Secondary health risks a consideration with AREDS nutritional supplements

Nutritionists say more research is needed to determine the systemic health effects of taking high levels of beta-carotene, zinc and vitamin E.

The Age-Related Eye Disease Study, published in 2001, was not only the longest study of age-related macular degeneration, but it also broke ground in the research on the effects of vitamin and mineral supplementation on ocular disease.

While there have been few reports of complications resulting from the regimens evaluated during the 10-year AREDS, the long-term systemic effects of taking high levels of vitamin E, beta-carotene and zinc have yet to be determined conclusively, according to Frederick L. Ferris, MD, lead AREDS investigator.

Dr. Ferris said that the general medical literature on vitamin and mineral supplementation is confusing and often contradicts the AREDS results. He advised ophthalmologists to weigh the patient’s individual risk of developing advanced AMD against the risk of adverse effects from supplements.

“We’re trying to balance apparently low-risk complications with possible benefits,” Dr. Ferris said. “These benefits are differential depending on where you are in the spectrum of age-related macular degeneration.”

Methodology

The AREDS, a National Eye Institute-sponsored 10-year study, included 3,640 AMD patients at 11 centers across the United States.

In the study, patients at high risk of developing advanced AMD lowered their risk of progression of the disease by about 25% by taking a daily combination of 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc and 2 mg of cupric oxide.

The AREDS data reported in 2001 were based on a 5-year median length follow-up, and 6.5-year follow-up data were reported at this year’s Association for Research in Vision and Ophthalmology meeting. When compared to that of the placebo group, the age- and gender-adjusted mortality rates for the groups taking either the antioxidant plus zinc, the zinc-only or the antioxidant-only formulations continue to show low risk due to supplementation.

Yet some nutritionists caution that the AREDS formula, which is recommended indefinitely for patients with the highest risk of developing advanced AMD, may cause health risks in some patients.

The risks are highest for smokers, patients with a history of stroke and patients on blood thinners, according to nutritionists interviewed by Ocular Surgery News. Other data suggest that the regimen may also produce genitourinary effects and anemia.

Smokers

In the past decade, studies have linked lung cancer to smoking and beta-carotene, a precursor to vitamin A that is converted inside the body.

In 1996, the Beta-Carotene and Retinol Efficacy Trial found that smokers, former smokers and workers exposed to asbestos who took a combination of 30 mg of beta-carotene and 25,000 IU of retinol (vitamin A) had a 28% greater risk of lung cancer after 4 years. It should be noted that the AREDS supplement formulation contained only half the 30-mg dosage of beta-carotene in this 1996 study, and there was no retinol in the AREDS formulation.

“People who are smokers should probably be very, very cautious” about taking the AREDS formula chronically, according to John W. Erdman, PhD, a professor of food science and human nutrition at the University of Illinois, Urbana. “Of course, smokers have a much higher risk of AMD.”

Dr. Ferris noted that 9% of the AREDS population consisted of smokers, but the incidence of lung cancer was too small to draw any conclusions about relative risk.

“What I tell my smoking patients is that if they’re worried about lung cancer, it’s 70 times more effective to stop smoking than to stop beta-carotene,” Dr. Ferris said. “However, in general, we don’t recommend that smokers take this formulation until they’ve stopped smoking for at least a year.”

Dr. Ferris noted that it is possible to approximate the AREDS formulation minus beta-carotene by taking a combination of the other recommended vitamins and minerals. There is no prospective controlled data, however, measuring the effect of such combinations on AMD progression.

Upper limit guidelines

Beta-carotene supplementation does not pose a risk to nonsmokers, according to Diane Feskanich, ScD, who has studied the changing nutritional needs of aging men and women at Harvard University’s Channing Laboratory.

She said that the Institute of Medicine of the National Academies did not set an upper limit on beta-carotene consumption because there is “no science” indicating that high levels could pose a risk to nonsmokers. (Beta-carotene is different from the retinol form of vitamin A, which can cause a decrease in bone density at high levels, according to Dr. Feskanich’s research.)

The Institute of Medicine established a committee in 1998 to determine the upper limits for vitamins and minerals. While the levels of vitamins C and E in the AREDS formula conform to the upper limit guidelines, the level of zinc is double the upper limit determined by the committee.

