<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02255682</url>
  </required_header>
  <id_info>
    <org_study_id>LIFESTAT - Observational Study</org_study_id>
    <nct_id>NCT02255682</nct_id>
  </id_info>
  <brief_title>Living With Statins - The Impact of Cholesterol Lowering Drugs on Health, Lifestyle and Well-being</brief_title>
  <acronym>LIFESTAT</acronym>
  <official_title>Living With Statins - The Impact of Cholesterol Lowering Drugs on Health, Lifestyle and Well-being</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Copenhagen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Copenhagen</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background Statins are cholesterol lowering drugs that are prescribed to lower the risk of&#xD;
      cardio-vascular diseases. The use of statins has increased markedly and it is now one of the&#xD;
      most prescribed drugs in the world. 600,000 people in Denmark are taking statins on a daily&#xD;
      basis, 40 % of these are taking the medication without having any other risk factors for&#xD;
      cardio-vascular diseases than elevated blood-cholesterol i.e. they are in primary prevention.&#xD;
&#xD;
      Statins are not without side effects and studies have shown that there is an elevated risk of&#xD;
      developing diabetes when taking statins. This has led to an increased debate about the use of&#xD;
      statins in primary prevention. Furthermore a large meta-analysis has shown that to prevent&#xD;
      one event of cardio-vascular disease, it is necessary to treat 200 people for 3-5 years.&#xD;
      These data suggest that more conservative use of statins to prevent CVD in otherwise healthy&#xD;
      individuals at low risk for future CVD may be warranted.&#xD;
&#xD;
      Other side effects of statins are muscle myalgia, muscle cramps and fatigue which potentially&#xD;
      can prevent a physically active lifestyle. The biomedical background of these side effects is&#xD;
      not fully elucidated but it has been shown that there is a link to decreasing levels of an&#xD;
      important enzyme, Q10, which plays a role in muscle energy metabolism.&#xD;
&#xD;
      Hypothesis&#xD;
&#xD;
      The overarching research question is: why does statin treatment cause muscle pain? Does&#xD;
      statin treatment impair (or even prevent) physical exercise training? Furthermore we would&#xD;
      like to answer the following questions:&#xD;
&#xD;
        1. Does statin treatment impair (or even prohibit) physical exercise training?&#xD;
&#xD;
        2. Does statin treatment cause:&#xD;
&#xD;
             -  Decreased muscle strength?&#xD;
&#xD;
             -  Skeletal muscle inflammation?&#xD;
&#xD;
             -  Decreased mitochondrial respiratory function?&#xD;
&#xD;
        3. Abnormal glucose homeostasis?&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background&#xD;
&#xD;
      HYPERCHOLESTEROLEMIA AND STATIN USE IN DENMARK&#xD;
&#xD;
      Simvastatin is the most commonly prescribed statin, a class of drugs that inhibit&#xD;
      hydroxyl-methyl-glutaryl (HMG) coenzyme A reductase, and thereby blocking biosynthesis of&#xD;
      cholesterol in the liver. Simvastatin is prescribed for individuals with elevated low-density&#xD;
      lipoprotein cholesterol (LDL-C) and/or total cholesterol, because these clinical parameters&#xD;
      are viewed as a risk factor for cardiovascular-disease (CVD), even in the absence of other&#xD;
      health problems or risk factors, such as previous myocardial infarction, diabetes or&#xD;
      hypertension.&#xD;
&#xD;
      Approximately 40% of the prescriptions for statins are issued for primary prevention of&#xD;
      elevated cholesterol by general practitioners to patients without bodily symptoms or signs.&#xD;
      Only the &quot;cholesterol number&quot; makes the risk of heart attack and stroke visible. The lack of&#xD;
      symptoms is likely to be of importance for patients' adherence to treatment as is adverse&#xD;
      effects. A number of factors, such as information in mass media and changes in daily life,&#xD;
      may affect the decision to take the treatment&#xD;
&#xD;
      TREATMENT GUIDELINES FOR HYPERCHOLESTEROLEMIA&#xD;
&#xD;
      The guidelines (8; 10) indicate preventive treatment with statins is appropriate in&#xD;
      individuals with &gt;10% predicted risk of a major vascular event within 5 years, while, some,&#xD;
      but not all opinion-leaders advocate a 5% threshold (2; 8). Nevertheless, statin therapy&#xD;
      failed to reduce all-cause mortality in a meta-study of 65,229 patients without CVD, some of&#xD;
      whom had diabetes (11). Similarly, a Cochrane review analysis, which included some studies in&#xD;
      which more than 10% of the patients had history of CVD, showed only 0.5% reduction in&#xD;
      all-cause mortality, indicating that for every 200 patients taking statins daily for 5 years,&#xD;
