ORIGINAL
ARTICLE
Vitamin D 20 000 IU per Week for Five Years Does Not
Prevent Progression From Prediabetes to Diabetes
Rolf Jorde, Stina T. Sollid, Johan Svartberg, Henrik Schirmer,
Ragnar M. Joakimsen, Inger Njølstad, Ole M. Fuskevåg, Yngve Figenschau,
and Moira Y. S. Hutchinson
Tromsø Endocrine Research Group (R.J., S.T.S., J.S., R.M.J., Y.F.), Department of Clinical Medicine,
Department of Clinical Medicine (H.S.), Epidemiology of Chronic Diseases Research Group (I.N.),
Department of Community Medicine, Department of Medical Biology (Y.F.), UiT The Arctic University of
Norway, 9037 Tromsø, Norway; Division of Internal Medicine (R.J., S.T.S., J.S., R.M.J.), Division of
Diagnostic Services (O.M.F., Y.F.), University Hospital of North Norway, 9038 Tromsø, Norway; and
Division of Head and Motion (M.Y.S.H.), Department of Rheumatology, Nordland Hospital, 8092 Bodø,
Norway
Context: Vitamin D deficiency is associated with insulin resistance and risk of future diabetes.
Objective: The objective of the study was to test whether supplementation with vitamin D to
subjects with prediabetes will prevent progression to type 2 diabetes mellitus (T2DM).
Design: This was a randomized controlled trial performed in 2008 through 2015.
Setting: The study was conducted at the clinical research unit at a teaching hospital.
Patients: Five hundred eleven subjects (mean age 62 y, 314 males) with prediabetes diagnosed with
an oral glucose tolerance test as part of the Tromsø Study 2007–2008 were included. A total of 256
were randomized to vitamin D and 255 to placebo. Twenty-nine subjects in the vitamin D and 24
in the placebo group withdrew because of adverse events.
Interventions: Interventions included vitamin D (cholecalciferol) 20 000 IU/wk vs placebo for 5
years. Annual oral glucose tolerance tests were performed.
Main Outcome Measure: Progression to T2DM was the main outcome measure. Secondary outcomes were change in glucose levels, insulin resistance, serum lipids, and blood pressure.
Results: The mean baseline serum 25-hydroxyvitamin D level was 60 nmol/L (24 ng/mL). One hundred three in the vitamin D and 112 in the placebo group developed T2DM (hazard risk 0.90; 95%
confidence interval 0.69 –1.18, Cox regression, P ⫽ .45, intention to treat analysis). No consistent
significant effects on the other outcomes were seen. Subgroup analyses in subjects with low
baseline 25-hydroxyvitamin D yielded similar results. No serious side effects related to the intervention were recorded.
Conclusions: In subjects without vitamin D deficiency, vitamin D supplementation is unlikely to
prevent progression from prediabetes to diabetes. Very large studies with inclusion of vitamin
D-deficient subjects will probably be needed to show such a putative effect. (J Clin Endocrinol
Metab 101: 1647–1655, 2016)
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA
Copyright © 2016 by the Endocrine Society
Received November 17, 2015. Accepted January 28, 2016.
First Published Online February 1, 2016
doi: 10.1210/jc.2015-4013
Abbreviations: BP, blood pressure; CI, confidence interval; HbA1c, glycated hemoglobin;
HDL, high-density lipoprotein; HOMA-IR, homeostasis model assessment index of insulin
resistance; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; LDL, low-density
lipoprotein; LOCF, last observation carried forward; OGTT, oral glucose tolerance testing;
25(OH)D, 25-hydroxyvitamin D; QUICKI, quantitative insulin sensitivity check index; RCT,
randomized controlled trial; T2DM, type 2 diabetes mellitus.
J Clin Endocrinol Metab, April 2016, 101(4):1647–1655
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Jorde et al
Vitamin D and Prevention of Type 2 Diabetes
nce established, type 2 diabetes mellitus (T2DM) is
difficult to treat and is associated with cardiovascular complications and increased mortality (1). Prevention of T2DM is also difficult, although lifestyle as well as
pharmacological interventions may have some effect (2,
3). However, in the long run, it is difficult to adhere to
lifestyle advice, and drugs may be expensive and carry risk
of side effects (4). Other or additional means of prevention
are therefore needed, and supplementation with vitamin D
has been suggested as one such option (5).
The vitamin D receptor is found in the pancreatic
␤-cells (6), and vitamin D deficiency in experimental animals leads to reduced insulin secretion which may be restored with vitamin D supplementation (7). In line with
this, subjects with low levels of 25-hydroxyvitamin D
(25[OH]D), the vitamin D metabolite used to evaluate a
subject´s vitamin D status, have higher blood glucose levels (8), are insulin resistant (9, 10), and are at greater risk
of later T2DM than subjects with adequate vitamin D
status (11, 12). However, randomized controlled trials
(RCTs) with vitamin D supplementation for improving
glucose tolerance or prevention of T2DM have so far not
shown convincingly positive results (13).
One reason may be that the effect of vitamin D on
glucose metabolism at best is small and that the duration
of the published RCTs have been short (14, 15). Because
T2DM develops gradually over many years through a prediabetic stage, it is conceivable that an effect of vitamin D
supplementation on prevention of T2DM may take years
to become evident.
