Safety and tolerability of high-dose daily vitamin D3 supplementation in the vitamin D and type 2 diabetes (D2d) study-a randomized trial in persons with prediabetes

Eur J Clin Nutr. 2022 Aug;76(8):1117-1124. doi: 10.1038/s41430-022-01068-8. Epub 2022 Feb 9.


Background/objectives: Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D3 in the vitamin D and type 2 diabetes (D2d) study.

Subjects/methods: In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D3 (the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations.

Results: A total of 8304 AEs occurred during 3 years of follow-up and were less frequent in the vitamin D group compared to placebo (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98). The overall frequency of protocol-specified AEs of interest, which included nephrolithiasis, hypercalcemia, hypercalciuria, or low estimated glomerular filtration rate, was low and did not differ by group. There were no significant between-group differences in total SAEs (IRR = 0.96 (0.81, 1.14)).

Conclusion: Vitamin D3 supplementation at 4000 IU per day was safe and well tolerated among overweight/obese participants at high risk for diabetes who were appropriately monitored for safety. In this population, this dose of vitamin D3 did not increase risk of AEs or SAEs, including those previously associated with vitamin D such as hypercalcemia, hypercalciuria, or nephrolithiasis.

Clinical trial registration: NCT01942694, prospectively registered September 16, 2013.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Cholecalciferol
  • Diabetes Mellitus, Type 2* / drug therapy
  • Dietary Supplements / adverse effects
  • Double-Blind Method
  • Humans
  • Hypercalcemia* / chemically induced
  • Hypercalcemia* / drug therapy
  • Hypercalcemia* / epidemiology
  • Hypercalciuria / chemically induced
  • Hypercalciuria / drug therapy
  • Nephrolithiasis* / chemically induced
  • Nephrolithiasis* / drug therapy
  • Obesity / drug therapy
  • Overweight / complications
  • Overweight / drug therapy
  • Prediabetic State* / drug therapy
  • Vitamin D
  • Vitamins


  • Vitamins
  • Vitamin D
  • Cholecalciferol

Associated data