Supplements had no impact on disease progression, incidence

Patients with age-related macular degeneration (AMD) can put the dietary supplements away — supplementation with vitamin D3 or marine ω-3 fatty acid had no significant impact on disease incidence or progression, according to results from a randomized trial.

As researchers strive to find new therapeutic options for patients with AMD, observational evidence suggests that individuals who have higher dietary intake of vitamin D or ω-3 fatty acids have lower rates of the disease. However, to date, randomized trial data of the efficacy of these supplements for AMD have been limited, William G. Christen, ScD, of the department of medicine at Brigham and Women’s Hospital at Harvard Medical School in Boston, and colleagues noted in JAMA Ophthalmology. To help determine the effect, if any, that these supplements might have, Christen and colleagues conducted an AMD-specific ancillary study of the double-blind, placebo-controlled, randomized Vitamin D and Omega-3 (VITAL) trial.

“In this large randomized trial of initially healthy men and women, daily supplementation with vitamin D3 (2000 IU/d) and marine ω-3 fatty acids (1 g/d) for a median of 5.3 years had no overall effect on the primary vision end point of total AMD events (a composite of incident AMD and progression to advanced AMD),” they found. “Exclusion of events confirmed early in follow-up had no material influence on effect estimates. For each intervention, the apparent lack of effect on total AMD did not vary by baseline categories of possible AMD risk factors but did appear to vary according to the other treatment assignment.”

Robert N. Frank, MD, of the Kresge Eye Institute at Wayne State University School of Medicine in Detroit, writing in an invited commentary, called the findings from VITAL-AMD “discouraging.”

“This is especially the case,” he wrote, “because the prior successes of AREDS and AREDS2 have led to considerable optimism that at least 1, and possibly other, common and highly disabling eye diseases can be substantially reduced in severity, or even prevented, by large but safe doses of commonly used and inexpensive vitamins and dietary supplements. That possibility has not been supported in the present instance…”

The VITAL-AMD analysis included 25,871 participants (mean [SD] age, 67.1 [7.0] years; 50.6% women; 71.3% non-Hispanic white, 20.2% Black) from the VITAL study — of these, 6,463 were randomized to receive vitamin D3 2,000 IU/d and marine ω-3 fatty acids 1 g daily, 6,464 were randomized to vitamin D and placebo, 6,470 were randomized to ω-3 and placebo, and 6,474 were randomized to receive two placebos. Study participants received baseline questionnaires requesting information on clinical and lifestyle risk factors, and 16,956 (65.5%) participants provided baseline blood samples, which were assayed for plasma ω-3 index and serum 25-hydroxyvitamin D. Participants also completed annual health questionnaires to assess compliance with randomized treatments, development of major illness (including AMD), and potential adverse effects.

The study’s primary end point was total AMD events, “a composite of incident cases of AMD plus cases of progression to advanced AMD among participants with AMD at baseline, based on self-report confirmed by medical record review,” Christen and colleagues explained.

“During a median (range) of 5.3 (3.8-6.1) years of treatment and follow-up, 324 participants experienced an AMD event (285 incident AMD and 39 progression to advanced AMD),” they found. “For vitamin D3, there were 163 events in the treated group and 161 in the placebo group (hazard ratio [HR], 1.02; 95% CI, 0.82-1.27). For ω-3 fatty acids, there were 157 events in the treated group and 167 in the placebo group (HR, 0.94; 95% CI, 0.76-1.17). In analyses of individual components for the primary end point, HRs comparing vitamin D3 groups were 1.09 (95% CI, 0.86-1.37) for incident AMD and 0.63 (95% CI, 0.33-1.21) for AMD progression. For ω-3 fatty acids, HRs were 0.93 (95% CI, 0.73-1.17) for incident AMD and 1.05 (95% CI, 0.56-1.97) for AMD progression.”

Christen and colleagues also found that there was no evidence “for any modification of the lack of effect of vitamin D3 or ω-3 fatty acids on the primary end point of total AMD events by baseline categories of possible risk factors for AMD. The lack of effect of vitamin D3 did not vary by baseline serum 25-hydroxyvitamin D level or by outside use of vitamin D supplements, and the lack of effect of ω-3 fatty acids did not vary by baseline plasma ω-3 level.” However, they noted, the effect of interventions on total AMD did appear to be modified by the other treatment assignment.

“Compared with participants assigned vitamin D3 placebo and ω-3 fatty acid placebo, HRs were 0.80 (95% CI, 0.59-1.09) in the vitamin D3 alone group, 0.73 (95% CI, 0.53-1.00) in the ω-3 fatty acid alone group, and 0.96 (95% CI, 0.72-1.29) in the combined group (P= .02 for interaction),” they found.

“Findings for secondary end points representing more advanced stages of the disease were in the direction of benefit for ω-3 fatty acids and included a significant reduction in incident advanced AMD when early follow-up was excluded,” the study authors wrote; however, while they noted that these observations were “suggestive,” they added that the “study power of these analyses was limited.

While Frank acknowledged that these results were disappointing, he also noted that “as in other of the several components of the VITAL trials, these investigators have shown that large-scale clinical trials in ophthalmology, as in other areas of medicine, can be successfully conducted remotely,” a positive precedent for future research. And, while vitamin D and ω-3s might not move the needle, “it has been abundantly clear over the last number of years that overall progress in other areas of research in the causes and treatment of AMD remains considerable,” he added.

Christen and colleagues pointed out several limitations to their study: “The median duration of the trial intervention was 5.3 years, and detection of supplement-related benefits, if present, may require longer follow-up,” they wrote. “No adjustment was made for multiple comparisons, and some subgroup analyses were based on small numbers of events. The subadditive interaction we observed, if real, may have influenced power of our primary analyses, which did not take this interaction into account. Finally, the AMD end point was based on participant reports followed by medical record review. Consequently, some under ascertainment of AMD is likely.”

  1. Supplementation with vitamin D3 and ω-3 fatty acids had no significant impact on incidence or progression of age-related macular degeneration (AMD), according to results from a prespecified ancillary study of the VITAL trial.

  2. These results do not support previous findings from the AREDS and AREDS 2 trials, which suggested that common and highly disabling eye diseases can be substantially reduced in severity, or even prevented, by large but safe doses of commonly used and inexpensive vitamins and dietary supplements.

John McKenna, Associate Editor, BreakingMED™

Christen and colleagues had no relationships to disclose.

Frank had no relationships to disclose.

Cat ID: 240

Topic ID: 92,240,494,141,192,94,925,240