Study: Participants assigned to zinc supplements had lower mortality than patients not assigned to supplements

November 1, 2008

Results from the Age-Related Eye Disease Study (AREDS) showed that participants assigned to take zinc dietary supplements had lower mortality than participants not assigned to zinc supplements. The long-term study also indicated that poorer survival was associated with AMD.

Key Points

Rockville, MD-In a long-term study of the natural history and risk factors of age-related macular degeneration (AMD) and cataract, all-cause mortality significantly was increased among participants with unilateral advanced AMD, nuclear opacity, or cataract surgery. The study also evaluated the effect of high doses of antioxidants and zinc on the progression of AMD and cataract and found a significant beneficial association with zinc.

Outlining results from the Age-Related Eye Disease Study (AREDS), Traci E. Clemons, PhD, also noted that unilateral advanced AMD and nuclear opacity significantly were associated with cardiovascular deaths but that zinc supplementation was found to be protective. Cataract surgery significantly was associated with mortality due to neoplasms. Dr. Clemons is a statistician and senior investigator at EMMES Corp., a contract research organization based in Rockville, MD.

AREDS was a long-term, multicenter, prospective study of the clinical course of AMD and cataract as well as the effect of high-dose vitamins and minerals. Enrollment began in November 1992, and follow-up ended Dec. 31, 2005. Mortality data were obtained throughout the study by the collection of death certificates. A search of the National Death Index was performed in 2006 to gather information on individuals lost to follow-up.

Baseline lens photographs were taken to assess the presence and severity of nuclear, cortical, and posterior subcapsular lens opacities using the AREDS Cataract Classification. Baseline nuclear opacity was classified into two groups: Group 1: no or mild opacity in both eyes, and Group 2: at least moderate opacity in at least one eye. Two groups also were identified for cortical opacity; moderate opacity was defined as greater than 5% involvement in the central 5 mm area in at least one eye. The same criterion was used to define moderate posterior subcapsular lens opacities.

Dietary supplements

For the clinical trial of the effects of high daily doses of dietary supplements, patients randomly were assigned in a factorial design to receive either antioxidant vitamins, zinc, antioxidants and zinc, or placebo. The formulations included vitamin C, 500 mg; vitamin E, 400 IU; beta-carotene, 15 mg; zinc oxide, 80 mg; and copper (cupric oxide), 2 mg.

The model was adjusted by age and gender and included several potential health status indicators as covariates. The primary outcome of the analysis was all-cause mortality from death certificates and the National Death Index search. Secondary outcomes were cause-specific mortality from ICD-9 or ICD-10 codes, including cardiovascular deaths, deaths from neoplasms, and all other deaths.

A Cox proportional hazards model was used to identify the predictive health status indicators for the covariate models. Significant health status indicators were added to models that examined the effects of the ocular characteristics on mortality.

During the course of the study, follow-up data were available on 4,753 participants, with a median follow-up of 10.5 years; 22% (1,057) of the participants died.

"Looking at some of the significant health factors, as expected, death increased with age, and males had a higher rate of death. Those of non-white race and also those with less education had a higher rate of death," Dr. Clemons said. "Extremely lean and extremely obese participants had a higher rate of death, and current smokers had almost a doubling of all-cause mortality compared with never smokers. Those with diabetes, cancer, angina, and hypertension also had a higher rate of death."

Ocular characteristics

The analysis of ocular characteristics demonstrated a significant increase in deaths for participants with advanced AMD compared with those with no AMD in age-and gender-adjusted models. This finding remained significant after covariate adjustment.

For nuclear opacity, also revealed was an increase in the risk of death for participants with at least moderate opacity in one eye. No associations were found with cortical or posterior subcapsular lens opacities. Cataract surgery at baseline was associated with an increased risk of all-cause mortality, a finding that remained significant after covariate adjustment, Dr. Clemons said.

Outcomes for the dietary supplements showed no association between long-term antioxidant use and all-cause mortality. A significant decrease in all-cause mortality, however, was found among participants randomly assigned to take zinc at baseline compared with those not assigned to take zinc (RR, 0.83; 95% CI, 0.73 to 0.95).

For the secondary outcome of cause-specific mortality, investigators found an increased risk of cardiovascular death among patients with advanced AMD compared with those with no AMD.

Coronary heart disease, stroke

Investigators also evaluated the risks associated with coronary heart disease and stroke, mimicking the analysis that had been used in a recently published population-based study. They had similar results when analyzing the AREDS data, finding an increased risk of deaths from coronary heart disease and stroke for individuals with advanced AMD. Looking separately by age, these differences mainly were driven by individuals aged fewer than 75 years, according to Dr. Clemons. Moderate nuclear opacity was associated with cardiovascular disease, whereas no association with any cause-specific deaths was found for cortical opacity.

Investigators also found that individuals with cataract surgery at baseline had a significantly higher rate of death from neoplasms compared with those with no cataract surgery. A decreased rate of cardiovascular mortality existed among those randomly assigned to take zinc.

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