In the last survey in the Tromsø Study in 2007–2008,
glycated hemoglobin (HbA1c) was measured in close to
13 000 subjects and subsequent oral glucose tolerance
testing (OGTT) performed in 3476 (16). We therefore had
the opportunity to identify a large group of subjects at risk
of developing T2DM and invite them to the present 5-year
intervention study with vitamin D during which annual
OGTTs were performed.
O
Subjects and Methods
Design
The design of the study and the 1-year results have been described in detail previously (15). In short, men and women aged
25– 80 years with impaired fasting glucose (IFG) (serum glucose
6.0 – 6.9 mmol/L [108 –124 mg/dL]) and/or impaired glucose tolerance (IGT) (fasting serum glucose ⬍7.0 mmol/L [126 mg/dL]
and 2 h value 7.8 –11.0 mmol/L [140 –198 mg/dL]) at the OGTT
with 75 g glucose were included. The subjects were principally
recruited from the sixth survey in The Tromsø Study 2007–2008,
in which subjects with HbA1c in the range 5.0%– 6.9% (39.9 –
51.9 mmol/mol) and not previously diagnosed diabetes were
invited to an OGTT (16). Among the 4393 subjects invited, 3476
J Clin Endocrinol Metab, April 2016, 101(4):1647–1655
completed the OGTT, and 713 had IFG and/or IGT and were
invited by letter to participate in the present study. In addition,
a few other subjects were recruited from follow-up OGTTs performed in participants in a previous obesity study (17) and in a
kidney function study (18). Subjects with primary hyperparathyroidism, granulomatous disease, history of urolithiasis, cancer diagnosed in the past 5 years, unstable angina pectoris, myocardial infarction, or stroke in the past year were excluded.
Pregnant or lactating women, or women of fertile age with no use
of contraception, were not included.
All visits were performed at the Clinical Research Unit at the
University Hospital of North Norway. At the first visit, a brief
clinical examination was performed, and questionnaires on medical history, medication, and vitamin D supplementation were
filled in. Height and weight were measured wearing light clothing. Blood pressure was measured three times with an automatic
device, and the median value used in the statistical analyses.
Fasting blood samples for glucose, insulin, and lipids had been
collected at the OGTT, and supplementary nonfasting blood
samples were drawn at this visit. The subjects were then randomized (nonstratified) in a 1:1 ratio to one capsule vitamin D
(cholecalciferol 20 000 IU/wk [Dekristol; Mibe]) or an identicallooking placebo capsule containing arachis oil (Hasco-Lek).
New medication was supplied every 6 months and unused capsules were returned and counted. The subjects were not allowed
to take vitamin D supplements (including cod liver oil) exceeding
400 IU/d.
For the next 5 years, the subjects met every sixth month;
annually for new OGTT, supplemental serum sampling, height,
weight, and blood pressure (BP) measurements, and the same
questionnaires as at baseline; and met in between the annual
visits for measurement of serum calcium and creatinine for safety
reasons. At all visits adverse events were asked for.
If at the annual OGTT the fasting blood glucose was greater
than 6.9 mmol/L (124 mg/dL) and/or the 2-hour value greater
than 11.0 mmol/L (198 mg/dL), the subject was considered to
have T2DM, thus ending their participation in the study and
thereafter were retested (if necessary) and followed up by their
general practitioner. Due to the inclusion of HbA1c (alone or in
combination with glucose criteria) as a diagnostic criterion for
diabetes in the WHO report from 2011 (19), and the acceptance
of this in Norway the year later, it was also implemented in the
present study from November 2012. Thus, if HbA1c alone was
6.5% or greater (ⱖ48 mmol/mol), the subject was retested with
a new HbA1c measurement and if still 6.5% or greater (ⱖ48
mmol/mol), the subject was diagnosed as T2DM, thus ending
their participation in the study. Also, if diagnosed elsewhere with
T2DM between visits in the study, participation was ended.
If serum calcium at any visit was greater than 2.55 mmol/L
(10.2 mg/dL), a retest was performed, and if still greater than
2.55 mmol/L (10.2 mg/dL), the subject was excluded from the
study. Subjects who developed renal stones, or symptoms compatible with renal stones, were also excluded. In the initial protocol, subjects who during the study were diagnosed with cancer,
coronary infarction, unstable angina pectoris, or stroke were to
be excluded from the study. From October 2011, this was
changed to exclusion of subjects who during the study developed
serious disease, making it difficult or impossible to attend scheduled visits.
Serum glucose, insulin, C-peptide, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein
(HDL) cholesterol, triglycerides, apolipoprotein A1 and B, HbA1c,
doi: 10.1210/jc.2015-4013
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and PTH were analyzed, and estimates of insulin sensitivity (homeostasis model assessment index of insulin resistance [HOMAIR] and quantitative insulin sensitivity check index [QUICKI])
were calculated, as previously described (11, 20). Serum concentrations of 25(OH)D were measured by an in-house liquid
chromatography-tandem mass spectrometry method that detects both 25(OH)D3 and 25(OH)D2 and the sum of these presented as 25(OH)D in the results (15).
Statistical analyses
Normal distribution was evaluated with visual inspection of
histograms and by kurtosis and skewness. Log transformation
was performed where appropriate. Comparison between the two
groups at baseline, end of intervention (last observation carried
forward [LOCF] [intention to treat]), or at the 5-year visit were
performed with a Student’s t test or a Mann-Whitney U test.
