Vitamins and Age-related Macular Degeneration

Vitamins and Age-Related Macular Degeneration

Comments and Opinions from the
Minnesota Lions Macular Degeneration Center
University of Minnesota Department of Ophthalmology
Based on the Original
 Age-Related Eye Disease Study (AREDS)¹
Report #8 and other published data
(updated 3/6/2007)

If you or someone you know has Age-related Macular Degeneration (AMD), you should be aware of an important recent study called the Age-Related Eye Disease Study (AREDS).¹  The study reports the beneficial effect of antioxidants (Vitamin C, E, beta-carotene and zinc-copper supplements) delay progression of AMD.  Estimates reported from the AREDS report² indicate that if all individuals with category 3 or 4 macular degeneration took these supplements, approximately 300,000 people in the United States alone would be spared from suffering vision loss that they would have suffered had they not taken antioxidants over the ensuing 5 years.  

• Those over 50 or with a family history of AMD should be evaluated by an ophthalmologist to determine their level of AMD.
• Individuals with levels 3 or 4 AMD should consider taking vitamins.
• There is an increased association of lung cancer in smokers treated with beta-carotene.
• Zinc supplements may increase the risk of genitourinary complications.
• Individuals taking cholesterol or lipid-modifying medications should consult their physician.

IMPORTANT CONCEPT:  A vitamin pill is no substitute for a healthy lifestyle:

• DON’T SMOKE
• Low-fat diet
• Plenty of fresh fruits and especially green leafy vegetables, & nuts
• Fish intake (>3x/wk)
• Regular exercise (walking counts!)
• Wearing sunglasses and/or hat to protect against chronic sun exposure.

What exactly was the dose of antioxidants used in this trial?
Antioxidants:          Vitamin C             500 mg
                                Vitamin E             400 IU
                                Beta-carotene      15 mg
Zinc:                                                   80 mg zinc oxide
                                                           + 2 mg of copper as cupric oxide
(Note:  The use of zinc alone may lead to copper deficiency)
                  
OCUVITE PRESERVISION          PLUS            CENTRUM SILVER
SMOKER’S VERSION:  NO Beta Carotene, Adds Lutein instead (** See next page)
GEL CAPSULES:  Easier to take; One Gel-Cap 2x/day (Morning and Evening)

**RECENT ARTICLE: Researchers from Denmark³ examined 68 trials that compared various anti-oxidants in "low-bias-risk" studies (including nearly 181,000 participants).  They found:

• Taking vitamin A supplements increased the risk of death by 16 percent
• Taking beta-carotene supplements increased the risk of death by 7 percent
• Taking vitamin E supplements increased the risk of death by 4 percent
• Taking vitamin C supplements did not have any effect on risk of death
• Selenium may have a beneficial effect on longevity

Many of the studies reviewed, used anti-oxidant dosages much higher than those used in AREDS.  An important point from this analysis is that if a little of a vitamin is good, a lot (higher doses) may not be good.  In fact, it may be harmful.  This study looks at a highly variable population, open to criticism.

Other Common Questions about the AREDS Study

1)   What is AMD?
Age-related macular degeneration is an aging change in the back of the eye that may lead to loss of the central vision.  It is the leading cause of “legal blindness” in the western world in individuals over age 50.  The early stages are extremely common.  The eye is like a camera, and the retina is the film in the back of the camera.  Aging results in the accumulation of yellow pigment deposits, or drusen, under the retina.  Drusen are common, and they come in many shapes and sizes.  The AREDS categorized and counted the drusen to determine the effects of vitamin therapy on various categories of drusen in volunteers who participated in the study.

2)   What should I do if I may have AMD?
Contact your ophthalmologist to determine whether you have AMD, and if so, what category of drusen is present.  The ophthalmologist will examine the back of your eye using dilating drops to check for drusen or other changes.

3)   What was the beneficial effect for those with certain types of drusen?
Beneficial effect was classified as either a decrease in the progression to advanced AMD or less progression of vision loss from AMD.  For the intermediate level of drusen, the risk of reduction in progression to advanced AMD in those taking antioxidants plus zinc compared with placebo was 20-30%.  The reduction in progression to advanced AMD is also reflected in visual acuity scores.

