RESEARCH

Tetsuya Kawahara,1,2 Gen Suzuki,3 Shoichi Mizuno,4 Tetsuya Inazu,5 Fumiyoshi Kasagi,6Chie Kawahara,1 Yosuke Okada,1 Yoshiya Tanaka1
1
University of Occupational
and Environmental Health,
Kitakyushu, Japan
2
Shin Komonji Hospital,
Kitakyushu, Japan
3
International University Healthand Welfare Clinic, Ohtawara,Japan
4
National Cancer Center EPOC,
Kashiwa, Japan
5
Ritsumeikan University, Kusatsu,
Japan
6
Radiation Effects Association,
Tokyo, Japan
Correspondence to: T Kawahara
k-tetsuy@med.uoeh-u.ac.jp(ORCID 0000-0002-1268-4871)
Additional material is published
online only. To view please visit
the journal online.

Cite this as: BMJ 2022;377:e066222
http://dx.doi.org/10.1136/
bmj‑2021‑066222

Accepted: 07 April 2022

Abstract
Objective
To assess whether eldecalcitol, an active vitamin
D analogue2, can reduce the development of type2 diabetes among adults with impaired glucose
tolerance.
DesignDouble blinded, multicentre, randomised, placebo
controlled trial.
Setting
Three hospitals in Japan, between June 2013 andAugust 2019.
Participants
People aged 30 years and older who had impaired
glucose tolerance defined by using a 75 g oral glucose
tolerance test and glycated haemoglobin level.
Interventions
Participants were randomised to receive active vitamin
D (eldecalcitol 0.75 μg per day; n=630) or matchingplacebo (n=626) for three years.
Main outcomes
The primary endpoint was incidence of diabetes.
Prespecified secondary endpoints were regression
to normoglycaemia and incidence of type 2 diabetes
after adjustment for confounding factors at baseline.
In addition, bone densities and bone and glucose
metabolism markers were assessed.
Results
Of the 1256 participants, 571 (45.5%) were
women and 742 (59.1%) had a family history oftype 2 diabetes. The mean age of participants was
61.3 years. The mean serum 25-hydroxyvitamin D
concentration at baseline was 20.9 ng/mL (52.2
nmol/L); 548 (43.6%) participants had concentrations

What is already known on this topic
Observational studies have shown that vitamin D deficiency is associated withinsulin resistance and an increased risk of future diabetes
However, results of randomised controlled trials of vitamin D supplementation
for preventing type 2 diabetes are not consistent
A previous study suggested that vitamin D supplementation was beneficial for
people with pre-diabetes and vitamin D deficiency

What this study adds
Active vitamin D might be beneficial for people with insufficient insulin secretion
among the pre-diabetic population
Treatment with eldecalcitol was effective in increasing bone mineral densities
and serum osteocalcin concentrations

the bmj | BMJ 2022;377:e066222 | doi: 10.1136/bmj-2021-066222

below 20 ng/mL (50 nmol/L). During a median followup of 2.9 years, 79 (12.5%) of 630 participants inthe eldecalcitol group and 89 (14.2%) of 626 in theplacebo group developed type 2 diabetes (hazard
ratio 0.87, 95% confidence interval 0.67 to 1.17;
P=0.39). Regression to normoglycaemia was achievedin 145 (23.0%) of 630 participants in the eldecalcitolgroup and 126 (20.1%) of 626 in the placebo group(hazard ratio 1.15, 0.93 to 1.41; P=0.21). After
adjustment for confounding factors by multivariablefractional polynomial Cox regression analysis,
eldecalcitol significantly lowered the development ofdiabetes (hazard ratio 0.69, 0.51 to 0.95; P=0.020).
In addition, eldecalcitol showed its beneficial effectamong the participants with the lower level of basal
insulin secretion (hazard ratio 0.41, 0.23 to 0.71;
P=0.001). During follow-up, bone mineral densitiesof the lumbar spine and femoral neck and serum
osteocalcin concentrations significantly increased
with eldecalcitol compared with placebo (all P<0.001).
No significant difference in serious adverse events
was observed.
Conclusions
Although treatment with eldecalcitol did not
significantly reduce the incidence of diabetes amongpeople with pre-diabetes, the results suggested thepotential for a beneficial effect of eldecalcitol on
people with insufficient insulin secretion.
Trial registration
UMIN Clinical Trials Registry UMIN000010758.