“Zinc is a nutrient that’s been studied for a long time, but we really don’t know on the everyday level what long-term consumption will do,” said Robert J. Cousins, PhD, a professor of nutrition at the University of Florida, Gainesville. “The macular degeneration study (AREDS) is probably one of the longer zinc supplement trials that’s ever been run.”

Complications from zinc

One of the few documented side effects to taking zinc is anemia, Dr. Cousins said. This risk can be managed if patients increase the amount of copper in their diets because the two minerals compete for absorption, he said.

Dr. Ferris said that the AREDS researchers conducted yearly hematocrit testing on all participants, and while there was an increased risk of reported anemia in the participants taking zinc, there were no differences in hematocrit levels. He attributes this finding to the addition of copper to the study formulation. However, researchers did see an increased incidence of genitourinary complications, he said.

“This sounds vague, but it’s vague because it only becomes statistically significant if you pool all of the problems together, all of the reasons people might go to the hospital for genitourinary problems,” he said. “There is some biologic plausibility to the fact that maybe this would increase (genitourinary) problems because … there is a high concentration of zinc in the prostate.”

Dr. Ferris also said that he would advise patients who are taking anticoagulants such as Coumadin (warafin sodium, DuPont) to avoid high levels of vitamin E.

Vitamin E causes red blood cells to become fragile and at high levels will increase the risk of hemorrhagic stroke, according to Dr. Erdman. While the overall risk of stroke is small, he said, risk could be increased by as much as 45% in patients taking vitamin E.

Supplements on the market

Bausch & Lomb collaborated with the NEI on developing the AREDS formula and was the sole corporate sponsor of the AREDS trial. The formula, which Bausch & Lomb markets under the trade name Ocuvite PreserVision, was the only vitamin and mineral formulation tested in the trial.

“The most meaningful difference between the high-potency antioxidant and zinc formulation used in the AREDS trial and other nutritional supplements is that no other supplement has ever been tested or evaluated in such a large, well-controlled clinical trial,” said Stephen P. Bartels, PhD, vice president of pharmaceuticals new product development at Bausch & Lomb. He said that in addition to PreserVision, Bausch & Lomb markets the Ocuvite line of eye health vitamins, including Ocuvite Lutein, which contains 6 mg of lutein per tablet with no beta-carotene.

Since the release of the AREDS results, a number of other pharmaceutical companies have developed supplements based on the study formulation. A daily dose of Bausch & Lomb’s Ocuvite PreserVision or Alcon’s ICaps contains 28,640 IU of beta-carotene, 400 IU of vitamin E and 69.6 mg of zinc.

Suzie DeMent, a spokeswoman for Alcon, said that the company believes that AREDS demonstrated the benefit of this combination of vitamins and minerals with little observed side effects for a disease with no current available treatment. Alcon offers an ICaps AREDS formula as well as another formula containing lutein and zeaxanthin, natural pigments also thought to be important in the age-related disease process, she said. The ICaps lutein and zeaxanthin formulation contains a lower level of beta-carotene, amounting to 6,600 IU, Ms. DeMent said.

ScienceBased Health also offers three MacularProtect formulations, including one that is appropriate for smokers, according to the company. At 2,500 IU, MacularProtect Plus contains 90% less beta-carotene than the company’s other two products. All three formulations contain 400 IU of vitamin E and 80 mg of zinc.

Penny Edwards, MPH, CNS, a nutrition scientist for ScienceBased Health, said that many of the potential adverse effects associated with zinc are prevented by the addition of copper, and for those with AMD the demonstrated benefits of high-dose zinc surpass any theoretical downsides.

She added, however, that the nutrients might interact with or affect the absorption of certain antibiotics, such as quinolones, taken concomitantly.

Careful monitoring

“We feel that high-dose supplementation really needs to be administered by and monitored by a physician,” Ms. Edwards said. “We encourage eye care practitioners to communicate with a patient’s primary care doctor.”

ScienceBased Health offers eye care practitioners a letter that they can send to a patient’s primary care physician, alerting him or her about the benefits and possible side effects from the supplements, she said.

Dr. Ferris emphasized that the therapy has the most benefit for patients who have already lost vision in one eye and are at the greatest risk of developing advanced AMD in their fellow eye. “So for them, it would seem to me, that the risks of supplements are well outweighed by the benefits,” he said.

chart
Source: Information supplied by the investigating companies.