Comparison between the two groups regarding change from
baseline values (1–5 y values minus value at baseline, ␦ values)
were performed with linear regression adjusting for baseline values (21). Development of T2DM (the primary end point) in the
two groups was evaluated with Cox regression with gender, age,
and baseline BMI and HbA1c as covariates.
P ⬍ .05 (two tailed) was considered statically significant.
Data are presented as mean ⫾ SD for normally distributed values
and as median (fifth, 95th percentiles) for nonnormally distrib-
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uted. All statistical analyses were performed using IBM SPSS
version 22 software.
In the power calculation for the primary end point, it was
assumed that an equal number would be included in each group,
that 10% in the placebo group would develop T2DM annually,
that supplementation with vitamin D would reduce this by 30%
during the 5-year intervention, and that the dropout rate would
be 20% and equal in both groups. For the study to have a power
of 0.80, an ␣ of .05 and a ␤ of .20, 505 subjects with IFG and/or
IGT had to be included.
Ethics
The study was approved by the Regional Committee for
Medical Research Ethics (REK NORD 81/2007) and by the Norwegian Medicines Agency (2007-002167-27).
Results
Seven hundred forty-three subjects were invited to participate; 556 accepted the invitation, 278 subjects were allocated to vitamin D and 278 subjects to placebo, 45 subjects were excluded at baseline, and 256 in the vitamin D
group and 255 in the placebo group received the study
Table 1. Baseline Characteristics and Values at End of Intervention (Last Value Carried Forward) and Values at Final
Five-Year Visit in the Vitamin D and Placebo Groups (The Tromsø Vitamin D and T2DM Trial)
Baseline
Male sex, n, %
Age, y
BMI, kg/m2
Current smokers, n, %
Antihypertensive drug use, n, %
Statin use, n, %
Vitamin D supplement use, n, %a
Serum 25(OH)D, nmol/L
Serum 25(OH)D, ng/mL
Serum calcium, mmol/L
Serum PTH, pmol/L
Serum creatinine, ␮mol/L
Fasting serum glucose, mmol/L
Fasting serum glucose, mg/dL
2-Hour serum glucose, mmol/L
2-Hour serum glucose, mg/dL
Fasting serum insulin, pmol/L
2-Hour serum insulin, pmol/L
Fasting serum C-peptide, pmol/L
HbA1c, %
HbA1c, mmol/mol
HOMA-IR
QUICKI
Serum total cholesterol, mmol/L
Serum LDL cholesterol, mmol/L
Serum HDL cholesterol, mmol/L
Serum triglycerides, mmol/L
Serum apolipoprotein A1, mmol/L
Serum apolipoprotein B, mmol/L
Systolic BP, mm Hg
Diastolic BP, mm Hg
a
End of Intervention
Vitamin D
(n ⴝ 256)
Placebo
(n ⴝ 255)
161 (62.9)
62.3 ⫾ 8.1
30.1 ⫾ 4.1
59 (23.0)
121 (47.3)
74 (28.9)
87 (34.0)
59.9 ⫾ 21.9
24.0 ⫾ 8.8
2.31 ⫾ 0.08
5.5 (3.4, 9.7)
69.7 ⫾ 13.6
6.12 ⫾ 0.47
110 ⫾ 8
7.26 ⫾ 2.11
131 ⫾ 38
73 (33, 198)
413 (81, 1547)
1095 ⫾ 345
5.98 ⫾ 0.28
41.8 ⫾ 3.1
3.37 (1.44, 8.96)
0.33 (0.29, 0.37)
5.72 ⫾ 1.06
3.72 ⫾ 0.92
1.36 ⫾ 0.34
1.4 (0.7, 3.2)
1.53 ⫾ 0.25
1.09 ⫾ 0.24
135.6 ⫾ 17.2
83.8 ⫾ 10.5
153 (60.0)
61.9 ⫾ 9.2
29.8 ⫾ 4.4
47 (18.3)
119 (46.7)
62 (24.3)
92 (36.1)
61.1 ⫾ 21.2
24.4 ⫾ 8.5
2.31 ⫾ 0.08
5.2 (3.1, 9.6)
69.5 ⫾ 13.9
6.08 ⫾ 0.50
109 ⫾ 9
7.40 ⫾ 1.84
133 ⫾ 33
78 (31, 207)
427 (101, 1418)
1081 ⫾ 397
5.97 ⫾ 0.34
41.7 ⫾ 3.7
3.56 (1.39, 9.47)
0.32 (0.29, 0.37)
5.80 ⫾ 1.08
3.73 ⫾ 0.92
1.38 ⫾ 0.37
1.3 (0.7, 3.6)
1.53 ⫾ 0.26
1.09 ⫾ 0.24
136.3 ⫾ 16.9
83.2 ⫾ 9.5
Including cod liver oil.
b
P ⬍ .01 vs placebo group, Student’s t test or Mann-Whitney U test.
c
P ⬍ .05 vs placebo group, Student’s t test or Mann-Whitney U test.
