The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. 105, No. 12, 3721–3733
doi:10.1210/clinem/dgaa594
Mini-Review

Mini-Review

Vitamin D Supplementation for Prevention ofType 2 Diabetes Mellitus: To D or Not to D?
Jorde,2

Tetsuya

Kawahara,3and

1Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, Massachusetts
02111; 2Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway; and 3Divisionof Internal Medicine, Kokura Medical Association Health Testing Center, Kitakyushu, Japan

Received: 21 August 2020; Accepted: 24 August 2020; First Published Online: 26 August 2020; Corrected and Typeset: 19 October
2020.

Abstract
Context: Over the last decade, vitamin D has emerged as a risk determinant for type 2 diabetes andvitamin D supplementation has been hypothesized as a potential intervention to lower diabetes risk.
Recently, several trials have reported on the effect of vitamin D supplementation on diabetes preventionin people with prediabetes.
Evidence Acquisition: A comprehensive literature review was performed using PubMed, Embase, andClinicalTrials.gov to identify: (1) recent meta-analyses of longitudinal observational studies that reporton the association between blood 25-hydroxyvitamin D (25[OH]D) level and incident diabetes, and (2)clinical trials of adults with prediabetes that have reported on the effect of vitamin D supplementation
on incident diabetes.
Evidence Synthesis: Longitudinal observational studies report highly consistent associations between
higher blood 25(OH)D levels and a lower risk of incident diabetes in diverse populations, including
populations with prediabetes. Trials in persons with prediabetes show risk reduction in incident diabetes
with vitamin D supplementation. In the 3 large trials that were specifically designed and conducted forthe prevention of diabetes, vitamin D supplementation, when compared with placebo, reduced the riskof developing diabetes by 10% to 13% in persons with prediabetes not selected for vitamin D deficiency.
Conclusions: Results from recent trials are congruent with a large body of evidence from observational
studies indicating that vitamin D has a role in modulating diabetes risk. Participant-level meta-analysisof the 3 largest trials should provide a more refined estimate of risk reduction and identify patient
populations that are likely to benefit the most from vitamin D supplementation.

Freeform/Key Words: vitamin D, diabetes, prediabetes, type 2 diabetes, prevention

Diabetes is one of the fastest growing health challenges ofthe 21st century, as the number of adults living with diabetes
has more than tripled over the past 20 years. It is estimatedthat 9.3% of adults aged 20–79 years worldwide (approximately 463 million) and 12% of US adults aged older than
18 years (approximately 30 million) are living with diabetes(1). More than 9/10 people with diabetes have type 2 diabetes. An estimated one-third of the adult US population (approximately 84 million) is at risk for type 2 diabetes (ie, haveprediabetes), based on having a fasting glucose (FG) or hemoglobin A1c (HbA1c) level above the normal range but below
the threshold for diabetes (2, 3). People with prediabetes

ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any
medium, provided the original work is properly cited.

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Anastassios G. Pittas,1 Rolf
Bess Dawson-Hughes1

3722 The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. 105, No. 12

Review Strategy and Literature Search
Although results from high-quality randomized controlled
trials are typically considered to be the highest level of evidence to establish whether an intervention has an effect on
the outcome of interest, the totality of evidence from different
lines of research should be considered when establishing causality. In synthesizing the available evidence, we have used theBradford Hill general guidelines for causality and have structured our review to address these guidelines in relation tovitamin D and the prevention of type 2 diabetes (Table 1) (20).
A comprehensive literature review was performed using
PubMed, Embase, and ClinicalTrials.gov to identify: (1)Table 1. Prerequisites for Effect (Causal Association) of
Vitamin D for Prevention of Type 2 Diabetes.
• Plausible mechanism(s)• Temporal relationship• Strength of the association• Dose response• Consideration of alternative explanations• Experimental evidence (ie, clinical trials)• Challenges of vitamin D clinical trials• Coherence/consistency among studies

recent meta-analyses of longitudinal observational studies
that report on the association between blood 25(OH)Dlevel and incident diabetes, and (2) clinical trials of adults
with prediabetes that have reported on the effect of vitamin
D supplementation on incident diabetes.

Overview of vitamin D physiology and plausible
mechanistic links to the pathophysiology of type2 diabetes
Vitamin D, obtained either from oral sources or cutaneous
biosynthesis upon sun exposure, is hydroxylated first in
the liver to 25(OH)D, and then in the kidneys to become
the active form 1,25-dihydroxyvitamin D (1,25[OH]2D).
These vitamin D metabolites are transported in the circulation bound primarily to vitamin D binding protein andonly a small fraction circulates in the free form. The free1,25(OH)2D form binds to the nuclear vitamin D receptor(VDR), which regulates hundreds of genes (21). Circulating
25(OH)D has a long half-life, can be readily measured, andcorrelates well with known vitamin D effects; therefore,
it is used in clinical and research settings as a marker ofvitamin D status.
The main effect of vitamin D is to increase the intestinal absorption of calcium. Severe vitamin D deficiency
leads to rickets in children and osteomalacia in adults.
However, due to the wide tissue distribution of the VDR
and extrarenal activation of 25(OH)D to 1,25(OH)2D, it
is believed that vitamin D has extraskeletal effects (22).
Accordingly, low blood 25(OH)D levels have been associated with numerous diseases, including the risk ofdeveloping type 2 diabetes (23).
The hypothesis that vitamin D status may influence therisk of type 2 diabetes is biologically plausible, because both
impaired pancreatic beta-cell function and insulin resistance have been reported with low blood 25(OH)D levels(10). Importantly, critical tissues in the physiology of glucose homeostasis, such as the beta cell, express 1-alphahydroxylase (CYP27B1) and can convert inactive vitamin
D to its active metabolite (24). Furthermore, vitamin D deficiency in mice leads to reduced insulin secretion that canbe restored by vitamin D supplementation (25). Systemic
inflammation is another component in the pathophysiology
of type 2 diabetes, and low blood 25(OH)D levels have been
associated with high levels of inflammatory markers (26).
In humans, mechanistic studies show inconsistent results. Vitamin D supplementation for participants athigh risk for or with newly diagnosed type 2 diabetes
has shown an effect (27) as well as no effect (28) on insulin sensitivity and secretion. However, such studies areinconclusive because they are underpowered; have included populations with sufficient vitamin D status, with

