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November 8, 2019

Vitamin D and Health Outcomes: Then Came the Randomized Clinical Trials

Author Affiliations
  • 1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
  • 2Duke Clinical Research Institute, Duke University School of Medicine, Durham, North Carolina
JAMA. Published online November 8, 2019. doi:https://doi.org/10.1001/jama.2019.17302

Not long ago, vitamin D was riding high. Beyond its role in calcium homeostasis and bone health, animal studies linked vitamin D deficiency to numerous chronic illnesses including hypertension, diabetes, autoimmunity, and malignancy.1 Corroborating human observational studies reported associations between vitamin D deficiency and increased risks of hypertension, diabetes, cardiovascular disease, autoimmunity, and cancer.2 The lay press seized on this chorus of observational studies, testing of serum 25-hydroxyvitamin D levels proliferated, and supplementation with cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) increased substantially.3

Then came the randomized clinical trials.

Multiple trials have failed to demonstrate significant benefits of vitamin D supplementation. For example, vitamin D supplementation, compared with placebo, failed to reduce systolic blood pressure in patients with prehypertension and stage 1 hypertension.4 High-dose monthly oral vitamin D3, compared with placebo, did not reduce risk of incident cardiovascular disease or death.5 In the Vitamin D and Type 2 Diabetes (D2d) trial, vitamin D supplementation, compared with placebo, failed to lower risk of incident type 2 diabetes in patients with prediabetes.6

The largest vitamin D trial was the Vitamin D and Omega-3 Trial (VITAL), a randomized, double-blind, placebo-controlled clinical trial of 25 871 participants.7 Using a 2 × 2 factorial design, VITAL tested whether supplementation with cholecalciferol, 2000 IU/d, and the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid, 1 g/d, would reduce risk of cancer and the composite cardiovascular outcome of myocardial infarction, stroke, or cardiovascular death compared with placebo. During a median follow-up of 5.3 years, neither vitamin D supplementation nor omega-3 fatty acid supplementation was significantly better than placebo.

In this issue of JAMA, de Boer et al report the results of the VITAL-DKD study, which was a prespecified secondary ancillary study involving 1312 participants in the VITAL study who had type 2 diabetes and agreed to undergo additional testing of kidney function and urinary albumin excretion at baseline and at 2 and 5 years after randomization.8 The authors tested the hypothesis that supplementation with cholecalciferol and omega-3 fatty acids would reduce the rate of kidney functional decline in type 2 diabetes, which is the leading cause of end-stage kidney disease (ESKD) in the developed world. The primary outcome was change in estimated glomerular filtration rate (eGFR) from baseline to year 5. Prespecified secondary outcomes included time to the composite outcome of 40% reduction in eGFR or ESKD or death, and change in albuminuria from baseline to year 5.

At baseline, the mean eGFR was 85.8 mL/min/1.73 m2, 16% of participants had eGFR less than 60 mL/min/1.73 m2, and 9% had microalbuminuria greater than 30 mg/g creatinine. The mean 25-hydroxyvitamin D level was 29.7 ng/mL, and 50% of study participants had 25-hydroxyvitamin D levels less than 30 ng/mL; only 16% had levels less than 20 ng/mL, which is considered inadequate. Self-reported adherence to the interventions was excellent and corroborated by substantial differences in serum 25-hydroxyvitamin D and omega-3 fatty acid levels between the intervention and placebo groups at year 2.

By year 5, mean eGFR had declined to 73.5 mL/min/1.73 m2. Despite this substantial loss of eGFR, there were no significant differences in eGFR decline between the vitamin D and placebo groups or between the omega-3 fatty acid and placebo groups. Mean change in eGFR from baseline to year 5 was –12.3 mL/min/1.73 m2 in the vitamin D3 group vs –13.1 mL/min/1.73 m2 in the placebo group (difference, 0.9 [95% CI, –0.7 to 2.5] mL/min/1.73 m2) and –12.2 mL/min/1.73 m2 in the omega-3 fatty acid group vs –13.1 mL/min/1.73 m2 in the placebo group (difference, 0.9 [95% CI, –0.7 to 2.6] mL/min/1.73 m2), with no significant interaction between the 2 interventions.

Likewise, there were no beneficial effects of vitamin D or omega-3 fatty acid supplementation on albuminuria and no between-group differences in the secondary composite outcome, which occurred in 164 patients. In addition, no differences were observed in a series of post hoc and sensitivity analyses, and there was no association between longitudinal changes in 25-hydroxyvitamin D levels and concomitant changes in eGFR. In summary, VITAL-DKD was a well-designed, well-executed, well-powered study with a definitive main message: in patients with type 2 diabetes, routine supplementation with vitamin D or omega-3 fatty acids has no role in primary prevention of incident chronic kidney disease (CKD) or slowing of eGFR loss.

Vitamin D is essential for gastrointestinal absorption of calcium. In healthy individuals, vitamin D deficiency jeopardizes calcium homeostasis and stimulates secondary increases in parathyroid hormone. This form of secondary hyperparathyroidism mitigates hypocalcemia by enhancing renal conversion of 25-hydroxyvitamin D stores to the activated hormonal form, 1,25-dihydroxyvitamin D, but can contribute to bone loss induced by chronic parathyroid hormone excess. This is the physiological basis for the established justification to preserve vitamin D sufficiency: to maintain normal calcium homeostasis to protect skeletal health.

