Frame
2 weeks
Title
lipid accumulation in ectopic tissue (cardiac and skeletal muscle)
Time Frame
2 weeks
Secondary Outcome Measure Information:
Title
insulin sensitivity
Time Frame
2 weeks
Title
oxidative stress markers
Time Frame
2 weeks

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Patrick Schrauwen, PhD
Organizational Affiliation
Maastricht University Medical Centre
Official's Role
Principal Investigator
Facility Information:
Facility Name
Maastricht University Medical Centre
City
Maastricht
ZIP/Postal Code
6200MD
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
17093944
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. doi: 10.1007/s00125-006-0475-1. Epub 2006 Nov 9.
Results Reference
background
PubMed Identifier
18678616
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.
Results Reference
background
PubMed Identifier
18653763
Citation
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.
Results Reference
background
PubMed Identifier
18089950
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. doi: 10.1097/MCO.0b013e3282f0eca9.
Results Reference
background
PubMed Identifier
33258025
Citation
Houzelle A, Jorgensen JA, Schaart G, Daemen S, van Polanen N, Fealy CE, Hesselink MKC, Schrauwen P, Hoeks J. Human skeletal muscle mitochondrial dynamics in relation to oxidative capacity and insulin sensitivity. Diabetologia. 2021 Feb;64(2):424-436. doi: 10.1007/s00125-020-05335-w. Epub 2020 Nov 30.
Results Reference
derived
PubMed Identifier
24310562
Citation
Phielix E, Jelenik T, Nowotny P, Szendroedi J, Roden M. Reduction of non-esterified fatty acids improves insulin sensitivity and lowers oxidative stress, but fails to restore oxidative capacity in type 2 diabetes: a randomised clinical trial. Diabetologia. 2014 Mar;57(3):572-81. doi: 10.1007/s00125-013-3127-2. Epub 2013 Dec 6.
Results Reference
derived
Links:
URL
http://www.maastrichtuniversity.nl
Description
Website of location of trail.
URL
http://www.hb.unimaas.nl/
Description
Website of department of Human Biology, who conduct trail.

Learn more about this trial

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

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