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progress to diabetes at a rate of about 5% to 10% per year(4). Persons at high risk for type 2 diabetes who are overweight or obese and who have an impaired glucose tolerance
and elevated FG levels can slow the progression to diabetes
with intensive lifestyle changes that lead to weight loss (5).
However, sustaining lifestyle changes long-term is challenging, and there is always residual risk even after successful
weight loss and maintenance. Therefore, simple, inexpensive,and sustainable approaches that can be applied at the publichealth level to complement lifestyle changes are needed tolower the risk of type 2 diabetes in persons with prediabetes.
Over the last decade, low blood 25-hydroxyvitamin
D (25[OH]D) level has emerged as a risk factor for type2 diabetes, and vitamin D supplementation has been hypothesized as a potential intervention to lower diabetes
risk (6, 7). Observational studies strongly support an inverse association between blood 25(OH)D level and riskof developing type 2 diabetes in diverse cohorts of variable diabetes risk, especially in persons with prediabetes(8, 9). Results from short-term mechanistic studies offer abiologic plausibility to the hypothesis (10, 11). Recently,
several trials testing the effect of vitamin D supplementation to reduce the rate of progression to diabetes in people
with prediabetes have been completed (12–19).
We sought to evaluate and synthesize the available evidence to determine the role of vitamin D in the preventionof type 2 diabetes.

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Temporal relationship, strength of association,and dose response
Evidence to support the prerequisites of the temporal
relationship, strength of the association, and dose response (Table 1) comes from observational studies. Manycross-sectional studies have reported inverse associations
between vitamin D status and glucose intolerance; however, cross-sectional studies are not informative and can
only be considered hypothesis-generating, as the directionality of the association cannot be established.
Several observational, longitudinal studies conductedin diverse cohorts have reported consistent inverse associations between blood 25(OH)D levels and the risk of incident diabetes. Results have been summarized in recent
meta-analyses with similar findings. Song et al combined
data from 21 longitudinal cohorts (total of 76 220 participants; 4996 incident diabetes cases) and estimated a 38%
risk reduction for incident diabetes in the highest versus
the lowest category of blood 25(OH)D level (8). The association did not differ by sex, duration of follow-up, cohort
sample size, 25(OH)D assay method, or diabetes diagnostic criteria. Afzal et al combined data from 16 longitudinal cohorts (total of 72 204 participants; 4877 incident
diabetes cases) and reported that the bottom quartile ofblood 25(OH)D level was associated with a 50% higher
risk for incident diabetes compared with the top quartile(29). Ye et al included data from 22 longitudinal cohorts(89 698 noncases; 8492 diabetes cases) and reported that a
10-ng/mL lower 25(OH)D level was associated with a 22%
higher risk of incident diabetes (30).
Notably, in the observational studies, the highest category of 25(OH)D level (conferring the lowest risk of diabetes) was in the 25 to 30 ng/mL range, and the lowest
category (conferring the highest risk of diabetes) was in the
10 to 15 ng/mL range. In the meta-analysis by Song et al, aspline regression model showed that higher blood 25(OH)Dlevels were monotonically associated with a lower diabetes

risk, without an apparent plateau (8). However, few observational studies have included enough participants with
25(OH)D levels higher than 30 ng/mL; therefore, it is notclear whether achieving and maintaining higher 25(OH)Dlevels are associated with an even lower risk of diabetes.
Observational studies using Mendelian randomization
approaches, which offer the potential advantage that thereported genetic associations with phenotypes may overcome the challenges of confounding and reverse causation,
have shown inconsistent associations between certain alleles relevant to vitamin D physiology and incident type 2
diabetes (30–34). In a Danish study of 96 423 adults, genetic variants associated with low blood 25(OH)D levels predicted incident type 2 diabetes (33). However, other studies
in different cohorts have reported no associations between
genetic variants that specifically affect blood 25(OH)D level
and incident diabetes (30–32, 34). Mendelian randomization studies center upon certain assumptions that may not
apply to vitamin D. Specifically, the tested alleles accounted
for less than 5% of the variance in blood 25(OH)D level.
Furthermore, Mendelian randomization studies did notpredict the amounts of bioavailable or biologically active
vitamin D and cannot distinguish between endogenous
versus exogenous sources of vitamin D or long-term versus
short-term exposure to vitamin D. In the study by Afzal
et al, variation in the DHCR7 gene, which is associatedwith lower vitamin D biosynthesis, predicted risk of type 2
diabetes, suggesting that sustained, long-term exposure tovitamin D may be important for the prevention of diabetes(33). Mendelian randomization studies may also be confounded by pleiotropic effects of genetic variants and arefurther limited by the assumption of a linear association between genetic variants, blood 25(OH)D level, and diabetes
risk, which may not hold. Despite their theoretical appeal,
Mendelian randomization studies can neither support nor
exclude a causal relationship between vitamin D and type2 diabetes.
Most longitudinal observational studies have included
people with an average risk of type 2 diabetes at baseline.
The inverse association between blood 25(OH)D level andincident diabetes may be more pronounced among persons
who are already at a high risk for type 2 diabetes (9).

