Effects of long-term vitamin D and n-3 fatty acid supplementation on inflammatory and cardiac biomarkers in patients with type 2 diabetes: secondary analyses from a randomised controlled trial

Diabetologia. 2021 Feb;64(2):437-447. doi: 10.1007/s00125-020-05300-7. Epub 2020 Oct 24.


Aims/hypothesis: Interventions that reduce inflammation may delay progression of microvascular and macrovascular complications in diabetes. We examined the effects of vitamin D3 and/or n-3 fatty acid supplementation vs placebo on 5 year changes in serum inflammatory and cardiac biomarkers in adults with type 2 diabetes.

Methods: This study reports pre-specified secondary outcomes of the Vitamin D and Omega-3 Trial to Prevent and Treat Diabetic Kidney Disease, in which 1312 US adults with type 2 diabetes and without known cardiovascular disease, malignancy, or end-stage kidney disease were randomised using computer-generated random numbers in blocks of eight to vitamin D3 (2000 IU/day) vs placebo and n-3 fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]; 1 g/day) vs placebo in a 2 × 2 factorial design. Participants, examiners, and researchers assessing outcomes were blinded to intervention assignment. We measured serum IL-6, high-sensitivity C-reactive protein (hsCRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) at baseline and after 2 and 5 years.

Results: A total of 333 participants were randomised to vitamin D3 and placebo n-3 fatty acids, 289 to n-3 fatty acids and placebo vitamin D3, 370 to vitamin D3 and n-3 fatty acids, and 320 to 2 placebos; 989 (75%) and 934 (71%) participants returned blood samples at 2 and 5 years, respectively. Participants had a mean age of 67.6 years (46% women). Overall, baseline geometric means of IL-6, hsCRP and NT-proBNP were 1.2 pg/ml, 1.9 mg/l and 262 ng/l, respectively. After 5 years, mean IL-6 and hsCRP remained within 6% of their baseline values while mean NT-proBNP increased by 55% overall. Compared with placebo, participants assigned to vitamin D3 had a 1.24-fold greater increase in NT-proBNP over 5 years (95% CI 1.09, 1.41; p = 0.003), while IL-6 and hsCRP did not have a significant difference in change. Comparing n-3 fatty acids with placebo, there was no significant difference in change in IL-6, hsCRP or NT-proBNP. No heterogeneity was observed in subgroup analyses accounting for baseline eGFR, urine albumin to creatinine ratio, initial biomarker concentration, 25-hydroxyvitamin D level or EPA+DHA index.

Conclusions/interpretation: Among adults with type 2 diabetes, supplementation with vitamin D3 or n-3 fatty acids did not reduce IL-6, hsCRP or NT-proBNP over 5 years.

Trial registration: ClinicalTrials.gov NCT01684722 FUNDING: The study was funded by grant R01DK088762 from the National Institute of Diabetes and Digestive and Kidney Diseases. Graphical abstract.

Keywords: Biomarkers; IL-6; Inflammation; NT-proBNP; Type 2 diabetes; Vitamin D; hsCRP; n-3 Fatty acids.

Publication types

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

MeSH terms

  • Aged
  • C-Reactive Protein / metabolism*
  • Cholecalciferol / therapeutic use*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism*
  • Dietary Supplements
  • Docosahexaenoic Acids / metabolism
  • Docosahexaenoic Acids / therapeutic use
  • Eicosapentaenoic Acid / metabolism
  • Eicosapentaenoic Acid / therapeutic use
  • Fatty Acids, Omega-3 / therapeutic use*
  • Female
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Inflammation
  • Interleukin-6 / metabolism*
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / metabolism*
  • Peptide Fragments / metabolism*
  • Vitamin D / analogs & derivatives


  • Fatty Acids, Omega-3
  • Hypoglycemic Agents
  • Interleukin-6
  • Peptide Fragments
  • pro-brain natriuretic peptide (1-76)
  • Natriuretic Peptide, Brain
  • Vitamin D
  • Cholecalciferol
  • Docosahexaenoic Acids
  • C-Reactive Protein
  • 25-hydroxyvitamin D
  • Eicosapentaenoic Acid

Associated data

  • ClinicalTrials.gov/NCT01684722