For Your Information:
  • Stephen P. Bartels, PhD, can be reached at 1400 N. Goodman St., Rochester, NY 14609; (585) 338-5399; e-mail: stephen_bartels@bausch.com.
  • Robert J. Cousins, PhD, can be reached at 201A Food Science and Human Nutrition Building, PO Box 110370, Gainesville, FL 32611; (352) 392-2133; e-mail: cousins@ufl.edu.
  • John W. Erdman, PhD, can be reached at 449 Bevier Hall, 905 South Goodwin Ave., Urbana, IL 61081; (217) 333-2527; fax: (217) 333-9368; e-mail: jwerdman@uiuc.edu.
  • Frederick L. Ferris, MD, can be reached at the National Eye Institute, 31 Center Drive, MSC 2510 Building 31, Room 6A52, Bethesda, MD 20892; (301) 496-6583; fax: (301) 496-2297; e-mail: rickferris@nei.nih.gov.
  • Diane Feskanich, ScD, can be reached at Channing Laboratory, Harvard Medical School, 181 Longwood Ave., Boston, MA 02115; (617) 525-0343; e-mail: diane.feskanich@channing.harvard.edu.
  • Alcon Laboratories, manufacturer of ICaps, can be reached at 6201 South Freeway, Fort Worth, TX 76134; (800) 862-5266; fax: (817) 241-0677; Web site: www.alconlabs.com.
  • Bausch & Lomb, manufacturer of Ocuvite PreserVision, can be reached at 1400 N. Goodman St., Rochester, NY 14609; (585) 338-5212; fax: (585) 338-0898; Web site: www.bausch.com.
  • ScienceBased Health, manufacturer of the MacularProtect product line, can be reached at 3579 Highway 50 East, Carson City, NV 89701; (888) 433-4726; fax: (888) 433-6726; Web site: www.sciencebasedhealth.com.
References:
  • Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol. 2001;119:1417-1436.
  • Supplementation with antioxidants, zinc may delay AMD progression. Ocular Surgery News. November 15, 2001.
  • Omenn GS, Goodman GE, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150-1155.
  • Virtamo J, Pietinen P, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA. 2003;290:476-485.

The Age-Related Eye Disease Study, published in 2001, was not only the longest study of age-related macular degeneration, but it also broke ground in the research on the effects of vitamin and mineral supplementation on ocular disease.

While there have been few reports of complications resulting from the regimens evaluated during the 10-year AREDS, the long-term systemic effects of taking high levels of vitamin E, beta-carotene and zinc have yet to be determined conclusively, according to Frederick L. Ferris, MD, lead AREDS investigator.

Dr. Ferris said that the general medical literature on vitamin and mineral supplementation is confusing and often contradicts the AREDS results. He advised ophthalmologists to weigh the patient’s individual risk of developing advanced AMD against the risk of adverse effects from supplements.

“We’re trying to balance apparently low-risk complications with possible benefits,” Dr. Ferris said. “These benefits are differential depending on where you are in the spectrum of age-related macular degeneration.”

Methodology

The AREDS, a National Eye Institute-sponsored 10-year study, included 3,640 AMD patients at 11 centers across the United States.

In the study, patients at high risk of developing advanced AMD lowered their risk of progression of the disease by about 25% by taking a daily combination of 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta-carotene, 80 mg of zinc and 2 mg of cupric oxide.

The AREDS data reported in 2001 were based on a 5-year median length follow-up, and 6.5-year follow-up data were reported at this year’s Association for Research in Vision and Ophthalmology meeting. When compared to that of the placebo group, the age- and gender-adjusted mortality rates for the groups taking either the antioxidant plus zinc, the zinc-only or the antioxidant-only formulations continue to show low risk due to supplementation.

Yet some nutritionists caution that the AREDS formula, which is recommended indefinitely for patients with the highest risk of developing advanced AMD, may cause health risks in some patients.

The risks are highest for smokers, patients with a history of stroke and patients on blood thinners, according to nutritionists interviewed by Ocular Surgery News. Other data suggest that the regimen may also produce genitourinary effects and anemia.

Smokers

In the past decade, studies have linked lung cancer to smoking and beta-carotene, a precursor to vitamin A that is converted inside the body.

