Metabolic Syndrome and Insulin Resistance at Allina (MISURA)

Randomized, Controlled Trial of Vitamin D Replenishment in Metabolic Syndrome

Vitamin D deficiency is widespread and appears to represent one easily and inexpensively modifiable risk factor for diabetes and cardiovascular disease. More than 40 years of data link hypovitaminosis D to metabolic syndrome, insulin resistance, hyperglycemia, type 2 diabetes and increased cardiovascular risk.

Screening for vitamin D deficiency followed by supplementation in appropriate individuals could be among the simplest and most cost-effective measures for reducing metabolic syndrome and insulin resistance in the general population.

This study will test the hypothesis that increasing vitamin D status in vitamin D deficient individuals with metabolic syndrome will:

1. reduce multiple serum cardiometabolic risk factors for both diabetes and cardiovascular disease,
2. stabilize or reverse the stage of pre-diabetes,
3. improve quality of life, and,
4. improve the ability to make health-related behavioral changes.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome
• Intervention / Treatment: Dietary supplement: vitamin D3 (cholecalciferol)

Detailed Description

Longitudinal observational studies suggest a significant inverse association between vitamin D status and both incident and prevalent metabolic syndrome/type II diabetes. Results from small underpowered trials and post-hoc analyses of data from larger trials designed for bone-specific outcomes suggest that vitamin D may slow the progression to diabetes in adults with glucose intolerance. However, at this time, no randomized trials of sufficient size exist to assess effectiveness.

Importantly, in the investigators' own study of over 10,000 Allina employees, the investigators found that 6% of these employees had levels less than 10 ng/mL, 30% less than 20 ng/ml and 60% less than 30 ng/ml. Recently, the Intermountain Heart Collaborative Study Group reviewed 41,504 patient records with at least one measured vitamin D level. Surprisingly, both the Intermountain and the Allina Employee study demonstrate vitamin D deficiency (≤30 ng/ml) in more than 60% of people tested with only minor differences by gender or age (Plotnikoff GA, Finch M, Dusek JA. Impact of Vitamin D Deficiency on the Productivity of a Health Care Workforce. J Occup Environ Med (in press)).

Furthermore, the Intermountain group demonstrated that vitamin D levels less than 30 ng/ml, compared to levels greater than 30 ng/ml, were associated with highly significant (p <0.0001) increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. Also, those without risk factors but with severe deficiency had an increased likelihood of developing diabetes, hypertension, and hyperlipidemia. The vitamin D levels were also highly associated with coronary artery disease, myocardial infarction, heart failure, and stroke (all p <0.0001), as well as with incident death, heart failure, coronary artery disease/myocardial infarction (all p <0.0001), stroke (p = 0.003), and their composite (p <0.0001).

Numerous prevention efforts are underway to minimize the predicted economic and human burdens from these increasingly common diseases. However, few, if any, prospective clinical trials are underway with vitamin D interventions. This trial is specifically designed to prospectively test the impact of vitamin D replenishment on both metabolic syndrome and insulin resistance.

The 2011 Endocrine Society guidelines assert that vitamin D intakes above the current recommendations may be associated with better health outcomes. However, there is no consensus on the optimal 25(OH)D concentration necessary to minimize metabolic syndrome, insulin resistance and progression to diabetes. This trial is designed to prospectively identify optimal serum levels for reduction of cardiometabolic risk factors.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55407
      • Allina Health

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Please Note: All participants must be an employee of Allina Health or the spouse of an Allina employee.

Inclusion Criteria:

• Vitamin D deficiency, defined as 25-OH vitamin D ≤ 25 ng/ml
• Metabolic syndrome as defined by more than three or more of the following:

Elevated waist circumference

• Men - Equal to or greater than 40 inches
• Women - Equal to or greater than 35 inches
• Elevated serum triglycerides (≥150 mg/dL)
• Men - Less than 40 mg/dL
• Women - Less than 50 mg/dL
• Elevated blood pressure (≥130/85 or use of medication for hypertension)
• Elevated fasting glucose (≥100 mg/dL or use of medication for hyperglycemia)

Exclusion Criteria:

• Known cardiovascular disease defined as current or prior coronary heart disease, stroke/transient ischemic attack, heart failure, or peripheral vascular disease.
• During the study, addition of any medications known to change outcome measures including medications or supplements for hyperlipidemia, hypertension, weight loss, diabetes.
• Current Vitamin D supplementation beyond that found in a multivitamin (400 IU)
• Current calcium supplementation greater than 600 mg
• Untreated blood pressure greater than 159/99 at baseline
• Treated blood pressure greater than 150/90 at baseline
• Any condition which could limit the ability to complete and comply with 6-month study
• Unwillingness or inability to comply with study requirements
• Known allergy to coconut or coconut oil

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Regular Dose; Intervention: 600 IUs of cholecalciferol taken by mouth daily.	Dietary supplement: vitamin D3 (cholecalciferol); Active intervention: 6,000 IUs taken by mouth daily for 6 months Active Comparator: 600 IUs taken by mouth daily for 6 months; Other Names: D-Drops
Experimental: High Dose D; Intervention: 6,000 IUs of cholecalciferol taken by mouth daily.	Dietary supplement: vitamin D3 (cholecalciferol); Active intervention: 6,000 IUs taken by mouth daily for 6 months Active Comparator: 600 IUs taken by mouth daily for 6 months; Other Names: D-Drops