Introduction
Diabetes mellitus is a major risk factor for various
cardiovascular and renal diseases. The global
prevalence of diabetes was 425 million adults in 2015,
with an anticipated increase to 629 million by 2040.1
Moreover, a further 352 million people with impaired
glucose tolerance are at high risk for developing
diabetes and cardiovascular disease.1 2 Although
lifestyle modifications may delay the development oftype 2 diabetes,3 4 maintaining long term behaviouralchanges is difficult.5 6 Therefore, new strategies toreduce the incidence of type 2 diabetes are needed forpeople with impaired glucose tolerance.
Vitamin D receptors have been found in various
cell types, including the pancreatic β cells,7 8 andactive vitamin D is reportedly involved in insulin
biosynthesis and secretion.9 Genetic studies inmice have shown that inter-organ communication
and bone metabolism seem to be closely associatedwith insulin resistance.10-12 Observational studies
1

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Effect of active vitamin D treatment on development of type 2
diabetes: DPVD randomised controlled trial in Japanese
population

RESEARCH

Methods
This randomised, double blind, placebo controlled trial
evaluated the effect of eldecalcitol on incidence of type2 diabetes in people with impaired glucose tolerance inJapan. It was designed and supervised by the steeringcommittee and approved by the institutional review
boards at three participating centres. The trial protocolhas been previously published.24 Written informed
consent was obtained from all participants before
enrolment in the trial.
Study participants
Male and female patients who were aged 30 years
or older and had impaired glucose tolerance wererecruited to the study. We defined impaired glucose
tolerance as meeting all three of the following
glycaemic criteria: fasting glucose concentration <126
mg/dL (7.0 mmol/L), two hour glucose concentration
140-199 mg/dL (7.8-11.0 mmol/L) during a 75 g oral
glucose tolerance test, and glycated haemoglobin<6.5% (48 mmol/L).25 26 The complete list of inclusionand exclusion criteria, published previously,24 isprovided in the supplementary appendix.
Randomisation and masking
Sub-investigators in the three trial hospitals applied tothe assignment centre for registration and treatment
assignment. Participants were assigned to one of
two treatment groups in a one to one ratio by using acentral randomisation method. A responsible personat the assignment centre made a randomisation list
for each hospital separately by using a stratified
permuted block procedure before the first participant’s
entry. The number of strata was eight according tosex (male, female), age (30-54 years, ≥55 years), and
75 g oral glucose tolerance test two hour post-load
plasma glucose (<170 mg/dL, ≥170 mg/dL), because
we considered these factors to affect the incidence ofdiabetes. The block sizes were six for five permute cycles
and four for the next five permute cycles, and the last
17 participants were allocated using two block sizes—
that is, a total of 417 participants per hospital. On the2basis of the assignment list, which was kept in a locked
safe located in the assignment centre, the responsible
person enrolled and allocated participants to either theeldecalcitol group or the placebo group in the order ofregistration. The assignment list was inaccessible tothe investigators or sub-investigators for the durationof the trial except in the event of emergencies. The
key was retrieved only after the trial concluded anddata were fixed. Participants were randomly assigned
to take a single, once daily, hard gel pill containing
either 75 µg of eldecalcitol or matching placebo, whichlooks exactly the same. A standard dose of 0.75 µg ofeldecalcitol is used for the prevention and/or treatmentof osteoporosis in Japan. Eldecalcitol and placebo wereprescribed by a sub-investigator (physician) at every
three monthly visit and exchanged for the prescription
at an independent pharmacy that had no association
with any members of the DPVD Research Group. The
placebo was purchased from Sunsho Pharmaceutical,
which was responsible for the manufacturing, packing,and distribution of the placebo. This company had norole in the design or conduct of the trial.

Procedures
Study visits were scheduled at three month intervals,
with the follow-up period concluding after three
years. A routine clinical examination, including
measurement of fasting plasma glucose and glycatedhaemoglobin, was performed at each study visit. Eachparticipant received a brief (five to 10 minutes long) talkon appropriate calorie intake from diet and exercise ateach study visit, using an information sheet. A 75 goral glucose tolerance test, serum 25-hydroxyvitamin
D and 1,25-dihydroxyvitamin D concentrations, andbone mineral density were measured at baseline
and at yearly intervals. Serum 25-hydroxyvitamin D
and 1,25-dihydroxyvitamin D concentrations were
measured by liquid chromatography-tandem mass
spectrometry at LSI Medience Corporation (Tokyo,
Japan). All data were collected in the assignment
centre.
Outcomes
The primary endpoint was the development of type 2
diabetes, defined as meeting at least two of the following
criteria: glycated haemoglobin ≥6.5%, fasting plasma
glucose concentration ≥126 mg/dL, two hour postload plasma glucose concentration ≥200 mg/dL (11.1mmol/L), or random plasma glucose concentration≥200 mg/dL. The first secondary endpoint was theregression to normoglycaemia, defined as meeting
all three glycaemic criteria—glycated haemoglobin<6.5%, fasting plasma glucose concentration <110
mg/dL (6.1 mmol/L), and two hour post-load plasma
glucose concentration <140 mg/dL—or both of thefollowing criteria: glycated haemoglobin <5.7% andfasting plasma glucose concentration <100 mg/dL.27
The other secondary endpoint was the hazard ratio of
eldecalcitol compared with placebo for the incidenceof type 2 diabetes after adjustment for 11 confounding
factors at baseline: age, sex (male/female), presence ordoi: 10.1136/bmj-2021-066222 | BMJ 2022;377:e066222 | the bmj

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have shown an association between low serum
25-hydroxyvitamin D concentrations and increased
incidence of type 2 diabetes.13 14 Although several
intervention studies and a recent meta-analysis havesuggested that vitamin D supplementation may havea beneficial effect on glycaemic control,15-18 relatively
large scale clinical studies and other meta-analysesof randomised clinical trials have not supported thisfinding.19-23 Whether vitamin D supplementation isbeneficial only for children with vitamin D deficiency
is unclear,20 as is which bone metabolism markers
may be associated with the improvement in insulin
resistance after treatment. Hence, we did a prospective
trial, the Diabetes Prevention with active Vitamin
D (DPVD) study, to assess whether 0.75 μg per dayof eldecalcitol, an active vitamin D analogue, could
reduce the incidence of type 2 diabetes among people
with impaired glucose tolerance.

