[X]Statin Causing Adverse Effect in Therapeutic Use Clinical Trial
Official title:
Effect of Vitamin D Supplementation on Exercise Adaptations in Patients on Statin Therapy
The health benefits of exercise have been widely described, the most notable of which is an
increase in cardiorespiratory fitness.Cardiorespiratory fitness has been identified as the
strongest independent predictor of both all cause and cardiovascular disease mortality in
nearly every population in which it has been examined.
Statins, a class of hydroxymethylglutaryl-coenzyme A reductase inhibitors that lower
low-density lipoprotein cholesterol, are commonly prescribed to patients with the metabolic
syndrome. Statins are widely prescribed in combination with exercise to lower risk of
cardiovascular disease morbidity and mortality. Every 1 millimole per liter reduction in LDL
is associated with a 10-20% reduction in risk of cardiovascular events and all-cause
mortality , while every 1 MET (3.5 milliters 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. Although the mechanisms are poorly
understood, some statins have been shown to reduce skeletal muscle mitochondrial content and
oxidative capacity in humans .
The muscle is a special potential target for the vitamin D endocrine system. Myopathy is
well recognized in patients with severe vitamin D deficiency. This myopathy can be rapidly
and impressively corrected by the appropriate vitamin D therapy. The beneficial effect of
vitamin D supplementation of severely deficient but otherwise healthy adults on muscle
weakness, has been reported by improved mitochondrial function.
Despite the potential public health implications, studies examining the benefits and risks
of combining statins and exercise in humans are limited. Moreover, Vitamin D may play a role
in statin mediated changes in exercise adaptations.This study is being done to look for
effect of simvastatin on exercise mediated cardiorespiratory fitness and the effect of
vitamin D supplementation in these settings.
Metabolic syndrome is common in adult Asian Indians and was present in 41.1% of the study
subjects in a study by Ramachandran et al in 2003. Among the total, only 8.6% were without
any abnormality of the various components of metabolic syndrome. Therapeutic lifestyle
changes, including exercise, are the first line of treatment for patients with the metabolic
syndrome. The health benefits of exercise have been widely described, including an increase
in cardiorespiratory fitness.Cardiorespiratory fitness has been identified as the strongest
independent predictor of both all cause and cardiovascular disease mortality in nearly every
population in which it has been examined Statins, a class of hydroxyl methyl
glutaryl-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.
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 mortality3,4 , while
every 1 MET (3.5 milliters of oxygen per kilogram of body weight per minute) increase in
fitness is associated with an 18% reduction in cardiovascular disease mortality5 and an
11-50% reduction in all-cause mortality. Some statins (simvastatin, atorvastatin,
fluvastatin) have been shown to reduce skeletal muscle mitochondrial content and oxidative
capacity in humans.
Catherine et al examined the effects of simvastatin on changes in cardiorespiratory fitness
and skeletal muscle mitochondrial content in response to aerobic exercise training.
Sedentary overweight or obese adults with at least 2 metabolic syndrome risk factors
(defined according to National Cholesterol Education Panel Adult Treatment Panel III
criteria) were randomized to 12 weeks of aerobic exercise training or to exercise in
combination with simvastatin (40 mg per day). 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 for group by time interaction).
Since vitamin D deficiency is common in the general population, and can be associated with
reversible myalgias, Duell et al hypothesized that vitamin D deficiency may contribute to
myopathic symptoms in some patients on statins.
Sinha et al examined the effects of cholecalciferol therapy on skeletal mitochondrial
oxidative function in vitamin D deficient subjects using 31P magnetic resonance
spectroscopy. This longitudinal study assessed mitochondrial oxidative phosphorylation in
the gastrosoleus compartment using phosphorus-31 magnetic resonance spectroscopy
measurements of phosphocreatine recovery kinetics in 12 symptomatic, severely vitamin
D-deficient subjects before and after treatment with cholecalciferol therapy to document
serum 25-hydroxyvitamin D (25OHD) and bone profiles. Fifteen healthy controls also underwent
31P-magnetic resonance spectroscopy and serum 25OHD assessment. 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). This was associated with an improvement in mean serum 25OHD levels (8.8
±4.2 nmol/L to 113.8 ± 51.5 nmol/L, P < .001). There was no difference in phosphate
metabolites at rest. All patients reported an improvement in fatigue after cholecalciferol
therapy.
In recent years, there has been a growing movement to begin prescribing statins to low-risk
patients and to all patients over the age of 50 for the primary prevention of cardiovascular
disease making the case for statins to be used in primary prevention.Despite the potential
public health implications, studies examining the benefits and risks of combining statins
and exercise in humans are limited
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Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment