Baseline median zinc dietary intake levels of AREDS participants are similar to those of the NHANES III population. Serum levels of zinc and copper are not available for NHANES III, but median zinc concentrations from NHANES II of ~13 μmol/L each for women and men, respectively (24
), are similar to the median values observed for the AREDS population of 12–13 μmol/L. The similarity of these cohorts with respect to intake and serum levels suggests that the effect on serum levels of the AREDS formulation observed in this study may be similar to values that would be obtained with these formulations in the general population.
Despite homeostatic mechanisms that regulate zinc absorption, secretion and redistribution, previous studies have shown that dietary zinc supplementation increases plasma zinc levels (25
). Similarly, we found that daily supplementation with 80 mg of zinc as zinc oxide combined with 2 mg of copper as cupric oxide resulted in a median increase in zinc levels of 17% after 5 y of supplementation in a cohort for which high adherence to study medications was estimated to be present in 79% of the group. This increase is much greater than the 2% median increase in the group not receiving zinc. The median increase in serum zinc levels in the group not receiving zinc may be due in part to supplementation by 65% of participants with daily Centrum, which contains 15 mg of zinc as zinc oxide.
Changes in mean serum zinc levels from baseline were uniform over the period from 1 through 5 y of follow-up. Baseline zinc intake and serum concentrations were higher in men than women, and the percentage of increase in serum zinc over the study period decreased with an increase in the baseline zinc level. Overall, the percentages of change in zinc levels with supplementation were similar in men and women. Within each quartile of baseline zinc at the 5-y visit, the difference in the median percentage of change in serum zinc between the zinc group and no zinc group was similar, except for the high baseline serum zinc quartile for men. In this group, the difference in the median percentage of change was only 4%. Whether this finding is a result of a combination of bioregulation preventing increase beyond threshold levels and regression to the mean requires further study.
The combination of 80 mg of zinc as zinc oxide and 2 mg of copper as cupric oxide increased serum zinc, but had no effect on copper levels. The absence of an effect on copper levels is consistent with the findings of an earlier study reporting that supplementation with 150 mg/d of zinc alone (~10 times the RDA) in healthy volunteers had no effect on plasma copper levels over 6 wk, suggesting no effect of even this relatively high zinc intake on copper transport (27
). Long-term effects on hematopoiesis were not investigated in that study, but other toxicities were observed, including headaches, abdominal cramps, nausea, loss of appetite and vomiting. A summary of adverse experiences occurring in the AREDS population was described as part of the primary results from the clinical trial, reported in the fall of 2001 (18
The effect of zinc levels on lipids has been studied in cross-sectional studies (3
). Between 1987 and 1990, fasting serum zinc and serum lipid levels were examined in individuals aged 22–80 y (28
). In that study, serum zinc levels, particularly those above the highest quintile, were found to be associated with higher levels of total serum cholesterol, LDL cholesterol and triglycerides. No association was found between zinc and HDL cholesterol. Baseline serum zinc in AREDS was positively associated with total cholesterol, calculated LDL cholesterol and triglycerides, and negatively with HDL cholesterol levels. Zinc supplements in AREDS did result in increases in zinc levels but no associations were found with lipids or hematocrit over 5 y of follow-up. The effect of increased zinc levels over longer periods may still be a concern.
A study in atherosclerotic men reported a decreased Zn/Cu ratio and a high correlation between copper levels and both total and LDL cholesterol (3
). In another study, decreased dietary zinc and decreased plasma zinc levels were reported to be associated with coronary artery disease and diabetes, as well as with the coronary artery disease risk factors of hypertension and hypertriglyceridemia (9
). The results of these two studies contradict the notion that higher zinc levels predispose to coronary heart disease by elevating LDL cholesterol and triglycerides. In AREDS, we found lipid metabolism, as indicated by serum measurements of total cholesterol, calculated LDL cholesterol, triglycerides and HDL cholesterol, to be unchanged by moderately high, long-term supplementation with zinc plus copper. Differences in lipid levels may have been masked by the initiation of cholesterol-modifying medications, but no difference between the zinc and no zinc treatment groups was found in the frequency of new onset use of cholesterol-modifying medications at 5 y. Furthermore, no changes in lipid levels were observed among those who had never used lipid-lowering medications. Our findings suggest that the positive associations between baseline serum zinc levels and lipids found in AREDS and in cross-sectional studies may not necessarily reflect a causal relationship between zinc and these measures, but may rather result from zinc being a surrogate for unknown factors that influence serum cholesterol.
In conclusion, 5 y of daily, oral supplementation with 80 mg of zinc as zinc oxide and 2 mg of copper as cupric oxide in AREDS participants did not influence the laboratory parameters of greatest health concern, namely, hematopoiesis as measured by hematocrit, and lipid metabolism as determined from total cholesterol, HDL cholesterol, calculated LDL cholesterol and triglyceride levels. Because zinc plays a role in many major metabolic pathways and is a constituent of many enzymes, there could be adverse or beneficial effects of oral zinc supplementation on physiologic endpoints that we did not investigate.