Prediabetics not helped by weekly vitamin D (perhaps D2) – RCT Oct 2013

High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D.

Diabetes Care. 2013 Feb;36(2):260-6. doi: 10.2337/dc12-1204. Epub 2012 Oct 1.
Davidson MB, Duran P, Lee ML, Friedman TC.
Department of Internal Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Charles R. Drew University, Los Angeles, CA, USA. mayerdavidson at cdrewu.edu

OBJECTIVE: Low vitamin D levels predict the development of diabetes. This double-blind, randomized, control study in subjects with prediabetes and hypovitaminosis D evaluated whether high doses of vitamin D for 1 year affected insulin secretion, insulin sensitivity, and the development of diabetes.

RESEARCH DESIGN AND METHODS: A total of 1,551 subjects ≥40 years of age not known to have diabetes were screened with A1C levels. Subjects with A1C levels of 5.8-6.9% underwent an oral glucose tolerance test (OGTT). Subjects with prediabetes and 25-OH vitamin D (25-OHD) levels <30 ng/mL were randomized to receive weekly placebo (n = 53) or vitamin D (n = 56) with doses based on body weight and baseline 25-OHD levels. OGTTs were performed 3, 6, 9, and 12 months later. Insulin secretion and sensitivity were measured, and the proportion of subjects developing diabetes was assessed.

RESULTS: 25-OHD levels rapidly rose from 22 to nearly 70 ng/mL after vitamin D supplementation with a mean weekly dose of 88,865 IU.
There were no differences between the placebo and vitamin D groups regarding

• fasting plasma glucose,
• 2-h glucose, or
• insulin secretion and sensitivity or
• in the percent developing diabetes or
• returning to normal glucose tolerance.

No subjects experienced increased serum or urinary calcium levels.
At 12 months, A1C levels were significantly slightly less (0.2%) in the vitamin D group.

CONCLUSIONS: In individuals with prediabetes and hypovitaminosis D, doses of vitamin D supplementation designed to raise serum 25-OHD levels into the upper-normal range for 1 year had no effect on insulin secretion, insulin sensitivity, or the development of diabetes compared with placebo administration.

Comment on:

Davidson et al. High-Dose Vitamin D Supplementation in People With Prediabetes and Hypovitaminosis D. Diabetes Care 2013;36:260–266
Norbert J. Tripolt, PHD1,2,
Michaela Eder1,2,
Tatjana Stojakovic, MD3,
Stefan Pilz, MD, PHD1,
Thomas R. Pieber, MD1 and
Harald Sourij, MD1,2 ha.sourij at medunigraz.at.

1Department for Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Graz, Austria
2Department of Endocrinology and Metabolism, Cardiovascular Diabetology Research Group, Medical University of Graz, Graz, Austria; and the
3Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria

We have read with interest the work by Davidson et al. (1) reporting in this journal that in a non-Caucasian population with impaired fasting glycemia or impaired glucose tolerance and low vitamin D levels, vitamin D supplementation had no effect on estimates of insulin secretion, insulin sensitivity, or incident diabetes.

Our research group started a similar study (ClinicalTrials.gov number, NCT01183442) in Caucasians with postchallenge hyperglycemia (i.e., 2-h glucose ≥140 mg/dL), vitamin D deficiency, and coronary artery disease. As in the study by Davidson et al. (1) we had to prescreen a high number of patients (n = 1,814). Five hundred seventy-nine were potentially eligible, of which only 178 were willing to undergo an oral glucose tolerance test and to participate in this 12-month study. Fifty-three (30%) had postchallenge hyperglycemia, and out of these only 42% had hypovitaminosis D. Finally, only 22 patients were randomized and the trial committee decided to stop the trial prematurely due to unfeasibility to recruit the intended number of 140 subjects.

Previous large-scale outcome trials in patients with impaired glucose tolerance have already demonstrated the need for screening large numbers of subjects to finally enroll the required number of participants. In the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial 21.9% of the 43,502 subjects screened were finally randomized (2) while the Study To Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial randomized 9.6% of the 14,742 subjects screened (3).