RESEARCH

Statistical analysis
We assessed the intention-to-treat population,
comprising all participants who were randomised andreceived at least one dose of the study drug, for the
primary analysis. However, we also show the resultsof Cox regression analyses using the per protocol
population and the “complete” population in thesensitivity analyses. The complete population was a
study population with a complete set of measurements
throughout the three year study period, which excluded
participants who dropped out other than those whoachieved the normal glucose tolerance status. We
analysed progression to diabetes and regression tonormoglycaemia with the log-rank test and two by
four χ2 test, respectively. We compared treatments
by estimation of hazard ratios and 95% confidence
intervals. Additionally, we did Cox regression analysis
using a multivariable fractional polynomial (mfp)
method by an mfp package for R with eldecalcitol andthe 11 baseline covariates, described above.28 We did
subgroup analyses of continuous covariables by using
splines with an mgcv package for R.29
Values were missing for covariates such as bodyweight, blood pressure, glycated haemoglobin, plasma

glucose concentrations. To evaluate the time trendsof covariates, we used a multiple imputation method
for replacing missing values separately in each groupwith other plausible values by creating multiple fillingin patterns to avoid bias caused by missing data.30 In
this study, we replaced each missing value with a set
substituted plausible value by 20 filled-in complete
datasets by using a multiple imputation by chained
equation method.31 In the imputation process, weused the following covariates to create 20 complete
datasets: age, sex, body mass index, blood pressure,family history of diabetes, glycated haemoglobin,plasma glucose, HOMA-IR, lipids concentrations,serum 25-hydroxyvitamin D concentrations, andserum 1,25-dihydroxyvitamin D concentrations ineach group. We used Rubin’s rules to calculate standard
errors.32 These standard errors take into account thevariability in results between imputed datasets andreflect the uncertainty associated with the missing
data.33 We averaged estimated associations in each of
the imputed datasets together to give overall estimatedassociations. We also did a repeated measure analysis
of variance and Dunnett test for the time trends ofmeasurements.
In the original trial design, approximately 750
patients were needed on the basis of the following
assumptions: 8.4% per year incidence of diabetes in theplacebo group, participant accrual period of 2.3 years,
study duration of 5.3 years, and a 7% dropout rate.
The study had 80% power to detect a 36% lower rateof the primary endpoint in the active vitamin D groupthan in the placebo group, with a two sided type I error

3875
Assessed for eligibility
2619
Excluded
2361 Did not meet inclusion criteria
156 Declined to participate
102 Other reasons
1256
Randomised

630
Allocated to eldecalcitol andreceived intervention

626
Allocated to placebo andreceived intervention

74
Discontinued
26 Adverse events
1 Died1 Poor compliance
4 Withdrew consent
42 Achieved normoglycaemia

71
Discontinued
20 Adverse events
1 Died2 Poor compliance
7 Withdrew consent
41 Achieved normoglycaemia

Analysed primary outcomes
630 Intention to treat
627 Per protocol set

Analysed primary outcomes
626 Intention to treat
623 Per protocol set

Fig 1 | Flow diagram of study
the bmj | BMJ 2022;377:e066222 | doi: 10.1136/bmj-2021-066222

3

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absence of hypertension (systolic blood pressure ≥140mm Hg, diastolic blood pressure ≥90 mm Hg, or both),body mass index, family history of diabetes (yes/no), glycated haemoglobin, fasting plasma glucose,
two hour plasma glucose, 25-hydroxyvitamin D,
homoeostasis model assessment of insulin resistance(HOMA-IR), and insulinogenic index.

RESEARCH

Patient and public involvement
Patients and the public were not involved in setting
the research question or outcome measures or in thewriting of the results. However, patient representatives
asked us to measure bone mineral densities for allparticipants yearly. As a result, we added the annual
measurement of bone mineral density to the protocol.
Results
From 1 June 2013 through 31 August 2015, a
total of 3875 participants were recruited from 32
institutions in Japan (fig 1), and 1256 participants
were randomly assigned to receive either eldecalcitol