In 1996, the Beta-Carotene and Retinol Efficacy Trial found that smokers, former smokers and workers exposed to asbestos who took a combination of 30 mg of beta-carotene and 25,000 IU of retinol (vitamin A) had a 28% greater risk of lung cancer after 4 years. It should be noted that the AREDS supplement formulation contained only half the 30-mg dosage of beta-carotene in this 1996 study, and there was no retinol in the AREDS formulation.

“People who are smokers should probably be very, very cautious” about taking the AREDS formula chronically, according to John W. Erdman, PhD, a professor of food science and human nutrition at the University of Illinois, Urbana. “Of course, smokers have a much higher risk of AMD.”

Dr. Ferris noted that 9% of the AREDS population consisted of smokers, but the incidence of lung cancer was too small to draw any conclusions about relative risk.

“What I tell my smoking patients is that if they’re worried about lung cancer, it’s 70 times more effective to stop smoking than to stop beta-carotene,” Dr. Ferris said. “However, in general, we don’t recommend that smokers take this formulation until they’ve stopped smoking for at least a year.”

Dr. Ferris noted that it is possible to approximate the AREDS formulation minus beta-carotene by taking a combination of the other recommended vitamins and minerals. There is no prospective controlled data, however, measuring the effect of such combinations on AMD progression.

Upper limit guidelines

Beta-carotene supplementation does not pose a risk to nonsmokers, according to Diane Feskanich, ScD, who has studied the changing nutritional needs of aging men and women at Harvard University’s Channing Laboratory.

She said that the Institute of Medicine of the National Academies did not set an upper limit on beta-carotene consumption because there is “no science” indicating that high levels could pose a risk to nonsmokers. (Beta-carotene is different from the retinol form of vitamin A, which can cause a decrease in bone density at high levels, according to Dr. Feskanich’s research.)

The Institute of Medicine established a committee in 1998 to determine the upper limits for vitamins and minerals. While the levels of vitamins C and E in the AREDS formula conform to the upper limit guidelines, the level of zinc is double the upper limit determined by the committee.

“Zinc is a nutrient that’s been studied for a long time, but we really don’t know on the everyday level what long-term consumption will do,” said Robert J. Cousins, PhD, a professor of nutrition at the University of Florida, Gainesville. “The macular degeneration study (AREDS) is probably one of the longer zinc supplement trials that’s ever been run.”

Complications from zinc

One of the few documented side effects to taking zinc is anemia, Dr. Cousins said. This risk can be managed if patients increase the amount of copper in their diets because the two minerals compete for absorption, he said.

Dr. Ferris said that the AREDS researchers conducted yearly hematocrit testing on all participants, and while there was an increased risk of reported anemia in the participants taking zinc, there were no differences in hematocrit levels. He attributes this finding to the addition of copper to the study formulation. However, researchers did see an increased incidence of genitourinary complications, he said.

“This sounds vague, but it’s vague because it only becomes statistically significant if you pool all of the problems together, all of the reasons people might go to the hospital for genitourinary problems,” he said. “There is some biologic plausibility to the fact that maybe this would increase (genitourinary) problems because … there is a high concentration of zinc in the prostate.”

Dr. Ferris also said that he would advise patients who are taking anticoagulants such as Coumadin (warafin sodium, DuPont) to avoid high levels of vitamin E.

Vitamin E causes red blood cells to become fragile and at high levels will increase the risk of hemorrhagic stroke, according to Dr. Erdman. While the overall risk of stroke is small, he said, risk could be increased by as much as 45% in patients taking vitamin E.

Supplements on the market

Bausch & Lomb collaborated with the NEI on developing the AREDS formula and was the sole corporate sponsor of the AREDS trial. The formula, which Bausch & Lomb markets under the trade name Ocuvite PreserVision, was the only vitamin and mineral formulation tested in the trial.

“The most meaningful difference between the high-potency antioxidant and zinc formulation used in the AREDS trial and other nutritional supplements is that no other supplement has ever been tested or evaluated in such a large, well-controlled clinical trial,” said Stephen P. Bartels, PhD, vice president of pharmaceuticals new product development at Bausch & Lomb. He said that in addition to PreserVision, Bausch & Lomb markets the Ocuvite line of eye health vitamins, including Ocuvite Lutein, which contains 6 mg of lutein per tablet with no beta-carotene.