      1 death would be prevented (13). These data suggest that more conservative use of statins to&#xD;
      prevent CVD in otherwise healthy individuals at low risk for future CVD may be warranted.&#xD;
&#xD;
      THE DOWN-SIDE&#xD;
&#xD;
      Rhabdomyolysis (skeletal muscle cell death) is an infrequent but serious side-effect of&#xD;
      statin use, that can on rare occasion lead to acute renal failure and death (i.e., 1.5 deaths&#xD;
      per 106 prescriptions (9)). Statin use is much more frequently associated with muscle&#xD;
      dysfunction, including myalgia (muscle pain), cramps, and weakness. The reported incidence of&#xD;
      myalgia varies from 1% (pharmaceutical company reports) to as high as 75% in statin-treated&#xD;
      athletes (7; 9). Mild to severe myalgia is a strong disincentive to regular exercise, and&#xD;
      because regular exercise is one of the critical life-style approaches to preventing CVD and&#xD;
      reducing blood cholesterol, this is a significant down-side of statin use. Regular exercise&#xD;
      is also effective in preventing and treating obesity and type 2 diabetes, which themselves&#xD;
      are risk factors for CVD (16).&#xD;
&#xD;
      The mechanism behind the myalgia is not known. However, we have recently demonstrated that&#xD;
      muscle mitochondrial function is impaired with statin treatment and the Q10 protein may play&#xD;
      a key role in this (6). In addition, the statins also negatively affect the glucose tolerance&#xD;
      (6), increasing the risk of type 2 diabetes.&#xD;
&#xD;
      RESEARCH QUESTIONS:&#xD;
&#xD;
      The overarching research question is: why does statin treatment cause muscle pain? We are not&#xD;
      the only research group in the world that try to answer that question, but we are the only&#xD;
      one that has indeed provided a mechanistic explanation, and provided a proof-of-concept (6).&#xD;
      We will now test this in a larger patient population.&#xD;
&#xD;
      Our background in muscle and exercise physiology and in bioenergetics makes it natural to&#xD;
      further ask:&#xD;
&#xD;
        1. Does statin treatment impair (or even prohibit) physical exercise training?&#xD;
&#xD;
        2. Does statin treatment cause:&#xD;
&#xD;
             -  Decreased muscle strength?&#xD;
&#xD;
             -  Skeletal muscle inflammation?&#xD;
&#xD;
             -  Decreased mitochondrial respiratory function?&#xD;
&#xD;
        3. Abnormal glucose homeostasis?&#xD;
&#xD;
      Re question B &amp; C: If so, can physical training counteract this effect of statin treatment?&#xD;
&#xD;
      Methodology&#xD;
&#xD;
      COHORT&#xD;
&#xD;
      Patients that fulfil defined inclusion and exclusion criteria will be recruited from General&#xD;
      Practice clinics in Copenhagen and news paper advertisements. The vast majority of these&#xD;
      patients are being treated on basis of the HeartScore risk estimation system that offers&#xD;
      direct estimation of the ten-year risk of fatal cardiovascular disease in a format suited to&#xD;
      the constraints of clinical practice (14) (www.HeartScore.org).&#xD;
&#xD;
      60 patients both men and women (age: 40-70 years; BMI: 25-35 kg/m2) taking Simvastatin as&#xD;
      primary prevention are recruited. No other risk factors for CVD except elevated total&#xD;
      cholesterol and/or elevated LDL cholesterol and mild hypertension (&lt;145/100 mm Hg) must be&#xD;
      present.&#xD;
&#xD;
      The patients will be allocated (randomization by drawing a lot) to one of two groups:&#xD;
&#xD;
        -  Simvastatin 40 mg/day and Q10-supplementation 400 mg/day&#xD;
&#xD;
        -  Simvastatin 40 mg/day and Q10-placebo The intervention period is 8 weeks with a series&#xD;
           of experimental days before and after.&#xD;
&#xD;
      Experimental days (identical before and after the interventions):&#xD;
&#xD;
      Day 1 (½ day - overnight fasting):&#xD;
&#xD;
        -  Medical history; clinical examination + ECG. Measurements: Blood pressure, weight,&#xD;
           height, W/H-ratio, thigh circumference.&#xD;
&#xD;
        -  Dual Energy X-ray Absorptiometry-scan (DXA) (body composition and body fat).&#xD;
&#xD;
        -  FatMax test and maximal oxygen uptake test (VO2-max) or ergometer bike.&#xD;
&#xD;
      Day 2 (½ day - overnight fasting):&#xD;
&#xD;
        -  Oral glucose tolerance test + score questionnaire for muscle pain/discomfort (Visual&#xD;
           Analog Scale) and a questionnaire regarding the extent of muscle pain/discomfort.&#xD;
&#xD;
        -  Isokinetic strength and Rate of Force Development (PowerRig and KinCom dynamometer).&#xD;
&#xD;
        -  Repeated VO2-max-test&#xD;
&#xD;
      Day 3 (1 day - overnight fasting):&#xD;
&#xD;
        -  Muscle biopsy, vastus lateralis (before and after clamp), fat biopsy from subcutaneus&#xD;