Table 1 | Baseline characteristics of study participants. Values are means (standard
deviations) unless stated otherwise
Characteristic
Overall (n=1256) Eldecalcitol (n=630)
Age, years
61.3 (8.9)
61.1 (8.8)
No (%) female sex
571 (44.5)
288 (45.7)
Body mass index
24.3 (2.3)
24.1 (2.7)
Blood pressure, mm Hg:
Systolic
134.3 (11.0)
134.4 (12.4)
Diastolic82.9 (9.1)
82.8 (10.3)
No (%) family history of diabetes
742 (59.1)
380 (60.3)
Glycated haemoglobin, %6.0 (0.2)
5.9 (0.2)
Plasma glucose, mg/dL:
Fasting state
109.9 (9.2)
110.0 (9.5)
30 min after oral glucose load
176.3 (20.1)
177.4 (19.8)
2 h after oral glucose load
168.4 (17.8)
168.9 (20.1)
Plasma insulin, μU/dL:
Fasting state
6.9 (2.6)
7.0 (3.0)
49.4 (23.2)
48.5 (24.9)
30 min after oral glucose load
2 h after oral glucose load
63.4 (33.8)
64.9 (38.4)
Homoeostasis model assessment
1.89 (0.71)
1.89 (0.79)
insulin resistance
Lipids, mg/dL:
Low density lipoprotein cholesterol 130.2 (29.1)
128.8 (26.2)
High density lipoprotein
56.3 (17.6)
57.5 (14.2)
cholesterol
Triglycerides
140.1 (42.9)
139.5 (47.2)
Serum 25-hydroxyvitamin D, ng/mL
20.9 (6.1)
21.0 (6.2)
Distribution, No (%):  <20 ng/mL
548 (43.6)
270 (42.9)  20-29 ng/mL
622 (49.5)
322 (51.1)  ≥30 ng/mL
86 (6.8)
38 (6.0)
Serum 1,25-dihyroxyvitamin D, μg/dL 47.7 (22.2)
48.8 (23.5)

4

Placebo (n=626)
61.4 (9.1)
283 (45.2)
24.5 (1.8)

134.2 (9.4)
83.1 (7.6)
362 (57.8)
6.0 (0.2)
109.8 (8.9)
175.3 (20.2)
168.0 (15.0)
6.8 (2.2)
50.3 (21.3)
62.0 (28.3)
1.88 (0.64)

131.8 (31.6)
55.1 (20.3)
140.7 (38.2)
20.7 (6.1)
278 (44.4)
300 (47.9)
48 (7.7)
46.7 (20.8)(630 participants) or placebo (626 participants) (621
participants had impaired glucose tolerance alone and635 had impaired glucose tolerance with impaired
fasting glucose). Of the 1256 participants, 45.5%
were women and 59.1% had a family history of type2 diabetes. The mean age of participants was 61.3
(range 30-78) years. No clinically relevant differences
in baseline characteristics existed between the twogroups (table 1; supplementary table A). The mean
serum 25-hydroxyvitamin D concentration at baseline
was 20.9 ng/mL (52.2 nmol/L); 43.6% of participants
had concentrations of <20 ng/mL (50 nmol/L). The
classification of vitamin D concentrations in Japan is≥30 ng/mL (≥75 nmol/L) as normal, 20 to <30 ng/mL(50 to <75 nmol/L) as insufficiency, and <20 ng/mL(<50 nmol/L) as deficiency.34-36 The trial was finishedin August 2019. The median follow-up was 2.9(interquartile range 2.8-3.0) years.

Primary outcome
During the three year follow-up period, 79 (12.5%)of 630 participants in the eldecalcitol group and
89 (14.2%) of 626 in the placebo group developed
diabetes. We found no difference between treatmentgroups (hazard ratio for eldecalcitol versus placebo
0.87, 95% confidence interval 0.67 to 1.17; P=0.39)(fig 2, top panel).
Secondary outcomes
Similarly, we found no difference between treatmentgroups in regression to normoglycaemia. By the endof the study, 145 (23.0%) of 630 participants in theeldecalcitol group and 126 (20.1%) of 626 in theplacebo group achieved normoglycaemia (hazard ratio
1.15, 0.93 to 1.41; P=0.21) (fig 3).
We did a multivariable Cox regression analysis
after adjusting for 11 prespecified covariables (age,sex, hypertension, body mass index, family historyof diabetes, glycated haemoglobin, fasting plasma
glucose, two hour plasma glucose, 25-hydroxyvitamin
D, HOMA-IR, and insulinogenic index) by using a
multivariable fractional polynomial method. Figure
2 (bottom panel) shows the Kaplan-Meier curve after
adjustment. We showed that eldecalcitol was effective
for preventing the development of type 2 diabetes after
adjustment for these covariables (hazard ratio 0.69,
0.51 to 0.95) at the significant level of P=0.020.
Sensitivity analysis
Sensitivity analyses for the per protocol populationand complete population assessed the robustnessof the primary outcome based on the intention-totreat population. The result showed hazard ratios
for eldecalcitol of 0.88 (0.65 to 1.19; P=0.39) and
0.88 (0.65 to 1.19; P=0.39) for the per protocol andcomplete populations, respectively, which were
substantially the same as the primary analysis. In
addition, the distributions of parameters related toglucose metabolism at the beginning of the study did
not differ between the intention-to-treat and complete
populations (supplementary table B).
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of 0.05. However, in the middle of the study, regression
to normoglycaemia occurred, and the dropout ratio ofparticipants who reached the normoglycaemic state
was greater than anticipated, suggesting that the
number of participants developing diabetes would bemuch smaller than originally planned. Therefore, we
amended the protocol so that the cumulative incidenceof type 2 diabetes in the control group was 16.9%(6.0% annually)—that is, the active vitamin D groupwas 11.1% (3.8% annually) and the dropout ratio
was 12% in the recruitment phase of the study. Thus,
the relative risk reduction was assumed at 36%. As aresult, 625 participants were needed in each group (atotal of 1250).
We used R software, version 4.05, for statisticalanalyses. We considered two sided P values less than
0.05 to be statistically significant.

