November 12, 2019 -- Supplementation with vitamin D and omega-3 fatty acids failed to improve standard lab markers for inflammation and kidney function in two ancillary studies of the landmark Vitamin D and Omega-3 Trial (VITAL) that were reported in early November. The results reinforce a cautionary stance on supplementation and testing.
The incorporation of VITAL findings into guidelines and practice is partly dependent on results from several ancillary trials testing supplementation in different patient populations.
The randomized placebo-controlled VITAL study evaluated the effect of supplementation with high-dose vitamin D (2,000 IU, daily) and omega-3 fatty acids (1 g of eicosapentaenoic acid [EPA]/docosahexaenoic acid [DHA], daily) on cancer and cardiovascular events over five years in almost 26,000 older adults with no known heart disease.
As it turned out, vitamin D did not significantly reduce the rates of cancer or cardiovascular disease, though there appeared to be signs of reduced risk of cancer-related death that needed to be followed up (Manson et al, New England Journal of Medicine, January 3, 2019, Vol. 380:1, pp. 33-44). Omega-3 supplementation was associated with a lower risk for heart attack when it was considered as an individual event. Looking at events overall, a lower risk was reported for a subgroup that had lower consumption of fish. A significant benefit was not noted for omega-3 supplements when it came to cancer.
Missing the mark in inflammation
One of the new ancillary studies looked at the effect of supplementation on markers of harmful inflammation in 1,561 trial participants. Three markers of inflammation were evaluated: interleukin-6 (IL-6), tumor necrosis factor receptor 2 (TNFR2), and high sensitivity C-reactive protein (hsCRP). Results were reported on November 7 in the journal Clinical Chemistry.
The study measured results after one year of supplementation compared to baseline. Researchers reported that neither vitamin D nor omega-3 fatty acid supplementation had reduced any of the three inflammatory biomarkers after one year. Indeed, in a surprise finding, vitamin D supplementation was associated with an IL-6 level that was 8.2% higher than baseline.
The researchers noted that hsCRP was reduced in some past randomized controlled trials in certain populations, such as in people with diabetes. But one key difference this time around was that supplements were given for a full year, rather than on a short-term basis for six to 24 weeks. In a subgroup with low fish intake at baseline, defined as 1.5 servings per week, a 10.5% reduction in hsCRP was reported, but for those with higher fish intake, hsCRP increased by 10.5%.
Lead author Dr. Karen Costenbader, a rheumatologist at Brigham and Women's Hospital, and colleagues acknowledged that the study doesn't address the effects of a higher dose of vitamin D or different omega-3 fish oil products. However, they concluded that considering use across the population broadly, it's unlikely that the supplements have major anti-inflammatory effects.
"The results address real-world over-the-counter use of these supplements by older community-dwelling Americans from a variety of sociodemographic backgrounds, with common comorbidities increasing the risk of systemic inflammation, such as smoking, obesity, and diabetes," Costenbader and colleagues wrote in Clinical Chemistry.
However, the researchers acknowledged that it's unclear whether results would be different with an even higher dose of vitamin D or a different fish oil regimen. Amarin's pure EPA omega-3 fatty acid product Vascepa, for example, is approved in the U.S.
More disappointing data
A separate newly reported ancillary study of VITAL that focused on diabetic kidney disease (DKD) -- known as VITAL-DKD -- was also disappointing. The study was led by University of Washington nephrologist Dr. Ian H de Boer, and results were published online November 8 in the Journal of the American Medical Association.
In this study, the researchers evaluated the effects on kidney function of supplementing with vitamin D or omega-3 fatty acids in a subset of 1,320 VITAL participants with diabetes at baseline. The researchers tested urine and blood samples and measured estimated glomerular filtration rate (eGFR).
At baseline, the mean age of participants was 67.6 years, and the median length of time for a diagnosis of diabetes ranged from six to 10 years.
The study assessed any effects on eGFR decline, which is associated with risk for end-stage kidney disease. However, compared with baseline, the researchers found no significant slowing in eGFR decline after five years of supplementation.
"The findings do not support the use of vitamin D or omega-3 fatty acid supplementation for preserving kidney function in patients with type 2 diabetes," the group concluded.
In an accompanying editorial in JAMA, Duke University nephrologists Dr. Myles Wolf and Dr. Anika Lucas commented on the hype surrounding testing for vitamin D levels and subsequent supplementation, based on encouraging observational studies touted by the lay press. Vitamin D is said to have benefits for many diseases; however, testing and supplementation with vitamin D has not been supported by randomized trials, the largest of which is the VITAL trial, Wolf and Lucas noted.
Though there was a substantial decline in eGFR, significant differences for either supplement versus placebo were not shown in VITAL-DKD.
"It now seems safe to conclude that many prior epidemiological associations between vitamin D deficiency and adverse health outcomes were driven by unmeasured residual confounding or reverse causality," Wolf and Lucas wrote.