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

NCT02030041 | Completed Phase 3 Results DMC

• 1 other identifier: Simvavitd
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

Dyslipidemias

Keywords

simvastatin; cardiorespiratory fitness; vitamin D; exercise; mitochondria

Outcome Measures

Primary Outcomes (2)

• Peak Oxygen Consumption

  Peak oxygen consumption( VO2peak) is defined as the highest rate at which oxygen can be taken up and utilized by the body during severe exercise. The participants were encouraged to exercise to exhaustion with progressive 2-minutes increments in the power output during the test. VO2peak was obtained when participants reached volitional exhaustion and met at least one of the following criteria: plateau in oxygen consumption despite increase in workload, rating of perceived exertion \>18, Respiratory exchange ratio \> 1.10 and peak heart rate within 10 beats of age predicted maximum. . As VO2peak (expressed as liters of oxygen consumed per minute) is also dependent on age, sex, and body size, it was expressed as percentage of the predicted value(VO2peak%).

  Twelve weeks

• Skeletal Muscle Mitochondrial Content

  Skeletal muscle citrate synthase activity is a validated marker of mitochondrial content. Skeletal muscle biopsy was obtained from vastus lateralis muscle of five patients in either groups before and after the intervention. Under aseptic conditions, samples were taken in protease inhibitor cocktail and stored at -80ºC. Mitochondrial citrate synthase activity (the working range of the kit was 1.56-100 µg/mL, with intra and inter assay CV of 4.35-6.55 % and 8.3 % respectively) was measured using ELISA Kit (Abcam, Cambridge, UK) as per manufacturer's instructions.Skeletal muscle citrate synthase activity is a validated marker of mitochondrial content.

  Twelve weeks

Study Arms (3)

Simvastatin and placebo

EXPERIMENTAL

Eleven participants will be vitamin D deficient with LDL-C between 100 to 130mg/dl. This arm will receive Simvastatin 40 mg once daily and placebo once weekly, and will perform moderate intensity exercise for twelve weeks. Participants will be advised to walk a minimum of 3000 steps in 30 minutes on 5 days each week

Drug: Simvastatin; Drug: Placebo

Simvastatin and vitamin D

ACTIVE COMPARATOR

Eleven participants will be vitaminD deficient with LDL-C between 100 to 130mg/dl. This arm will receive simvastatin 40 mg once daily and vitaminD 60,000 units once weekly , and will perform moderate intensity exercise for twelve weeks. Participants will be advised to walk a minimum of 3000 steps in 30 minutes on 5 days each week

Drug: Vitamin D; Drug: Simvastatin

Vitamin D and placebo

ACTIVE COMPARATOR

Eleven participants will be vitamin D deficient with LDL-C between 100 to 130mg/dl This arm will receive vitamin D 60,000 units once weekly and placebo once daily, and will perform moderate intensity exercise for twelve weeks. Participants will be advised to walk a minimum of 3000 steps in 30 minutes on 5 days each week

Drug: Vitamin D; Drug: Placebo

Interventions

Vitamin D DRUG

Vitamin D will be given to achieve normal serum levels

Also known as: Cholecalciferol

Simvastatin and vitamin D; Vitamin D and placebo

Simvastatin DRUG

Simvastatin in a dose of 40 mg will be provided to the study participants

Also known as: Statin

Simvastatin and placebo; Simvastatin and vitamin D

Placebo DRUG

Placebo will be provided to the study participants

Simvastatin and placebo; Vitamin D and placebo

Eligibility Criteria

• Age: 25 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Type 2 Diabetes Mellitus
• No significant microvascular complication
• Age between 25 and 50 yrs
• HbA1c\<7.5%
• LDL-C between 100 to 130mg/dl
• Overweight or obese (BMI 25 -39 kg/m2)
• Low physical activity(WHO-GPAQ)
• Euthyroid , Eugonadal
• Vitamin D deficient (\<20 ng/ml)
• Normal ECG

You may not qualify if:

• Use of statins in past 3 months
• Use of Thiazolidinediones, Glucagon like peptide -1agonists, Dipeptidyl Peptidase -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
• Significant microvascular complication of DM
• Macrovascular disease
• Musculoskeletal problems resulting in inability to exercise
• Pregnancy

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (1)

PGIMER

Chandigarh, Chandigarh, 160012, India

Location

MeSH Terms

Conditions

Dyslipidemias; Motor Activity

Interventions

Vitamin D; Cholecalciferol; Simvastatin; Hydroxymethylglutaryl-CoA Reductase Inhibitors

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Behavior

Intervention Hierarchy (Ancestors)

Secosteroids; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Cholestenes; Cholestanes; Sterols; Membrane Lipids; Lipids; Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Enzyme Inhibitors; Lipid Regulating Agents; Therapeutic Uses

Limitations and Caveats

The limitations include short duration of follow up and lack of direct supervision of exercise program. Although participants didn't perform exercise under direct supervision, adherence to exercise program was monitored by pedometer readings weekly.

Results Point of Contact

• Title: Anil Bhansali
• Organization: PGIMER

ashuendo@gmail.com

01722756583

Study Officials

• Anil Bhansali, DM

  PGIMER, Chandigarh

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, CARE PROVIDER
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Asst Professor, Department of Endocrinology, Postgraduate Institute of Medical Education and Research, Chandigarh

Study Record Dates

• First Submitted: December 23, 2013
• First Posted: January 8, 2014
• Study Start: December 1, 2013
• Primary Completion: December 1, 2015
• Study Completion: December 1, 2015
• Last Updated: March 31, 2017
• Results First Posted: March 31, 2017

Record last verified: 2017-02

Data Sharing

• IPD Sharing: Will not share

Locations

IN (1)