Since the release of the AREDS results, a number of other pharmaceutical companies have developed supplements based on the study formulation. A daily dose of Bausch & Lomb’s Ocuvite PreserVision or Alcon’s ICaps contains 28,640 IU of beta-carotene, 400 IU of vitamin E and 69.6 mg of zinc.

Suzie DeMent, a spokeswoman for Alcon, said that the company believes that AREDS demonstrated the benefit of this combination of vitamins and minerals with little observed side effects for a disease with no current available treatment. Alcon offers an ICaps AREDS formula as well as another formula containing lutein and zeaxanthin, natural pigments also thought to be important in the age-related disease process, she said. The ICaps lutein and zeaxanthin formulation contains a lower level of beta-carotene, amounting to 6,600 IU, Ms. DeMent said.

ScienceBased Health also offers three MacularProtect formulations, including one that is appropriate for smokers, according to the company. At 2,500 IU, MacularProtect Plus contains 90% less beta-carotene than the company’s other two products. All three formulations contain 400 IU of vitamin E and 80 mg of zinc.

Penny Edwards, MPH, CNS, a nutrition scientist for ScienceBased Health, said that many of the potential adverse effects associated with zinc are prevented by the addition of copper, and for those with AMD the demonstrated benefits of high-dose zinc surpass any theoretical downsides.

She added, however, that the nutrients might interact with or affect the absorption of certain antibiotics, such as quinolones, taken concomitantly.

Careful monitoring

“We feel that high-dose supplementation really needs to be administered by and monitored by a physician,” Ms. Edwards said. “We encourage eye care practitioners to communicate with a patient’s primary care doctor.”

ScienceBased Health offers eye care practitioners a letter that they can send to a patient’s primary care physician, alerting him or her about the benefits and possible side effects from the supplements, she said.

Dr. Ferris emphasized that the therapy has the most benefit for patients who have already lost vision in one eye and are at the greatest risk of developing advanced AMD in their fellow eye. “So for them, it would seem to me, that the risks of supplements are well outweighed by the benefits,” he said.

chart
Source: Information supplied by the investigating companies.

For Your Information:
  • Stephen P. Bartels, PhD, can be reached at 1400 N. Goodman St., Rochester, NY 14609; (585) 338-5399; e-mail: stephen_bartels@bausch.com.
  • Robert J. Cousins, PhD, can be reached at 201A Food Science and Human Nutrition Building, PO Box 110370, Gainesville, FL 32611; (352) 392-2133; e-mail: cousins@ufl.edu.
  • John W. Erdman, PhD, can be reached at 449 Bevier Hall, 905 South Goodwin Ave., Urbana, IL 61081; (217) 333-2527; fax: (217) 333-9368; e-mail: jwerdman@uiuc.edu.
  • Frederick L. Ferris, MD, can be reached at the National Eye Institute, 31 Center Drive, MSC 2510 Building 31, Room 6A52, Bethesda, MD 20892; (301) 496-6583; fax: (301) 496-2297; e-mail: rickferris@nei.nih.gov.
  • Diane Feskanich, ScD, can be reached at Channing Laboratory, Harvard Medical School, 181 Longwood Ave., Boston, MA 02115; (617) 525-0343; e-mail: diane.feskanich@channing.harvard.edu.
  • Alcon Laboratories, manufacturer of ICaps, can be reached at 6201 South Freeway, Fort Worth, TX 76134; (800) 862-5266; fax: (817) 241-0677; Web site: www.alconlabs.com.
  • Bausch & Lomb, manufacturer of Ocuvite PreserVision, can be reached at 1400 N. Goodman St., Rochester, NY 14609; (585) 338-5212; fax: (585) 338-0898; Web site: www.bausch.com.
  • ScienceBased Health, manufacturer of the MacularProtect product line, can be reached at 3579 Highway 50 East, Carson City, NV 89701; (888) 433-4726; fax: (888) 433-6726; Web site: www.sciencebasedhealth.com.
References:
  • Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta-carotene and zinc for age-related macular degeneration and vision loss. AREDS Report No. 8. Arch Ophthalmol. 2001;119:1417-1436.
  • Supplementation with antioxidants, zinc may delay AMD progression. Ocular Surgery News. November 15, 2001.
  • Omenn GS, Goodman GE, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334:1150-1155.
  • Virtamo J, Pietinen P, et al. Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA. 2003;290:476-485.