Living With Statins - The Impact of Cholesterol Lowering Drugs on Health, Lifestyle and Well-being
Condition: Cardiovascular Disease; Diabetes Mellitus
MeSH terms: Cardiovascular Diseases; Diabetes Mellitus
Study type: Interventional
Phase: Phase 4

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. 600,000 people in Denmark are taking statins on a daily
      basis, 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 prevent) physical exercise training? Furthermore we would
      like to answer the following questions:

        1. Does statin treatment impair (or even prohibit) physical exercise training?

        2. Does statin treatment cause:

             -  Decreased muscle strength?

             -  Skeletal muscle inflammation?

             -  Decreased mitochondrial respiratory function?

        3. Abnormal glucose homeostasis?
    

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 (8; 10) 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 (2; 8). Nevertheless, statin therapy
      failed to reduce all-cause mortality in a meta-study of 65,229 patients without CVD, some of
      whom had diabetes (11). 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 (13). 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 DOWN-SIDE

      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 (9)). 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 (7; 9). 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 (16).

      The mechanism behind the myalgia is not known. However, we have recently demonstrated that
      muscle mitochondrial function is impaired with statin treatment and the Q10 protein may play
      a key role in this (6). In addition, the statins also negatively affect the glucose tolerance
      (6), increasing the risk of type 2 diabetes.

      RESEARCH QUESTIONS:

      The overarching research question is: why does statin treatment cause muscle pain? We are not
      the only research group in the world that try to answer that question, but we are the only
      one that has indeed provided a mechanistic explanation, and provided a proof-of-concept (6).
      We will now test this in a larger patient population.

      Our background in muscle and exercise physiology and in bioenergetics makes it natural to
      further ask:

        1. Does statin treatment impair (or even prohibit) physical exercise training?

        2. Does statin treatment cause:

             -  Decreased muscle strength?

             -  Skeletal muscle inflammation?

             -  Decreased mitochondrial respiratory function?

        3. Abnormal glucose homeostasis?

      Re question B & C: 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 treated 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 (14) (www.HeartScore.org).

      60 patients both men and women (age: 40-70 years; BMI: 25-35 kg/m2) taking Simvastatin as
      primary prevention are recruited. No other risk factors for CVD except elevated total
      cholesterol and/or elevated LDL cholesterol and mild hypertension (<145/100 mm Hg) must be
      present.

      The patients will be allocated (randomization by drawing a lot) to one of two groups:

        -  Simvastatin 40 mg/day and Q10-supplementation 400 mg/day

        -  Simvastatin 40 mg/day 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):

      Day 1 (½ day - overnight fasting):

        -  Medical history; clinical examination + ECG. Measurements: Blood pressure, weight,
           height, W/H-ratio, thigh circumference.

        -  Dual Energy X-ray Absorptiometry-scan (DXA) (body composition and body fat).

        -  FatMax test and maximal oxygen uptake test (VO2-max) or ergometer bike.

      Day 2 (½ day - overnight fasting):

        -  Oral glucose tolerance test + score questionnaire for muscle pain/discomfort (Visual
           Analog Scale) and a questionnaire regarding the extent of muscle pain/discomfort.

        -  Isokinetic strength and Rate of Force Development (PowerRig and KinCom dynamometer).

        -  Repeated VO2-max-test

      Day 3 (1 day - overnight fasting):

        -  Muscle biopsy, vastus lateralis (before and after clamp), fat biopsy from subcutaneus
           adipose tissue in the abdomen.

        -  Intravenous glucose tolerance test (IVGTT)

        -  Euglycemic, hyperinsulinaemic clamp.

      Statistical considerations

      The major end-points are all end-point which we have tested before in other clinical
      populations. In general, in order to detect a 10% difference in these parameters before vs.
      after a training program or between statin users and control, requires 15-20 subjects in each
      group if an alpha level of <0.05 and risk of type 2 error is set to 10%. 10-15 subjects are
      necessary if the "conventional" 20% type 2 error risk is implemented. Thus, the present study
      has a considerable safety-margin in terms of statistical power.
    

Intervention name(s): Simvastatin; Q10
Intervention type(s): Drug; Dietary Supplement
Other intervention name(s): Simvastatin Actavis; Simvastatin Hexal; Simvastatin KRKA; Simvastatin Orion; Simvastatin Sandoz; Simvastatin Stada; Simvastatin Teva; Zocor; Bioquinon Q10
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Basic Science
Keywords: physical activity; statin therapy; diabetes mellitus; cardiovascular disease; Q10-supplementation