Vitamin D
(n ⴝ 256)
30.3 ⫾ 4.4
50 (19.6)
135 (52.7)
90 (35.1)
88 (34.4)
110.3 ⫾ 29.1b
44.1 ⫾ 11.6 b
2.30 ⫾ 0.08
5.1 (3.2, 8.8)b
72.4 ⫾ 15.7
6.27 ⫾ 0.72
113 ⫾ 13
8.65 ⫾ 2.64
156 ⫾ 48
100 (39, 272)
528 (133, 1891)
1198 ⫾ 397
6.09 ⫾ 0.36
43.1 ⫾ 3.9
4.59 (1.75, 12.9)
0.31 (0.28, 0.36)
5.44 ⫾ 1.08
3.59 ⫾ 0.98
1.35 ⫾ 0.37
1.3 (0.7, 3.2)
1.49 ⫾ 0.27
1.11 ⫾ 0.26
133.9 ⫾ 17.1
78.7 ⫾ 10.0
5-Year Visit
Placebo
(n ⴝ 255)
30.0 ⫾ 4.7
43 (16.7)
135 (52.9)
83 (32.5)
96 (37.6)
64.1 ⫾ 20.3
25.6 ⫾ 8.1
2.29 ⫾ 0.08
5.6 (3.2, 9.3)
71.2 ⫾ 14.9
6.39 ⫾ 1.16
115 ⫾ 21
8.82 ⫾ 2.85
159 ⫾ 51
100 (41, 277)
534 (180, 1860)
1208 ⫾ 501
6.10 ⫾ 0.54
43.1 ⫾ 6.0
4.79 (1.83, 14.6)
0.31 (0.27, 0.36)
5.48 ⫾ 1.02
3.61 ⫾ 0.92
1.39 ⫾ 0.42
1.4 (0.7, 3.4)
1.52 ⫾ 0.28
1.11 ⫾ 0.26
135.5 ⫾ 17.5
79.0 ⫾ 9.4
Vitamin D
(n ⴝ 116)
Placebo
(n ⴝ 111)
73 (62.9)
72 (64.9)
29.2 ⫾ 4.2
19 (16.4)
66 (56.9)
31 (26.7)
34 (29.3)
122.3 ⫾ 25.3b
48.9 ⫾ 10.1b
2.31 ⫾ 0.07
4.9 (3.3, 8.3)c
71.7 ⫾ 13.2
6.01 ⫾ 0.51
108 ⫾ 9
7.40 ⫾ 1.92
133 ⫾ 35
85 (41, 236)
400 (112, 1163)
1069 ⫾ 363
5.94 ⫾ 0.28
41.4 ⫾ 3.1
3.83 (1.75, 11.1)
0.32 (0.28, 0.36)
5.31 ⫾ 1.02
3.58 ⫾ 0.92
1.45 ⫾ 0.38
1.2 (0.6, 3.1)
1.58 ⫾ 0.27
1.15 ⫾ 0.24
134.1. ⫾ 17.0
78.6 ⫾ 10.0
29.5 ⫾ 4.0
11 (9.9)
56 (50.5)
20 (18.0)
45 (40.5)
66.7 ⫾ 18.6
26.7 ⫾ 7.4
2.29 ⫾ 0.08
5.5 (3.0, 9.1)
73.3 ⫾ 14.0
6.08 ⫾ 0.59
109 ⫾ 11
7.58 ⫾ 2.24
136 ⫾ 40
98 (41, 245)
455 (158, 1374)
1100 ⫾ 332
5.91 ⫾ 0.29
41.1 ⫾ 3.2
4.51 (1.70, 11.1)
0.31 (0.28, 0.36)
5.30 ⫾ 1.00
3.55 ⫾ 0.92
1.42 ⫾ 0.37
1.4 (0.6, 3.4)
1.56 ⫾ 0.26
1.14 ⫾ 0.26
134.9 ⫾ 17.2
78.0 ⫾ 8.7
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Vitamin D and Prevention of Type 2 Diabetes
medication. The first subject was included in March 2008,
and the last subject came to the final visit in May 2015. At
baseline the two study groups were almost identical (Table
1). The compliance rate was between 95% and 99% at all
visits in both groups.
The baseline serum 25(OH)D level was 59.9 ⫾ 21.9
nmol/L (24.0 ⫾ 8.8 ng/mL) in the vitamin D group and
61.1 ⫾ 21.2 nmol/L (24.4 ⫾ 8.5 ng/mL) in the placebo
group. During the intervention period, the mean serum
25(OH)D levels in the vitamin D group increased to 122
nmol/L (48 ng/mL) at the end of the study, whereas the
levels remained stable in the placebo group (Figure 1).
The flow of the participants during the study is shown
in Figure 2. One hundred sixteen subjects in the vitamin D
group and 111 subjects in the placebo group completed
the 5-year intervention. Fifty subjects in the vitamin D
group and 45 subjects in the placebo group were excluded
due to illness or dropping out during the study (Supplemental Table 1). The two dropout groups did not differ
significantly in any measures at baseline or at the end of
intervention (last value carried forward) (Supplemental
Table 2).
Glycemic status
One hundred three subjects in the vitamin D group
(40.2%) and 112 in the placebo group (43.9%) developed
T2DM, but the difference between the two groups was not
statistically significant in Cox regression analysis (hazard
Figure 1. Serum 25(OH)D levels during the study in the 256 subjects
in the vitamin D and the 255 subjects in the placebo group. *, P ⬍ .01
vs the control group. To convert serum 25(OH)D values from
nanomoles per liter to nanograms per milliliter, multiply with 0.4 (the
Tromsø vitamin D and T2DM trial).