1.0
0.8

Eldecalcitol
Placebo

0.6
0.4

Hazard ratio for diabetes 0.87 (95% CI 0.67 to 1.17)
P=0.390.2
0No at risk
Eldecalcitol
630 617 605 586 565 552 539 527 514 504 493 482 477

Probability of diabetes-free survival

Placebo
626 613 599 578 557 547 535 521 504 495 482 472 466
1.0
0.8
0.6
0.4

Hazard ratio for diabetes 0.69 (95% CI 0.51 to 0.95)
P=0.02

0.2
0
0

3

6

9

12

15

18

21

24

27

30

33

36

Months since randomisation

Fig 2 | Kaplan-Meier curves for survival free from type 2 diabetes among adults with
impaired glucose tolerance. Top: before adjustment for 11 covariables. Bottom: after
adjustment for 11 covariables

Participants with normoglycaemia (%)

We investigated confounding covariables by using
spline curve analysis one by one for 11 continuous
covariables: age, body mass index, systolic bloodpressure, glycated haemoglobin, fasting plasma
glucose, fasting immunoreactive insulin, two hour
plasma glucose, 25-hydroxyvitamin D, HOMA-IR,
homoeostasis model assessment β cell function(HOMA-β), and insulinogenic index. We observed aconfounding effect for glycated haemoglobin and twohour plasma glucose (supplementary figure A).

25
20

Eldecalcitol
Placebo15
10
5
0

1 year

2 years

3 years

Fig 3 | Number of participants with impaired glucose tolerance who achieved
normoglycaemia
the bmj | BMJ 2022;377:e066222 | doi: 10.1136/bmj-2021-066222

Post hoc analysis
As a post hoc analysis, we re-examined theinteractions of nine continuous covariables with
eldecalcitol one by one after adjusting for glycatedhaemoglobin and two hour plasma glucose by using
multivariable fractional polynomial Cox analysis. As
shown in supplementary figure B, interactions withthe eldecalcitol effect were seen for HOMA-β, HOMAIR, and fasting immunoreactive insulin (HOMAβ=fasting immunoreactive insulin×360/fasting plasma
glucose–63;
HOMA-IR=fasting
immunoreactive
insulin×fasting plasma glucose/405) After we divided
the three covariables into three groups at their 33.3
centile and 66.6 centile values, we did Kaplan-Meieranalyses and multivariable fractional polynomial
Cox regression. Supplementary figure C shows that
eldecalcitol had a significant preventive effect on thedevelopment of type 2 diabetes among the lowest
divisions of HOMA-β (hazard ratio 0.35, 0.21 to 0.59;
P<0.001), HOMA-IR (0.37, 0.20 to 0.67; P=0.001), andfasting immunoreactive insulin (0.41, 0.23 to 0.71;
P=0.001). These results indicate that eldecalcitol had abeneficial effect on insufficient basal insulin secretion.
Time trends of glycaemic status and body massindex
With regard to glycaemic status at the end of thetrial, plasma glucose and immunoreactive insulin
concentrations at fasting state and after 120 minutes
did not differ between the two groups (fig 4). However,plasma glucose concentrations after 30 minutes ofloading were significantly improved from those atbaseline in the eldecalcitol group. We observed nosignificant differences in glycated haemoglobin andinsulinogenic index between the two groups. HOMA-IR
was significantly lower and HOMA-β was significantly
higher in the eldecalcitol group than in the placebogroup after the three year treatment period. Body
mass index did not differ significantly between the twogroups after treatment.
Time trends of bone metabolism markers
Although serum 25-hydroxyvitamin D concentration
did not differ between the two groups, serum
1,25-dihydroxyvitamin D and bone alkaline
phosphatase concentrations were significantly lower
with eldecalcitol compared with placebo (fig 5). In
addition, bone mineral densities of the lumbar spineand femoral neck were significantly higher with
eldecalcitol than with placebo. Serum osteocalcin
concentrations were significantly higher with
eldecalcitol than with placebo. We found no significant
differences between the two groups in serum leptin,
receptor activator of nuclear factor-κ B ligand (RANKL),
and osteoprotegerin concentrations.
Adverse events
A total of 26 (4.1%) participants in the eldecalcitolgroup and 21 (3.4%) in the placebo group discontinued
the study owing to adverse events (hazard ratio 1.23,
0.70 to 2.16; P=0.47). Rates and types of adverse
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Probability of diabetes-free survival

