<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/NCT02250677</url>
  </required_header>
  <id_info>
    <org_study_id>LIFESTAT - Cross Sectional</org_study_id>
    <nct_id>NCT02250677</nct_id>
  </id_info>
  <brief_title>LIFESTAT - Living With Statins, a Cross Sectional Study</brief_title>
  <official_title>LIFESTAT - Living With Statins, a Cross Sectional Study on 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 (CVD). The use of statins has increased markedly and it is now one&#xD;
      of the most prescribed drugs in the world. 600,000 people in Denmark are taking statins on a&#xD;
      daily basis, 40 % of these are taking the medication without having any other risk factors&#xD;
      for CVD 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 CVD, it is necessary to treat 200 people for 3-5 years. These data suggest that&#xD;
      more conservative use of statins to prevent CVD in otherwise healthy individuals at low risk&#xD;
      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 prohibit) physical exercise training? Furthermore we would&#xD;
      like to answer the following questions:&#xD;
&#xD;
      a Does statin treatment impair (or even prohibit) physical exercise training?&#xD;
&#xD;
      b Does statin treatment cause:&#xD;
&#xD;
        -  Decreased muscle strength?&#xD;
&#xD;
        -  Skeletal muscle inflammation?&#xD;
&#xD;
        -  Decreased mitochondrial respiratory function?&#xD;
&#xD;
      c 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 (10; 12) 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 (3; 10). 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 (13). 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 (15). 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 (11)). 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 (9; 11). 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 (18).&#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 (8). In addition, the statins also negatively affect the glucose tolerance&#xD;
      (8), 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 (8).&#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;
      a Does statin treatment impair (or even prohibit) physical exercise training?&#xD;
&#xD;
      b Does statin treatment cause:&#xD;
&#xD;
        -  Decreased muscle strength?&#xD;
&#xD;
        -  Skeletal muscle inflammation?&#xD;
&#xD;
        -  Decreased mitochondrial respiratory function?&#xD;
&#xD;
      c 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&#xD;
      pharmacies and through advertisement in newspapers in Copenhagen. 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 (16) (www.HeartScore.org). A staggered recruitment will&#xD;
      be implemented.&#xD;
&#xD;
      60 patients both men and women (age: 40-70 years; BMI: 25-35 kg/m2) that are being treated&#xD;
      with Simvastatin minimum 40 mg/day as primary prevention are recruited. No other risk factors&#xD;
      for CVD except elevated total cholesterol and/or elevated LDL cholesterol and mild&#xD;
      hypertension (&lt;145/100 mm Hg) must be present.&#xD;
&#xD;
      The test subjects will undergo three experimental days as described below:&#xD;
&#xD;
      Experimental days:&#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 (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 (incl.&#xD;
           Visual Analog Scale)&#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) and fat biopsy from the&#xD;
           subcutaneous 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 20-25 subjects in each&#xD;
      group if an alpha level of &lt;0.05 and risk of type 2 error is set to 10%. 20-25 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>April 2014</start_date>
  <completion_date type="Actual">September 2016</completion_date>
  <primary_completion_date type="Actual">September 2016</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Differences in physical performance between two groups of statin treated patients</measure>
    <time_frame>Three experimental days</time_frame>
    <description>Differences in physical performance is measured by VO2-max and muscle strength</description>
  </primary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">75</enrollment>
  <condition>Cardiovascular Disease</condition>
  <condition>Diabetes Mellitus</condition>
  <arm_group>
    <arm_group_label>Patients with myalgia</arm_group_label>
    <description>Patients with myalgia as a side effect to treatment with Simvastatin (minimum 20 mg daily)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Patients without myalgia</arm_group_label>
    <description>Patients treated with Simvastatin (minimum 20 mg daily) without any side effects to the treatment</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <description>Patients with elevated serum cholesterol not treated with cholesterol lowering drugs</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Samples with plasma, muscle and fat biopsies are retained for analysis after enrolment of the&#xD;
      last subject.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        The patients will be recruited through advertisement in pharmacies and through newspapers.&#xD;
        The patients will be recruited among statin users that are in primary prevention.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  40-70 years&#xD;
&#xD;
          -  BMI 25-35&#xD;
&#xD;
          -  Taking Simvastatin minimum 40 mg daily&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Diabetes Mellitus&#xD;
&#xD;
          -  Cardiovascular disease such as arrythmia, ischaemic heart disease&#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>Meador BM, Huey KA. Statin-associated myopathy and its exacerbation with exercise. Muscle Nerve. 2010 Oct;42(4):469-79. doi: 10.1002/mus.21817.</citation>
    <PMID>20878737</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 M, 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; European Association for Cardiovascular Prevention &amp; Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). 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). Eur Heart J. 2012 Jul;33(13):1635-701. doi: 10.1093/eurheartj/ehs092. Epub 2012 May 3. No abstract available. Erratum In: Eur Heart J. 2012 Sep;33(17):2126.</citation>
    <PMID>22555213</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>September 2016</verification_date>
  <study_first_submitted>September 12, 2014</study_first_submitted>
  <study_first_submitted_qc>September 24, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 26, 2014</study_first_posted>
  <last_update_submitted>September 23, 2016</last_update_submitted>
  <last_update_submitted_qc>September 23, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 26, 2016</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>cardiovascular disease</keyword>
  <keyword>diabetes mellitus</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>
  <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/NCT02250677
org study id: LIFESTAT - Cross Sectional
nct id: NCT02250677
lead sponsor: 
has dmc: No
Background Statins are cholesterol lowering drugs that are prescribed to lower the risk of
      cardio-vascular diseases (CVD). 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 CVD 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 CVD, 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 we would
      like to answer the following questions:

