Effect of Vitamin D Supplementation on Exercise Adaptations in Patients on Statin Therapy
Condition: Dyslipidemias
MeSH terms: Dyslipidemias
Study type: Interventional
Phase: Phase 3

Summary: 
      Statins along with lifestyle modifications including exercise are commonly prescribed to
      patients with type 2 diabetes. American diabetes association recommends using
      moderate-intensity statin and lifestyle therapy for patients with diabetes aged ≥40 years,
      even without additional cardiovascular disease(CVD) risk factors.. Myopathy is a well known
      adverse effect of statins, which occurs in 1-7% of patients. The spectrum of statin-related
      myopathy ranges from common benign myalgia to rare but life threatening rhabdomyolysis. Being
      lipophilic, simvastatin diffuses nonselectively into extrahepatic tissues such as muscle,
      leading to higher incidence of myopathy among statin users.

      In addition, simvastatin attenuates the exercise-induced increase in cardiorespiratory
      fitness, and reduces the skeletal muscle mitochondrial content and oxidative capacity in
      humans. Impaired cardiorespiratory fitness and mitochondrial function is possibly due to
      reduction in Coenzyme Q10, which is a component of the electron transport chain and is
      indispensable for generation of adenosine triphosphate (ATP) during oxidative phosphorylation
      in mitochondria. Statins or hydroxyl-methylglutaryl coenzyme A (HMA CoA) reductase inhibitors
      interfere with the production of mevalonic acid, which is a precursor in the synthesis of
      coenzyme Q10.

      Mitochondrial dysfunction has also been reported in vitamin D deficient individuals which has
      been attributed to intra-mitochondrial calcium deficiency or deficient enzyme function of the
      oxidative pathway ( by direct effect of vitamin D on enzyme gene or protein expression).
      Thus, vitamin D may improve the statin-mediated changes in cardiorespiratory fitness and
      mitochondrial function by improving the enzymatic machinery involved in oxidative
      phosphorylation which is blocked by statin. This study is being done to look for the effect
      of vitamin D supplementation on simvastatin-mediated change in exercise-mediated
      cardiorespiratory fitness and skeletal muscle mitochondrial content in adults with type 2
      diabetes
    

Detailed description: 
      Statins, a class of hydroxyl methylglutaryl-coenzyme A reductase inhibitors that lower
      low-density lipoprotein cholesterol, are commonly prescribed to patients with the metabolic
      syndrome or those with multiple cardiovascular disease risk factors when lifestyle changes
      fail to achieve LDL targets to reduce the risk of coronary heart disease morbidity and
      mortality. American Diabetes Association (ADA) recommends moderate intensity statin for
      patients with diabetes without additional CVD risk factors aged >40.Statins are widely
      prescribed in combination with exercise to lower risk of cardiovascular disease morbidity and
      mortality. Every 1millimole per liter reduction in LDL is associated with a 10-20% reduction
      in risk of cardiovascular events and all-cause mortality, while every 1 Metabolic equivalent
      [MET] (3.5 milliliters of oxygen per kilogram of body weight per minute) increase in fitness
      is associated with an 18% reduction in cardiovascular disease mortality and an 11-50%
      reduction in all-cause mortality.Statins are generally safe, but myotoxicity, including fatal
      rhabdomyolysis can occur. Although severe muscle-related side effects occur in <0.1% of
      statin users, less severe symptoms, such as myalgia and muscle cramps, occur in 1-7% of
      users.

      The mechanisms mediating statin myopathy are unclear, but possibilities include decreased
      sarcolemmal or endoplasmic reticulum cholesterol, reduced production of prenylated proteins
      including the mitochondrial electron transport protein coenzyme Q10, reduced fat catabolism,
      increased myocellular concentrations of cholesterol and plant sterols, failure to repair
      damaged skeletal muscle, vitamin D deficiency, and inflammation. Increasingly, interest has
      focused on altered cellular energy use and mitochondrial dysfunction, with the dysfunction
      activating pathways leading to muscle atrophy. Although the mechanisms are poorly understood,
      some statins (simvastatin, atorvastatin, fluvastatin) have been shown to reduce skeletal
      muscle mitochondrial content and oxidative capacity in humans.