Consideration of alternative explanations
Despite very promising and consistent data from observational studies, relying on observational data alone to establish causality is not sufficient, as evidenced by carefully
examining the multiple determinants of the one’s vitamin D
status, as reflected in one’s blood 25(OH)D level.
Vitamin D is obtained from oral sources or cutaneous
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a low risk for diabetes or with established diabetes; haveco-administered vitamin D with other interventions, which
may confound the effect of vitamin D; or have followed
participants for short periods of time (about 2–6 months),
which are likely inadequate to affect the pathophysiology
of type 2 diabetes.
Despite basic research studies providing some support
for mechanisms in favor of vitamin D having an effect on
the pathophysiology of type 2 diabetes, one needs to becareful of arguments in favor of biologic rationale, as theresearch history is filled with large trials that did not confirm a hypothesis that had a strong biological rationale
from basic research.

3723

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increased cutaneous biosynthesis of vitamin D increases thecirculating 25(OH)D level. Collectively, these factors arepotential confounders in observational studies reporting on
the association between blood 25(OH)D levels and the riskof developing type 2 diabetes.
Many other conditions, although not directly related
to diabetes risk, affect 25(OH)D levels and may alter thereported association of 25(OH)D level with diabetes risk.
For example, the association of 25(OH)D level with diabetes risk may not be linear, thus observational studies in
populations that do not have a broad distribution of blood
25(OH)D levels may provide a misleading or incomplete
picture of the true relationship between vitamin D status
and diabetes risk.

Experimental evidence (clinical trials)
There are 10 trials published between 2008 and 2019 thathave reported on the effect of vitamin D supplementation on incident diabetes (12–19, 38, 39) (Table 2). Twolarge trials were designed and conducted for nondiabetes
outcomes and reported data on incident diabetes in post
hoc analyses (38, 39). These 2 trials enrolled patients who
were at average risk for diabetes (ie, not prediabetes), theintervention included low-dose vitamin D (400 and 800
IU daily) co-administered with calcium, and diabetes was
ascertained by participants’ self-report based on a diagnosis made outside of the study in routine clinical practice. Eight trials that have reported data on the effect ofvitamin D supplementation and incident diabetes included

Figure 1. Factors (determinants) that contribute to low blood 25-hydroxyvitamin D (25[OH]D) concentration. Factors shown in bold are also associated with a risk of type 2 diabetes.

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routes (Figure 1). The amount of vitamin D that reaches
the circulation from oral sources is influenced by food selection, food fortification, supplement use, and absorption
efficiency. For example, absorption is increased when supplemental vitamin D is co-ingested with a meal containing
fat and it is decreased by medical conditions that produce
intestinal malabsorption (35). Cutaneous biosynthesis declines with age and is reduced by higher levels of melanin in
the skin (36). Season, latitude, altitude, time of day, ozone
layer, and pollution also influence the degree of effective cutaneous biosynthesis. Individuals with a higher body weight
have lower circulating vitamin D levels, probably reflecting
the larger pool size over which vitamin D metabolites are
distributed (37). Assuming that the supply of the precursor(vitamin D) is not rate-limiting, the blood 25(OH)D levelreflects the balance between liver production, the genetically determined amount of vitamin D binding protein, andthe metabolism of 25(OH)D to 1,24-dihydroxyvitamin D(1,24[OH]2D) or to 24,25-dihydroxyvitamin D (inactive
metabolite).
Several factors that influence the blood 25(OH)D levelalso independently influence the risk of developing type 2
diabetes (Fig. 1). Chief among these are body weight andfatness, most frequently assessed by the body mass index(BMI). Specifically, a higher BMI is associated with bothan increased risk of diabetes and a lower blood 25(OH)Dlevel; hence, it is a potentially large source of confounding.
Related to this, persons who are more physically active
also tend to have a lower BMI and a lower risk of diabetes. When physical activity takes place out-of-doors, theParticipants

Not available

Baseline25(OH)D
Concentration

19 ng/mL

24 ng/mL

13 ng/mL

Prediabetes (n = 137)
Kuchay et al,2015 (North
India)

Prediabetes (n = 511)

Prediabetes and 25(OH)D < 30 ng/mL (n = 162)

Jorde et al,
2016(Norway)
Niroomand
et al, 2018
(Iran)

14 ng/mL

Study
Duration,Years

D3 50 000 IU weekly [~7143 IU
daily] for 3 months then monthly(n = 81) vs placebo (n = 81)

D3 88 865 IU weekly [~12 695 IU/d](n = 56) vs placebo (n = 53)
D3 60 000 IU weekly for 8 weeks,then monthly [~3000 daily
over 12 months] (n = 68) vs notreatment (n = 57); all received
calcium 1250 mg daily.
D2 50 000 IU weekly [~7142 UI
daily] adjusted to achieve 25(OH)D 40–100 ng/mL (n = 103) vsplacebo (n = 102). All participantsreceived 400 IU of D3.
D3 60 000 IU weekly for 4 weeks
then monthly [~2000 IU daily
over 12 months] (n = 69) vs notreatment (n = 68)
D3 20 000 IU weekly [~2857 IU daily](n = 256) vs placebo (n = 255)
Up to
6 months

Up to 5 years

Up to 1 year

Up to 1 year

Mean of
2.3 years

Up to 1 year

D3 400 IU daily plus calcium
Median of
7 years
carbonate 1000 mg daily(n = 16 999) vs placebo(n = 16 952)
D3 800 IU daily (n = 2649) vs placebo Range of
2–5 years(n = 2643) [2x2 factorial design
with calcium carbonate 1000 mg/
daily]

Interventions (Number ofParticipants)

No

No

No

Moderate (small sample Yes
size)
Poor (small sample size, Yes
open label)

No

Yes

No

Poor (small sample size, Yes
open label)

Yes

Poor (small sample size, Yes
completers only
analysis [50% of
randomized])

Good

No

Fair (small sample size, Yes
single race andgender)No

No

Designed for Was Incident Diabetes
the Primary Outcome (ie,Glycemic
Designed, Conducted, andOutcomes?
Powered for Prevention of
Diabetes)?

