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Living With Statins - Interventional Exercise Study (LIFESTAT)

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ClinicalTrials.gov Identifier: NCT02796378
Recruitment Status : Unknown
Verified January 2017 by Flemming Dela, University of Copenhagen.
Recruitment status was:  Recruiting
First Posted : June 10, 2016
Last Update Posted : January 4, 2017
Sponsor:
Information provided by (Responsible Party):
Flemming Dela, University of Copenhagen

Tracking Information
First Submitted Date  ICMJE May 27, 2016
First Posted Date  ICMJE June 10, 2016
Last Update Posted Date January 4, 2017
Study Start Date  ICMJE June 2016
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 6, 2016)
Physical performance measured by VO2-max [ Time Frame: 8 weeks ]
Difference in physical performance measured by VO2-max (mlO2/min/kgBW) in the three different intervention groups.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02796378 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: June 6, 2016)
  • Myalgia measured by VAS [ Time Frame: 8 weeks ]
    Difference in potential myalgia, measured by visual analog scale (VAS) between the three different intervention groups.
  • Difference in muscle strength measured by KinCom dynamometer and PowerRig [ Time Frame: 8 weeks ]
    Difference in muscle strength between the three different intervention groups.
  • Difference in glucose metabolism measured by hyperinsulinemic euglycemic clamp [ Time Frame: 8 weeks ]
    Difference in glucose metabolism between the three different intervention groups.
  • Difference in mitochondrial function measured by respirometry [ Time Frame: 8 weeks ]
    Difference in mitochondrial function between the three different intervention groups.
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Living With Statins - Interventional Exercise Study
Official Title  ICMJE Living With Statins - The Impact of Cholesterol Lowering Drugs on Health, Lifestyle and Well-being
Brief Summary

Background. Statins are cholesterol lowering drugs that are prescribed to lower the risk of cardio-vascular diseases. The use of statins has increased markedly and it is now one of the most prescribed drugs in the world. More than 600,000 people in Denmark are taking statins on a daily basis, approximately 40 % of these are taking the medication without having any other risk factors for cardio-vascular diseases than elevated blood-cholesterol i.e. they are in primary prevention.

Statins are not without side effects and studies have shown that there is an elevated risk of developing diabetes when taking statins. This has led to an increased debate about the use of statins in primary prevention. Furthermore a large meta-analysis has shown that to prevent one event of cardio-vascular disease, it is necessary to treat 200 people for 3-5 years. These data suggest that more conservative use of statins to prevent CVD in otherwise healthy individuals at low risk for future CVD may be warranted.

Other side effects of statins are muscle myalgia, muscle cramps and fatigue which potentially can prevent a physically active lifestyle. The biomedical background of these side effects is not fully elucidated but it has been shown that there is a link to decreasing levels of an important enzyme, Q10, which plays a role in muscle energy metabolism.

Hypothesis

The overarching research question is: why does statin treatment cause muscle pain? Does statin treatment impair (or even prohibit) physical exercise training? Furthermore the following questions will be investigated:

A. Does statin treatment cause:

  1. Decreased muscle strength?
  2. Skeletal muscle inflammation?
  3. Decreased mitochondrial respiratory function? B. Abnormal glucose homeostasis?

Re question A & B: If so, can physical training counteract this effect of statin treatment?

Detailed Description

Background:

Hypercholesterolemia and statin use in Denmark

Simvastatin is the most commonly prescribed statin, a class of drugs that inhibit hydroxyl-methyl-glutaryl (HMG) coenzyme A reductase, and thereby blocking biosynthesis of cholesterol in the liver. Simvastatin is prescribed for individuals with elevated low-density lipoprotein cholesterol (LDL-C) and/or total cholesterol, because these clinical parameters are viewed as a risk factor for cardiovascular-disease (CVD), even in the absence of other health problems or risk factors, such as previous myocardial infarction, diabetes or hypertension.

Approximately 40% of the prescriptions for statins are issued for primary prevention of elevated cholesterol by general practitioners to patients without bodily symptoms or signs. Only the "cholesterol number" makes the risk of heart attack and stroke visible. The lack of symptoms is likely to be of importance for patients' adherence to treatment as is adverse effects. A number of factors, such as information in mass media and changes in daily life, may affect the decision to take the treatment

Treatment guidelines for hypercholesterolemia:

The guidelines indicate preventive treatment with statins is appropriate in individuals with >10% predicted risk of a major vascular event within 5 years, while, some, but not all opinion-leaders advocate a 5% threshold. Nevertheless, statin therapy failed to reduce all-cause mortality in a meta-study of 65,229 patients without CVD, some of whom had diabetes. Similarly, a Cochrane review analysis, which included some studies in which more than 10% of the patients had history of CVD, showed only 0.5% reduction in all-cause mortality, indicating that for every 200 patients taking statins daily for 5 years, 1 death would be prevented. These data suggest that more conservative use of statins to prevent CVD in otherwise healthy individuals at low risk for future CVD may be warranted.

The downside:

Rhabdomyolysis (skeletal muscle cell death) is an infrequent but serious side-effect of statin use, that can on rare occasion lead to acute renal failure and death (i.e., 1.5 deaths per 106 prescriptions). Statin use is much more frequently associated with muscle dysfunction, including myalgia (muscle pain), cramps, and weakness. The reported incidence of myalgia varies from 1% (pharmaceutical company reports) to as high as 75% in statin-treated athletes. Mild to severe myalgia is a strong disincentive to regular exercise, and because regular exercise is one of the critical life-style approaches to preventing CVD and reducing blood cholesterol, this is a significant down-side of statin use. Regular exercise is also effective in preventing and treating obesity and type 2 diabetes, which themselves are risk factors for CVD.

