Diabetes mellitus is recognised as a significant global health challenge, serving as a major risk factor for various cardiovascular and renal diseases. In 2015, the global prevalence of diabetes was estimated to include 425 million adults, with projections indicating an increase to 629 million by 2040. Additionally, approximately 352 million individuals globally experience impaired glucose tolerance (IGT), placing them at an elevated risk for the development of diabetes and cardiovascular disease. Although lifestyle modifications such as dietary adjustments and regular exercise have demonstrated efficacy in delaying the onset of type 2 diabetes, maintaining these behavioural changes over extended periods proves challenging. This highlights the necessity for innovative strategies to reduce the incidence of type 2 diabetes in individuals with IGT.
Vitamin D has been identified as a potential candidate for diabetes prevention due to its biological role in glucose metabolism. Vitamin D receptors are present in various cell types, including pancreatic β cells, which are integral to insulin biosynthesis and secretion. Observational studies have established an association between low serum 25-hydroxyvitamin D levels and an increased incidence of type 2 diabetes. However, despite promising results from certain intervention studies and meta-analyses suggesting that vitamin D supplementation could improve glycaemic control, other large-scale clinical trials and meta-analyses have not corroborated these benefits. These conflicting findings emphasise the need for further research to determine whether vitamin D supplementation provides a meaningful preventive effect against type 2 diabetes, particularly in individuals with vitamin D deficiency or IGT.
The DPVD Trial
To address this research gap, the Diabetes Prevention with active Vitamin D (DPVD) trial was conducted. This prospective, multicentre, randomised controlled trial sought to evaluate whether daily supplementation with 0.75 μg of eldecalcitol, an active vitamin D analogue, could reduce the incidence of type 2 diabetes in individuals with IGT. Eldecalcitol is recognised for its physiological effects similar to 1,25-dihydroxyvitamin D, the active form of vitamin D, while exhibiting distinct mechanisms of action. Unlike conventional vitamin D supplements, eldecalcitol is unaffected by dietary vitamin D intake and provides a more reliable measure of supplementation adherence.
The primary outcomes of the DPVD trial revealed that eldecalcitol did not significantly reduce the incidence of type 2 diabetes or enhance the rate of regression to normoglycaemia. However, after adjusting for covariables using a multivariable fractional polynomial Cox regression analysis, a preventive effect of eldecalcitol was observed, particularly among participants with insufficient insulin secretion. This discrepancy between unadjusted and adjusted findings is likely attributable to a lack of statistical power, unbalanced distribution of two-hour plasma glucose concentrations between the eldecalcitol and placebo groups, or both.
Key Insights from Biomarker Analysis
The trial was designed to detect a 36% reduction in diabetes risk with eldecalcitol compared to placebo; however, the observed risk reduction was only 13%. This smaller effect size likely limited the trial’s ability to achieve statistical significance in the primary analysis. Furthermore, a 2020 meta-analysis of vitamin D supplementation in prediabetic individuals reported an 11% reduction in diabetes risk, suggesting that the DPVD trial findings align with broader evidence but may have been underpowered to detect such modest benefits without covariable adjustment.
Key findings from the trial highlight the role of biomarkers in identifying subpopulations that could benefit from vitamin D supplementation. Glucose intolerance results from insufficient insulin secretion, insulin resistance, or a combination of both. The DPVD trial assessed these factors using several biomarkers, including HOMA-κ, HOMA-IR, and fasting immunoreactive insulin. HOMA-κ, a measure of insulin secretion, indicated that participants in the lower third (less than 40%) benefited more significantly from eldecalcitol. Similarly, participants with lower HOMA-IR values (≤1.49) and fasting immunoreactive insulin levels (≤5.6 μU/mL) demonstrated improved outcomes. These results suggest that eldecalcitol’s preventive effects may be concentrated in individuals with impaired basal insulin secretion or sensitivity.
Mechanisms and Physiological Impact of Eldecalcitol
Eldecalcitol exerts its influence on vitamin D metabolism by suppressing the expression of the CYP27B1 gene, which facilitates the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. This suppression leads to reduced serum and intracellular levels of active vitamin D while maintaining its physiological effects. Notably, eldecalcitol increased bone mineral density in the lumbar spine and femoral neck during the trial, a finding consistent with its established effects on bone health. These enhancements in bone density may also be associated with increased physical activity, which could indirectly benefit glucose metabolism.
Additional biomarkers measured during the trial provided further insight into the relationship between vitamin D and glucose metabolism. Serum osteocalcin, a bone formation marker associated with insulin sensitivity, significantly increased in the eldecalcitol group compared to the placebo group by the second year of the trial. This finding aligns with previous studies linking osteocalcin to improved glucose metabolism, although inconsistent results in shorter trials highlight the necessity of extended follow-up periods for validation. Other biomarkers, including serum leptin, RANKL, and osteoprotegerin, exhibited minimal or non-significant changes, indicating that their roles in glucose metabolism may be secondary or less influential in the context of vitamin D supplementation.
Strengths and Limitations of the DPVD Trial
The DPVD trial included several strengths, such as its large sample size, high adherence to the intervention, and regular outpatient follow-ups every three months. Additionally, it represents the first randomised controlled trial to examine the effects of active vitamin D on diabetes prevention in a prediabetic population. The baseline serum 25-hydroxyvitamin D concentration (20.9 ng/mL) in this trial was lower than in comparable studies, suggesting that eldecalcitol may be particularly effective in individuals with vitamin D deficiency.
However, the trial faced limitations. The fixed dose of 0.75 μg of eldecalcitol, based on standard treatment for osteoporosis, may not have been optimal for diabetes prevention. Furthermore, the study’s exclusive focus on Japanese participants limits the generalisability of its findings to other ethnicities, considering the potential influence of geographic, occupational, and racial factors on vitamin D metabolism. Lastly, the allocation method employed in this multicentre study may have contributed to imbalances in critical variables, such as baseline two-hour plasma glucose concentrations, between treatment groups. These limitations underline the need for more sophisticated allocation methods in future trials.
Conclusion
The DPVD trial provides important insights into the role of active vitamin D supplementation in diabetes prevention. Although eldecalcitol did not significantly reduce the incidence of type 2 diabetes in the overall study population, it demonstrated potential benefits in subgroups with impaired insulin secretion and sensitivity after covariable adjustment. These findings highlight the importance of targeted interventions for individuals with specific metabolic profiles and suggest that active vitamin D may contribute to diabetes prevention among those with vitamin D deficiency or impaired glucose tolerance. Further research is required to optimise dosing strategies, explore the effects in diverse populations, and elucidate the mechanisms underlying the observed benefits. Addressing these challenges will enable future studies to build upon the DPVD trial findings and develop more effective strategies for combating the global diabetes epidemic.
Reference
Kawahara, T., Suzuki, G., Mizuno, S., Inazu, T., Kasagi, F., Kawahara, C., Okada, Y., & Tanaka, Y. (2022). Effect of active vitamin D treatment on development of type 2 diabetes: DPVD randomised controlled trial in Japanese population. BMJ (Clinical Research Ed.), 377, e066222. https://doi.org/10.1136/bmj-2021-066222
Zhang Y, Tan H, Tang J, et al. Effects of Vitamin D Supplementation on Prevention of Type 2 Diabetes in Patients With Prediabetes: A Systematic Review and Meta-analysis. Diabetes Care 2020;43:16508. doi:10.2337/dc19-1708
Jorde R, Sollid ST, Svartberg J, et al. Vitamin D 20,000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes. J Clin Endocrinol Metab 2016;101:1647-55. doi:10.1210/ jc.2015-4013