No

Fair (post hoc analysis,
self-report ofdiabetes, single
gender)Fair (post hoc analysis,
self-report ofdiabetes)

Study Quality(Reasoning)

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Barengolts et al, African American men with2015 (US)prediabetes and 25(OH)D
5–29 ng/mL and prevalent
medical problems (n = 205)

17 ng/ml

22 ng/mL

Healthy, aged ≥70 years, history Not availableof fracture (n = 5292)

Populations with prediabetes
Davidson et al, Prediabetes and 25(OH)2013 (US)D < 30 ng/mL (n = 109)
Dutta et al,
Prediabetes and 25(OH)2014 (India)
D < 25 ng/mL (n = 125)

Avenell et al,2009 (UK)

Populations at average risk for diabetes
De Boer et al,
Healthy, postmenopausal
2008 (US)women (n = 33 951)

First Author,
Year of
Publication(Country)

Table 2. Trials That Have Reported on Vitamin D Supplementation and New-onset Diabetes

The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. 105, No. 12

3725

3726 To convert the values of 25(OH)D to nmol/L, multiple by 2.496. The study quality for Kawahara et al was determined to be “good” based on the publication that describes the methods of the study. Study results have been
published in abstract form only.
Abbreviations: 25(OH)D, 25-hydroxyvitamin D; US, United States.

Yes
Good
D3 4000 IU daily (n = 1211) vsplacebo (n = 1212)

Prediabetes (n = 1256)

Kawahara
et al, 2018
(Japan)Pittas et al,2019 (US)Prediabetes (n = 2423)

28 ng/mLUp to
4.5 years

Yes

Yes
Good
Eldecalcitol 0.75 micrograms daily(n = 630) vs placebo (n = 626)
Not available

Up to 3 years

Yes

Designed for Was Incident Diabetes
the Primary Outcome (ie,Glycemic
Designed, Conducted, andOutcomes?
Powered for Prevention of
Diabetes)?
Study Quality(Reasoning)
Study
Duration,
Years
Interventions (Number ofParticipants)
Baseline25(OH)D
Concentration
ParticipantsFirst Author,
Year of
Publication(Country)

persons with prediabetes (12–19). Five of these trials have
major limitations, including a small sample size (109–205
participants) (12–15, 18), not being designed for incident
diabetes as the primary outcome (12, 14, 15, 18), a shortduration (≤1 year) (12, 14, 15, 18), and open-label study
design (13, 15). Therefore, results from these 5 trials (12–15, 18) and the 2 large trials where incident diabetes wasa post-hoc outcome (38, 39) are not informative in our
understanding of the role of vitamin D supplementation
for diabetes prevention in the clinical setting.
Three double-blind, placebo-controlled, randomized
trials have been designed and conducted specifically to test
the hypothesis that vitamin D supplementation lowers therisk of diabetes among persons with prediabetes (16, 17,
19, 40, 41). Below, we describe these most relevant trials
in detail.
The Tromsø study. The Tromsø study was a single-sitetrial that took place from March 2008 through March
2015 in Norway (16). The study randomly assigned 511
adults (mean age 62 years, mean BMI 30 kg/m2) who met
at least 1 of 2 glycemic criteria for prediabetes (FG 108–125 mg/dL; glucose 2 hours after a 75-gram oral glucose
load [2hG] 140–199 mg/dL) to treatment with 20 000 IUof vitamin D3 weekly (about 2857 IU per day) or placebo.
The primary outcome was time-to-incident diabetes
based on annual glycemic testing through FG, HbA1c,
and 2hG. Mean baseline serum 25(OH)D level was 24 ng/mL(60.0 nmol/L) and 68% of participants had a level ≥20 ng/
mL (49.1 nmol/L) (Table 3). During follow-up, mean serum
25(OH)D level in the vitamin D group rose to 44.1 ng/
mL compared to 25.6 ng/mL in the placebo group. Aftera median follow-up of 2.5 years, 215 diabetes events had
occurred: 103 in the vitamin D group and 112 in the placebogroup (11.8 events vs 13.1 events per 100 person-years,
respectively). In the intention-to-treat (ITT) analysis, therisk of diabetes was not significantly lower in the vitamin
D group (hazard ratio 0.90; 95% confidence interval [CI]:0.69–1.18) (16).
Diabetes Prevention with Active Vitamin D study. The
Diabetes Prevention with Active Vitamin D (DPVD)
study was a 3-site trial that took place from June 2013
through August 2018 in Japan (17, 41). The study
randomly assigned 1256 adults (mean age 61 years, mean
BMI 24 kg/m2) who met the impaired glucose tolerance
criterion for prediabetes (2hG 140–199 mg/dL) and had
no diabetes (FG < 126 mg/dL and HbA1c < 6.5%) totreatment with 0.75 mg of eldecalcitol (an analog of
the active form of vitamin D3) daily or placebo. The
primary outcome was time-to-incident diabetes basedon annual glycemic testing through FG, HbA1c andDownloaded from https://academic.oup.com/jcem/article/105/12/3721/5897217 by guest on 21 April 2023

Table 2. Continued

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The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. 105, No. 12

Table 3. Main Characteristics of the Key Randomized, Placebo-controlled Clinical Trials on Vitamin D Supplementation andPrevention of Diabetes Among Adults at Risk for Type 2 Diabetes (Prediabetes)
Study name, first author, year of
publication (reference)
Country (number of sites)Year of trial completion
Number of randomized participants
Prediabetes glycemic criteria for
eligibility

Vitamin D amount from supplementsallowed outside of the study
Definition of the primary outcome of
new onset diabetesb

Expected incidence of diabetes
in the placebo group, per 100
person-years
Expected relative risk reduction,
vitamin D vs placebo, %Median (range) duration of follow-up,
yearscHazard ratio (95% CI) for incident
diabetes, vitamin D vs placebo
Hazard ratio (95% CI) for incident
diabetes among participants
with starting serum 25(OH)Dlevel < 12 ng/mL, vitamin D vsplacebo

The DPVD study,
Kawahara et al, 2018(17)
Norway (1 site)
Japan (3 sites)
2015
2018
511
1256
IGT (2hG 140–199 mg/
IFG (FG 108–125 mg/dL) and no criterion indL) and/or IGT (2hG
the diabetes category
140–199 mg/dL) and no
criterion in the diabetes
category
24
Not available
62
Not available
Cholecalciferol (vitaminD3), 20 000 IU weekly(~2857 IU daily) vsplacebo≤400 IU/day

The D2d study, Pittas et al, 2019(19)
United States (22 sites)
2018
2423
Two or 3 glycemic criteria (IFG [FG 100–
125 mg/dL], IGT [2hG 140–199 mg/dL], HbA1c 5.7–6.4%) and no
criterion in the diabetes category
28
78

Eldecalcitol, 0.75
micrograms daily vsplacebo

Cholecalciferol (vitamin D3), 4000 IU
daily vs placebo

No amount was allowed≤1000 IU/day
Two or 3 glycemic-positive criteria:
FG ≥ 126 mg/dL, 2hG ≥ 200 mg/dL,
HbA1c ≥ 6.5%, or 1 criteria positive
with confirmation

HbA1c ≥ 6.5% andAny glycemic-positive
either: FG ≥ 126 mg/
criteria: FG ≥ 126 mg/
dL, 2hG ≥ 200 mg/
dL, 2hG ≥ 200 mg/
dL, or casualdL, HbA1c ≥ 6.5% (aglucose ≥ 200 mg/dL
positive HbA1c required
confirmation)
10.0
8.4

10.5

30

36

25

4 (0–5)2.8 (not available)

2.5 (0–4.5)

0.90 (0.69–1.18)

0.87 (0.68–1.09)

0.88 (0.75–1.04)

Data not available

Data not available

0.38 (0.18–0.80)

Abbreviations: 2hG, 2-hour glucose after a 75-gram oral glucose load; 25(OH)D, 25-hydroxyvitamin D; CI, confidence interval; FG, fasting glucose; HbA1c, hemoglobin A1c; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.
aRandomization ratio was 1:1 in all trials.
b
In the Tromsø study (N = 2 participants) and D2d study (N = 38 participants), diabetes was diagnosed outside of the study and confirmed by adjudication. In the
DPVD study, no participant was diagnosed with diabetes outside of the study.
c
The Tromsø study followed participants for up to 5 years. The D2d study was designed as an event-driven trial and follow-up varied among participants. The
DPVD study followed participants for up to 3 years.

2hG, and quarterly with FG and HbA1c. Information onmean baseline blood 25(OH)D level and proportion ofparticipants with a level ≥20 ng/mL is not yet available.
Based on results published in abstract form, after amedian follow-up of 2.8 years, 121 diabetes events had
occurred: 57 in the vitamin D group and 64 in the placebogroup. In the ITT analysis, the risk of diabetes was not

significantly lower in the vitamin D group (hazard ratio
0.87; 95% CI: 0.68–1.09) (17).
The Vitamin D and Type 2 Diabetes trial. The Vitamin D
and Type 2 Diabetes (D2d) study was a 22-site trial thattook place from October 2013 through December 2018 in
the United States (19, 40). The study randomly assigned

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Serum 25(OH)D level, ng/mL
Participants with blood 25(OH)Dlevel above 20 ng/mL, %Interventiona

The Tromsø study, Jordeet al, 2016 (16)

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Challenges of vitamin D clinical trials
A clinical trial is often labeled as “positive” or “negative”
based on whether the P-value for the statistical test for the
primary outcome falls below or above (respectively) thetraditional threshold of 0.05. This “dichotomania,” which
is based on an arbitrary threshold, provides clarity for
regulatory agencies when deciding whether to approve a
pharmaceutical agent for clinical use; however, it is overly
simplistic when trying to determine whether an intervention has a real and clinically meaningful effect (42). Whenthe primary outcome in a clinical trial “fails,” there are several considerations that may clarify whether the intervention may still have clinical value (43). We modified a setof questions, described in the article by Pocock and Stone(43), for relevance to trials on vitamin D supplementation
for the prevention of type 2 diabetes (Table 4). Below weaddress these questions in relation to the 3 major trials
described above.
Is there some indication of potential benefit? When the
primary outcome result is entirely neutral, concludingthat the intervention has no effect is straightforward.
Individually, each trial reported a result for the primary
outcome of incident diabetes that did not reach thetraditional 5% level of statistical significance; yet there
is an indication of benefit from vitamin D, as all trials
reported hazard ratios favoring the vitamin D treatment

Table 4. Questions to Address When the Primary Outcome“Fails” in Trials of Vitamin D Supplementation for Diabetes
Prevention
1. Is there some indication of potential benefit?
2. Was the trial underpowered?
3. Was the trial population appropriate?
4. Was the treatment regimen appropriate?
5. Was the primary outcome appropriate or accurately defined?
6. Was the intervention/follow-up duration appropriate?
7. Were there deficiencies in trial conduct (eg, under-recruitment,poor retention, poor adherence, use of rescue medication)?
8. Do subgroup findings elicit positive signals?
9. Can alternative analyses help?
10. Were there any safety issues with the intervention?