           adipose tissue in the abdomen.&#xD;
&#xD;
        -  Intravenous glucose tolerance test (IVGTT)&#xD;
&#xD;
        -  Euglycemic, hyperinsulinaemic clamp.&#xD;
&#xD;
      Statistical considerations&#xD;
&#xD;
      The major end-points are all end-point which we have tested before in other clinical&#xD;
      populations. In general, in order to detect a 10% difference in these parameters before vs.&#xD;
      after a training program or between statin users and control, requires 15-20 subjects in each&#xD;
      group if an alpha level of &lt;0.05 and risk of type 2 error is set to 10%. 10-15 subjects are&#xD;
      necessary if the &quot;conventional&quot; 20% type 2 error risk is implemented. Thus, the present study&#xD;
      has a considerable safety-margin in terms of statistical power.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>January 2015</start_date>
  <completion_date type="Actual">December 2016</completion_date>
  <primary_completion_date type="Actual">December 2016</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Difference in myalgia</measure>
    <time_frame>8 weeks</time_frame>
    <description>Difference in myalgia, measured by visual analog scale (VAS) between Simvastatin treated patients receiving Q10 or Q10-placebo.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Difference in VO2-max</measure>
    <time_frame>8 weeks</time_frame>
    <description>Difference in VO2-max in Simvastatin treated patients receiving Q10 or Q10-placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in muscle strength</measure>
    <time_frame>8 weeks</time_frame>
    <description>Difference in muscle strength in Simvastatin treated patients receiving Q10 or Q10-placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in glucose metabolism</measure>
    <time_frame>8 weeks</time_frame>
    <description>Difference in glucose metabolism in Simvastatin treated patients receiving Q10 or Q10-placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Difference in mitochondrial function</measure>
    <time_frame>8 weeks</time_frame>
    <description>Difference in mitochondrial function in Simvastatin treated patients receiving Q10 or Q10-placebo.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">35</enrollment>
  <condition>Cardiovascular Disease</condition>
  <condition>Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>Simvastatin and Q10-placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Simvastatin 40 mg orally administered daily and Q10-placebo for 8 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Simvastatin and Q10</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Simvastatin 40 mg orally administered daily for 8 weeks in combination with Q10 supplementation of 400 mg/daily</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Simvastatin</intervention_name>
    <arm_group_label>Simvastatin and Q10</arm_group_label>
    <arm_group_label>Simvastatin and Q10-placebo</arm_group_label>
    <other_name>Simvastatin Actavis</other_name>
    <other_name>Simvastatin Hexal</other_name>
    <other_name>Simvastatin KRKA</other_name>
    <other_name>Simvastatin Orion</other_name>
    <other_name>Simvastatin Sandoz</other_name>
    <other_name>Simvastatin Stada</other_name>
    <other_name>Simvastatin Teva</other_name>
    <other_name>Zocor</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Q10</intervention_name>
    <arm_group_label>Simvastatin and Q10</arm_group_label>
    <other_name>Bioquinon Q10</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  40-70 years.&#xD;
&#xD;
          -  BMI 25-35.&#xD;
&#xD;
          -  prescribed Simvastatin 40 mg/daily by their general practitioner.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diabetes Mellitus.&#xD;
&#xD;
          -  Cardiovascular disease such as arrythmia, ischaemic heart disease.&#xD;
&#xD;
          -  Musculoskeletal disorders preventing the subject to perform physical.&#xD;
&#xD;
          -  Mental disorders preventing the subject to understand the project description.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Flemming Dela, MD, MDSci</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Copenhagen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Copenhagen</name>
      <address>
        <city>Copenhagen</city>
        <zip>2200</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <reference>
    <citation>Boushel R, Gnaiger E, Schjerling P, Skovbro M, Kraunsoe R, Dela F. Patients with type 2 diabetes have normal mitochondrial function in skeletal muscle. Diabetologia. 2007 Apr;50(4):790-6. doi: 10.1007/s00125-007-0594-3. Epub 2007 Feb 15.</citation>
    <PMID>17334651</PMID>
  </reference>
  <reference>
    <citation>Ebrahim S, Casas JP. Statins for all by the age of 50 years? Lancet. 2012 Aug 11;380(9841):545-7. doi: 10.1016/S0140-6736(12)60694-1. Epub 2012 May 17. No abstract available.</citation>