In patients with CKD, however, the pathophysiology is more complex. Patients with CKD are at least as susceptible as individuals without CKD to typical vitamin D deficiency, marked by low 25-hydroxyvitamin D levels, but they also manifest a “second hit,” a secondary excess of fibroblast growth factor 23, which inhibits activation of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (and accelerates its degradation) regardless of 25-hydroxyvitamin D stores. As in the general population, observational studies suggested that deficiencies of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were associated with mortality and other adverse outcomes in patients with CKD and ESKD.9 Pharmacoepidemiological studies that reported associations between treatment with activated forms of vitamin D and improved survival in ESKD further stoked enthusiasm for repletion of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D in patients with CKD and ESKD.10

Then came the randomized clinical trials.

One randomized placebo-controlled trial (coincidentally also called VITAL; n = 281 patients) suggested modest antiproteinuric effects of the activated vitamin D analog paricalcitol when added to blockers of the renin-angiotensin-aldosterone system in patients with type 2 diabetes mellitus and CKD.11 Other randomized placebo-controlled trials (range, 60-227 patients) found no beneficial effects of paricalcitol on left ventricular structure and function in patients with non–dialysis-dependent CKD.12,13 In ESKD, a placebo-controlled clinical trial reported no benefit of another activated form of vitamin D on cardiovascular outcomes in 976 Japanese patients without secondary hyperparathyroidism.14 Although no well-powered clinical trial has tested whether vitamin D2 or D3, exogenous 25-hydroxyvitamin D, or 1,25-dihydroxyvitamin D or its analogs can slow CKD progression to ESKD, the totality of published trial data offer little support for parathyroid hormone–independent benefits of correcting deficiencies in the vitamin D axis in patients along the spectrum of CKD. Furthermore, no clinical trials have investigated whether the vitamin D repletion strategies that are widely used by nephrologists to specifically treat secondary hyperparathyroidism reduce fracture risk or improve other clinical outcomes in patients with CKD and ESKD.

The VITAL-DKD study reported in this issue of JAMA8 and the recently reported D2d trial6 provide strong clinical trial–grade evidence against meaningful kidney-protective effects of routine vitamin D3 supplementation in the vast majority of patients with prediabetes or established type 2 diabetes, but do not completely preclude future investigation of vitamin D and CKD outcomes. The VITAL-DKD study population had nearly normal mean 25-hydroxyvitamin D levels at baseline, leaving open the question of whether the results would have differed had recruitment been restricted to patients with moderate or severe vitamin D deficiency. The post hoc subgroup analysis of patients with lower baseline 25-hydroxyvitamin D levels (<20 and 20-30 ng/mL) suggested nonsignificant benefits of vitamin D supplementation, raising the possibility of conducting a new and sufficiently powered trial restricted to this subpopulation. However, given the known benefits of vitamin D on skeletal health, it would be ethically challenging to randomize patients known to be vitamin D deficient to receive placebo for the duration needed to assess effects on CKD outcomes. Another open question is whether vitamin D supplementation might be beneficial for patients with more advanced CKD or more severe albuminuria at baseline. Without certainty about the ideal approach to vitamin D treatment in advanced CKD, a randomized trial that compared cholecalciferol, exogenous 25-hydroxyvitamin D, and an activated vitamin D analogue vs placebo could definitively lay to rest multiple remaining questions in the area.

In the meantime, contrasting the results of VITAL-DKD and its predecessor vitamin D trials with the impressive body of epidemiological research that implicated vitamin D deficiency in various adverse health outcomes offers a stark lesson on the chasm between association and causation. It now seems safe to conclude that many prior epidemiological associations between vitamin D deficiency and adverse health outcomes were driven by unmeasured residual confounding or reverse causality. For many of the chronic conditions previously mapped to vitamin D deficiency, their preclinical stages likely contributed to the vitamin D deficiency that subsequently “predicted” onset of overt clinical disease in observational studies rather than vice versa. For example, decreased physical activity due to illness could reduce sunlight-mediated vitamin D production, alterations in diet could reduce vitamin D intake, and subclinical reductions in kidney function could induce significant changes in vitamin D regulation due to subclinical increases in fibroblast growth factor 23. With each new and carefully conducted negative trial of vitamin D supplementation, the Institute of Medicine’s 2010-2011 report that emphasized the bone benefits of attaining sufficient vitamin D stores over other theoretical benefits based on observational data looks ever more prescient.15

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Article Information

Corresponding Author: Myles Wolf, MD, MMSc, 2 Genome Ct, Room 1009, Durham, NC 27710 (myles.wolf@duke.edu).

Published Online: November 8, 2019. doi:10.1001/jama.2019.17302

Conflict of Interest Disclosures: Dr Wolf reports having served as a consultant for Akebia, AMAG, Amgen, Ardelyx, Diasorin, and Pharmacosmos. No other disclosures were reported.

Funding/Support: Dr Wolf is supported by grant UH3DK118748 from the National Institutes of Health and a Strategically Focused Research Network from the American Heart Association.

Role of the Funder/Sponsor: The funders had no role in the preparation, review, or approval of the manuscript or decision to submit the manuscript for publication.

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