J Clin Endocrinol Metab, April 2016, 101(4):1647–1655
risk 0.90; 95% confidence interval (CI) 0.69 –1.18, P ⫽
.45) (Figure 3). In the remainder, the final glycemic status
(LOCF) was normal in 55 subjects in the vitamin D group
and 41 in the placebo group, and IFG and/or IGT in 98
subjects in the vitamin D group and 102 in the placebo
group (␹2 test, P ⫽ .29).
Regarding serum glucose and insulin, HbA1c or measures of insulin resistance, there were no significant differences between the two groups at the end of the intervention (last value carried forward) as well as at the 5-year
visit (Table 1), in change from baseline until last observation, and in change from baseline to each of the annual visits
(except for a slight decrease in fasting glucose at the end of the
intervention and increase in the QUICKI index in the vitamin
D group vs the placebo group at the 5 y visit) (Table 2).
Serum lipids
At baseline the two groups did not differ in any of the
measured lipids or at the end of intervention (LOCF) or at
the 5-year visit (Table 1). When looking at change from
baseline (␦-values), in the vitamin D group vs the placebo
group, there was a significant decrease in LDL cholesterol
after 1 year but not for any other time points or lipid
measures (Table 2). Similar results were obtained if excluding subjects on lipid medication (data not shown).
Blood pressure
Similarly, the two groups did not differ in systolic or
diastolic BP at baseline, at the end of intervention, or at the
5-year visit (Table 1) or in changes from baseline except
for change from baseline until the 4-year visit (Table 2).
Similar results were obtained if excluding subjects on BP
medication (data not shown).
Side effects
A total of 3885 adverse events were recorded and the
pattern was similar in both groups (Table 3). Most the
adverse events affected the respiratory system (822 in
the vitamin D group and 812 in the placebo group), and
most of these events were upper respiratory infections.
Among the events, 115 in the vitamin D group and 134 in
the placebo group were considered serious (requiring hospital admission); most of these were related to the cardiovascular system (Table 3). The numbers of subjects with their
first myocardial infarction, percutaneous coronary intervention without infarction, coronary bypass operation without
infarction, stroke, cancer, or death did not significantly differ
between the groups (Supplemental Table 3). Two subjects in
the vitamin D group and one subject in the placebo group
developed renal stones and were excluded.
At the first 6-month visit, one subject in the vitamin D
group had a serum calcium of 2.64 mmol/L (10.6 mg/dL),
doi: 10.1210/jc.2015-4013
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1651
vitamin D group, 63 subjects had serum 25(OH)D less than 50 nmol/L
(20 ng/mL) at baseline and at the last
visit serum 25(OH)D in the range
80 –150 nmol/L (32– 60 ng/mL); in
the placebo group, 49 subjects had
serum 25(OH)D less than 50 nmol/L
(20 ng/mL) at baseline as well as at
the last visit. During the intervention
period, 30 subjects in this vitamin
D group (47.6%) and 26 in this
placebo group (53.1%) developed
T2DM (hazard risk 0.79; 95% CI
0.46 –1.37, P ⫽ .40) (Supplemental
Figure 1). No statistically significant
differences between these vitamin D
and placebo subgroups were found
in any measures at baseline, end of
the intervention, or 5-year visit or
when evaluating ␦-values (data not
shown).
Discussion
The present study is the largest and
longest-running RCT on prevention
of T2DM by vitamin D supplementation so far. However, in 511 subjects with IFG and/or IGT, we were
not able to demonstrate a positive effect by vitamin D 20 000 IU/wk for 5
years on progression toward T2DM
or measures of glucose metabolism,
serum lipids, or BP. There were no
major side effects, and the dose given
appeared to be safe.
In addition to our study, there are
Figure 2. Flow chart of the study (the Tromsø vitamin D and T2DM trial).
only three RCTs in which vitamin D
retesting shortly after showed a value of 2.63 mmol/L has been given alone without calcium supplementation for
(10.5 mg/dL), and the subject was excluded from the the prevention of T2DM (14, 22, 23). In the study by
study. Later testing showed normal serum calcium and Avenell et al (22), which was a substudy in the RosiglitaPTH values. Two subjects in the vitamin D group and one zone Evaluated for Cardiovascular Outcomes in Oral
in the placebo group had single serum calcium values in the
Agent Combination Therapy for Type 2 Diabetes trial,
range 2.56 –2.61 mmol/L (10.2–10.4 mg/dL) that normal2.5% (60 of 4216) of those randomized to vitamin D (800
ized at the second testing, and the subjects continued in the
IU daily) developed diabetes compared with 2.2% (54 of
study.
2413) in the placebo group (P ⫽ NS). However, these
subjects were not classified for glycemic status at baseline,
Subgroup analyses
To examine whether an effect of vitamin D could be the observation time was only 2 years, the data were selfdisclosed if including only subjects with low baseline levels reported, and baseline 25(OH)D levels were not meaand with the intended serum 25(OH)D levels during the sured. On the other hand, in the study by Davidson et al
study, a subgroup analysis was performed. Thus, in the (14), only subjects with prediabetes were included (n ⫽
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Jorde et al
Vitamin D and Prevention of Type 2 Diabetes
Figure 3. Cumulative probability of T2DM based on Cox regression
with gender, age, and baseline BMI and HbA1c as covariates in the 256
subjects in the vitamin D and the 255 subjects in the placebo group
(the Tromsø vitamin D and T2DM trial).
