Effect of Vitamin D Supplementation on the Incidence of Diabetes Mellitus

Mahmoud Barbarawi; Yazan Zayed; Owais Barbarawi; Areeg Bala; Ahmad Alabdouh; Inderdeep Gakhal; Fatima Rizk; Mariam alkasasbeh; Ghassan Bachuwa; JoAnn E. Manson

Disclosures

J Clin Endocrinol Metab. 2020;105(8)

Abstract and Introduction

Abstract

Context: The effect of vitamin D supplementation on the risk of type 2 diabetes mellitus (T2DM) remains controversial because most randomized controlled trials (RCTs) have been small or have reported low doses of vitamin D.

Objective: To conduct a meta-analysis of RCTs testing vitamin D supplementation in the prevention of T2DM.

Data Sources: Database search of PubMed/MEDLINE, EMBASE, and the Cochrane Library was performed by 2 reviewers from inception through September 15, 2019.

Study Selection: We included RCTs that reported the effect of vitamin D supplementation for at least 1 year on T2DM prevention.

Data Extraction: Two independent reviewers extracted the data. The risk ratios (RRs) and 95% confidence intervals (CIs) were reported. Primary outcome of the meta-analysis was the incidence of T2DM.

Data Synthesis: Nine RCTs were included (43 559 participants). The mean age (standard deviation) was 63.5 (6.7) years. The RR for vitamin D compared with placebo was 0.96 (95% CI, 0.90–1.03); P = 0.30. In trials testing moderate to high doses of supplementation (≥1000 IU/day), all conducted among participants with prediabetes, the RR for vitamin D compared with placebo was 0.88 (95% CI, 0.79–0.99). In contrast, the trials testing lower doses, which were conducted in general population samples, showed no risk reduction (RR, 1.02; 95% CI, 0.94–1.10; P, interaction by dose = 0.04).

Conclusion: In patients with prediabetes, vitamin D supplementation at moderate to high doses (≥1000 IU/day), significantly reduced the incidence risk of T2DM, compared with placebo.

Introduction

Diabetes mellitus (DM) is an important public health problem, affecting more than 500 million persons worldwide.^[1] Patients who have abnormally elevated glucose levels but do not meet the criteria of DM can be classified as having impaired glucose tolerance, impaired fasting glucose, or abnormally high average blood glucose level as manifested by high hemoglobin A1c (HbA_1c). In the United States, almost one-third of the population has impaired fasting glucose, impaired glucose tolerance, or elevated HbA_1c and are at elevated risk of developing DM within 5 years.^[2,3]

Several risk factors for type 2 DM (T2DM) and abnormal glucose metabolism have been identified, including obesity and low physical activity.^[2,4] In the past 10 to 15 years, increasing data from large-scale observational studies have shown an association between low 25-hydroxyvitamin D levels and development of T2DM,^[5,6] with vitamin D supplementation being proposed as a potential intervention to lower the incidence of T2DM.^[7] An association between low vitamin D blood levels and impaired insulin secretion and increased insulin resistance has led to the hypothesis that vitamin D supplementation may reduce the risk of developing T2DM.^[8,9] A short-term experimental study suggested that vitamin D supplementation leads to an improvement in pancreatic beta cell functioning and marginally lowers patients' HbA_1c.^[10] Furthermore, vitamin D supplementation decreased fasting blood glucose level and HbA_1c in patients with DM in some studies^[11] but not others.^[12] Clinical data remain unclear regarding the benefit of vitamin D supplementation in prevention of T2DM in patients already classified as prediabetic^[13,14] or in those without glucose intolerance.^[15] Recently, several randomized controlled trials (RCTs) have evaluated whether vitamin D supplementation can reduce the incidence of T2DM, but most of these trials have been small or tested low doses of vitamin D. We therefore conducted a meta-analysis of RCTs of vitamin D supplementation in reducing the risk of T2DM.