4)   What should individuals do who have “mild” drusen?
Current recommendations are to defer consideration of the supplementation used in this trial until the risk of progression is higher.  There is no evidence from the AREDS Study at this time that either antioxidants or zinc, at the higher doses, decrease the rate of progression from category 1 or 2 to categories 3 or 4. Some may suggest that this study provides “Proof of Principle” that antioxidant vitamins for the treatment of AMD and therefore taking vitamins is beneficial for decreasing progression of all AMD.  The study does not support this statement.  This is the first study to clearly demonstrate that a relatively safe systemic therapy does effectively decrease progression of AMD.  A “neutral” recommendation about antioxidant therapy for earlier stages seems warranted at this time. 

5)   What was the placebo group taking, and should I continue taking a Multivitamin in addition to the special supplement?
All patients took a vitamin pill twice daily of identical size, shape and color.  The placebo group’s vitamin did not contain antioxidants or zinc.  However, in all groups (including placebo controls), patients were allowed to take a Centrum multivitamin.  Approximately 68% of participants continued to take a Centrum during the course of the study.  It is reasonable to continue taking a multivitamin in addition to the supplements.

6)   Were blood tests used to document systemic levels of antioxidants?
Four clinical centers collected baseline samples for various antioxidants plus total cholesterol, high-density lipoproteins, triglycerides, lutein, zeaxanthin, lycopene and cryptoxanthin.  Three centers continued to collect samples annually.  Hematocrit was also measured regularly at all centers.  No significant anemia or blood lipid changes were found.

7)   Were there safety issues involved with the use of antioxidants and/or zinc?
Individuals on zinc therapy were slightly more prone to urinary tract infections, prostatic hyperplasia (in men) and stress incontinence (in women).  Based on the harmful effects of beta-carotene associated with smokers,⁴ participants who were current or former smokers were given the opportunity to be assigned to a study medication that excluded the antioxidant component because of the association reported with lung cancer.  For these reasons, people who smoke cigarettes should avoid taking the beta-carotene component of the antioxidants.  In 2004 AREDS report #13⁵ reported lower mortality in those on zinc supplements than those not taking zinc (suggesting a protective effect that remains unexplained for those on zinc).  More data is required to investigate this unexpected finding.  

8)   Were there minor side effects or complications?
Individuals who took antioxidant vitamins had a higher incident of “yellow skin.”  Also, individuals in the antioxidant groups had less frequent “circulatory” events than the placebo group.  No statistical changes in mortality were reported in any of the groups as compared to controls.

9)  What is the impact of Lutein and Zeaxanthin based on the AREDS results?
Unfortunately, neither Lutein nor Zeaxanthin were studied as part of the AREDS trial, and no definitive comment can be made regarding their use.  Lutein and zeaxanthin are the predominant carotenoids in the human macula.  Studies have shown an increased level of macular Lutein in those supplemented with Lutein.⁶  Theoretically, yellow macular pigment may act as a filter to the shorter wavelength, higher energy blue light.  Most common multivitamins, such as Centrum, some of the Ocuvite formulations and I-caps, include Lutein in their formulation. Lutein is found in many vegetables, probably the best source.

10) Are there criticisms of the AREDS Study?
The power of the study is supported by a large number of participants:  category 1 (1117), category 2 (1063), category 3 (1621), category 4 (956).  Another important consideration is to consider the trends of the study that do not reach statistical significance.  Many trends did show a potential treatment benefit.  Only time will more definitively answer questions regarding some of these trends.  Alternatively, long-term effects of supplemen­tation may reveal side effects that were not apparent in this initial report.  Future results from this study will add important information to these results.