If studies require vitamin D insufficiency as an additional inclusion criterion, recruitment becomes even more difficult. One reason could be that low vitamin D levels might represent a marker of reduced health status, and these subjects might be less likely to participate in intervention trials. In addition, because of the increasing number of epidemiological publications, suggesting a beneficial association of vitamin D with several health outcomes, the number of patients with vitamin D supplementation is steadily increasing.

Interestingly, currently 19 intervention trials investigating the impact of vitamin D supplementation on various outcome measures in subjects with impaired glucose tolerance or prediabetes are registered on www.clinicaltrials.gov. However, results have been published for only 2 of these mainly short-term studies, although half of the trials commenced at least 3 years ago.

Note: There were 121 Clinical Trails of Diabetes and Vitamin D intervention as of Jan 2017

Although subjects with postchallenge hyperglycemia seem to be an interesting target cohort to study the effect of vitamin D supplementation on glucose metabolism, investigators need to keep in mind that recruitment is challenging and that the number of patients needed to screen will likely be more than 10- to 15-fold higher than the number of patients finally enrolled when designing this kind of study.

The work was supported by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number 13699 to H.S.) and the Styrian Government (project A3-16.M-1/2011-25 to. H.S.).

References
Davidson MB, Duran P, Lee ML, Friedman TC
. High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care 2013;36:260–266, Abstract/FREE Full Text
↵
Holman RR, Haffner SM, McMurray JJ, et al.,
NAVIGATOR Study Group
. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;362:1463–1476

Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M,
STOP-NIDDM Trial Research Group
. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 2002;359:2072–2077

Comment on:

Davidson et al. High-Dose Vitamin D Supplementation in People With Prediabetes and Hypovitaminosis D. Diabetes Care 2013;36:260–266
Stefan Pilz, MD, PHD1,2, s.pilz at vumc.nl
Femke Rutters, PHD1 and
Jacqueline M. Dekker, PHD1
From the 1Department of Epidemiology and Biostatistics, EMGO Institute for Health and Care Research, VU University Medical Centre Amsterdam, the Netherlands; and the
2Department of Internal Medicine, Division of Endocrinology and Metabolism, Medical University of Graz, Austria.

In their recently published randomized, controlled trial (RCT), Davidson et al. (1) found no significant effect of high-dose vitamin D supplementation on insulin secretion, insulin sensitivity, and incident diabetes. Their RCT is of particular importance because the researchers included subjects with diabetes and vitamin D insufficiency, i.e., a cohort that according to previous observational studies should most likely benefit from vitamin D treatment (2). Although the findings of Davidson et al. clearly show no relevant effect of vitamin D supplementation, it must also be underlined that their mean dose of 88,865 IU per week, corresponding to a daily dose of 12,695 IU, was safe without causing hypercalcemia or hypercalciuria. These are crucial new data regarding vitamin D safety. In this context, there is an ongoing debate on tolerable upper intake levels for vitamin D, which are 4,000 IU according to the Institute of Medicine and 10,000 IU according to The Endocrine Society (3,4). Along with their finding that even more than 10,000 IU vitamin D per day for 1 year does not cause adverse effects, Davidson et al. also showed that maintaining a 25-hydroxyvitamin D (25OHD) level of nearly 70 ng/mL (175 nmol/L) is safe. It must, however, be stressed that such high 25(OH)D concentrations should not be regarded as target levels. We do not have sufficient long-term outcome data on 25(OH)D levels of 70 ng/mL (175 nmol/L). By contrast, observational studies suggest that 25(OH)D concentrations of 30–35 (or 40) ng/mL (75–87.5 or 100 nmol/L) are optimal for multiple health outcomes including mortality, with some studies even reporting a U-shaped association (5). Therefore, and taking into account the increasing number of negative RCT results, which suggest that vitamin D is not a wonder drug for everyone, it will be important for future research to 1) focus on vitamin D–sensitive individuals, e.g., vitamin D–deficient individuals, and 2) use vitamin D doses to achieve optimal 25(OH)D levels. Several vitamin D hopes for outcomes with relevance for diabetic patients such as blood pressure or cardiovascular events still remain to be further evaluated in such RCTs. While waiting for these trial results, we want to note finally that, regardless of the current disappointing data on vitamin D and glycemic control, diabetic patients are prone to osteoporosis and fractures, for which vitamin D supplementation is indeed an established treatment (3,4).

