Effect of Vitamin D Supplementation on Exercise Adaptations in Patients on Statin Therapy

[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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02030041
• Other study ID #: Simvavitd
• Status: Recruiting
• Phase: Phase 3
• First received: December 23, 2013
• Last updated: October 27, 2014
• Start date: December 2013
• Est. completion date: December 2014

Study information

• Verified date: October 2014
• Source: Postgraduate Institute of Medical Education and Research
• Contact: Anil Bhansali, DM
• Phone: 01722756583
• Email: anilbhansaliendocrine[@]gmail.com
• Is FDA regulated: No
• Health authority: India: Indian Council of Medical Research
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 30
• Est. completion date: December 2014
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 25 Years to 50 Years

Eligibility

Inclusion Criteria:

• Type 2 DM

• No significant microvascular complication

• Age between 25 and 50 yrs

• HbA1c<7.5%

• LDL >100mg/dl

• Overweight or obese (BMI 25 -39 kg/m2)

• Low physical activity(WHO-GPAQ)

• Euthyroid , Eugonadal

• Vitamin D deficient (<20 ng/ml)

• Normal ECG

Exclusion Criteria:

• Use of statins in past 3 months

• Use of Thiazolidinediones, GLP -1agonists, DPP -IV inhibitors, Steroids, Orlistat or other medicines affecting lipid profile or body weight

• Smoking

• On Vitamin D supplementation

• Uncontrolled DM with HbA1c>7.5

• Uncontrolled hypertension

• CAD and PVD in past 6 months

• Musculoskeletal problems resulting in inability to exercise

• Pregnancy

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• [X]Statin Causing Adverse Effect in Therapeutic Use

Intervention

Drug:
• vitaminD
Vitamin D will be given to achieve normal serum levels
• Simvastatin
Simvastatin in a dose of 40 mg will be provided to the study participants
• Placebo
Placebo will be provided in an arm with simvastatin

Locations

Country	Name	City	State
India	PGIMER	Chandigarh

Sponsors (1)

Lead Sponsor	Collaborator
Postgraduate Institute of Medical Education and Research

Country where clinical trial is conducted

India, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	exercise adaptations	Thirty obese, vitamin D deficient ,dyslipidemic, type 2 diabetes patients will be recruited. Baseline mitochondrial function will be assessed by VO2max, P31 MR spectroscopy and muscle citrate synthase levels. Fifteen patients each will be given simvastatin and vitamin D or simvastatin and placebo. They will exercise for 12 weeks.Mitochondrial function will be reassessed by VO2max, P31MR spectroscopy and muscle citrate synthase levels.	Twelve weeks	No