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Methods
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Table 1. Features of the included trials.
Study/Author Name	Year	Patients (n)		Study Period	Vitamin D Dose and Type	Study Follow-Up_Year	Country	Major Inclusion Criteria	Primary Outcome
Study/Author Name	Year	Vitamin D	Placebo	Study Period	Vitamin D Dose and Type	Study Follow-Up_Year	Country	Major Inclusion Criteria	Primary Outcome
WHI/de Boer	2008	16 999	16 952	1995–2000	Vitamin D3, 400 IU/day and calcium 1000 mg/day	Median, 7	USA	Women aged 50–79 years with no evidence of a medical condition associated with anticipated survival <3 years and no safety, adherence, or retention risks	Total number of fractures; post hoc analysis outcome was the incidence of diabetes
RECORD/Avenell	2009	2416	2413	1999–2002	Vitamin D3, 800 IU/daily	2–5.2	UK	Participants aged ≥70 years who had had a low trauma, osteoporotic fracture in the previous 10 years	The incidence of new low-energy fractures; post hoc analysis outcome was the incidence of diabetes
Davidson	2013	56	53	-	Vitamin D3, mean ± SD, 88 865 ± 16 154 IU/weekly	1	USA	Aged ≥40 years who may have prediabetes (waist circumference ≥40 inches in men and ≥35 inches in women, family history of diabetes in first-degree relatives, hypertension, and history of gestational diabetes	The change in FBG, 2-hour glucose or insulin secretion level, and the incidence of diabetes
Dutta	2014	68	102	2009–2013	Vitamin D3, 60 000 IU/weekly	28.3 ± 8	India	Aged 30–80 years; persistent IFG and/or IGT over 2 OGTTs done within a week	Change in FBG and 2-hour post glucose blood glucose, HbA_1c, 25-hydroxyvitamin D3, insulin, TNF-α, IL-6, hsCRP, and lipid profile
DIVA/Barengolts	2015	87	86	-	Vitamin D2 50 000 IU/weekly	1	USA	African American veteran men, aged 35–85 years, BMI 28–39 kg/m², fasting glucose 95–125 mg/dL and/or HbA_1c 5.7–6.4% (38.8–46.5 mmol/mol)	Change in oral glucose tolerance test results
Kuchay	2015	64	65	-	Vitamin D3 60 000 IU/week for 4 weeks then maintenance dose of 60 000 IU/month	1 year	India	Patients diagnosed with prediabetes on the basis of elevated HbA_1C levels, FPG, and 2-hour plasma glucose during an OGTT	Change in FBG, 2-hour plasma glucose and HbA_1c levels
Tromsø/Jorde	2016	256	255	2007–2008	Vitamin D3 20 000 IU/week	5	Norway	Patients aged 25–80 years with IFG and/or IGT at the OGTT with 75 g glucose	Incidence of new-onset diabetes
DPVD/Kawahara	2018	630	626	-	eldecalcitol	2.6	Japan	Patients with impaired glucose tolerance	Incidence of new-onset Diabetes
D2d/Pittas	2019	1211	1212	2013–2017	Vitamin D3 4000 IU/day	Median (IQR), 2.5 (1.9–3.5)	USA	Patients met at least 2 of 3 glycemic criteria for prediabetes as defined by the 2010 American Diabetes Association guidelines: IFG level; impaired plasma glucose level 2 hours after a 75-g OGTT; and elevated HbA_1c	Incidence of new-onset diabetes

Abbreviations: BMI, body mass index; D2d, Vitamin D and Type 2 Diabetes; DIVA, D Vitamin Intervention in Veteran Administration; DPVD, Diabetes Prevention with active Vitamin D; FBG, fasting blood glucose; HbA_1c, glycated hemoglobin; hsCRP, highly sensitive C-reactive protein; IFG, impaired fasting glucose; IGT, impaired glucose tolerance; IL-6, interleukin-6; IQR, interquartile range; OGTT, oral glucose tolerance test; RECORD, Randomized Evaluation of Calcium or Vitamin D; SD, standard deviation; TNF, tumor necrosis factor; WH,: Women's Health Initiative.

Table 2. Demographic features of the involved studies.
Study/Author Name	Patient (n)	Subgroup	Age_Mean (SD)_Year	Female n (%)	Race_n (%)				Body Mass Index_Mean (SD)	FBG_Mean (SD) - mg/dL	2-Hr Postload Plasma Glucose _Mean (SD) - mg/dL	Glycated Hemoglobin_Mean (SD) - %	Serum 25-hydroxyvitamin D Level_Mean-(SD) ng/mL
Study/Author Name	Patient (n)	Subgroup	Age_Mean (SD)_Year	Female n (%)	White	Black	Asian	Other	Body Mass Index_Mean (SD)	FBG_Mean (SD) - mg/dL	2-Hr Postload Plasma Glucose _Mean (SD) - mg/dL	Glycated Hemoglobin_Mean (SD) - %	Serum 25-hydroxyvitamin D Level_Mean-(SD) ng/mL
WHI/deBoer	16 999	Vitamin D3 and calcium	No. of patients 50–59: 6384 60–69: 7696 70–79: 2919	16 999 (100)	14 260 (83.9)	1430 (8.4)	338 (2)	971 (5.7)	No. of patients <25: 4628 25–30: 6166 >30: 6120	No. of patients <100: 767 ≥100: 261	-	-	No. of patients <12.9: 381 12.9–17.4: 371 17.5–24.0: 366 ≥ 24 1: 395
	16 952	Placebo	No. of patients 50–59: 6358 60–69: 7674 70–79: 2920	16 952 (100)	14 297 (84.3)	1409 (8.3)	313 (1.8)	933 (5.5)	No. of patients <25: 4720 25–30: 6183 >30: 5958	No. of patients <100: 777 ≥100: 275	-	-	No. of patients <12.9: 391 12.9–17.4: 394 17.5–24.0: 402 ≥ 24 1:397
RECORD/Avenell 2009	2416	Vitamin D3 and calcium	77 ± 6	2240 (84·6)	2629 (99)	-	-	-	Weight in kg =65 ± 13	-	-	-	-
RECORD/Avenell 2009	2413	Placebo	77 ± 6	2241 (84·8)	2623 (99)	-	-	-	Weight in kg =65 ± 12	-	-	-	-
Davidson, 2013	56	Vitamin D3	52.3 ± 8.0	36 (64)	0	5 (9)	0	Latino 51 (91)	32.1 ± 4.7	98.7 ± 8.7	158 ± 22	6.1 ± 0.3	22.0 ± 4.5
Davidson, 2013	53	Placebo	52.5 ± 7.0	38 (71)	0	9 (17)	0	Latino 44 (83)	32.9 ± 4.3	97.5 ± 9.4	162 ± 18	6.1 ± 0.4	22.0 ± 4.8
Dutta, 2014	68	Vitamin D3 and calcium	48.37 ± 10.47	43 (63.2)	-	-	-	-	26.32 ± 4.52	109.91 ± 9.06	152.84 ± 27.6	6.15 ± 0.6	17.04 ± 7.66
	57	Placebo and calcium	47.4 ± 11.51	31 (54.4)					26.83 ± 4.63	110 ± 9.25	155.16 ± 25.1	6.05 ± 0.57	18 ± 7.16
	45	Placebo and calcium	46.6 ± 11.01	27 (60)					25.51 ± 4.44	109.56 ± 10.2	155.69 ± 23.8	6.19 ± 0.54	37.89 ± 8.26
DIVA/Barengolts, 2015	87	Vitamin D2	58.2 ± 6.0	0	-	87 (100)	-	-	32.4 ± 2.9	98.3 ± 9.3	131.9 ± 31.8	6.14 ± 0.26	<10: 20 (22.7) 10–19: 52 (59.1) 20–29: 15 (18.2)
DIVA/Barengolts, 2015	86	Placebo	59.8 ± 6.0	0	-	86 (100)	-	-	31.5 ± 2.4	97.7 ± 10.3	129.7 ± 34.6	6.08 ± 0.20	<10: 24 (27.9) 10–19: 51 (59.3) 20–29: 11 (12.8)
Kuchay, 2015	64	Vitamin D3	47.6 ± 9.5	-	-	-	-	-	25.9 ± 2.6	109 ± 6	144 ± 24	5.9 ± 0.3	19.8 ± 15.5
Kuchay, 2015	65	Placebo	48.5 ± 11.8	-	-	-	-	-	25.2 ± 3.1	110 ± 6	149 ± 23	5.9 ± 0.2	18.9 ± 13.4
Tromsø/Jorde, 2016	256	Vitamin D3	62.3 ± 8.1	95 (37.1)	-	-	-	-	30.1 ± 4.1	110 ± 8	131 ± 38	5.98 ± 0.28	24.0 ± 8.8
Tromsø/Jorde, 2016	255	Placebo	61.9 ± 9.2	102 (40.0)	-	-	-	-	29.8 ± 4.4	109 ± 9	133 ± 33	5.97 ± 0.34	24.4 ± 8.5
Kawahara, 2018	630	Eldecalcitol	-	-	-	-	-	-	-	-	-	-	-
Kawahara, 2018	626	Placebo	-	-	-	-	-	-	-	-	-	-	-
D2d/Pittas, 2019	1211	Vitamin D3	59.6 ± 9.9	541 (44.7%)	810 (66.9)	301 (24.9)	66 (5.5)	34 (2.8)	32.0 ± 4.5	108.0 ± 7.4	136.9 ± 34.3	5.9 ± 0.2	27.7 ± 10.2
D2d/Pittas, 2019	1212	Placebo	60.4 ± 10.0	545 (45.0)	806 (66.5)	315 (26.0)	64 (5.3)	27 (2.2)	32.1 ± 4.4	107.8 ± 7.4	137.6 ± 34.3	5.9 ± 0.2	28.2 ± 10.1

Abbreviations: D2d, Vitamin D and Type 2 Diabetes; DIVA, D Vitamin Intervention in Veteran Administration; FBG, fasting blood glucose; RECORD, Randomized Evaluation of Calcium or Vitamin D; SD, standard deviation; WHI, Women's Health Initiative.

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Effect of Vitamin D Supplementation on the Incidence of Diabetes Mellitus

Abstract and Introduction

Abstract

Introduction

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Tables

References

Authors and Disclosures

Authors and Disclosures

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