109), the mean 25(OH)D baseline levels were approximately 55 nmol/L (22 ng/mL), a high dose of vitamin D
was given (88 865 IU/wk), and repeated OGTTs were performed. After 1 year, 12% in the vitamin D group and 9%
in the placebo group were classified as T2DM (P ⫽ NS).
J Clin Endocrinol Metab, April 2016, 101(4):1647–1655
Similarly, in an open-label study by Kuchay at al (23), 137
subjects with prediabetes and mean serum 25(OH)D approximately 48 nmol/L (19 ng/mL) were randomized to
60 000 IU vitamin D for 4 weeks followed by 60 000 IU
for the next 11 months. In the vitamin D group, 13.8% and
in the placebo group 10.9% developed T2DM (P ⫽ NS).
These results are similar to our results in which 40.2% in
the vitamin D group and 43.9% in the placebo group
developed T2DM during the 5-year intervention period.
These four studies taken together do suggest that supplementation with vitamin D should not be given for the
sake of T2DM prevention. However, all of these studies
have shortcomings, including our own study. First, most
of our subjects had an adequate vitamin D status at inclusion, and therefore, an effect of additional vitamin D
might not be expected. Ideally, all subject should at baseline have serum 25(OH)D levels less than 50 nmol/L (20
ng/mL) (24) and, for a proof-of-principle study, probably
even lower. Furthermore, because the serum 25(OH)D
response to supplementation shows great individual variations, depending on baseline levels, BMI, and vitamin
D-related genotypes (25), the vitamin D dose should be
tailored during the study to achieve prespecified levels in
all subjects. We tried to do such a post hoc analysis by
including subjects in the vitamin D group with baseline
25(OH)D levels less than 50 nmol/L (20 ng/mL) and final
25(OH)D value in the range of 80 –150 nmol/L (32– 60
Table 2. Difference Between Vitamin D and Placebo Group in Change (␦-Values) From Baseline Until End of
Intervention (Last Value Carried Forward) and from baseline until 1-, 2-, 3-, 4-, and 5-Year Visits (The Tromsø Vitamin
D and T2DM Trial)
From Baseline
Subjects (vitamin D/placebo)
BMI, kg/m2
Fasting serum glucose, mmol/L
Fasting serum glucose, mg/dL
2-Hour serum glucose, mmol/L
2-Hour serum glucose, mg/dL
Fasting serum insulin, pmol/L
2-Hour serum insulin, pmol/L
Fasting serum C-peptide, pmol/L
HbA1c, %
HbA1c, mmol/mol
HOMA-IR
QUICKI
Serum total cholesterol, mmol/L
Serum LDL cholesterol, mmol/L
Serum HDL cholesterol, mmol/L
Serum triglycerides, mmol/L
Serum apolipoprotein A1, mmol/L
Serum apolipoprotein B, mmol/L
Systolic BP, mm Hg
Diastolic BP, mm Hg
To End of
Intervention
To 1-Year Visit
To 2-Year Visit
To 3-Year Visit
To 4-Year Visit
To 5-Year Visit
256/255
0.03 (⫺0.19, 0.26)
⫺0.16 (⫺0.31, ⫺0.07)a
⫺2.88 (⫺5.58, ⫺1.26)a
⫺0.08 (⫺0.50, 0.34)
⫺1.44 (⫺9.00, 6.12)
⫺7 (⫺17, 4)
⫺18 (⫺104, 69)
⫺21 (⫺75, 32)
⫺0.01 (⫺0.08, 0.06)
⫺0.12 (⫺0.88, 0.64)
⫺0.47 (⫺1.05, 0.12)
0.002 (⫺0.001, 0.006)
0.00 (⫺0.14, 0.15)
⫺0.01 (⫺0.14, 0.11)
⫺0.03 (⫺0.07, 0.01)
0.06 (⫺0.09, 0.02)
⫺0.02 (⫺0.05, 0.01)
0.00 (⫺0.03, 0.04)
⫺1.21 (⫺3.69, 1.27)
⫺0.58 (⫺2.01, 0.84)
242/241
0.01 (⫺0.18, 0.20)
⫺0.08 (⫺0.18, 0.03)
⫺1.44 (⫺3.24, 0.54)