The mechanism behind the myalgia is not known. However, the investigators behind this study has recently demonstrated that muscle mitochondrial function is impaired with statin treatment and the Q10 protein may play a key role in this. In addition, the statins also negatively affect the glucose tolerance, increasing the risk of type 2 diabetes.

Research questions:

The overarching research question is: why does statin treatment cause muscle pain? Does statin treatment impair (or even prohibit) physical exercise training? Furthermore the following questions will be investigated:

A. Does statin treatment cause:

  1. Decreased muscle strength?
  2. Skeletal muscle inflammation?
  3. Decreased mitochondrial respiratory function? B. Abnormal glucose homeostasis?

Re question A & B: If so, can physical training counteract this effect of statin treatment?

Methodology:

Cohort

Patients that fulfil defined inclusion and exclusion criteria will be recruited from General Practice clinics in Copenhagen and news paper advertisements. The vast majority of these patients are being assessed on basis of the HeartScore risk estimation system that offers direct estimation of the ten-year risk of fatal cardiovascular disease in a format suited to the constraints of clinical practice. A staggered recruitment will be implemented.

30 men (age: 40-70 years; BMI: 25-35 kg/m2) before initiation of a statin treatment as primary prevention are recruited. No other risk factors for CVD except elevated total cholesterol (>6 mmol/l) and/or elevated LDL cholesterol (>3,5 mmol/l) and mild hypertension (<160/100 mm Hg) must be present.

The patients will be allocated (randomization by drawing a lot) to one of three groups:

  • Physical exercise training and Simvastatin 40 mg/day and Q10 placebo
  • Physical exercise training and Simvastatin 40 mg/day and Q10 400 mg/day supplementation
  • Physical exercise training, Simvastatin placebo and Q10 placebo

The intervention period is 8 weeks with a series of experimental days before and after.

Experimental days (identical before and after the interventions):

Information day: health examination, ECG and Maximal oxygen uptake take (VO2 max).

Day 1 (overnight fasting, approximately 5 hours):

  • Dual energy x-ray absorptiometry (DXA) scan (body composition and body fat).
  • Oral glucose tolerance test + score questionnaire for muscle pain/discomfort (incl. Visual Analog Scale)
  • Isokinetic strength and Rate of Force Development (PowerRig and KinCom dynamometer).
  • Repeated VO2-max-test

Day 2 (overnight fasting approximately 7 hours):

  • Muscle biopsy, vastus lateralis
  • 2 step Euglycemic, hyperinsulinaemic clamp.

Training programme All training is supervised and takes place at the department. The training is aerobic, bicycle ergometer training (45 min/session at 60-70% of VO2max) three times a week for 8 weeks.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Condition  ICMJE
  • Cardiovascular Disease
  • Diabetes Mellitus
Intervention  ICMJE
  • Drug: Training+Simvastatin+Q10-placebo
    8 weeks of exercise training on a bycycle ergometer 3 times/week combined with Simvastatin 40 mg/day and Q10-placebo.
    Other Name: Simvastatin KRKA
  • Drug: Training+Simvastatin-placebo+Q10-placebo
    8 weeks of exercise training on a bycycle ergometer 3 times/week combined with Simvastatin-placebo and Q10-placebo.
  • Drug: Training+Simvastatin+Q10
    8 weeks of exercise training on a bycycle ergometer 3 times/week combined with Simvastatin 40 mg/day and Q10 400 mg/day.
    Other Names:
    • Simvastatin KRKA
    • Bioquinone Q10
Study Arms  ICMJE
  • Active Comparator: Training+Simvastatin+Q10-placebo
    Training+Simvastatin+Q10-placebo. 8 Weeks of exercise training on a bicycle ergometer three times a week and 40 mg of Simvastatin pr day and Q10-placebo.
    Intervention: Drug: Training+Simvastatin+Q10-placebo
  • Placebo Comparator: Training+Simvastatin-placebo+Q10-placebo
    Training+Simvastatin-placebo+Q10-placebo. 8 Weeks of exercise training on a bicycle ergometer three times a week, Simvastatin-placebo and Q10-placebo.
    Intervention: Drug: Training+Simvastatin-placebo+Q10-placebo
  • Active Comparator: Training+Simvastatin+Q10
    Training+Simvastatin+Q10. 8 Weeks of exercise training on a bicycle ergometer three times a week and 40 mg of Simvastatin pr day in combination with 400 mg of oral supplementation with Q10.
    Intervention: Drug: Training+Simvastatin+Q10
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Unknown status
Estimated Enrollment  ICMJE
 (submitted: June 6, 2016)
30
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2017
Estimated Primary Completion Date December 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Elevated blood-cholesterol

Exclusion Criteria:

  • Cholesterol-lowering drugs
  • Diabetes Mellitus
  • Cardiovascular disease such as arrythmia, ischaemic heart disease.
  • Musculoskeletal disorders preventing the subject to perform physical training
  • Mental disorders preventing the subject to understand the project description.
Sex/Gender  ICMJE
Sexes Eligible for Study: Male
Ages  ICMJE 40 Years to 70 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02796378
Other Study ID Numbers  ICMJE LIFESTAT - Exercise study
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Flemming Dela, University of Copenhagen
Study Sponsor  ICMJE University of Copenhagen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Flemming Dela, MD, MDSci University of Copenhagen
PRS Account University of Copenhagen
Verification Date January 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP