Vitamin D supplementation and glycemic control in type 2 diabetes patients: A systematic review and meta-analysis

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Available online at www.sciencedirect.com

Metabolism www.metabolismjournal.com

Vitamin D supplementation and glycemic control in type 2 diabetes patients: A systematic review and meta-analysis Chunhua Wu, Shanhu Qiu, Xiangyun Zhu, Ling Li⁎ Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, Medical School, Southeast University, China

A R T I C LE I N FO

AB S T R A C T

Article history:

Introduction. Low vitamin D status has been found to be associated with impaired

Received 11 November 2016

glycemic control in patients who suffer from type 2 diabetes; however, whether vitamin D

Accepted 2 May 2017

supplementation is associated with improved glycemic status remains controversial. The aim of this study was to summarize evidence from randomized controlled trials (RCTs) to

Keywords:

assess the efficacy of vitamin D supplementation in reducing glycosylated haemoglobinA1c

Vitamin D

(HbA1c) and fasting blood glucose (FBG) levels. Materials/Methods. We searched PubMed, Web of Science and the Cochrane Library for

Glycosylated hemoglobinA1c Fasting blood glucose

reports published up to March 2017. We selected parallel RCTs investigating the effect of

Body mass index

vitamin D or vitamin D analogues on HbA1c or FBG levels in type 2 diabetes patients. Cohen's d was calculated to represent the standardized mean difference (SMD) for each study, and the SMDs with 95%confidence intervals (CIs) were pooled using a random effects model. Results. Twenty-four studies were included that evaluated HbA1c levels and 18 studies were included that evaluated FBG levels. Meta-analyses showed that vitamin D supplementation was associated with reduced HbA1c levels (standardized mean difference (SMD) − 0.25 [− 0.45 to − 0.05]) but had no influence on FBG levels (SMD −0.14 [−0.31 to 0.03]). However, the subgroup analyses suggested that vitamin D supplementation was associated with reduced HbA1c levels (SMD −0.39 [− 0.67 to −0.10]) and FBG (SMD − 0.27 [− 0.46 to −0.07]) among patients with 25-hydroxyvitamin D (25(OH) D) deficiency at baseline. Significantly reduced HbA1c levels were also observed in association with vitamin D supplementation in the subgroup including type 2 diabetes patients with a body mass index (BMI) < 30 kg m−2 (SMD −0.30 [− 0.54 to − 0.07]). Conclusions. Vitamin D supplementation could be effective at improving glycemic control in vitamin D deficient or non-obese type 2 diabetes patients. © 2017 Published by Elsevier Inc.

1.

Introduction

The number of individuals with type 2 diabetes has increased rapidly. Currently, over 400 million people are suffering from diabetes, and it has been predicted that the number of diabetic

patients will reach 642 million by 2040, indicating that while 1 in 11 adults currently have diabetes, the prevalence of diabetes is expected to rise to 1 adult in 10 over the next thirty years [1]. Although there are many different methods of treating type 2 diabetes, innovative approaches for preventing and managing

⁎ Corresponding author at: Department of Endocrinology, Zhongda Hospital, Southeast University, 87 Dingjia Qiao Road, Nanjing 210009, PR China. Tel.: +86 25 025 83272012; fax: +86 25 83272011. E-mail address: [email protected] (L. Li). http://dx.doi.org/10.1016/j.metabol.2017.05.006 0026-0495/© 2017 Published by Elsevier Inc.

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the disease are urgently needed. Recently, vitamin D has been identified as a potential prevention and treatment strategy [2]. Low 25-hydroxyvitamin D (25(OH) D) levels are highly prevalent among type 2 diabetic patients [2–6]. The association between vitamin D and type 2 diabetes may be explained by the effects of vitamin D on the regulation of insulin secretion or sensitivity or the attenuation of systemic inflammation [7]. Most cross-sectional observational studies [8,9] have reported an inverse association between vitamin D status and the prevalence of hyperglycaemia. A longitudinal study [10] also reported that higher 25(OH)D levels were associated with lower diabetes risk. In addition, in the study conducted by Afzal S et al. [11], an association between low plasma 25(OH)D levels and increased risk of type 2 diabetes was observed. However, this causal relationship should be addressed by a randomized trial of vitamin D supplementation. Recently, the effect of vitamin D supplementation on prediabetes has been reported. Studies have found that vitamin D supplementation was associated with improved beta cell function [12] and insulin sensitivity [13] among persons who were at high risk for diabetes but not in individuals with normal fasting glucose at baseline. Several randomized control trials (RCTs) have been conducted to evaluate the effect of vitamin D supplementation on subjects with type 2 diabetes, but the findings of these trials have been inconsistent. A recent systematic review and meta-analysis [14] suggested the presence of weak associations between vitamin D supplementation and reduced fasting glucose and improved insulin resistance in patients with type 2 diabetes or impaired glucose tolerance. However, patients with both glucose intolerance and type 2 diabetes were included in the previous meta-analysis, leading to heterogeneity. Further, the number of included studies was small. Therefore, the main objective of this study was to use the meta-analysis procedure to systematically review the effects of vitamin D supplementation on glycemic measures in type 2 diabetes patients only.

2.

Materials and Methods

The Preferred Reporting Items for Systematic Reviews and Metaanalyses (PRISMA) statement was followed in this study [15].

2.1.

2.2.

Study Selection

The inclusion criteria were a parallel RCT design and inclusion of type 2 diabetes patients. The exclusion criteria were as follows: studies including other populations, studies involving hemodialysis patients who have supplementation with vitamin D, studies conducted in animal models, studies that were not available, and studies that did not report an association between vitamin D supplementation and glycemic status.

2.3.

Data Extraction and Analysis

Two authors (CH.W, SH.Q) selected relevant studies based upon the inclusion and exclusion criteria. First, we screened the titles of all retrieved studies to identify potentially relevant articles. Second, we reviewed the abstracts of these articles to determine their relevance, and once judged to be relevant, reviewed the full text of the studies. Lastly, we analyzed each article and determined whether the article was qualified for inclusion. When disagreements about study inclusion occurred, we consulted a third author (L L). Additionally, if data were not available or unclear in the published papers, we contacted the author by e-mail to request this information. Afterwards, we determined whether the article provided sufficient data for analysis. We also evaluated the methodological quality of each included trial using a validated 5-point scale, as described by Jadad et al. [17]. Using this scale, the descriptions of randomization, blinding and withdrawals in each study were evaluated and assigned scores ranging from 0 to 5. We extracted the major demographic and clinical data from each included study, such as the authors, year of publication, clinical characteristics of study participants (sample size, age, % men, duration of type 2 diabetes, medication status, and body mass index [BMI]), metabolic variables (HbA1c, FBG, and 25(OH)D levels) and vitamin D supplementation characteristics (dosage, method and duration of the intervention). Vitamin D deficiency was defined as serum 25(OH)D concentrations < 50 nmol/l, while vitamin D insufficiency was defined as serum 25(OH)D concentrations 50–75 nmol/l, and vitamin D sufficiency was defined as serum 25(OH)D concentrations > 75 nmol /l. Serum 25(OH) D concentrations > 75 nmol/l has been suggested that at this level, the noncalcemic benefits of vitamin D may be maximized [18].

Data Sources and Searches 2.4.

We searched PubMed, Web of Science and the Cochrane Library for reports published up to March 2017 using the search terms “type 2 diabetes mellitus”, “type 2 diabetes” and “T2DM” in combination with the terms “vitamin D”, “cholecalciferol”, and “ergocalciferol”. We restricted the search to “human species”, and only RCTs were included. The searches were not restricted by the date of study publication, language of publication or age of study subjects. The exposure of interest was vitamin D, vitamin D analogues or vitamin D and calcium supplementation, and the primary outcome measure was haemoglobinA1c (HbA1c) or fasting blood glucose (FBG). HbA1c is a parameter commonly used for assessing glucose status that indicates the average plasma glucose level over the prior 8–12 weeks [16] and FBG is applied to diagnose diabetes and reflects daily glycemic fluctuation.

Statistical Analysis

The meta-analyses and statistical analyses were undertaken using STATA (version 11.0; College Station, Texas). We compared changes from baseline to endpoint when the mean and standard deviation (SD) of the baseline and endpoint values were provided; otherwise, we used the endpoint values. To overcome a unit-of-analysis error, for studies with multiple intervention groups, these groups were combined into 1 group to create a single pairwise comparison. If there were four groups evaluated in a study, such as vitamin D, placebo, vitamin D and calcium, calcium supplementation, we compared data from the vitamin D and calcium group with data from the calcium group. We analyzed outcomes reported at the last available time point when studies reported outcome variables at different time points throughout the intervention period [19].

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We assessed heterogeneity among studies using I2 statistics, and an I2 value >50% was defined as heterogeneous. We used Cohen's d to represent the standardized mean difference (SMD) for each included study because of the use of different measurement techniques to assess glycemic status, the SMDs and 95% confidence intervals (CIs) for each study were pooled using a random effects model. Potential moderating factors were evaluated by subgroup analysis, including baseline 25(OH)D, BMI, dosage of vitamin D supplementation, length of intervention, and change of 25(OH)D concentration. A meta-regression analysis was performed to further explore which variables best predicted post-intervention SMDs in HbA1c and FBG levels, such as age, % male, BMI, duration of type 2 diabetes, and baseline HbA1c, FBG, and 25(OH)D levels. We conducted sensitivity analyses to evaluate the robustness of our conclusions. We used the Egger's test and Begg's test to evaluate publication bias. If publication bias was detected, we performed a trim-and-fill analysis [20] to estimate the number of missing studies. P values less than 0.05 were considered statistically significant.

3.

Results

3.1.

Search Results

In total, 637 articles were identified, with 114 articles identified in PubMed, 145 articles identified in Web of Science, 377 articles identified in the Cochrane Central Register of Controlled Trials, and 1 article identified through other searches. Of the 349 identified unique studies (without duplicates), 270 were excluded because they included other study populations (n = 66), were not randomized control trials (n = 7), were conference abstracts and had no full text articles available (n = 18) or were irrelevant to our present meta-analysis (n = 179). We obtained and reviewed the full texts of the remaining 79 papers and excluded an additional 55 articles for the following reasons: no data of interest (n = 16), lack of control group (n = 8), included other study populations (n = 2), not RCTs (n = 4), data not available after sending requests to the authors (n = 2), duplicate data (n = 10), unit of 25(OH)D measurement was not valid (n = 2), study protocol (n = 4), only ranges of variation provided (n = 2), no changes in serum 25(OH)D in the intervention group (n = 1), both significant differences in serum 25(OH)D in the intervention group and control group (n = 1), and differences in baseline characteristics of subjects (n = 3). Finally, 24 and 18 papers were included in the meta-analyses that evaluated HbA1c and FBG levels, respectively. The flow chart for the multi-phase study selection process is shown in Fig. 1.

3.2.

Study Characteristics

The characteristics of the included studies are summarized in Table 1. Most of the included participants were vitamin D deficient. The length of the vitamin D intervention varied from 4 to 48 weeks. The results of the quality assessment are shown in Supplementary Table 1. Twenty-six studies [21–46] were included in the qualitative synthesis. The studies scored between 2 and 5 points on the Jadad scale (range 0–5).

3.3.

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Meta-Analyses

In this systematic review and meta-analysis, we pooled and analyzed data from 23 RCTs evaluating the effects of vitamin D supplementation on HbA1c and 17 studies evaluating the effects of vitamin D supplementation on FBG. The forest plots for the effects of vitamin D supplementation on glycemic status are shown in Figs. 2–3. For HbA1c, the pooled SMD was −0.25 (−0.45 to −0.05, P = 0.01, I2 = 75.5%), indicating a significantly greater reduction in HbA1c concentrations in patients receiving vitamin D supplementation than patients receiving no vitamin D supplementation. For fasting glucose concentrations, the pooled SMD was − 0.14 (− 0.32 to 0.05, P = 0.10, I 2 = 58.0%), which suggested that vitamin D supplementation did not significantly impact glucose concentrations in type 2 diabetic patients.

3.4.

Subgroup Analyses

To evaluate the presence of heterogeneity in this metaanalysis, we conducted subgroup analyses. Significant reductions in both HbA1c and FBG levels were observed in association with vitamin D supplementation in the subgroup of type 2 diabetes patients with vitamin D deficiency (SMD −0.38 [−0.67 to − 0.10], P = 0.009, I 2 = 81.2%; SMD − 0.27 [− 0.46 to − 0.07], P = 0.007, I 2 = 42.8%, respectively) but not in the subgroups of type 2 diabetes patients with vitamin D insufficiency (SMD − 0.00 [− 0.18 to 0.17], P = 0.96, I 2 = 0; SMD 0.04 [− 0.16 to 0.23], P = 0.73, I 2 = 17.6%, respectively) or sufficiency (SMD − 0.02 [− 0.34 to 0.31], P = 0.92, I 2 = 12.2%; SMD 0.29 [− 0.81, 1.39], P = 0.60, I 2 = 87.1%, respectively). Significantly reduced HbA1c levels were observed in the subgroup of type 2 diabetes patients with a baseline BMI < 30 kg m− 2 (SMD − 0.30 [− 0.54 to − 0.07], P = 0.01, I 2 = 79.1%) but not in the subgroup of type 2 diabetes patients with a baseline BMI ≥ 30 kg m − 2 (SMD − 0.13 [− 0.48 to 0.22], P = 0.54, I 2 = 48.4%). However, similar results were not observed in FBG levels (P = 0.16, 0.46, respectively). Vitamin D administration on non-obese with vitamin D deficiency resulted in an improvement of HbA1c (SMD −0.41 [−0.77 to −0.06], P = 0.02, I2 = 84.3%) and FBG (SMD −0.30 [−0.52 to −0.07], P = 0.01, I2 = 51.6%) levels. There were no significant changes in HbA1c and FBG levels (P = 0.46, P = 0.08; respectively) between vitamin D combined with calcium supplementation and calcium supplementation alone groups. The dose of vitamin D supplementation ≥ 1000 IU/day resulted in an improvement of FBG levels (SMD −0.22 [−0.44 to −0.00], P = 0.049, I2 = 44.9%) but had no effect on HbA1c levels (SMD −0.25 [−0.56 to 0.06], P = 0.11, I2 = 76.3%). In addition, the length of vitamin D intervention ≥ 12 weeks reduced HbA1c levels (SMD − 0.30 [− 0.52 to − 0.09], P = 0.006, I 2 = 77.9%) but did not affect FBG levels (SMD − 0.16 [− 0.34 to 0.03], P = 0.10, I 2 = 62.2%). There were significant decreases in HbA1c (SMD −0.45[−0.72 to −0.18], P = 0.001, I2 = 81.3%) and FBG levels (SMD −0.24[−0.43 to −0.04], P = 0.03, I2 = 61.2%), when the changes of their 25[OH]D were less than 50 nmol/L or between 25 and 50 nmol/L. The complete results of the subgroup analysis are shown in Supplemental Tables 2–3. The results of the random-effects meta-regression analyses showed that none of the potential moderating factors (age, gender, BMI, duration of type 2 diabetes, HbA1c, FBG, and

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Records identified through database

Records identified through other

search (n=636)

search (n=1)

Records after duplicates removed (n=349)

Records screened (n=349)

Records excluded after title/abstract review (n=270) Not related (n=179) Not randomize controlled studies (n=7) Not type 2 diabetes (n=66) Conference abstract and no full texts (n=15) No full texts (n=3)

Full text articles assessed for eligibility (n=79) Articles exclude after full-text review (n=55) No data for interest (n=16) No proper control group (n=8) Not type 2 diabetes (n=2) Duplicate data (n=10) Study protocol (n=4) Inadequate raw data provided (n=2) Unit of 25(OH)D measurement was not valid (n=2) Only ranges of variation provided (n=2) Not randomize controlled studies (n=4) No changes in serum 25(OH)D in the intervention group (n= 1) Both significant differences in serum 25(OH)D in the intervention group and control group (n=1) Baseline characteristics of subjects were different (n=3) Articles include in the meta-analysis (n=26) -- HbA1c (24) -- Fasting glucose (18)

Fig. 1 – Flow chart of the multi-phase process for study selection.

25(OH)D) was the significant predictor of changes in HbA1c and FBG. Detailed results of these analyses are provided in Supplemental Tables 4–5.

3.5.

Sensitivity Analyses

To evaluate the robustness of our conclusions, we conducted sensitivity analyses. Only one study, which was conducted by Sigrid Jehle et al. [32], reported that the placebo group exhibited a “spontaneous” increase in 25(OH)D levels. The exclusion of this study from the meta-analysis resulted in generally similar results for HbA1c (SMD − 0.18 [− 0.34 to − 0.02] and FBG (SMD − 0.10 [− 0.26 to 0.06] though heterogeneity was present for both outcomes (I2 = 62.5%, 51.3%, respectively).

3.6.

Publication Bias

No statistical evidence of publication bias was found among the included studies overall for the outcomes of HbA1c and FBG levels (Begg's test, Pr > | z | = 0.17, Egger's test, P = 0.14; Begg's test, Pr > | z | = 0.88; Egger's test, P = 0.43; respectively) (Supplemental Table 6).

4.

Discussion

Beyond its traditionally recognized influence on skeletal medical conditions, vitamin D has also been found to be

Table 1 – Baseline characteristics of included study. Study, year of publication

n

Male (%)

Ctrl Vitamin D

Age T2DM (years) a duration (years) a

BMI (Kg m−2) b

Baseline of HbA1c (%) b

Baseline of FBG (mg/dL) b

Calcium supplementation

No calcium supplementation no calcium supplementation No calcium supplementation No calcium supplementation 170 mg, twice a day No calcium supplementation

Tina Jafari, et al., 2016 (21)

29

30

0

57.8

9.3

28 ± 1.92

62.23 ± 24.76

7.16 ± 1.26

168.8 ± 24.54

Ilaria Barchetta1, et al., 2016 (22)

29

26

64.7

57.4

5.9

29.3 ± 4.4

43.1 ± 23.7

6.36 ± 0.9

125.3 ± 36.8

Rinkoo Dalan, et al., 2016 (23)

30

31

51.6

52.2

N/R

27.3 ± 5.8

45 ± 12.96

7.9 ± 1.2

N/R

Wan Zhou, et al., 2015 (24)

29

27

61.3

58.85

9.31

25.05 ± 3.3

30.47 ± 20.58

7.38 ± 0.65

N/R

Sakineh Shab-Bidar, et al., 2015 (25) A Sadiya, et al., 2015 (26)

50 39

50 43

43 18.4

52.6 49

8.3 9.5

28.6 ± 4.0 37.9 ± 6.1

38.5 ± 20.2 28.5 ± 9.2

8.7 ± 1.8 8.2 ± 1.3

189 ± 55.8 167.4 ± 50.4

129

132

65.1

67

6

28.7 ± 4.6

60.6 ± 23.3

6.8 ± 0.5

138.6 ± 19.8

82

80

53.08 55

−

27.1 ± 5.5

39.34 ± 27.05

7.4 ± 0.8

136.8 ± 57.6

Ohk-Hyun Ryu, et al., 2013 (29) Ohk-Hyun Ryu, et al., 2014 (30) B. Nikooyeh et al., 2014 (31) Sigrid Jehle, et al., 2014 (32)

65 30 30 26

64 32 30 29

52.7 N/R 38.9 36.4

8.3 8.3 8.9 12.7

25 ± 3.3 24.4 ± 5.0 29.2 ± 4.4 28.9 ± 4.3

26.56 ± 12.54 30.25 ± 7.38 44.4 ± 28.7 36 ± 18.1

7.40 ± 0.90 7.54 ± 0.49 7.4 ± 1.8 7 ± 1.1

123.4 134.8 183.6 140.4

Saeid Ghavamzadeh, et al., 2014 (33) Shirley Elkassaby, et al., 2014 (34) Yuen-Fung Yiu, et al., 2013 (35)

25

26

41.18 52.26

N/R

28.9 ± 4.3

21.46 ± 4.65

6.78 ± 0.43

N/R

24

26

58

53

N/R

30.6 ± 7.26

59 ± 24.44

6.2 ± 4.44

122.4 ± 12

50

50

50

65.8

12

25.8 ± 4.8

51.88 ± 10.82

A. Breslavsky, et al., 2013 (36)

23

24

46.8

66.8

N/R

27.9 ± 5.2

31.75 ± 26.29

7.35 ± 1.26 7 ± 1.1

129.24 ± 41.94 144.3 ± 74.2

J. A. Sugden, et al., 2007 (37)

17

17

52.9

64.9

N/R

31.7 ± 6.4

40.2 ± 10.3

7.5 ± 1.6

N/R

Nooshin Ahmadi, et al., 2013 (38)

23

28

37.6

58.32

11.36

28.38 ± 4.11

34.57 ± 19.08

N/R

Ramin Heshmat, et al., 2012 (39)

21

21

35.7

56.2

6.7

27.7 ± 3.4

115.33 ± 85.33

7.13 ± 1.33 6.5 ± 0.9

133.5 ± 23.7

Mohammad Hassan Eftekhari, et al., 2014 (40) M. D. Witham, et al., 2010 (41)

35

35

50

53.8

6.3

28.3 ± 4.4

106.47 ± 78.93

7.08 ± 1.6

145.6 ± 52.1

21

37

74.3

64.27

N/R

30.38 ± 5.53

44.59 ± 18.05

6.9 ± 1.24

N/R

Deepal Parekh, et al., 2010 (42)

13

14

40.7

42.36

4.8

23.54 ± 1.28

36.66 ± 16.62

Rolf Jorde, et al., 2009 (43)

16

16

56.3

57.7

N/R

32.8 ± 6.8

60 ± 14.0

7.58 ± 0.57 8 ± 1.3

126.21 ± 41.97 176.4 ± 55.8

8

7

53.3

61.6

5.6

35.3 ± 7.67

31 ± 12.96

6.8 ± 0.53

138.6 ± 19.05

Hamid Nasri1, et al., 2014 (45)

30

30

28.3

55

N/R

N/R

83.9 ± 52

7.65 ± 0.4

N/R

E. Shaseb, et al., 2016 (46)

47

48

62

54

3.9

27.47 ± 2.79

72.78 ± 51.15

8.2 ± 2.0

186.5 ± 64

Yvonne H.M. Krul-Poel, et al., 2015 (27) Zhou J, et al., 2014 (28)

Ulla Kampmann, et al., 2014 (44)

54.8 54.5 51.4 66.9

± ± ± ±

21.2 26.7 63 41.4

No calcium supplementation No calcium supplementation 100 mg per day 200 mg per day 150 mg, twice per day No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation No calcium supplementation

No Insulin therapy

No insulin therapy

Vitamin D intervention Dosage (IU)

Duration (weeks)

Administration

2000 IU per day

12

Oral

24

Oral

8 or 16

Oral

12

Oral

12 12 + 12

Drinking Oral

24

Oral

12

Oral

No excluded insulin 2000 IU per day therapy No excluded insulin 4000 IU per day or therapy 2000 IU per day Not excluded insulin 1000 IU per day therapy No insulin therapy 500 IU, twice a day Not excluded insulin 6000 IU vitamin D3 therapy per day +3000 IU vitamin D3 per day No insulin therapy 50,000 IU once a month No insulin therapy

Calcitriol, 20 IU per day

No insulin therapy 1000 IU per day 24 No insulin therapy 2000 per day 24 No insulin therapy 500 IU, twice per day 12 Not excluded insulin 300,000 IU a single 24 therapy intramuscular injection No insulin therapy 400 IU per day 14

Oral Oral Drinking Intramuscularly

No insulin therapy

6000 IU per day

24

Oral

Not excluded insulin therapy Not excluded insulin therapy Insulin therapy

5000 per day

12

Oral

1000 IU per day

48

Oral

vitamin D2, 100, 000 IU a single dose 50,000 IU per week

8

Oral

12

Oral

Not excluded insulin therapy No insulin therapy No insulin therapy Not excluded insulin therapy No insulin therapy Not excluded insulin therapy Not excluded insulin therapy Not excluded insulin therapy Not excluded insulin therapy

300,000 IU a single 12 intramuscular injection Calcitriol, 20 IU per day 12

Oral

Intramuscular Oral

100,00 IU or 200,000 IU a single oral dose 300,000 IU, a single intramuscular injection 40,000 IU per week

16

Oral

4

Intramuscularly

24

Oral

11,200 IU daily for 2 weeks, 5600 IU daily for 10 weeks 50,000 IU per week

12

Oral

12

Oral

300,000 IU, a single intramuscular injection

8

Intramuscularly

71

Abbreviations: T2DM, type 2 diabetes mellitus; BMI, body mass index; HbA1c, glycosylated hemoglobin; FBG, fasting blood glucose; 25(OH) D, 25-hydroxyvitamin D; N/R: not report. a Values are means. b Values are means ± standard deviations.

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Baseline of 25 (OH) D (nmol/L) b

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Fig. 2 – Forest plots of meta-analysis of the effect of vitamin D supplementation on HbA1c. Data are pooled SMDs with 95% CIs. HbA1c: hemoglobinA1c; SMD: standardized mean difference, CIs: confidence interval.

associated with metabolic diseases, such as type 2 diabetes and obesity. Vitamin D deficiency is relatively common in patients with type 2 diabetes [3,47]. Still, the causal relationship between vitamin D and type 2 diabetes remains unclear, and the results of previous vitamin D supplementation intervention studies have been inconsistent. A recent systematic review [48] found that vitamin D supplementation had a positive impact on glycemic control in short-term studies; however, no significant effect on HbA1c was observed in long term studies that had an intervention period longer than three months. However, the results of the present systematic review and meta-analysis showed that vitamin D supplementation was associated with a reduction in HbA1c levels in studies with long-term intervention durations, but such a reduction did not occur in FBG levels. Subgroup analyses revealed that vitamin D supplementation reduced both HbA1c and FBG levels in type 2 diabetes patients with vitamin D deficiency. Yet a recent meta-analysis [49] found that vitamin D supplementation had no significant effect on HbA1c or FBG level in type 2 diabetes

patients with vitamin D deficiency. There were several possible reasons that may explain the discrepancy from our main results. First, our selection criteria were different from that meta-analysis. We did not have any language restriction to included studies or excluded studies conducted in populations with mean age less than 18, although we later found that our meta-analysis actually did not include any study enrolling patients aged less than 18. Second, different subgroup analyses were conducted in our study compared with that study. We investigated the potential influences from confounders including baseline 25(OH)D level, calcium supplementation, BMI, dosage of vitamin D supplementation, length of intervention, and change of 25(OH)D concentration on our main outcomes using subgroup analyses. However, in that study, subgroup analyses were performed only based on the baseline 25(OH)D and HbA1c levels. Third, it seems likely that the statistical methods we used varied from that study. In our study, for studies with multiple intervention groups, these groups were combined into one group to create a single pairwise comparison.

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Fig. 3 – Forest plots of meta-analysis of the effect of vitamin D supplementation on FBG. Data are pooled SMDs with 95% CIs. FBG: fasting blood glucose SMD: standardized mean difference, CIs: confidence interval.

Yet for that study, they used the data from the group with the highest dose of vitamin D supplementation when there were more than two intervention groups. Finally, three studies [50–52] from the meta-analysis by Krul-Poel et al. were excluded from our metaanalysis. The reasons for the exclusion were that two studies [50,51] did not have sufficient data of interest for meta-analyzing even after sending requests to the corresponding authors, and the other one [52] did not have comparable levels of serum 25(OH)D between the intervention and control groups. Yet, more importantly, we included more RCTs for the analyses of HbA1c and FBG (versus the meta-analysis by Krul-Poel et al.). Most studies investigating the effect of vitamin D supplementation on patients with type 2 diabetes have not reported glycemic control to be significantly impacted [27]. A recent meta-analysis [14] reported that there is insufficient evidence of a beneficial effect to recommend vitamin D supplementation as a method of improving glycemic control in patients with type 2 diabetes. A systematic review of interventional studies [48] also found that vitamin D supplementation might not improve hyperglycaemia in patients with established type 2 diabetes. A number of confounding factors, such as patient

characteristics [e.g., baseline serum 25(OH)D level, BMI, age, antidiabetic medication use, and HbA1c and FBG levels], study duration, sample size, dosage or formulation of vitamin D supplement, and primary outcome of the studies, have been proposed as associated with these inconsistent results [48]. In this analysis, we found that 14 of the 26 studies included patients that had well-controlled glycemia at baseline, 4 studies included patients that used vitamin D combined with elemental calcium, while 15 studies excluded patients that were using insulin for diabetes control. Our findings were consistent with previous meta-analysis of studies assessing prediabetes patients [53] or poorly controlled diabetes [49] which showed that vitamin D was associated with significantly reduced FBG levels. However, the limited number of studies (only 4) included in the poorly controlled diabetes group may somehow weaken the robustness of our finding. 25(OH) D is the major circulating form of vitamin D, which may be derived from exposure of the skin to sunlight or dietary supplementation, and has been widely used as a surrogate for vitamin D status [7]. Low vitamin D status has been found to be associated with impaired glycemic control in