    <PMID>22607823</PMID>
  </reference>
  <reference>
    <citation>Larsen S, Hey-Mogensen M, Rabol R, Stride N, Helge JW, Dela F. The influence of age and aerobic fitness: effects on mitochondrial respiration in skeletal muscle. Acta Physiol (Oxf). 2012 Jul;205(3):423-32. doi: 10.1111/j.1748-1716.2012.02408.x. Epub 2012 Feb 11.</citation>
    <PMID>22212519</PMID>
  </reference>
  <reference>
    <citation>Larsen S, Nielsen J, Hansen CN, Nielsen LB, Wibrand F, Stride N, Schroder HD, Boushel R, Helge JW, Dela F, Hey-Mogensen M. Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. J Physiol. 2012 Jul 15;590(14):3349-60. doi: 10.1113/jphysiol.2012.230185. Epub 2012 May 14.</citation>
    <PMID>22586215</PMID>
  </reference>
  <reference>
    <citation>Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Andersen JL, Madsbad S, Worm D, Helge JW, Dela F. Increased mitochondrial substrate sensitivity in skeletal muscle of patients with type 2 diabetes. Diabetologia. 2011 Jun;54(6):1427-36. doi: 10.1007/s00125-011-2098-4. Epub 2011 Mar 18.</citation>
    <PMID>21424396</PMID>
  </reference>
  <reference>
    <citation>Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, Nielsen LB, Helge JW, Dela F. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013 Jan 8;61(1):44-53. doi: 10.1016/j.jacc.2012.09.036.</citation>
    <PMID>23287371</PMID>
  </reference>
  <reference>
    <citation>Singh P, Kohr D, Kaps M, Blaes F. Skeletal muscle cell MHC I expression: implications for statin-induced myopathy. Muscle Nerve. 2010 Feb;41(2):179-84. doi: 10.1002/mus.21479.</citation>
    <PMID>19813190</PMID>
  </reference>
  <reference>
    <citation>Cholesterol Treatment Trialists' (CTT) Collaborators; Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012 Aug 11;380(9841):581-90. doi: 10.1016/S0140-6736(12)60367-5. Epub 2012 May 17.</citation>
    <PMID>22607822</PMID>
  </reference>
  <reference>
    <citation>Parker BA, Thompson PD. Effect of statins on skeletal muscle: exercise, myopathy, and muscle outcomes. Exerc Sport Sci Rev. 2012 Oct;40(4):188-94. doi: 10.1097/JES.0b013e31826c169e. Erratum In: Exerc Sport Sci Rev. 2013 Jan;41(1):71.</citation>
    <PMID>23000957</PMID>
  </reference>
  <reference>
    <citation>Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WM, Albus C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvanne M, Scholte Op Reimer WJ, Vrints C, Wood D, Zamorano JL, Zannad F; Comitato per Linee Guida Pratiche (CPG) dell'ESC. [European Guidelines on Cardiovascular Disease Prevention in Clinical Practice (version 2012). The Fifth Joint Task Force of the European Society of Cardiology and other societies on cardiovascular disease prevention in clinical practice (constituted by representatives of nine societies and by invited experts)]. G Ital Cardiol (Rome). 2013 May;14(5):328-92. doi: 10.1714/1264.13964. No abstract available. Italian.</citation>
    <PMID>23612326</PMID>
  </reference>
  <reference>
    <citation>Ray KK, Seshasai SR, Erqou S, Sever P, Jukema JW, Ford I, Sattar N. Statins and all-cause mortality in high-risk primary prevention: a meta-analysis of 11 randomized controlled trials involving 65,229 participants. Arch Intern Med. 2010 Jun 28;170(12):1024-31. doi: 10.1001/archinternmed.2010.182.</citation>
    <PMID>20585067</PMID>
  </reference>
  <reference>
    <citation>Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet. 2012 Aug 11;380(9841):565-71. doi: 10.1016/S0140-6736(12)61190-8.</citation>
    <PMID>22883507</PMID>
  </reference>
  <reference>
    <citation>Taylor F, Ward K, Moore TH, Burke M, Davey Smith G, Casas JP, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2011 Jan 19;(1):CD004816. doi: 10.1002/14651858.CD004816.pub4.</citation>
    <PMID>21249663</PMID>
  </reference>
  <verification_date>January 2017</verification_date>
  <study_first_submitted>September 12, 2014</study_first_submitted>
  <study_first_submitted_qc>September 29, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 2, 2014</study_first_posted>
  <last_update_submitted>January 3, 2017</last_update_submitted>
  <last_update_submitted_qc>January 3, 2017</last_update_submitted_qc>
  <last_update_posted type="Estimate">January 4, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Copenhagen</investigator_affiliation>
    <investigator_full_name>Flemming Dela</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>physical activity</keyword>
  <keyword>statin therapy</keyword>
  <keyword>diabetes mellitus</keyword>
  <keyword>cardiovascular disease</keyword>
  <keyword>Q10-supplementation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Diabetes Mellitus</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Simvastatin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02255682
org study id: LIFESTAT - Observational Study
nct id: NCT02255682
lead sponsor: 
has dmc: No
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?
