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reference
Tobias DK, Luttmann-Gibson H, Mora S, et al. Association between body weight and response to vitamin D supplementation and metabolism.JAMA Network Open. 2023;6(1):e2250681.
Study objective
To investigate whether baseline body mass index (BMI) alters vitamin D metabolism and response to supplementation.
Key to take away
Higher BMI may be associated with decreased response to vitamin D supplementation, which may partially explain the observed decreased results of supplementation in various health conditions in individuals with higher BMI.
design
A post hoc analysis of a subset of participants in the Vitamin D and Omega 3 (VITAL) trial.
Participant
Eligible participants in VITAL were men aged 50 years and over and women aged 55 and over who were free of cancer and cardiovascular disease at the start of the study.
Among the 25,871 individuals in the original VITAL, there were 16,515 eligible participants who contributed baseline blood samples prior to randomization (October 2010 to March 2014). Of them, 2,742 provided a blood sample after two years of follow-up, which was used by the researchers for analysis.
Analyzes excluded participants with missing or extreme baseline BMI (BMI <12.0 or ≥60.0). Participants' baseline characteristics, demographics, and health status were stratified by baseline BMI categories of underweight (<18.5), normal weight (18.5–24.9), overweight (25.0–29.9), and obesity class I (30.0–34.9). and obesity class II (≥35.0). For analyzes that included repeated biomarkers at 2 years, researchers combined the underweight and normal weight categories due to an insufficient sample size for a BMI less than 18.5.
intervention
The researchers conducted a post hoc analysisa subgroupin VITAL, a completed randomized, double-blind, placebo-controlled 2 × 2 factorial trial of vitamin D3(cholecalciferol), 2,000 IU/day, and marine omega-3 fatty acids, 1 g/day, for primary prevention of cancer and cardiovascular disease.IIn this study, an analysis was conducted on a subset of VITAL participants who provided a blood sample at baseline and a repeat sample after two years. Treatment Outcomes of Vitamin D, 2,000 IU/day, Dietary Supplement vs. Placebo, Associated with Clinical and Novel Vitamin D–related biomarkers by BMI category adjusted for other factors related to vitamin D status.
Evaluated study parameters
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-OHD3free vitamin D (FVD), bioavailable vitamin D (BioD), vitamin D-binding protein, albumin, parathyroid hormone (PTH) and calcium and logarithmically transformed as required.
Primary outcome
To investigate whether baseline BMI alters vitamin D metabolism and response to supplementation
Key findings
This cohort study aims to provide an explanatory analysis of a large, randomized trial of vitamin D supplementation3increased at 2,000 IU/day25-OHD, 25-OHD3FVD and BioD vs. placebo after 2 years of intervention.
Before randomization, baseline serum total 25-OHD levels were lower in higher BMI categories, with adjusted mean: underweight, 32.3 (0.7) ng/mL; Normal weight: 32.3 (0.1) ng/ml; Obesity, 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 altered the outcomes of vitamin D supplementation, with lower response and peak values for these biomarkers at higher BMIs (all treatment effect interactions).P<0.001).
Vitamin D-binding protein and albumin levels remained unchanged with supplementation, and the reduction in PTH levels with increased circulating vitamin D levels was consistent across BMI categories.
transparency
VITAL was supported by grant R01AT011729 from the National Center for Complementary and Integrative Health and, during the intervention phase, by grants U01 CA138962 and R01 CA138962 from the National Cancer Institute; National Heart, Lung and Blood Institute; and other. Pharmavite LLC of Northridge, California (Vitamin D) and Pronova BioPharma of Norway and BASF (Omacor fish oil) donated the study active ingredients, matching placebos and packaging in the form of calendar packs. Quest Diagnostics measured serum 25-hydroxyvitamin D, parathyroid hormone and other biomarkers free of charge as part of 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 Heart, Blood, and Lung Institute of the National Institutes of Health (NIH) and nonfinancial support in the form of laboratory measurements from the Quest Diagnostics Study during the conduct of the study; and personal fees from Pfizer outside the submitted work. Danik reported that he received funding from the American Heart Association while conducting the study. Cook reported that he received grants from the NIH to the facility while conducting the study. Lee reported receiving grants from the NIH while conducting the study. Buring said she received grants from the NIH during the conduct of the study, and her husband was on the scientific advisory board of Pharmavite, which provided vitamin D and placebo. Manson reported receiving grants from the NIH while conducting the study and grants from the NIH and Mars Edge outside of the submitted work. No further disclosures were reported.
Implications and limitations for practice
Vitamin D is of great interest from the perspective of disease prevention and intervention, and in scientific research there are conflicting data about whether it can prevent various diseases or improve their outcomes. The accumulating evidence suggests so25-Hydroxyvitamin D (25-OHD) levels may be relevant to cancer incidence and progression1and cardiovascular diseases.2However, meta-analyses of randomized clinical trials of vitamin D supplementation, including VITAL, have reported no benefits for the primary endpoints of cancer or major cardiovascular disease.3
Previous studies have shown the impact of body mass index (BMI) on the adequacy of serum 25-hydroxyvitamin D levels in US adults and have shown higher levels of deficiencyamong overweight and obese adults in the US population.4Given that approximately two in three U.S. adults are currently overweight or obese (69%) and one in three are obese (36%),5We can safely assume that many of the current clinical trials on vitamin D involve overweight and obese individuals.
Interestingly, in secondary analyzes in VITAL, randomization to vitamin D supplementation vs. placebo was statistically associatedsignificant 24% lower cancer incidence, 42% lower cancer mortality and 22% lower incidence of autoimmune diseases There were no reductions in participants with normal body weight (defined by BMI <25.0), but in participants with overweight or obesity.6In addition, two meta-analyses of randomized clinical trials on vitamin D supplementation and type 2 diabetes risk indicated the same association with differences in outcomes based on BMI.7.8
There are several theories as to why higher BMI might be associated with lower circulating 25-OHD levels or lower activity. One theory posits that due to fat solubility, vitamin D is removed from the bloodstream to a greater extent at higher adiposity volumes due to increased storage capacity.9Evidence from weight loss intervention studies supports vitamin D sequestration as a function of obesity levels.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 the circulation and is enzymatically activated to 25-OHD in the liver by cytochrome P450 enzymes.12Metabolism disorders caused by obesity could be the resultThis results in a reduced response to vitamin D supplementation, thereby reducing the amount of circulating 25-OHD and its downstream activity. Studies on animal models and a study on humans also support this theory.13
This study has limitations. The study's hypothesis was that 2,000 IU/day of vitamin D3would uniformly increase serum 25-OHD levels. In practice, most doctors recommend that patients undergo a serum 25-OHD test and provide them with an adequate amount of vitamin D3, and test again to ensure that your serum 25-OHD is in the optimal range. In addition, 2,000 IU vitamin D3Patients are often not brought into the optimal range, and vitamin D is often not sufficient3The amount must be adjusted in particulardepending on the amount of sunlight the patient is exposed to. Finally, most studies report either 2,000 IU of vitamin D3as an intervention or determination of achieving an optimal level of 20 to 30 ng/ml serum 25-OHD, which many believe is too low to achieve therapeutic efficacy. The study highlights the need to test and treat patients individually. Further research is warranted with optimized 25-OHD values.