RESEARCH2.00

Insulinogenic index

58

HOMA-IR

*

1.95

0.80

54

1.85

52

1.80

50

1.75

0.55

114

180

170

110
108
106
104

30 min insulin (µU/mL)

7.5
7.3
7.1
6.9

178

170
54
52
50

44

23.8

5.90

23.6

5.85
2

3

†

0.65

169
168
167
166
165
66
64
62
60
58
56

0

1

2

3
Year

6.00
5.95

1

†

6.05

24.0

0

†

48

6.5

23.4

†

172

46

24.2

†

174

6.7

24.4

†

176

120 min plasma glucose (mg/dL)

112

0.70

0.60

120 min insulin (µU/mL)

30 min plasma glucose (mg/dL)

1.90

*

Eldecalcitol
Placebo0.75

56

HbA1c (%)

Fasting plasma glucose (mg/dL)
Fasting insulin (µU/mL)
Body mass index

60

5.80

0

1

2

Year

3
Year

Fig 4 | Changes in glycaemic status and body mass index. Bars indicate standard error. HbA1c=glycated haemoglobin; HOMA-β=homoeostasis model
assessment β cell function; HOMA-IR=homoeostasis model assessment insulin resistance. *P<0.001 compared with placebo. †P<0.001 comparedwith baseline

events did not differ significantly between the twogroups (table 2).

Discussion
In this DPVD trial, treatment with eldecalcitol (anactive vitamin D analogue), at a dose of 0.75 µg perday, did not show a preventive effect on the incidenceof type 2 diabetes, nor a beneficial effect on the rateof regression to normoglycaemia. However, we showeda preventive effect of eldecalcitol after adjusting6

for covariables (confounding factors) by using a
multivariable fractional polynomial Cox regression
analysis. The preventive effect of eldecalcitol ondevelopment of type 2 diabetes in a pre-diabetic
population was seen especially among participants
with insulin insufficiency. We believe that thisdiscrepancy is a result of lack of statistical power, an
unbalanced distribution of two hour plasma glucose
concentrations between participants in the eldecalcitol
and placebo groups, or both (supplementary figure D).
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HOMA-β (%)

RESEARCH

21.0
20.5
20.0

0.90
*

0.88
0.86

*

*

47
43
*

39

*

35

*

0.77
0.75
*
0.73

*

*

18
17
16

14

16.1
15.7

14.9

0.80

0.67

14.5

24

0.073

3.8

*
*

22

0.072
0.071

21

0.070

20

0.069

19

0

1

2

3

0.068

0

1

2

Year

3
Year

*

16.5

0.69

23

*

13

15.3

0.82

*

15

0.71

Osteoprotegelin (pmol/L)

0.84

RANKL (pmol/L)

Osteocalcin (ng/mL)

BMD (lumbar spine) (g/cm2)

19.5

51

Bone alkaline phosphatase (μg/L)

21.5

53

Leptin (ng/mL)

1,25-dihydroxyvitamin D (pg/mL)

Eldecalcitol
Placebo

BMD (femoral neck) (g/cm2)

22.0

3.7
3.6
3.5
3.4
3.3

0

1

2

3
Year

Fig 5 | Changes in bone metabolism markers. Bars indicate standard error. BMD=bone mineral density; RANKL=receptor activator of nuclear factor-κB ligand. *P<0.001 compared with placebo

Firstly, we powered our trial to detect a 36% lower risk of
diabetes with eldecalcitol than with placebo. However,
eldecalcitol treatment decreased the risk of diabetes bya smaller effect size (13%). A meta-analysis publishedin 2020 showed that vitamin D supplementation was
associated with an 11% lower risk of diabetes among
4896 patients with pre-diabetes.18 Therefore, we
suspect that our research was underpowered to detect
the beneficial effect of eldecalcitol before adjustment
for unbalanced covariables.
Glucose intolerance is associated with insufficientinsulin secretion, insulin resistance, or both.25 HOMA-β
is a biomarker of insulin secretion, with a value of lessthan 40% indicating decreased β cell function.37 38
HOMA-IR is a biomarker of insulin resistance, and avalue of 1.6 or above indicates that insulin is secreted
from the pancreas but the target organ’s sensitivity
to insulin is reduced and its action is slowed down—that is, insulin resistance.39 Fasting immunoreactive
insulin represents the amount of basal insulin; thenormal range in Japan is 2-10 μU/mL,25 but in Europe
and the US it is 2.6-24.9 μU/mL,40 which is a little
the bmj | BMJ 2022;377:e066222 | doi: 10.1136/bmj-2021-066222

higher. Eldecalcitol showed its beneficial effect among
the participants with the lower third of HOMA-β,
HOMA-IR, and fasting immunoreactive insulin values,of which cut-off values were 44.0%, 1.49, and 5.6 μU/
mL, respectively. This suggests that eldecalcitol might
have a preventive effect for development of type 2
diabetes in pre-diabetic patients with impaired basal
insulin secretion. Our results are backed by basic
experiments and mouse genetics.9 41
As expected, the serum 25-hydroxyvitamin
D concentration was not changed and the
1,25-dihydroxyvitamin D concentration was decreased
by eldecalcitol treatment in this study. Eldecalcitol, an
active vitamin D analogue, does not affect the serum
25-hydroxyvitamin D concentration, but it suppresses
the expression of the CYP27B1 gene in the kidney,
which promotes conversion of 25-hydroxyvitamin D to
1,25-dihydroxyvitamin D intracellularly.42 In addition,
it is relatively stable in the cell and strongly enhances
the expression of the CYP24 gene,43 which suppresses
1,25-dihydroxyvitamin D production. As a result,the serum and intracellular 1,25-dihydroxyvitamin
7