PMID: 23033239

Response to Comment on:

Davidson et al. High-Dose Vitamin D Supplementation in People With Prediabetes and Hypovitaminosis D. Diabetes Care 2013;36:260–266
Mayer B. Davidson, MD mayerdavidson at cdrewu.edu
Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles Drew University, Los Angeles, California.

This letter is in response to Pilz et al. (1) who are concerned about the possible long-term effects of high levels of vitamin D on mortality. In a sense, our study was a “proof of concept” one. As noted in our article (2) and in its Supplementary Table 3, there have been a number of studies evaluating the effect of vitamin D supplementation on diabetes, insulin secretion, and insulin sensitivity, almost all of which have been negative.
There are five possible reasons for these negative results:

• 1) some subjects did not have hypovitaminosis D;
• 2) the dose of vitamin D was too low;
• 3) relatedly, achieved serum vitamin D levels were not high enough;
• 4) duration of treatment was too short; or
• 5) vitamin D supplementation was truly ineffective.

We chose conditions to meet the first four situations, i.e., subjects with hypovitaminosis D at high risk for developing diabetes and treated them for 1 year with very high doses of vitamin D (88,865 IU per week or 12,695 per day) quickly achieving serum levels of nearly 70 ng/mL. Thus, our negative results strongly support the fifth reason, i.e., vitamin D supplementation is simply ineffective in delaying the development of diabetes in people at high risk who have low levels of vitamin D or in their ability to secrete or respond to insulin.

Pilz et al. (1) point out that in a meta-analysis of 14 prospective cohort studies evaluating serum vitamin D levels and mortality, a few suggested a U-shaped relationship (3). However, this suggestion was not confirmed in a recently published National Health and Nutrition Examination Survey study (4). Although our study was certainly not intended to help establish acceptable vitamin D doses, the lack of hypercalcemia and hypercalciuria while ingesting nearly 13,000 IU of vitamin D per day for a year may help meet potential reservations concerning the recommendations of The Endocrine Society that a tolerable dose of vitamin D is 10,000 IU per day.
References
1. Pilz S, Rutters F, Dekker J
. Comment on: Davidson et al. High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care 2013;36:260–266 (Letter). Diabetes Care 2013;36:e71. DOI: 10.2337/dc12-2089
2. Davidson MB, Duran P, Lee ML, Friedman TC
. High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care 2013;36:260–266
3. Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S
. Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr 2012;95:91–100, Abstract/FREE Full Text
4. Kramer H, Sempos C, Cao G, et al
. Mortality rates across 25-hydroxyvitamin D (25[OH]D) levels among adults with and without estimated glomerular firltraiton rate <60 ml/min/1.73 m2: the Third National Health and Nutrition Examination Survey. PLoS ONE 2012;7:e47458

Effect of Long Term Vitamin D Supplementation on Biomarkers of Inflammation in Latino and African-American Subjects with Pre-Diabetes and Hypovitaminosis D.

Horm Metab Res. 2014 Jul 10. [Epub ahead of print]
Sinha-Hikim I, Duran P, Shen R, Lee M, Friedman TC, Davidson MB.