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Difference in myalgia
time frame: 8 weeks
description: Difference in myalgia, measured by visual analog scale (VAS) between Simvastatin treated patients receiving Q10 or Q10-placebo.
measure: Difference in VO2-max
time frame: 8 weeks
description: Difference in VO2-max in Simvastatin treated patients receiving Q10 or Q10-placebo.
measure: Difference in muscle strength
time frame: 8 weeks
description: Difference in muscle strength in Simvastatin treated patients receiving Q10 or Q10-placebo.
measure: Difference in glucose metabolism
time frame: 8 weeks
description: Difference in glucose metabolism in Simvastatin treated patients receiving Q10 or Q10-placebo.
measure: Difference in mitochondrial function
time frame: 8 weeks
description: Difference in mitochondrial function in Simvastatin treated patients receiving Q10 or Q10-placebo.
arm group label: Simvastatin and Q10-placebo
arm group type: Placebo Comparator
description: Simvastatin 40 mg orally administered daily and Q10-placebo for 8 weeks
arm group label: Simvastatin and Q10
arm group type: Active Comparator
description: Simvastatin 40 mg orally administered daily for 8 weeks in combination with Q10 supplementation of 400 mg/daily
intervention type: Drug
intervention name: Simvastatin
arm group label: Simvastatin and Q10
arm group label: Simvastatin and Q10-placebo
other name: Simvastatin Actavis
other name: Simvastatin Hexal
other name: Simvastatin KRKA
other name: Simvastatin Orion
other name: Simvastatin Sandoz
other name: Simvastatin Stada
other name: Simvastatin Teva
other name: Zocor
intervention type: Dietary Supplement
intervention name: Q10
arm group label: Simvastatin and Q10
other name: Bioquinon Q10
criteria: 
gender: All
minimum age: 40 Years
maximum age: 70 Years
healthy volunteers: No
last name: Flemming Dela, MD, MDSci
role: Principal Investigator
affiliation: University of Copenhagen
facility: 
country: Denmark
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PMID: 17334651
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PMID: 22607823
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PMID: 22586215
citation: Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Andersen JL, Madsbad S, Worm D, Helge JW, Dela F. Increased mitochondrial substrate sensitivity in skeletal muscle of patients with type 2 diabetes. Diabetologia. 2011 Jun;54(6):1427-36. doi: 10.1007/s00125-011-2098-4. Epub 2011 Mar 18.
PMID: 21424396
citation: Larsen S, Stride N, Hey-Mogensen M, Hansen CN, Bang LE, Bundgaard H, Nielsen LB, Helge JW, Dela F. Simvastatin effects on skeletal muscle: relation to decreased mitochondrial function and glucose intolerance. J Am Coll Cardiol. 2013 Jan 8;61(1):44-53. doi: 10.1016/j.jacc.2012.09.036.
PMID: 23287371
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PMID: 19813190
citation: Cholesterol Treatment Trialists' (CTT) Collaborators; Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, Voysey M, Gray A, Collins R, Baigent C. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012 Aug 11;380(9841):581-90. doi: 10.1016/S0140-6736(12)60367-5. Epub 2012 May 17.
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PMID: 23000957
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PMID: 21249663
responsible party type: Principal Investigator
investigator affiliation: University of Copenhagen
investigator full name: Flemming Dela
investigator title: Associate Professor
mesh term: Cardiovascular Diseases
mesh term: Diabetes Mellitus
mesh term: Simvastatin
sharing ipd: No