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin resistance score by NMR lipid fractionation	additional insulin resistance measure	6 months
Reynolds Risk Score	The Reynolds Risk Score is designed to predict one's risk of having a future heart attack, stroke, or other major heart disease in the next 10 years. In addition to your age, blood pressure, cholesterol levels and whether you currently smoke, the Reynolds Risk Score uses information from two other risk factors, a blood test called hsCRP (a measure of inflammation) and whether or not either of your parents had a heart attack before they reached age 60 (a measure of genetic risk).	6 months
Pre-diabetes stage	The pre-diabetes stage, a marker of progression toward type 2 diabetes mellitus, is a calculated score based upon results of fasting adiponectin, insulin and proinsulin.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
blood pressure		6 months
weight		6 months
25-OH-vitamin D	25-OH-vitamin D is the best measure of vitamin D status.	6 months
fasting lipid profile		6 months
adiposity markers	Adiponectin: This adipocyte-derived protein increases hepatic and peripheral insulin sensitivity, moderates fat tissue growth, decreases lipid and glucose production in the liver and suppresses vascular inflammation. This measure declines as insulin resistance increases. Leptin: This adipocyte-derived hormone plays a key role in regulating neuroendocrine and immune function, appetite, metabolic rate and body weight. Many overweight individuals have elevated levels and leptin resistance.	6 months
TNF-alpha	Inflammatory markers: TNF-alpha, IL-6, IL-8. These inflammatory mediators are central to the pathophysiology of obesity and its systemic effects	6 months
PROMIS-29	PROMIS is a questionnaire data bank developed and made available by the National Institutes of Health for research purposes. It is used to measure the core domains of physical functioning, fatigue, pain, depression, anxiety, and social role participation.	6 months
Perceived Stress Scale (PSS)	The PSS is brief, validated and widely used psychological instrument for assessing a participant's perception of stress. The PSS-4 consists of 4 questions to measure the degree to which situations in the participant's life are perceived as stressful including questions related to perceived unpredictability and lack of control.	6 months
WPAI	This 6 item, validated instrument measures work and general activity impairment due to health problems. It uses a seven day recall and has been adapted for use in populations with differing health problems.	6 months
PROMIS-GH	PROMIS is a questionnaire data bank developed and made available by the National Institutes of Health for research purposes. The PROMIS-GH consists of 10 items, representing multiple domains and can be scored into a Global Physical Health component and a Global Mental Health component	6 months
International Physical Activity Questionnaire (IPAQ)	The International Physical Activity Questionnaire (IPAQ) short form (4 generic items) versions for use by either telephone or self-administered methods are available. The purpose of the questionnaire is to provide a common instrument that can be used to obtain internationally comparable data on health related physical activity. The development of this international measure for physical activity commenced in Geneva in 1998 and was followed by extensive reliability and validity testing undertaken in 12 countries (14 sites) across 6 continents during 2000.	6 months
IL-6	Inflammatory mediators, including IL-6, are central to the pathophysiology of obesity and its systemic effects.	6 months
IL-8	Inflammatory mediators, inlcuding IL-8, are central to the pathophysiology of obesity and its systemic effects.	6 months
HS-CRP	Elevated HS-CRP predicts the development of type II diabetes and is a crucial factor in calculating the Reynolds Risk Score.	6 months
Lp-PLA2 (PLAC)	This is an enzyme produced by inflammatory cells that hydrolyzes oxidized phospholipids in HDL and catalyzes the degradation of PAF, platelet activating factor. Levels are positively correlated with increased risk of developing coronary artery disease and stroke.	6 months
PAI-1	This is the primary inhibitor of plasminogen activation. Elevated levels predispose to clot formation by inhibiting fibrinolytic activity.	6 months
Fibrinogen	Fibrinogen is also known as coagulation Factor I. Elevated levels are associated with cardiovascular disease. This is an acute-phase protein that is elevated in any form of inflammation.	6 months

Collaborators and Investigators

• Sponsor: Allina Health System
• Investigators: Principal Investigator: Gregory Plotnikoff, MD, Allina Health; Study Director: Jeffery Dusek, PhD, Allina Health; Study Director: Shaina Biron, Allina Health

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Actual): February 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: February 28, 2012
• First Submitted That Met QC Criteria: March 6, 2012
• First Posted (Estimate): March 7, 2012

Study Record Updates

• Last Update Posted (Estimate): September 1, 2016
• Last Update Submitted That Met QC Criteria: August 30, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: Metabolic syndrome; Insulin resistance; Vitamin D deficiency
• Additional Relevant MeSH Terms: Pathologic Processes; Glucose Metabolism Disorders; Metabolic Diseases; Disease; Hyperinsulinism; Syndrome; Metabolic Syndrome; Insulin Resistance; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: SPA ID 3607