11) What other associations of supplementation with medical conditions should we be aware? 
Brown and colleagues⁷ examined patients with coronary artery disease and low levels of high-density lipoprotein (HDL or “good cholesterol”) were treated with one of four treatment groups:  simvastatin plus niacin, antioxidants, simvastatin plus niacin plus antioxidants, or placebo.  They found that the protective effect of increasing HDL cholesterol was attenuated by concurrent therapy with antioxidants.  While the dosages of antioxidants were higher (Vit. E 800 IU, Vit. C 1000 mg, Beta-carotene 25 mg, and selenium 100 mg.), the use of antioxidants in this setting requires further patient education. 

There is discussion⁸ that cerebral zinc may play a role in the evolution of Alzheimer’s disease.  Recent reviews⁹ have reached inconclusive recommendations on this association.  In fact too little may promote more rapid aging and mental decline, too much may also be harmful.  Like many nutrients, ‘just right’ dosing is best.  Hyperzincemia has also been suggested to aggravate glucose intolerance in non-insulin dependent diabetics.¹⁰

12) I have heard that higher dosages of Vitamin E are harmful. 
Miller and colleages¹¹ performed a large-scale analysis of individuals taking Vitamin E, pooling results from 19 clinical trials, approximately 136,000 people total.  They found that that those who took higher dosages of Vitamin E (>400 IU) had more deaths than those who used less Vitamin E:  39 deaths per 10,000 in higher dose vs. 19 deaths per 10,000 in the lower dose (a significant difference).  Experts from the AREDS trial have indicated that in the AREDS Study, there was no increase in mortality in those on 400-450 IU of Vitamin E in the trial.¹²  The addition of a multivitamin (Centrum) with the AREDS supplement increases the Vitamin E levels by approximately 45 IU for a total of 445 IU.  This study indicates caution with higher levels of Vitamin E (again, more is not always better!).  We feel that 445 IU is safe in the setting of level 3 or 4 AREDS AMD, but additional vitamin E supplementation should be avoided .

13) AREDS II
In 2006, a second phase of the AREDS study was initiated to look at the use of omega-3 fatty acids (version of fish oil), zeaxanthin (a macular pigment that may help protect the macula from oxidative injury and light damage), and lutein (found in green leafy vegetables).  This study is sponsored by the National Eye Institute with 2 years of recruitment and approximately 10 years of follow-up.  They will also study the use of lower dosages of zinc (40 mg instead of 80 mg).  Finally, the study will look at the use of lutein in place of beta-carotene in smokers.

1.     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;119:1417-36.
2.     Bressler NM, Bressler SB, Congdon NG, et al. Potential public health impact of Age-Related Eye Disease Study results: AREDS report no. 11. Arch Ophthalmol 2003;121:1621-4.
3.     Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in Randomized Trials of Antioxidant Supplements for Primary and Secondary Prevention: Systematic Review and Meta-analysis. Jama 2007;297:842-57.
4.     Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-5.
5.     Clemons TE, Kurinij N, Sperduto RD. Associations of mortality with ocular disorders and an intervention of high-dose antioxidants and zinc in the Age-Related Eye Disease Study: AREDS Report No. 13. Arch Ophthalmol 2004;122:716-26.
6.     Berendschot TT, Goldbohm RA, Klopping WA, van de Kraats J, van Norel J, van Norren D. Influence of lutein supplementation on macular pigment, assessed with two objective techniques. Invest Ophthalmol Vis Sci 2000;41:3322-6.
7.     Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med 2001;345:1583-92.
8.     Kaiser J. Alzheimer's: could there be a zinc link? Science 1994;265:1365.
9.     Exley C. Aluminium and iron, but neither copper nor zinc, are key to the precipitation of beta-sheets of Abeta_{42} in senile plaque cores in Alzheimer's disease. J Alzheimers Dis 2006;10:173-7.
10.    Raz I, Karsai D, Katz M. The influence of zinc supplementation on glucose homeostasis in NIDDM. Diabetes Res 1989;11:73-9.
11.    Miller ER, 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37-46.
12.    Chew EY, Clemons T. Vitamin E and the age-related eye disease study supplementation for age-related macular degeneration. Arch Ophthalmol 2005;123:395-6.