0.01 (⫺0.39, 0.40)
0.18 (⫺7.02, 7.20)
⫺2 (⫺10, 6)
35 (⫺52, 122)
6 (⫺39, 51)
⫺0.00 (⫺0.06, 0.05)
⫺0.01 (⫺0.60, 0.59)
⫺0.13 (⫺0.55, 0.31)
0.000 (⫺0.004, 0.004)
⫺0.12 (⫺0.26, 0.02)
⫺0.13 (⫺0.25, ⫺0.02)a
⫺0.03 (⫺0.07,0.01)
0.11 (⫺0.04, 0.25)
⫺0.03 (⫺0.06, 0.01)
⫺0.01 (⫺0.04, 0.02)
0.51 (⫺1.83, 2.85)
0.30 (⫺1.13, 1.73)
188/188
⫺0.08 (⫺0.33, 0.17)
0.01 (⫺0.010, 0.11)
0.18 (⫺0.180, 1.98)
0.15 (⫺0.25, 0.54)
2.70 (⫺4.50, 9.72)
⫺4 (⫺14, 6)
⫺20 (⫺119, 79)
⫺8 (⫺61, 44)
0.01 (⫺0.04, 0.07)
0.16 (⫺0.41, 0.72)
⫺0.17 (⫺0.68, 0.34)
0.001 (⫺0.003, 0.005)
⫺0.04 (⫺0.19, 0.10)
⫺0.06 (⫺0.19, 0.07)
⫺0.03 (⫺0.07, 0.01)
0.03 (⫺0.11, 0.16)
⫺0.03 (⫺0.06, 0.00)
⫺0.03 (⫺0.07, 0.01)
⫺2.27 (⫺4.95, 0.41)
⫺1.40 (⫺2.91, 0.12)
156/160
0.08 (⫺0.20, 0.37)
⫺0.15 (⫺0.35, 0.05)
⫺2.70 (⫺6.30, 0.90)
0.18 (⫺0.21, 0.57)
3.24 (⫺3.78, 10.26)
⫺6 (⫺17, 6)
42 (⫺45, 130)
⫺7 (⫺68, 54)
⫺0.00 (⫺0.10, 0.09)
⫺0.03 (⫺1.05, 0.98)
⫺0.44 (⫺1.06, 0.18)
0.002 (⫺0.002, 0.006)
⫺0.06 (⫺0.25, 0.12)
⫺0.08 (⫺0.23, 0.08)
0.01 (⫺0.04, 0.06)
⫺0.01 (⫺0.17, 0.16)
⫺0.01 (⫺0.05, 0.03)
⫺0.03 (⫺0.07, 0.02)
1.00 (⫺2.18, 4.17)
⫺0.18 (⫺1.88, 1.52)
140/133
0.08 (⫺0.24, 0.40)
0.05 (⫺0.08, 0.17)
0.90 (⫺1.44, 3.06)
0.09 (⫺0.41, 0.58)
1.62 (⫺7.38, 10.44)
⫺1 (⫺13, 10)
⫺4 (⫺108, 101)
5 (⫺60, 69)
0.02 (⫺0.04, 0.09)
0.26 (⫺0.47, 0.98)
⫺0.01 (⫺0.58, 0.55)
0.001 (⫺0.004, 0.006)
0.00 (⫺0.22, 0.22)
⫺0.04 (⫺0.23, 0.15)
⫺0.00 (⫺0.06, 0.05)
0.12 (⫺0.02, 0.25)
0.02 (⫺0.03, 0.07)
⫺0.00 (⫺0.06, 0.05)
⫺4.02 (⫺7.42, ⫺0,62)a
⫺2.42 (⫺4.30, ⫺0.54) a
116/111
⫺0.05 (⫺0.42, 0.33)
⫺0.10 (⫺0.23, 0.03)
⫺1.80 (⫺4.14, 0.54)
⫺0.04 (⫺0.54, 0.46)
⫺0.72 –⫺9.72, 8.28)
⫺8 (⫺19, 3)
⫺67 (⫺165, 30)
⫺27 (⫺93, 40)
0.02 (⫺0.05, 0.08)
0.19 (⫺0.51, 0.90)
⫺0.45 (⫺1.02, 0.12)
0.006 (0.001, 0.011)a
0.08 (⫺0.15, 0.30)
0.03 (⫺0.17, 0.23)
0.01 (⫺0.05, 0.07)
⫺0.04 (0.19, 0.11)
0.02 (⫺0.02, 0.07)
0.01 (⫺0.04, 0.07)
⫺1.46 (⫺5.27, 2.34)
⫺0.26 (⫺2.40, 1.88)
A positive value means there was an increase in the vitamin D group vs the placebo group.
a
P ⬍ .05, vitamin D group vs placebo group, linear regression adjusted for baseline value (adjusted mean [95% CI]).
b
P ⬍ .01, vitamin D group vs placebo group, linear regression adjusted for baseline value (adjusted mean [95% CI]).
doi: 10.1210/jc.2015-4013
press.endocrine.org/journal/jcem
1653
Table 3. Adverse Events During the Intervention Period in Relation to Organ System Affected in the Vitamin D and
Placebo Groups (The Tromsø Vitamin D and T2DM Trial)
Vitamin D (n ⴝ 256)
a
Placebo (n ⴝ 255)
Organ System
Affected
Serious Adverse
Eventa
Nonserious
Adverse Event
Serious Adverse
Eventa
Nonserious
Adverse Event
Gastrointestinal system
Respiratory system
Skin
Musculoskeletal system
Urogenital system
Circulatory system
Nervous system
Endocrine system
Miscellaneous
Total
17
7
1
17
17
35
11
1
9
115
76
822
169
232
112
83
40
33
220
1787
14
7
4
14
19
50
9
0
17
134
98
812
182
256
152
76
40
26
207
1849
Requiring hospital admission.
ng/mL) (n ⫽ 63) and subjects in the placebo group with
baseline and final serum 25(OH)D less than 50 nmol/L (20
ng/mL) (n ⫽ 49). However, no positive effects of vitamin
D were disclosed, and using different cutoffs yielded the
same result.