over placebo that were remarkably similar among the trials(0.87, 0.88, and 0.90).
Were the trials underpowered? Each trial was powered todetect a 25% to 36% relative risk reduction in incident
diabetes with vitamin D supplementation comparedwith placebo (16, 40, 41). Based on the results, vitamin
D supplementation appears to decrease diabetes risk
among people with prediabetes not selected for vitamin D
insufficiency by a smaller effect (~10–13%), but each trial
was individually underpowered to test modest treatment
effects. Of interest, in the Tromsø study and D2d study,
the hypothesized relative risk reductions (30% and 25%,
respectively) were within the reported 95% CI (0.69–1.18
and 0.75–1.04, respectively) (16, 19). Furthermore, as
the size of the trial population increased, the reported
95% CI narrowed (Table 3). Therefore, it would be more
appropriate to describe the findings of each individual trial
as inconclusive rather than “negative.”
Were the trial populations appropriate? Selection of an
appropriate trial population based on evidence fromobservational cohorts and mechanistic studies and goodclinical judgment is essential. It has been suggested thatvitamin D supplementation may be of benefit if started
early in the natural history of type 2 diabetes. Despite its
theoretical appeal, early supplementation presents multiple
challenges. For example, diabetes progression is expected
to be slow and vitamin D (or any intervention) is unlikely
to have a detectable and clinically meaningful effect ondiabetes risk if applied in people who are at an averagerisk for diabetes (38, 39). Furthermore, because the rate ofprogression from normal glucose tolerance to diabetes ishighly dependent upon specific population characteristics,
calculating study size and length of follow-up needed forsuch a clinical trial is complicated. For these reasons, all
3 trials appropriately enrolled people with prediabetes

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2423 adults (mean age 60 years, mean BMI 32 kg/m2) who
met at least 2 of 3 glycemic criteria for prediabetes (FG
100–125 mg/dL; 2hG 140–199 mg/dL; HbA1c 5.7–6.4%)
to treatment with 4000 IU of vitamin D3 daily or placebo.
The primary outcome was time-to-incident diabetes basedon annual glycemic testing through FG, HbA1c and 2hG,and semiannually with FG and HbA1c. The trial design
was event-driven, with a target number of diabetes eventsof 508. Mean baseline serum 25(OH)D level was 28 ng/mL(69 nmol/L) and 78% of participants had a level ≥20 ng/
mL (49 nmol/L) (Table 3). During follow-up, mean serum
25(OH)D level in the vitamin D group rose to 54 ng/mL
compared with 29 ng/mL in the placebo group. After amedian follow-up of 2.5 years, 616 diabetes events had
occurred: 293 in the vitamin D group and 323 in theplacebo group (9.4 events vs 10.7 events per 100 personyears, respectively). In the ITT analysis, the risk of diabetes
was not significantly lower in the vitamin D group (hazard
ratio 0.88; 95% CI: 0.75–1.04) (19).
In each of these 3 studies, protocol-specified adverse
events of interest (hypercalcemia, hypercalciuria, andnephrolithiasis) were rare, and there were no significant
differences between vitamin D and placebo.

The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. 105, No. 12

Were the treatment regimens appropriate? Determining
the appropriate formulation and dose of vitamin D andtiming of administration (eg, daily, weekly, monthly, yearly)
in vitamin D trials can be challenging. The Tromsø study
and D2d study administered vitamin D3 (cholecalciferol),the most commonly consumed vitamin D formulation,and thereby increased the studies’ translational potential.
The DPVD study administered eldecalcitol, an analog of
the active metabolite of vitamin D3 that does not require
activation in the liver and kidney. Although infrequent
dosing (eg, monthly, yearly) of vitamin D is convenient,
it produces fluctuating blood 25(OH)D levels and isconsidered nonphysiologic (45, 46); therefore, daily or
weekly dosing is preferred. The doses used (20 000 IU
weekly [~2857 IU per day] in the Tromsø study, 0.75 mcg
of eldecalcitol daily in the DPVD study, and 4000 IU daily
in the D2d study) provide an appropriate balance of safety
and efficacy in terms of obtaining an adequate differencein vitamin D status between the active and placebo groups.
All 3 trials appropriately compared vitamin D alone toplacebo in a double-blind design. For practical and ethicalreasons, all trials allowed participants to take outside-ofstudy vitamin D from all supplemental sources up to a certain amount and did not limit vitamin D intake from foodsources. Many vitamin D trials have combined vitamin Dwith calcium or administered vitamin D in foods (eg, yogurt)
and have used comparators other than placebo (13, 15, 38,
39). Such study designs are not informative regarding therole of vitamin D alone for diabetes prevention because theycannot isolate the effect of vitamin D from other components of the intervention.
Was the primary outcome appropriate or accurately
defined? In all 3 trials, ascertainment for diabetes took
place at regular intervals (every 3 or 6 months) byblood glucose testing using a single (central) laboratoryand diabetes was appropriately defined based on strict,trial-specific glycemic criteria. Such an approach is robust
and unbiased compared with other trials that relied on aself-reported diagnosis of diabetes outside of the study(38, 39), which is influenced by many uncontrolled factorsthat contribute random noise, potentially shifting the risk
difference between vitamin D and placebo towards thenull.
Was the duration of intervention and follow-up too short?
Trial duration is an important consideration and one that
requires careful weighing of competing factors. An adequate
intervention period is essential given the long latency period
for progression from prediabetes to diabetes and variable
rate of progression (5–10% per year). Long-term trials
encounter obligatory losses of participants due to a varietyof unrelated intercurrent events. Secular changes in theperception of the value of the intervention may occur andlead to altered outside-of-study use of vitamin D, often athigh doses. The adherence to study procedures may decline
as participants experience study fatigue, leading to losinginterest in continuing their participation. These occurrences
reduce study power and increase the opportunity for
postrandomization confounding.
The Tromsø study (mean 4 years, maximum 5 years),
the DPVD study in Japan (mean 2.6 years, maximum
3 years), and the D2d study (mean 2.5 years, maximum
4.5 years) appear to have achieved a reasonable balancewith regard to duration (16, 17, 19). In the D2d study, theKaplan-Meir curves for incident diabetes in the vitamin D
and placebo groups converged towards the end of the trial,
indicating a low likelihood of a latent benefit from vitamin
D supplementation.
Were there deficiencies in trial conduct? Based on full-text
publications describing study results, the Tromsø study
and D2d study were well conducted (16, 19). The designof the DPVD study is robust (41); however, results havebeen published in abstract form only (17), therefore the
DPVD study conduct cannot be evaluated. All 3 trials met
their recruitment goals. Retention in the Tromsø and D2dstudies was excellent, with more than 99% of participants
contributing follow-up data. Adherence to the trial regimen
in the Tromsø and D2d studies was also excellent, withmore than 85% of prescribed pills taken and fewer than
4% of trial participants taking out-of-study vitamin D
supplements above the trial limit. In the D2d study, 1% ofparticipants took diabetes or weight-loss medication before
the diagnosis of diabetes was established. In the Tromsøand DPVD studies, none did.
Do subgroup findings elicit positive signals? Response tovitamin D depends on vitamin D status at baseline (47).

