Opinion
EDITORIAL
Vitamin D and Health Outcomes
Then Came the Randomized Clinical Trials
Anika Lucas, MD; Myles Wolf, MD, MMSc
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, dia-
betes, autoimmunity, and
Related article malignancy.1 Corroborating
human observational stud-
ies 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 supplementa-
tion with cholecalciferol (vitamin D 3 ) 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, vita-
min D supplementation, compared with placebo, failed to
reduce systolic blood pressure in patients with prehyperten-
sion and stage 1 hypertension.4 High-dose monthly oral vita-
min D3, compared with placebo, did not reduce risk of inci-
dent 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 eicosa-
pentaenoic acid and docosahexaenoic acid, 1 g/d, would re-
duce risk of cancer and the composite cardiovascular out-
come 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 ancil-
lary 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 func-
tional 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 filtra-
tion rate (eGFR) from baseline to year 5. Prespecified second-
jama.com
© 2019 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 11/08/2019
ary outcomes included time to the composite outcome of 40%
reduction in eGFR or ESKD or death, and change in albumin-
uria 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 inter-
ventions was excellent and corroborated by substantial dif-
ferences 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 sensitiv-
ity analyses, and there was no association between longi-
tudinal changes in 25-hydroxyvitamin D levels and con-
comitant 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, rou-
tine 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 jeopar-
dizes 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 acti-
vated hormonal form, 1,25-dihydroxyvitamin D, but can con-
tribute 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.
(Reprinted) JAMA Published online November 8, 2019 E1
 Opinion Editorial

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 mani-
fest 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) re-
gardless of 25-hydroxyvitamin D stores. As in the general popu-
lation, observational studies suggested that deficiencies
of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were
associated with mortality and other adverse outcomes in pa-
tients 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 anti-
proteinuric effects of the activated vitamin D analog parical-
citol 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 pa-
tients without secondary hyperparathyroidism.14 Although
no well-powered clinical trial has tested whether vitamin D2
or D3, exogenous 25-hydroxyvitamin D, or 1,25-dihydroxy-
vitamin D or its analogs can slow CKD progression to ESKD,
the totality of published trial data offer little support for para-
thyroid hormone–independent benefits of correcting deficien-
cies 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 hyperparathy-
roidism reduce fracture risk or improve other clinical out-
comes 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 mod-
erate 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 possibil-
ity of conducting a new and sufficiently powered trial re-
stricted 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 base-
line. Without certainty about the ideal approach to vitamin D
treatment in advanced CKD, a randomized trial that com-
pared cholecalciferol, exogenous 25-hydroxyvitamin D, and
an activated vitamin D analogue vs placebo could defini-
tively 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 defi-
ciency 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 pre-
viously 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, de-
creased physical activity due to illness could reduce sunlight-
mediated vitamin D production, alterations in diet could re-
duce vitamin D intake, and subclinical reductions in kidney
function could induce significant changes in vitamin D regu-
lation 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 suf-
ficient vitamin D stores over other theoretical benefits based
on observational data looks ever more prescient.15

ARTICLE INFORMATION Conflict of Interest Disclosures: Dr Wolf reports REFERENCES

Author Affiliations: Division of Nephrology,
Department of Medicine, Duke University School of
Medicine, Durham, North Carolina (Lucas, Wolf);
Duke Clinical Research Institute, Duke University
School of Medicine, Durham, North Carolina (Wolf).
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
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.
1. Gunta SS, Thadhani RI, Mak RH. The effect of
vitamin D status on risk factors for cardiovascular
disease. Nat Rev Nephrol. 2013;9(6):337-347. doi:
10.1038/nrneph.2013.74
2. Holick MF. Vitamin D deficiency. N Engl J Med.
2007;357(3):266-281. doi:10.1056/NEJMra070553
3. Kim HJ, Giovannucci E, Rosner B, Willett WC,
Cho E. Longitudinal and secular trends in dietary
supplement use: Nurses’ Health Study and Health
Professionals Follow-Up Study, 1986-2006. J Acad
Nutr Diet. 2014;114(3):436-443. doi:10.1016/
j.jand.2013.07.039

E2 JAMA Published online November 8, 2019 (Reprinted) jama.com

© 2019 American Medical Association. All rights reserved.