      Sirvent et al evaluated the mitochondrial function and calcium signaling in muscles of
      patients treated with statins, who present or not muscle symptoms, by oxygraphy and recording
      of calcium sparks, respectively. Patients treated with statins showed impairment of
      mitochondrial respiration that involved mainly the complex I of the respiratory chain and
      altered frequency and amplitude of calcium sparks. The muscle problems observed in
      statin-treated patients appear thus to be related to impairment of mitochondrial function and
      muscle calcium homeostasis.

      Mikus et al examined the effects of simvastatin on changes in cardiorespiratory fitness and
      skeletal muscle mitochondrial content in response to aerobic exercise training. The primary
      outcomes were cardiorespiratory fitness and skeletal muscle (vastus lateralis) mitochondrial
      content (citrate synthase enzyme activity). Thirty-seven participants (exercise plus statins;
      n=18; exercise only; n=19) completed the study. Cardiorespiratory fitness increased by 10%
      (P<0.05) in response to exercise training alone, but was blunted by the addition of
      simvastatin resulting in only a 1.5% increase (P<0.005 for group by time interaction).
      Similarly, skeletal muscle citrate synthase activity increased by 13% in the exercise only
      group (P <0.05), but decreased by 4.5% in the simvastatin plus exercise group (P<0.05 )
      Impaired cardiorespiratory fitness and mitochondrial function is possibly due to reduction in
      Coenzyme Q10, which is a component of the electron transport chain and is indispensable for
      generation of ATP during oxidative phosphorylation in mitochondria. Statins or
      hydroxyl-methylglutaryl coenzyme A (HMA CoA) reductase inhibitors interfere with the
      production of mevalonic acid, which is a precursor in the synthesis of coenzyme Q10.

      Mitochondrial dysfunction has also been reported in vitamin D deficient individuals which has
      been attributed to intra-mitochondrial calcium deficiency or deficient enzyme function of the
      oxidative pathway ( by direct effect of vitamin D on enzyme gene or protein expression).

      Mukherjee et al conducted a study in which chicks were raised for 3 to 4 weeks either on a
      normal (vitamin D supplemented) or a rachitogenic diet. The Ca2+ content of the serum, heart
      tissue and heart mitochondria was significantly decreased in chicks raised on a rachitogenic
      diet. In mitochondria isolated from calcium deficient hearts, the rate of adenosine
      diphosphate induced state 3 respiration and 2,4-Dinitrophenol uncoupled respiration were
      significantly decreased.When vitamin D deficient chicks were orally dosed with vitamin D3,
      serum calcium level and state 3 respiration rate returned to normal indicating that the above
      changes are reversible In a longitudinal study, the effects of cholecalciferol therapy on
      skeletal mitochondrial oxidative function in vitamin D deficient subjects using 31Phosphorus
      magnetic resonance spectroscopy were examined.The phosphocreatine recovery half-time
      (t1/2PCr) was significantly reduced after cholecalciferol therapy in the subjects indicating
      an improvement in maximal oxidative phosphorylation (34.44 ±8.18 sec to 27.84 ±9.54 sec, P
      <.001).

      Thus, vitamin D may improve the statin-mediated changes in cardiorespiratory fitness and
      mitochondrial function by improving the enzymatic machinery involved in oxidative
      phosphorylation which is blocked by statin. Another proposed mechanism of interaction between
      statin and vitamin D is inhibition of CYP3A4 by statins, which displays 25-hydroxylase
      activity in vitro. Vitamin D deficiency leads to 'preferential shunting' of CYP3A4 for
      hydroxylation of vitamin D, thus decreasing the availability of CYP3A4 for statin metabolism
      leading to statin-induced toxicity.

      This study describes the effect of vitamin D supplementation on simvastatin-mediated change
      in exercise-mediated cardiorespiratory fitness and skeletal muscle mitochondrial content in
      adults with type 2 diabetes.
    

Intervention name(s): Vitamin D; Simvastatin; Placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Vitamin D will be given to achieve normal serum levels; Simvastatin in a dose of 40 mg will be provided to the study participants; Placebo will be provided to the study participants
Other intervention name(s): Cholecalciferol; Statin
Intervention MeSH terms: Vitamin D; Cholecalciferol; Simvastatin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: simvastatin; cardiorespiratory fitness; vitamin D; exercise; mitochondria