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who are most likely to benefit from interventions to lower
risk of progression to diabetes. Notably, all trials definedprediabetes by specific glycemic criteria (FG, HbA1c, 2hG),
expanding their translational potential.
For ethical and practical reasons, the trials did not include blood 25(OH)D level as an eligibility criterion anddid not measure blood 25(OH)D levels in real time. Becauseof frequent testing for vitamin D status in routine clinicalsettings and the widespread use of over-the-counter vitamin
D supplements (44), trial participants were mostly vitamin
D replete by current vitamin D recommendations (blood
25[OH]D level ≥ 20 ng/mL [50 nmol/L]) when the trials
started and participants in the placebo group remained
vitamin D replete during the follow-up (16, 19).

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Can alternative analyses help? The ITT analyses are
generally favored because of simplicity and because they
alleviate concerns about confounding. However, althoughlarge scale trials are free of confounding when they start,
biases may emerge during follow-up due to incomplete
adherence to the trial intervention or use of rescue
medications leading to postrandomization confounding,which may influence the estimate of treatment efficacy
and study power (50, 51). The ITT analyses are agnostic
to postrandomization confounding, including treatment
discontinuation and concomitant therapies (eg, rescue
medications such as high-dose vitamin D or metforminin trials for the prevention of diabetes with vitamin D)
not allowed by the study protocol; hence, ITT analyses
estimate the effect of treatment assignment, not the effectof treatment itself (51).
Differential adherence (for any reason) to the assigned
intervention and concomitant exogenous use of vitamin
D are common challenges in vitamin D trials given thewidespread laboratory testing for blood 25(OH)D in theroutine clinical setting and the availability of over-thecounter vitamin D supplements at high doses. These factors have the significant potential to influence the estimateof efficacy of vitamin D intervention for the prevention ofdiabetes in clinical trials. For example, in the D2d study,
although overall adherence to the protocol was high andoverall use of rescue medications was low, a different pattern among nonadherent participants emerged between the
2 groups. Specifically, during follow-up, more participantsin the placebo group started diabetes or weight-loss medications, which would make the detection of diabetes lesslikely. Furthermore, more participants in the placebo group
took personal vitamin D supplements above the trial limit,
likely due to testing outside of the study. These differences
may have shifted the relative risk reduction towards nullin the ITT analysis. In a prespecified, per-protocol analysis
that censored follow-up when a D2d participant started adiabetes or weight-loss medication, stopped study pills, ortook out-of-study vitamin D from supplements that wereabove the study limit, the risk of diabetes was significantly
lower in the vitamin D group (hazard ratio 0.84; 95% CI:
0.71–1.00) (19).
Were there any safety signals with the intervention? Noneof these trials reported a higher risk of adverse events withvitamin D supplementation versus placebo. In the Tromsø
study, there were no significant differences in the protocolspecified adverse events of interest (hypercalcemia andkidney stones) or serious adverse events. The D2d study
used cholecalciferol at 4000 IU/day, which is the tolerable
upper intake level set by the National Academy of Medicine
to avert potential toxicity. There were no significant groupdifferences in the protocol-specified adverse events ofinterest (hypercalcemia, hypercalciuria, low glomerular
filtration rate, and kidney stones) or serious adverse events.
In abstract form, the DPVD study reported no serious
adverse events with eldecalcitol, but the full determinationof safety will await publication of the complete report.

Coherence/Consistency Among Studies
Longitudinal observational studies show highly consistentassociations between higher blood 25(OH)D levels anda lower risk of incident diabetes in diverse populations,
including populations with prediabetes. Two meta-analyses
from 2 different groups that combined aggregate data fromtrials on vitamin D for diabetes prevention were recently
published. Zhang et al synthesized results from 8 trials(total of 4896 participants) in persons with prediabetes andreported a significant benefit of vitamin D supplementation
for incident diabetes (risk ratio 0.89; 95% CI: 0.80–0.99)(52). The authors also reported that participants assigned
to vitamin D supplementation were more likely to revert toeuglycemia than the nonvitamin D group (risk ratio 1.48;
95%: CI 1.14–1.92). Barbarawi et al synthesized resultsfrom 9 trials (total of 43 559 participants). Two trials notdesigned for diabetes prevention (total of 39 243 participants) were in persons of average diabetes risk randomized
to low-dose vitamin D (<1000 IU per day); 7 trials (total of4316 participants) designed for diabetes prevention were inpersons with prediabetes randomized to high-dose vitamin

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Thus, people with higher baseline levels of blood 25(OH)D would benefit less from vitamin D supplementation thanpeople with lower baseline levels (48). The high proportionof participants with adequate blood 25(OH)D levels atbaseline may have prevented the detection of statisticallysignificant differences between the vitamin D and placebogroups in the full trial cohorts. In all 3 trials, among
participants with baseline blood 25(OH)D levels < 20 ng/
mL, the risk of diabetes with vitamin D supplementation
was reported to be lower compared with participants withlevels ≥20 ng/mL, but the differences were not statisticallysignificant. In the D2d study, the risk of diabetes was
significantly lower in a small subgroup of participants
with a baseline 25(OH)D level < 12 ng/mL (hazard ratio
0.38; 95% CI: 0.18–0.80; p for interaction = 0.023) (19).
Results from subgroup analyses need to be interpreted
cautiously partly because of the potential of a type I error(false positive) due to multiple analyses (49). However,given strong preexisting biologic plausibility, vitamin D
supplementation may be more important in reducing
diabetes risk among persons with prediabetes and low
vitamin D status.

