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Natural Medicine Journal

April 5, 2023

The Vitamin D–Body Weight Connection

Does increased body weight modify metabolism and response to vitamin D supplementation?

Shauna M. Birdsall

ND, FABNO
Higher body mass index may translate to lower response to vitamin D supplementation.

Reference

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.

Study Objective

To investigate whether baseline body mass index (BMI) modifies vitamin D metabolism and response to supplementation.

Key Takeaway

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.

Design

A post hoc analysis of a subset of participants from the Vitamin D and Omega-3 Trial (VITAL). 

Participants

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.

Intervention

The investigators performed a post hoc analysis of a subgroup in VITAL, a completed randomized, double-blind, placebo-controlled 2 × 2 factorial trial of vitamin D3 (cholecalciferol), 2,000 IU/d, and marine omega-3 fatty acids, 1 g/d, for the primary prevention of cancer and cardiovascular disease. In this study, an analysis was conducted in a subset of VITAL participants who provided a blood sample at baseline and a repeated sample at 2 years’ follow-up. Treatment outcomes of vitamin D, 2,000 IU/d, supplementation vs placebo, associated with clinical and novel vitamin D–related biomarkers by BMI category adjusted for other factors associated with vitamin D status.

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.

Primary Outcome

To investigate whether baseline BMI modifies vitamin D metabolism and response to supplementation

Key Findings

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.

Transparency

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 significant 24% lower cancer incidence, 42% lower cancer mortality, and 22% lower incidence of autoimmune disease among participants with normal body weight (as defined by BMI <25.0), but there were no reductions among those with overweight or obesity.6 Moreover, 2 meta-analyses of randomized clinical trials of vitamin D supplementation and risk of type 2 diabetes similarly 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 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 in a decreased response to vitamin D supplementation, reducing the amount of circulating 25-OHD and its downstream activity. Research in animal models and a human study supports this theory as well.13

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 depending upon the amount of sun exposure to which the patient is exposed. Lastly, most of the studies are either giving 2,000 IU of vitamin D3 as the intervention or determining achievement of an optimal level at 20 to 30 ng/mL serum 25-OHD, which many would argue is too low of a level to reach therapeutic efficacy. The study reinforces the need to test and treat patients as individuals. Further research is warranted with optimized 25-OHD levels.

Categorized Under

Shauna M. Birdsall

Shauna M. Birdsall

ND, FABNO

Shauna Birdsall, ND, FABNO, graduated from National University of Natural Medicine in 2000 and completed a 2-year residency at Cancer Treatment Centers of America (CTCA) in Illinois in 2002. She provided patient care and supervised naturopathic medical residents at CTCA in Illinois until 2008, when she transferred to CTCA in Phoenix, Arizona, as director of naturopathic medicine. Birdsall was elected as vice chief of the CTCA Phoenix Medical Staff in 2011 and served in that elected role until 2018. She also chaired the Medical Executive Committee, Credentials Committee, and Peer Review Committee and served as the medical director of integrative oncology at CTCA until 2018. She joined Avante Medical Center in Anchorage, Alaska, in 2019, as well as Advanced Oncology Associates at Anchorage Radiation Oncology Center and Peninsula Radiation Oncology Center in Soldotna, Alaska. She is board-certified by the American Board of Naturopathic Oncology. Birdsall and her husband, Tim Birdsall, ND, FABNO, started a virtual practice in 2020, Resilience Health, providing telemedicine consultations to oncology and general medicine patients. She is strongly committed to providing individualized, compassionate, evidence-based care to empower and provide hope to her patients.

References

  1. Yin L, Ordóñez-Mena JM, Chen T, Schöttker B, Arndt V, Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and meta-analysis. Prev Med. 2013;57(6):753-764.
  2. Zhang R, Li B, Gao X, et al. Serum 25-hydroxyvitamin D and the risk of cardiovascular disease: dose-response meta-analysis of prospective studies. Am J Clin Nutr. 2017;105(4):810-819.
  3. Manson JE, Cook NR, Lee IM, et al. Vitamin D supplements and prevention of cancer and cardiovascular disease. N Engl J Med. 2019;380(1):33-44.
  4. Samuel L, Borrell LN. The effect of body mass index on adequacy of serum 25-hydroxyvitamin D levels in US adults: the National Health and Nutrition Examination Survey 2001 to 2006. Ann Epidemiol. 2014;24(10):781-784.
  5. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999-2010. JAMA. 2012;307(5):491-497.
  6. 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.
  7. Barbarawi M, Zayed Y, Barbarawi O, et al. Effect of vitamin D supplementation on the incidence of diabetes mellitus. J Clin Endocrinol Metab. 2020;105(8):dgaa335.
  8. Zhang Y, Tan H, Tang J, et al. Effects of vitamin D supplementation on prevention of type 2 diabetes in patients with prediabetes: a systematic review and meta-analysis. Diabetes Care. 2020;43(7):1650-1658.
  9. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity [published correction appears in Am J Clin Nutr.;77(5):1342]. Am J Clin Nutr. 2000;72(3):690-693.
  10. Mason C, Xiao L, Imayama I, et al. Effects of weight loss on serum vitamin D in postmenopausal women. Am J Clin Nutr. 2011;94(1):95-103.
  11. Aldenbäck E, Johansson HE. Anthropometric measurements and correlations to glucometabolic and cardiovascular risk in obese patients undergoing gastric bypass surgery. J Obes. 2021;2021:6647328.
  12. Jones G, Prosser DE, Kaufmann M. Cytochrome P450-mediated metabolism of vitamin D. J Lipid Res. 2014;55(1):13-31.
  13. Elkhwanky MS, Kummu O, Piltonen TT, et al. Obesity represses CYP2R1, the vitamin D 25-hydroxylase, in the liver and extrahepatic tissues. JBMR Plus. 2020;4(11):e10397. 

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