Downloaded From: https://jamanetwork.com/ on 11/08/2019


4. Arora P, Song Y, Dusek J, et al. Vitamin D
therapy in individuals with prehypertension or
hypertension: the DAYLIGHT trial. Circulation. 2015;
131(3):254-262. doi:10.1161/CIRCULATIONAHA.114.
011732
5. Scragg R, Stewart AW, Waayer D, et al. Effect of
monthly high-dose vitamin D supplementation on
cardiovascular disease in the Vitamin D Assessment
Study: a randomized clinical trial. JAMA Cardiol.
2017;2(6):608-616. doi:10.1001/jamacardio.2017.0175
6. Pittas AG, Dawson-Hughes B, Sheehan P, et al;
D2d Research Group. Vitamin D supplementation
and prevention of type 2 diabetes. N Engl J Med.
2019;381(6):520-530. doi:10.1056/NEJMoa1900906
7. Manson JE, Cook NR, Lee IM, et al; VITAL
Research Group. Vitamin D supplements and
prevention of cancer and cardiovascular disease.
N Engl J Med. 2019;380(1):33-44. doi:10.1056/
NEJMoa1809944
8. de Boer IH, Zelnick LR, Ruzinski J, et al. Effect of
vitamin D and omega-3 fatty acid supplementation
jama.com
© 2019 American Medical Association. All rights reserved.
Downloaded From: https://jamanetwork.com/ on 11/08/2019
on kidney function in patients with type 2 diabetes:
a randomized clinical trial [published online
November 8, 2019]. JAMA. doi:10.1001/jama.2019.
17380
9. Wolf M, Shah A, Gutierrez O, et al. Vitamin D
levels and early mortality among incident
hemodialysis patients. Kidney Int. 2007;72(8):
1004-1013. doi:10.1038/sj.ki.5002451
10. Teng M, Wolf M, Ofsthun MN, et al. Activated
injectable vitamin D and hemodialysis survival:
a historical cohort study. J Am Soc Nephrol. 2005;16
(4):1115-1125. doi:10.1681/ASN.2004070573
11. de Zeeuw D, Agarwal R, Amdahl M, et al.
Selective vitamin D receptor activation with
paricalcitol for reduction of albuminuria in patients
with type 2 diabetes (VITAL study): a randomised
controlled trial. Lancet. 2010;376(9752):1543-1551.
doi:10.1016/S0140-6736(10)61032-X
12. Thadhani R, Appelbaum E, Pritchett Y, et al.
Vitamin D therapy and cardiac structure and
(Reprinted) JAMA Published online November 8, 2019
Editorial Opinion
function in patients with chronic kidney disease:
the PRIMO randomized controlled trial. JAMA.
2012;307(7):674-684. doi:10.1001/jama.2012.120
13. Wang AY, Fang F, Chan J, et al. Effect of
paricalcitol on left ventricular mass and function in
CKD—the OPERA trial. J Am Soc Nephrol. 2014;25
(1):175-186. doi:10.1681/ASN.2013010103
14. Shoji T, Inaba M, Fukagawa M, et al; J-DAVID
Investigators. Effect of oral alfacalcidol on clinical
outcomes in patients without secondary
hyperparathyroidism receiving maintenance
hemodialysis: the J-DAVID randomized clinical trial.
JAMA. 2018;320(22):2325-2334. doi:10.1001/jama.
2018.17749
15. Calcium. In: Ross AC, Taylor CL, Yaktine AL,
Del Valle HB, eds; Institute of Medicine Committee
to Review Dietary Reference Intakes for Vitamin D.
Dietary Reference Intakes for Calcium and Vitamin D.
Washington, DC: National Academies Press; 2011.
E3