Age-related macular degeneration in a randomized trial of selenium and vitamin E in men: the Select Eye Endpoints (SEE) study (SWOG S0000B).

Abstract

Selenium and vitamin E are found in the human retina and retinal pigment epithelium and have been associated with risks of age-related macular degeneration (AMD) in observational epidemiological studies (Khoo et al. 2019). We examined a possible role for these nutrients in AMD prevention in the Select Eye Endpoints (SEE) Study, an ancillary study of the National Cancer Institute-sponsored Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized, placebo-controlled trial of selenium (200 μg/d) and/or vitamin E (400 IU/d) in prevention of prostate cancer among 35 533 apparently healthy men aged 50 years and older (Lippman et al. 2005; Lippman et al. 2009). The parent SELECT trial was activated in July 2001 and included 427 clinical sites in the United States, Canada and Puerto Rico. Planned treatment and follow-up was 7–12 years. The SEE ancillary study began in September 2003, with funding from the National Eye Institute, and participation was voluntary. At semi-annual clinic visits, participants reported new diagnoses of AMD which were subsequently confirmed through medical record review. The primary AMD endpoint was incident AMD responsible for best-corrected visual acuity of 20/30 or worse (AMD 20/30). Secondary endpoints were total AMD (with or without vision loss) and advanced AMD (neovascular AMD or geographic atrophy). A priori power analysis indicated adequate study power (80%) to detect a 20% reduction in the primary endpoint of AMD 20/30 assuming participation of all SELECT sites. In September 2008, after an average follow-up of 5.6 years, the SELECT Data and Safety Monitoring Committee recommended that supplements be discontinued due to a lack of efficacy on prostate cancer incidence. This early termination of the parent trial resulted in fewer than expected confirmed AMD events during the treatment period (by September 2008, 128 SELECT sites had agreed to participate in SEE) and thus limited statistical power for the primary vision endpoint of AMD 20/30. At the 128 participating SEE sites, 13 389 men did not report a prior diagnosis of AMD at baseline and were included in analyses (Table 1). A total of 133 incident cases of AMD were confirmed through medical record review. These included 21 cases of the primary endpoint of AMD 20/30. For selenium, there were 9 cases in the treated group and 12 in the placebo group (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.32–1.79). Similarly, for vitamin E, there were 9 cases in the treated group and 12 in the placebo group (HR, 0.75; 95% CI, 0.31–1.77). For the secondary endpoint of total AMD (with or without vision loss), HRs were near the null value of 1.0 for both selenium (HR, 1.05; 95% CI, 0.75–1.47) and vitamin E (HR, 1.04; 95% CI, 0.74–1.46). Cases of advanced AMD were limited (n = 14), and the CIs were wide (selenium; HR, 2.50; 95% CI, 0.79–7.98; vitamin E; HR, 0.99; 95% CI, 0.35–2.82). In summary, the early termination of the parent SELECT trial limited our ability in this ancillary study to conduct meaningful analyses of the primary endpoint of AMD 20/30 or to draw firm conclusions for any endpoint. Nonetheless, we thought it was of sufficient scientific interest to report the results of analyses of the secondary endpoint of total AMD (with or without vision loss). These analyses, which were based on 133 confirmed cases, provided little evidence that long-term daily supplementation with selenium or vitamin E is likely to have a major beneficial or harmful effect on AMD incidence. The findings for vitamin E appear broadly consistent with the null findings of previous supplementation trials conducted among persons with early or no AMD (Schmidl et al. 2015; Evans et al. 2017). To our knowledge, the results for selenium represent the first randomized trial data to assess the effect of selenium (with or without vitamin E) in AMD prevention.