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patients with type 2 diabetes, which is characterized by peripheral insulin resistance and pancreatic β-cell dysfunction. Vitamin D deficiency has been reported to impair glucose-mediated insulin secretion in rat pancreatic beta cells [54], and data suggest that normalization of vitamin D stimulates insulin secretion in the vitamin D deficient rats [55]. Our results also revealed that vitamin D supplementation was associated with reduced HbA1c and FBG levels in vitamin D deficient patients with type 2 diabetes. Vitamin D may decrease HbA1c and FBG levels by stimulating insulin secretion. However, we did not analyze insulin levels in our meta-analysis because many of the included patients are receiving insulin treatment. Unfortunately, the mechanism underlying the effect of vitamin D on glycemic control is not clearly understood. Obesity has been identified as a risk factor for vitamin D deficiency [56]. Most studies have found an inverse association between 25(OH)D and total body fat [57]. Proposed explanations for this association have included the possibility that vitamin D intake is low and exposure to sunlight is inadequate in obese individuals [58]. Moreover, increased storage of vitamin D in adipose tissue may be associated with increased rates of deficiency in obese individuals [56]. One study [59] reported that serum 25(OH)D decreased and HbA1C increased when BMI increased, suggesting that the association between vitamin D and glucose metabolism may depend on body size. In our study, we found that vitamin D supplementation was associated with reduced HbA1c levels in non-obese type 2 diabetes patients but not in type 2 diabetes patients with obesity. These findings suggest that the improvement of vitamin D status in obese individuals did not reduce the other unavoidable adverse effects of obesity on glucose metabolism. Hence, our results provide evidence that vitamin D supplementation may be clinically beneficial in non-obese type 2 diabetes patients. A major finding of our study was the identification of a distinct effect of vitamin D supplementation on glycemic control depending on the 25(OH)D, BMI, dosage, duration of supplementation, and change of 25(OH)D concentration among patients with type 2 diabetes. A strength of our study was the inclusion of randomized control studies that assessed complementary endpoints, providing a relatively comprehensive overview of the evidence on the subject. A second advantage was that in the sensitivity analysis performed in this study, excluding the study conducted by Sigrid Jehle et al. did not result in a substantial modification in the association between vitamin D supplementation and glycemic control, indicating stable results. There are also limitations that require consideration. First, although we performed a comprehensive search of the electronic literature, some studies could exist that were not been included. Second, most of the included studies did not report the effects of sun exposure, dietary intake, or regular exercise, all of which contribute to vitamin D synthesis. Only 6 studies [21,26,27,30,32,34] reported the level of sun exposure among patients, while 6 studies [21,25,27,31,33,40] reported the included patients' dietary vitamin D intake, and 5 studies reported whether patients engaged in regular exercise [21,27,29,30,33]. Use of medication, such as hypoglycemic agents, may be associated with glycemic control;

however, 7 studies [24,31,34,41,43–45] did not report baseline medication usage among patients. It was therefore difficult to interpret the results and confirm the independent effect of vitamin D supplementation on glycemic control. Third, the number of individuals who participated in most of the included studies was relatively small. Moreover, conflicting levels of vitamin D intake have been recommended by the IOM report and Endocrine Society guidelines. In most of the included studies, patients in the intervention group were given a lower oral dose of vitamin D once daily. Only six studies [32,37,39,41,42,46] were included in which the intervention patients had a single higher dose of vitamin D. In four studies [38,43–45], patients in the intervention group received a higher dose of vitamin D once a week, and one study [27] was included in which the intervention group received a higher dose of vitamin D once a month. The duration of vitamin D usage ranged from 4 weeks to 48 weeks. Although the intervention groups exhibited increases in serum 25(OH)D levels, changes of 25(OH)D more than 50 nmol/L did not reduce HbA1c or FBG levels, it would be difficult to identify the optimal intervention dose and duration. It should be noted that among some of the included subjects, treatment with insulin or other oral hypoglycemic agents might have masked a subtle effects of vitamin D. Furthermore, some studies were excluded so that a selection bias should be noted in this study.

5.

Conclusion

The current meta-analysis found that vitamin D supplementation was associated with a reduction in HbA1c and FBG levels among type 2 diabetes patients with vitamin D deficiency. However, vitamin D supplementation did not appear to impact the glycemic status of type 2 diabetes patients whose serum 25(OH)D levels indicated vitamin D insufficiency or sufficiency. Maintaining adequate levels of vitamin D and thereby preventing vitamin D deficiency may be useful in preventing the disruption of glucose homeostasis. In addition, non-obese type 2 diabetes patients may effectively reduce their HbA1c levels through vitamin D supplementation. However, further studies are necessary to establish the results.

Author Contributions CH. W and SH. Q wrote the main manuscript text and selected relevant studies. XY. Z contributed to the discussion. SH. Q reviewed and provided suggestions. L L conceived and designed the experiment. All authors reviewed the manuscript and approved the final manuscript.

Financial Disclosure This research was supported by the National Natural Science Foundation of China (No 81570739).

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Acknowledgments The authors would like to thank American journal experts for providing language help.

Conflict of Interest The authors declare no competing financial interests.

Appendix A Supplementary data Supplementary data to this article can be found online at http://dx.doi.org/10.1016/j.metabol.2017.05.006.

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