The Journal of Clinical Endocrinology & Metabolism, 2020, Vol. 105, No. 12

D (≥1000 IU per day). The authors reported a significant
benefit of vitamin D supplementation for incident diabetes
only after combining data from the diabetes prevention
trials among persons with prediabetes who also received
high-dose vitamin D (risk ratio 0.88; 95% CI: 0.79–0.99;
p = 0.043) (53).

Evidence Synthesis and Next Stepsof the reversal of prediabetes to euglycemia. If vitamin D
supplementation promotes regression to euglycemia, thenmore people will spend more time in the low-risk stateaway from prediabetes/diabetes. Therefore, the higher
likelihood of reversal to euglycemia with vitamin D supplementation (~48% more likely, as stated by Zhang
et al) may, by delaying time-to-onset of diabetes, represent an additional benefit to the 12% lower risk to progression to diabetes reported by the 2 meta-analyses ofclinical trials (52, 53).
Although the summary results reported by Zhang et al
and Barbarawi et al are concordant, meta-analyses thatcombine aggregate data from trials that vary in study design and quality should be interpreted cautiously (59).
Individual participant data meta-analyses that combine
data from high-quality clinical trials specifically designed
and conducted to test the hypothesis are necessary to (1) estimate with precision the benefit of vitamin D supplementation on diabetes progression and regression to euglycemia,(2) assess heterogeneity of the treatment effect in order todefine prediabetes subpopulations most likely to benefit
most likely to benefit from vitamin D supplementation, and(3) evaluate safety using time-to-event analyses.

Conclusion
Answers to clinically important questions are rarely dichotomous (“positive” or “negative”), and a recommendationof whether “to D or not to D” should be made based on
the best available data from both observational studies andclinical trials. Results from trials are congruent with a large
body of evidence from observational studies indicating thatvitamin D has a role in modulating diabetes risk. We areawaiting the full publication of the DPVD study and resultsfrom individual participant data meta-analyses. Even if therisk reduction with vitamin D supplementation may appear
relatively small, when applied in the expanding prediabetes
population, it can have important public health implications.

Acknowledgment
The authors would like to thank the research participants for theiroutstanding dedication and commitment to advancing knowledge
through research.
Financial Support: A.G.P. receives funding from the National Institutes of Health (U01DK098245) to conduct the D2d study. A.G.P. issupported in part by generous donations to the Tupper Research
Fund at Tufts Medical Center (Boston, MA, USA). B.D.-H. receives
funding from the National Institutes of Health (U01DK098245) andfrom the USDA under agreement #58-1950-7-707. R.J. is receiving a
grant from UiT The Arctic University of Norway.
Author Contributions: A.G.P. wrote the first draft of the manuscript. All authors contributed to the critical review and edits of subsequent drafts and the final approval of the manuscript.

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Given the highly consistent results from the existing longitudinal observational studies, it is unlikely that new
observational studies would modify the conclusion thatvitamin D status is inversely associated with diabetes risk.
A search of clinicaltrials.gov did not identify ongoing orplanned randomized controlled trials specifically designed
and being conducted to test the effect of vitamin D supplementation for the prevention of type 2 diabetes. Manylarge trials testing the effect of vitamin D supplementation
on nondiabetes outcomes in populations at average risk fordiabetes have been recently published or will be completedsoon (54–58). We expect many of these trials to present secondary results on incident diabetes; however, these reports
will require careful interpretation due to several limitations(eg, enrolled population at low/average risk, inadequately
defined diabetes outcome). Therefore, the conclusions wedraw on the role of vitamin D for the prevention of type 2
diabetes will depend on data we already have.
We also expect many of the completed trials to publish secondary results on the effect of vitamin D supplementation on micro- and macrovascular complicationsof diabetes. However, these trials are not powered for
detecting an effect because the risk of developing microand macrovascular complications in these trial populations
is very low.
Application of the Bradford Hill criteria to evaluate thetotality of available evidence from longitudinal observational studies and clinical trials indicates a causal relation
between vitamin D status and risk of type 2 diabetes. When
combining data from the 3 large trials that were specificallydesigned and conducted to test vitamin D for diabetes prevention, Zhang et al reported a 12% reduction in diabetes
risk with vitamin D supplementation (hazard ratio 0.88,
95% CI: 0.78–0.99) among participants with prediabetes
not selected for vitamin D deficiency (52). Vitamin D
supplementation may be more beneficial in adults withprediabetes and low vitamin D status, as suggested by the
subgroup analysis in the D2d study that showed a 62%
reduction (range 20–82%) in diabetes risk with vitamin D
supplementation compared with placebo among participants with baseline serum 25(OH)D level < 12 ng/mL.
When evaluating the potential benefit of vitamin D
supplementation, we should also not discount the benefit

3731

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Additional Information
Correspondence and Reprint Requests: Anastassios G. Pittas,
MD, MS, Division of Endocrinology, Diabetes and Metabolism,
Tufts Medical Center, 800 Washington Street, Box 268, Boston, MA
02111, USA. E-mail: apittas@tuftsmedicalcenter.org.
Disclosure Summary: The authors have nothing to disclose. The
views expressed in this article are those of the authors and do
not necessarily represent the views of the National Institutes of
Health.
Data Availability: Data sharing is not applicable to this article,
as no datasets were generated or analyzed during the current study.

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