Tobias DK, Luttmann-Gibson H, Mora S, et al. Association of body weight with response to vitamin D supplementation and metabolism. JAMA Netw Open. 2023;6(1):e2250681.
To investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation.
Higher BMI may be associated with a decreased response to vitamin D supplementation, which may partly explain the observed diminished outcomes of supplementation for various health conditions among individuals with higher BMI.
A post hoc analysis of a subset of participants from the Vitamin D and Omega-3 Trial (VITAL).
Eligible participants in VITAL were men aged 50 years or more and women aged 55 years or more who were free of cancer and cardiovascular disease at baseline enrollment.
Among the 25,871 individuals in the original VITAL, there were 16,515 eligible participants who contributed baseline blood samples before randomization (October 2010 to March 2014). Among them, 2,742 provided a blood sample at 2 years’ follow-up, and investigators used these in the analysis.
The analyses excluded participants with missing or extreme baseline BMI (BMI <12.0 or ≥60.0). Participants’ baseline characteristics, demographic characteristics, and health status at trial baseline were stratified by baseline BMI categories of underweight (<18.5), normal weight (18.5–24.9), overweight (25.0–29.9), obesity class I (30.0–34.9), and obesity class II (≥35.0). For analyses including repeated biomarkers at 2 years, the investigators combined the underweight and normal weight categories due to an insufficient sample size for BMI less than 18.5.
The investigators performed a post hoc analysis
Study Parameters Assessed
Multivariable-adjusted means (SE) or 95% confidence intervals of vitamin D–related serum biomarkers at baseline and follow-up: total 25-hydroxyvitamin D (25-OHD), 25-OHD3, free vitamin D (FVD), bioavailable vitamin D (BioD), vitamin D–binding protein, albumin, parathyroid hormone (PTH), and calcium, and log-transformed as needed.
To investigate whether baseline BMI modifies vitamin D metabolism and response to supplementation
In this cohort study designed to provide an explanatory analysis of a large, randomized trial, supplementation with vitamin D3 at 2,000 IU/day increased 25-OHD, 25-OHD3, FVD, and BioD vs placebo at 2 years of intervention.
Before randomization, baseline serum total 25-OHD levels were lower at higher BMI categories, with adjusted mean: underweight, 32.3 [0.7] ng/mL; normal weight, 32.3 [0.1] ng/mL; overweight, 30.5 [0.1] ng/mL; obesity class I, 29.0 [0.2] ng/mL; and obesity class II, 28.0 [0.2] ng/mL; P<0.001 for linear trend).
BMI status modified the results of the vitamin D supplementation, with lower response and achieved levels for these biomarkers at higher BMIs (all treatment effect interactions P<0.001).
Vitamin D–binding protein and albumin levels were unchanged with supplementation, and reductions in PTH levels with increased circulating vitamin D levels were consistent across BMI categories.
VITAL was supported by grant R01AT011729 from the National Center for Complementary and Integrative Health and, during the intervention phase, was supported by grants U01 CA138962 and R01 CA138962 from the National Cancer Institute; National Heart, Lung, and Blood Institute; and others. Pharmavite LLC of Northridge, California (vitamin D), and Pronova BioPharma of Norway and BASF (Omacor fish oil) donated the study agents, matching placebos, and packaging in the form of calendar packs. Quest Diagnostics measured serum 25-hydroxyvitamin D, parathyroid hormone, and other biomarkers at no cost to the study. LeBoff reported grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases RO1 AR070854 and grants from the National Institute of Arthritis and Musculoskeletal and Skin Diseases R01 AR059775.
Mora reported receiving grant R01HL134811 from the National Institutes of Health (NIH) National Heart, Blood, and Lung Institute and nonfinancial support in the form of laboratory measurements from Quest Diagnostics Study during the conduct of the study; and personal fees from Pfizer outside the submitted work. Danik reported receiving grants from the American Heart Association during the conduct of the study. Cook reported receiving grants from the NIH to the institution during the conduct of the study. Lee reported receiving grants from the NIH during the conduct of the study. Buring reported receiving grants from the NIH during the conduct of the study, and her spouse was on the scientific advisory board of Pharmavite, which provided vitamin D and placebo. Manson reported receiving grants from the NIH during the conduct of the study and grants from the NIH and Mars Edge outside the submitted work. No other disclosures were reported.
Practice Implications & Limitations
Vitamin D is of great interest from a disease-prevention and intervention standpoint, and conflicting data are prevalent in the scientific research on whether it can prevent or improve outcomes in various diseases. Accumulating evidence suggests 25-hydroxyvitamin D (25-OHD) levels may be relevant for the incidence and progression of cancer1 and cardiovascular disease.2 However, meta-analyses of randomized clinical trials of vitamin D supplementation, including in VITAL, have not reported benefits on the primary endpoints of cancer or major cardiovascular disease events.3
Previous studies have illustrated the effect of body mass index (BMI) on the adequacy of serum 25-hydroxyvitamin D levels in US adults, showing higher levels of deficiency among overweight and obese adults in the US population.4 Given the fact that currently, roughly 2 out of 3 US adults are overweight or obese (69%) and 1 out of 3 are obese (36%),5 we can safely assume that many of the current clinical trials on vitamin D involve overweight and obese individuals.
Interestingly, in secondary analyses in VITAL, randomization to vitamin D supplementation vs placebo was associated with a statistically
There are several theories as to why higher BMI might be associated with lower 25-OHD circulating levels or activity. One theory proposes that since vitamin D is fat-soluble, there is a greater removal of vitamin D from circulation due to increased storage capacity across higher adiposity volumes.9 Evidence from weight-loss intervention studies supports vitamin D sequestration as a function of the amount of adiposity.10,11
Another theory is that obesity causes liver dysfunction, which, in turn, contributes to impaired vitamin D metabolism. We know that oral vitamin D enters circulation and is activated enzymatically in the liver to 25-OHD by cytochrome P450 enzymes.12 Interference in metabolism by obesity could result
This study has limitations. The hypothesis of the trial was that 2,000 IU/day of vitamin D3 would uniformly increase serum 25-OHD. In practice, most clinicians recommend patients undergo serum 25-OHD testing, replete with an appropriate amount of vitamin D3, and retest to ensure their serum 25-OHD is in an optimal range. Furthermore, 2,000 IU of vitamin D3 often does not put patients into an optimal range, and often, the vitamin D3 amount needs to be adjusted, particularly