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25-hydroxyvitamin D (ng/mL)

RESEARCHRESEARCH

Table 2 | Frequency of adverse events*

EventsDiscontinuations due toadverse events
Laboratory tests:  Hypercalcaemia†  Hypercalciuria‡  Increased serum
creatinine§
Nephrolithiasis
Hives
Digestive symptoms
Liver dysfunction
Death
CancerSerious adverse events
Respiratory system
Cardiovascular system
Gastrointestinal system
Urogenital system
Musculoskeletal system
Skin

Placebo (n=626)

No ofevents26

Event rate:
No/100person years
1.38

No of
events21

Event rate:
No/100person years
1.12

Risk ratio (95%CI)
1.23 (0.70 to 2.16)

6
5
2

0.32
0.27
0.11

2
3
2

0.11
0.16
0.11

2.98 (0.60 to 14.71)
1.66 (0.40 to 6.90)
0.99 (0.14 to 7.03)

3
2
3
3
1
1
109
34
23
19
15
14
4

0.16
0.11
0.16
0.16
0.05
0.05
5.77
1.80
1.22
1.01
0.79
0.74
0.21

3
3
2
3
1
2
106
37
25
18
12
11
3

0.16
0.16
0.11
0.16
0.05
0.11
5.65
1.97
1.33
0.96
0.64
0.59
0.16

0.99 (0.20 to 4.90)
0.66 (0.11 to 3.95)
1.49 (0.25 to 8.89)
0.99 (0.20 to 4.90)
0.99 (0.06 to 15.85)
0.50 (0.05 to 5.47)
1.02 (0.80 to 1.30)
0.91 (0.58 to 1.44)
0.91 (0.53 to 1.59)
1.05 (0.56 to 1.98)
1.24 (0.59 to 2.63)
1.27 (0.58 to 2.76)
1.33 (0.30 to 5.90)*In participants who received at least one dose of eldecalcitol or placebo.
†Defined as corrected serum calcium >11.0 mg/dL (2.75 mmol/L), as confirmed on repeat testing.
‡Defined as fasting urine calcium:urine creatinine ratio ≥0.28.
§Defined as serum creatinine >1.5 mg/dL or upper limit of normal range for clinical laboratory at each clinical site.

D concentrations are decreased.44 45 However,
eldecalcitol has a similar physiological effect to1,25-dihydroxyvitamin D. Hence, it increased the bonemineral densities of the lumbar spine and femoral
neck in this study.
We also measured the changes in various factors(osteocalcin, leptin, RANKL, and osteoprotegerin) thatare reportedly associated with glucose metabolism aswell as bone metabolism after treatment with vitamin
D and active vitamin D. Serum osteocalcin is a boneformation marker, which affects insulin sensitivity
and glucose metabolism.10-12 46 In the second yearof the trial, serum osteocalcin concentrations
began increasing significantly in the eldecalcitolgroup compared with the placebo group. Changes
in serum osteocalcin concentrations by vitamin D
supplementation were inconsistent in many previous
studies.47-49 This may have been due to relatively shorttrial durations, with participants not followed beyond
three years. Our study also showed a decrease in 30
minute post-load plasma glucose concentrations andimprovement of insulin resistance at three years by
eldecalcitol. These results might be associated withchanges in serum osteocalcin concentrations.
Leptin, secreted by adipose tissues, increases thesensation of satiety, and is involved in regulating foodintake. Some trials have evaluated the effect of vitamin
D supplementation on serum leptin concentrations
in people with type 2 diabetic, but the results wereinconsistent.50-52 In our trial, serum leptin was slightly,
but not significantly, elevated by eldecalcitol comparedwith placebo. Serum RANKL concentration, reported
to be positively associated with insulin resistance,53
showed a slight decrease in both groups, albeit withno significant difference. Serum osteoprotegerin,
8Strengths and limitations of study
Our trial has many strengths including a large
population size, outpatient follow-up every threemonths, high rates of follow-up, and high adherence
to the trial regimen. Moreover, this is the firstpublished randomised controlled trial to assess thepreventive effect of active vitamin D treatment on
the development of type 2 diabetes in a pre-diabetic
population and showed its beneficial effect onparticipants with insufficient insulin secretion. The
mean serum 25-hydroxyvitamin D concentration atbaseline was 20.9 ng/mL in our trial, which was lower
than was obtained in previous studies (that is, 44.0
ng/mL and 28.0 ng/mL).19 20 From the result shownin supplementary figure A, eldecalcitol may be more
effective in patients with vitamin D deficiency than inpatients without vitamin D deficiency.
The trial also had some limitations. Firstly, we used
eldecalcitol at a regular dose of 0.75 µg. This is thestandard dose administered in the case of osteoporosis,
rickets, and hypocalcaemia in Japan. In studies inosteoporosis, a dose of 0.75 µg has shown noninferiority in increasing bone mass and in preventingbone fracture compared with a higher dose (1 µg) andnon-inferiority compared with a lower dose (0.5 µg) for
the onset of adverse events.44 58 However, whether it
was an appropriate dose for prevention of diabetes in
the context of this trial is unclear. Secondly, whether the
results of this study apply to all ethnicities is unclear,because the study involved only Japanese participants.
Latitude of living area, occupation, and racial or ethnic
differences are important factors that affect serum
25-hydroxyvitamin D concentration.62-64 Thirdly, theallocation method in this multicentre collaborative
study may have been inadequate to prevent theimbalance of a critical variable such as baseline twohour plasma glucose concentration between the twogroups. Therefore, a more sophisticated allocation
method should be developed.
doi: 10.1136/bmj-2021-066222 | BMJ 2022;377:e066222 | the bmj

