Oral daily vitamin D3 dosing may improve glycated hemoglobin (HbA1c) levels over 3- and 6-month periods in patients with type 2 diabetes mellitus (T2D) undergoing treatment with metformin, according to authors of a study published in Frontiers in Endocrinology.
In describing the goals of their study, the investigators noted that patients with T2D often have very low vitamin D levels and recent research suggests that this deficiency “could play an important role in [T2D] pathogenesis through altering several crucial processes in the development of diabetes and its complications.” For example, they wrote, T2D is characterized by decreased antioxidant capacity and increased formation of free radicals, and some studies have shown vitamin D “may have an antioxidant effect followed by the inhibition of free radicals generation, consequent lipid peroxidation and oxidative modification of other biomolecules.”
Consequently, they explained, “vitamin D supplementation has been proposed as a possible therapeutic tool for [T2D] to optimize [glycemic] control and to prevent the occurrence of complications.” To date, however, no research has determined the long-term effect of vitamin D supplementation on people with T2D, and research is lacking on use of vitamin D supplementation in patients receiving standard therapy for T2D (metformin), so investigators of the current study sought to elucidate this relationship.
This prospective, randomized controlled open-label study was conducted at a single center in Montenegro, Serbia. Between February 4, 2018 and December 15, 2018, investigators enrolled consecutive patients with T2D on metformin therapy with good metabolic control. The primary outcome was the change in insulin resistance and glycemic control measured via the homeostasis model of assessments (HOMA-IR) and glycemic parameters such as fasting blood glucose (FBG) and HbA1c.
Secondary outcomes included oxidative stress parameters (measurement of malondialdehyde, or MDA, a primary biomarker for lipid peroxidation), serum levels of advanced oxidation protein products (AOPP), and inflammation markers (levels of C-reactive protein). Additional secondary outcomes included alteration of vitamin D levels over time, blood pressure, lipid profile, body mass index (BMI), levels of total and ionized calcium, and atherogenic risk.
A total of 130 eligible patients were randomly assigned 1:1 to 1 of 2 groups: 65 patients received oral vitamin D3 therapy in addition to their current metformin therapy for a 6-month period, while the 65 patients in the control group continued their metformin therapy without vitamin D3 supplementation.
Participants in the intervention group who were vitamin D deficient — defined as having serum levels of 25(OH)D ≤50 nmol/L — took 50,000 IU of vitamin D3 weekly during the first 3 months, followed by 14,000 IU weekly during the next 3 months. Participants in the intervention group with 25(OH)D levels >50 nmol/L took 14,000 IU weekly through the end of the study.
Baseline clinical and biochemical parameters were balanced between the 2 study groups. Repeated measures 2-way analysis of variance (ANOVA) showed significant interaction, significant effect of group, and significant effect of time.
In the intervention group, serum 25(OH)D levels increased significantly during the intervention period; in the control group, these levels significantly increased during the first 3 months then decreased significantly through month 6. After 3 and 6 months of vitamin D3 supplementation, 25(OH)D levels differed significantly between groups; adjustments were made for age; sex; and baseline BMI, fasting insulin, and HbA1c.
Significant effects of group and time were noted for HbA1c levels. In the intervention group, HbA1c decreased significantly after 3 months, followed by a significant increase between months 3 and 6. After 3 and 6 months, significant between-group differences in HBA1c were noted.
Repeated measures 2-way ANOVA showed significant effects of time for FBG, systolic blood pressure, MDA, total cholesterol, total calcium total, and ionized calcium. There was no significant interaction or effect of group or time for BMI.
Results of regression analyses showed significant between-group differences in vitamin D at 3 months (B 42.25; 95% CI, 35.43-49.98; P <.001) and 6 months (B 38.76; 95% CI, 31.72-45.80; P <.001), as well as a significant mean difference in HbA1c levels at these 2 timepoints (0.20 mmol/L and 0.24 mmol/L, respectively).
Study limitations include the randomized but not placebo controlled nature of the research; the use of 25(OH)D but not other forms of vitamin D as markers of vitamin D status; the use of HOMA IR to assess insulin resistance rather than the proposed gold standard of hyperinsulinemic-euglycemic clamps; and the use of electrochemiluminescence immunoassay for serum 25(OH)D measurement rather than the gold standard method, liquid chromatography mass spectrometry.
“Oral daily doses of vitamin D proposed by [Endocrine Society] guidelines reduce the levels of HbA1c over a 3-month and over a 6-month period,” the investigators wrote. “Its effect on metabolic control, through the improvement on HOMA-IR and oxidative stress measured through AOPP improvement might have a promising effect if vitamin D could be maintained [at an] optimal dose.”
“Further investigation,” they added, “would reconsider vitamin D doses in patients with [T2D], which may attenuate the oxidative stress risk, the risk of metabolic syndrome, and the related cardiovascular events.”
Cojic M, Kocic R, Klisic A, Kocic G. The effects of vitamin D supplementation on metabolic and oxidative stress markers in patients with type 2 diabetes: a 6-month follow-up randomized controlled study. Front Endocrinol. Published online August 19, 2021. doi:10.3389/fendo.2021.610893