Low vitamin D levels are associated with minority subjects, the metabolic syndrome, and inflammation. The effect of vitamin D supplementation on markers of inflammation has not been well studied. The aim of the study was to evaluate the effects of high doses of vitamin D supplementation for 1 year on serum biomarkers of inflammation in Latino and African-American subjects with pre-diabetes and hypovitaminosis D. Latino (n=69) and African-American (n=11) subjects who had both pre-diabetes and hypovitaminosis D with a mean age of 52.0 years, a BMI of 32.7 kg/m2, and 70% of whom were females, were randomized to receive weekly doses (mean±SD) of vitamin D (85 300 IU±16 000) or placebo oil for 1 year.
Serum levels of

• interleukin-6,
• tumor necrosis factor,
• highly sensitive C-reactive protein),
• plasminogen activator inhibitor 1, and
• insulin-like growth factor-1

were measured at baseline, 6, and 12 months. Serum 25-OH vitamin D levels of 22 ng/ml at baseline quickly rose to nearly 70 ng/ml in subjects receiving vitamin D and did not change in the placebo group. Two-way repeated measures ANOVA showed no differences between the 2 groups in any of the 5 selected parameters. High dose vitamin D supplementation for 1 year in minority subjects with pre-diabetes and hypovitaminosis D failed to affect serum biomarkers of inflammation.Clinical trial reg. no.: NCT00876928, clinicaltrials.gov.

© Georg Thieme Verlag KG Stuttgart · New York.

PMID: 25011019

Assuming that the 0.2% reduction of A1C on the same scale as 5.8–6.9%

Then 0.2% of range of 1.1% (6.9-5.8) = 18 % of the prediabetes range

See also Vitamin D Life

• Overview Diabetes and vitamin D contains the following summary
• Diabetes is 5X more frequent far from the equator
• Children getting 2,000 IU of vitamin D are 8X less likely to get Type 1 diabetes
• Obese people get less sun / Vitamin D - and also vitamin D gets lost in fat
• Sedentary people get less sun / Vitamin D
• Worldwide Diabetes increase has been concurrent with vitamin D decrease and air conditioning
• Elderly get 4X less vitamin D from the same amount of sun
      Elderly also spend less time outdoors and have more clothes on
• All items in category Diabetes and Vitamin D 454 items: both Type 1 and Type 2

Vitamin D appears to both prevent and treat diabetes

• Appears that >2,000 IU will Prevent
• Appears that >4,000 IU will Treat , but not cure
• Appears that Calcium and Magnesium are needed for both Prevention and Treatment
  • which are just some of the vitamin D cofactors

Number of articles in both categories of Diabetes and:

• Dark Skin 22;   Intervention 49;   Meta-analysis 28;   Obesity 26;  Pregnancy 39;   T1 (child) 34;  Omega-3 10;  Vitamin D Receptor 18;  Genetics 10;  Magnesium 18    Click here to see details
• Normalizing vitamin D levels reduced prediabetic measure by 18 percent – RCT Oct 2012
• Insulin improvement in obese teens with 4000 IU of vitamin D – RCT Feb 2013
• 27 percent less likely to develop diabetes if prediabetic and have adequate vitamin D – Mar 2012
• 4000 IU RCT reduces type 2 diabetes HOMA by 24% and CRP by 64% April 2010
• Insulin resistance helped with 50000 IU of vitamin D weekly – Feb 2013
• Prediabetes reduced by monthly 60,000 IU of vitamin D – RCT May 2015
• Prediabetes treated by Vitamin D (34 ng, 3500 IU per day) – meta-analysis May 2018
• Fewer mice became prediabetic when given Vitamin D, even when on high fat, high sugar diet – March 2017
• Diabetes risk reduced 24 % for every 10 ng increase in vitamin D – Mar 2011
• 25 % reduction in diabetes risk if vitamin D great than 30 ng - June 2011
  • Data suggested 54 % reduction in Diabetes risk when vitamin D levels were > 50 ng/ml
• All items in Diabetes and Vitamin D 454 items
• Prediabetes progression to diabetes 25 % less for every 4 ng increase in vitamin D – April 2012