Second, the conversion rate to T2DM as well as every
measure of glucose metabolism and insulin resistance was
better in the vitamin D than the placebo group but not
statistically significant. However, our study was powered
to detect a 30% difference in the conversion rate to T2DM
and not the observed 8% difference. In retrospect, given all
the negative results from the recently performed RCTs on
vitamin D, glucose, and insulin levels (26 –29), our power
calculation was obviously too optimistic, and a larger
study might have disclosed statistically significant differences. On the other hand, the clinical importance of such
a vitamin D effect on glucose metabolism would probably
be small, at least in subjects without vitamin D deficiency.
Fortunately, a large ongoing study that was started in
2013 may give the answer (30). In that study (the Vitamin
D and Type 2 Diabetes study), 2382 subjects with prediabetes will be randomized to vitamin D 4000 IU daily vs
placebo and followed up for an average of 3 years with
development of T2DM as primary end point. A low serum
25(OH)D level is not an inclusion criterion, but the size of
the study will probably allow meaningful subgroup analyses in those with vitamin D insufficiency/deficiency.
Regarding the effects of vitamin D supplementation on
glucose levels and measures of insulin resistance like
HOMA-IR and QUICKI, there are a number of RCTs.
Systematic reviews and meta-analyses are also abundant,
and they all conclude that at present there is insufficient
evidence to recommend vitamin D supplementation to improve glycemia or insulin resistance (13, 26 –29). This is
contrary to what could have been expected from observational studies in which there is a strong association be-
tween vitamin D levels, glucose, and insulin resistance
(8 –10).
There could be several reason for this apparent discrepancy: the subjects included in the RCTs were not vitamin
D deficient; the vitamin D doses could have been insufficient; the intervention periods could have been too short;
the subjects included could have been too few; and finally,
the observational studies may simply reflect reverse causality. Thus, subjects in good health probably eat healthier
and vitamin D-containing food and spend more time outdoors in the sun. Their high serum 25(OH)D levels may
therefore be the result of, and not the cause of, their good
health and vice versa for low serum 25(OH)D levels and
diseases.
For serum 25(OH)D, it should be recalled that there is
no agreement on what are sufficient or optimal levels (24,
31). However, most would agree that in only a few RCTs
have true vitamin D deficiency been an inclusion criterion.
Thus, in the review by George et al (26) on glucose metabolism, only one 1 of 15 RCTs had baseline serum
25(OH)D less than 30 nmol/L (12 ng/mL). In the particular RCT by von Hurst et al (32), the included subjects
had a mean 25(OH)D at baseline of 20 nmol/L (8 ng/
mL), and illustrating the importance of baseline levels,
a significant improvement in insulin sensitivity was
found after supplementation with vitamin D 1000 IU/d
for 6 months.
On the other hand, insufficient vitamin D doses appear
not to be a problem in recent RCTs. In the meta-analysis
by Seida et al (13), the average increase in serum 25(OH)D
after supplementation was approximately 47 nmol/L (19
ng/mL), and accordingly, most subjects would have reached
levels above 75 nmol/L (30 ng/mL), which generally are
viewed as sufficient (24, 31). That also applies to our study
in which the vitamin D group reached mean serum 25(OH)D
levels of 110 –120 nmol/L (44 – 48 ng/mL).
1654
Jorde et al
Vitamin D and Prevention of Type 2 Diabetes
Deterioration of glucose tolerance is usually a slow and
gradual process. It is therefore not unlikely that interventions lasting a few months are too short for assessing the
benefit of vitamin D. However, even though we had a
5-year study period, there was no trend for a gradually
appearing positive effect of the vitamin D supplementation. And last but not least, the effect of vitamin D on
glucose metabolism, as for prevention of T2DM, must be
small if present at all. Accordingly, even larger study
groups that the 511 subjects included by us may be
required.
In addition to glucose and insulin, we also measured
serum lipids and BP. As for glucose metabolism, observational studies show strong correlations between low serum
25(OH)D levels and dyslipidemia and hypertension (33,
34). However, RCTs have in general been negative (35,
36), and we observed no consistent, significant effect on
serum lipids or BP.
In conclusion, our study does not support giving vitamin D for the prevention of T2DM or for improvement of
insulin resistance or hyperglycemia. If there is a positive
effect of vitamin D in this regard, the effect must be small.
Very large studies with inclusion of vitamin D-deficient
subjects will be needed to show such a putative effect.
Acknowledgments
The superb assistance from the staff at the Clinical Research Unit
(and in particular Aslaug Jakobsen) and the Department of Medical Biochemistry at the University Hospital of North Norway is
gratefully acknowledged.
Address all correspondence and requests for reprints to: Rolf
Jorde, MD, PhD, Division of Internal Medicine, The University
Hospital of North Norway, 9038 Tromsø, Norway. E-mail:
[email protected].
The study had a clinical trial registration number of
NCT00685594 (clinicaltrials.gov).
This work was supported by grants from the Novo Nordisk
Foundation (Grant R195-A16126), the North Norway Regional
Health Authorities (Grant 6856/SFP1029-12), UiT The Arctic
University of Norway, the Norwegian Diabetes Association, and
the Research Council of Norway (Grant 184766).
Disclosure Summary: The authors have nothing to disclose.
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