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Eldecalcitol (n=630)

reportedly correlated with insulin sensitivity,54 55
decreased slightly in the eldecalcitol group. However,
we found no significant difference between the twogroups.
We selected active vitamin D for this study forseveral reasons. Firstly, patients’ adherence andcontinuation of the study will be high when active
vitamin D is prescribed as a treatment.56 Secondly,
vitamin D supplements are abundant and ubiquitousin many foods and other sources, so simply evaluating
vitamin D intake levels among participants in a trial
is difficult. In contrast, active vitamin D is a medicine
and is not contained in any food; thus, the drug intake
can be easily evaluated. In addition, the effects withactive vitamin D seem to be stronger than with normal
vitamin D. Studies have shown that active vitamin D
treatment increased the bone mineral density,45 57 58
muscle strength,59 60 and mobility of participants.59 61
We also observed increased bone mineral density inthis study. This finding might be associated with the
improvement in participants’ activity.

RESEARCH

Contributors: TK wrote the first draft of the manuscript and was
responsible for the design of the methods. TK, GS, SS, FK, and CK
were responsible for the collection and assembly of data. TI was
responsible for data management. SM completed the main part of thedata analyses, and all authors discussed the analysis plan and results
and provided input to the manuscript. All authors were responsible forthe critical revision of the article for important intellectual content. All
authors had access to the final study results and were responsible forthe final approval of the manuscript. TK is the guarantor.
Funding: This study was supported by a grant from the Kitakyushu
Medical Association. The sponsor did not contribute to the study
design; the collection, management, analysis, or interpretation of
data; the writing of the manuscript; or the decision to submit themanuscript for publication.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at https://www.icmje.org/disclosure-of-interest/ anddeclare: support by a grant from the Kitakyushu Medical Association;no financial relationships with any organisations that might have aninterest in the submitted work in the previous three years; no otherrelationships or activities that could appear to have influenced thesubmitted work.
Ethical approval: This trial was approved by the institutional review
boards of Kokura Medical Association, University of Occupational andEnvironmental Health, and Fujisawa City Hospital. All participants gave
written informed consent.

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Data sharing: Relevant anonymised patient level data are available
from the corresponding author on reasonable request.
The lead author (the manuscript’s guarantor) affirms that themanuscript is an honest, accurate, and transparent account of thestudy being reported; that no important aspects of the study havebeen omitted; and that any discrepancies from the study as planned(and, if relevant, registered) have been explained.
Provenance and peer review: Not commissioned; externally peer
reviewed.
Dissemination to participants and related patient and public
communities: The results of the study will be sent to research
participants and research cooperation facilities via letters.
This is an Open Access article distributed in accordance with theCreative Commons Attribution Non Commercial (CC BY-NC 4.0)
license, which permits others to distribute, remix, adapt, build uponthis work non-commercially, and license their derivative works on
different terms, provided the original work is properly cited and theuse is non-commercial. See: http://creativecommons.org/licenses/
by-nc/4.0/.
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9

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Conclusions
Treatment with eldecalcitol, an active vitamin
D analogue, at a dose of 0.75 µg per day did not
significantly reduce the incidence of diabetes and failed
to increase the rate of regression to normoglycaemia
compared with placebo among patients with impaired
glucose tolerance who were at high risk for type 2
diabetes. Although our study suggested the potential
for a beneficial effect of active vitamin D treatment on
the prevention of type 2 diabetes after adjustment for
confounding factors, this finding should be replicatedin further populations before its significance for publichealth can be fully appreciated. Further research, suchas an appropriately randomised study focused on
pre-diabetic patients with insufficient basal insulin
secretion or a meta-analysis including the results ofthis study, would be needed to determine whether
vitamin D and/or active vitamin D is beneficial topeople with pre-diabetes.

RESEARCH

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