      a Does statin treatment impair (or even prohibit) physical exercise training?

      b Does statin treatment cause:

        -  Decreased muscle strength?

        -  Skeletal muscle inflammation?

        -  Decreased mitochondrial respiratory function?

      c 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 (10; 12) 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 (3; 10). Nevertheless, statin therapy
      failed to reduce all-cause mortality in a meta-study of 65,229 patients without CVD, some of
      whom had diabetes (13). 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 (15). 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 (11)). 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 (9; 11). 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 (18).

      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 (8). In addition, the statins also negatively affect the glucose tolerance
      (8), 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 (8).
      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:

      a Does statin treatment impair (or even prohibit) physical exercise training?

      b Does statin treatment cause:

        -  Decreased muscle strength?

        -  Skeletal muscle inflammation?

        -  Decreased mitochondrial respiratory function?

      c 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
      pharmacies and through advertisement in newspapers in Copenhagen. 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 (16) (www.HeartScore.org). A staggered recruitment will
      be implemented.

      60 patients both men and women (age: 40-70 years; BMI: 25-35 kg/m2) that are being treated
      with Simvastatin minimum 40 mg/day 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 test subjects will undergo three experimental days as described below:

      Experimental days:

      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 (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 (incl.
           Visual Analog Scale)

        -  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) and fat biopsy from the
           subcutaneous 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 20-25 subjects in each
      group if an alpha level of <0.05 and risk of type 2 error is set to 10%. 20-25 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.
observational model: Case-Control
time perspective: Cross-Sectional
measure: Differences in physical performance between two groups of statin treated patients
time frame: Three experimental days
description: Differences in physical performance is measured by VO2-max and muscle strength
arm group label: Patients with myalgia
description: Patients with myalgia as a side effect to treatment with Simvastatin (minimum 20 mg daily)
arm group label: Patients without myalgia
description: Patients treated with Simvastatin (minimum 20 mg daily) without any side effects to the treatment
arm group label: Control group
description: Patients with elevated serum cholesterol not treated with cholesterol lowering drugs
Samples with plasma, muscle and fat biopsies are retained for analysis after enrolment of the
      last subject.
study pop: 
sampling method: Non-Probability Sample
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
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.
PMID: 17334651
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.
PMID: 22607823
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.
PMID: 22212519
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.
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
citation: Meador BM, Huey KA. Statin-associated myopathy and its exacerbation with exercise. Muscle Nerve. 2010 Oct;42(4):469-79. doi: 10.1002/mus.21817.
PMID: 20878737
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.
PMID: 22607822
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.
PMID: 23000957
citation: Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, 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; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG). 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). Eur Heart J. 2012 Jul;33(13):1635-701. doi: 10.1093/eurheartj/ehs092. Epub 2012 May 3. No abstract available. Erratum In: Eur Heart J. 2012 Sep;33(17):2126.
PMID: 22555213
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.
PMID: 20585067
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.
PMID: 22883507
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.
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
sharing ipd: No