Preventing and Treating Macular Degeneration: Is TOZAL the Answer?

Nobody wants to lose their vision. Once you hit age 65, age-related macular degeneration (AMD) is the most common cause of vision impairment/loss, affecting about 1 in 5 people. [1] [2] There is some evidence that vitamin supplements can help protect your eyes. But can a new supplement actually improve your vision? If you have seen the marketing for the TOZAL supplement, you might think so. Let’s look at AMD, the science supporting supplements, and then the clinical study conducted with TOZAL.

What is Macular Degeneration?

The macula is a small area in the center of the retina of the eye that provides us with the highest resolution of vision, making activities like driving and reading possible. As we age, waste deposits called “drusen” accumulate under the retina. Large drusen indicate one is at high risk of future macular degeneration. Two forms of macular degeneration have been observed: atrophic (“Dry”) and neovascular (“Wet”), terms which describe the retina’s appearance under examination. Dry AMD is more common (90%), yet less severe than wet AMD. [3] [4] With dry AMD, rods and cones die. In wet AMD, central vision is distorted by blood vessels which grow under the retina and macula.

With both types of AMD, complete vision loss is infrequent – peripheral vision is usually maintained. [3] With AMD, if you were looking at a package of TOZAL, it might look like the image above. However, as the leading cause of adult blindness and severe visual impairment in industrialized countries, AMD is a significant and growing health concern in our ageing population.

Causes of AMD

Despite the prevalence of AMD, little is known about the cause. Age is the single biggest risk factor. [4]Other factors that may be important include smoking history, female gender, Caucasian race, high blood pressure, obesity, and diet. [4]

Prevention and Treatment

There are few treatment options for AMD, and no known cure. [4] Significant research has focused on prevention, particularly whether dietary manipulation (through supplements of antioxidants and minerals) can treat and even prevent AMD. Given the significance of vision loss, when evaluating treatments, we would be willing to accept less scientific rigor if the product is demonstrably safe and may show some efficacy in preventing vision. Given the slow onset of AMD, large, prolonged trials are necessary to demonstrate the effectiveness of different treatment strategies. Fortunately, some of this research exists.

Antioxidants plus zinc are recognized as an evidence-based treatment option to prevent and treat AMD in high-risk patients. The landmark National Eye Institue (NEI) Age-Related Eye Disease Study (AREDS) study determined that antioxidants plus zinc slow the progression of AMD in those already with the disease. [1] This massive trial studied 3640 participants aged 55­ – 80 over a six-year period. Patients were divided into four groups, and received either antioxidants, zinc, antioxidants with zinc, or a placebo. Patients and researchers did not know which treatment was being given (i.e., the study was double-blind). Patients received complete eye examinations at the beginning of the study, and then every six months thereafter. Vision was assessed using standard measurement tools.

The researchers wanted to determine if supplementation would (1) reduce progression to AMD and (2) reduce vision loss. This was a very well done, high quality, extensively documented clinical trial.

The results were as follows: Overall, the risk of developing AMD in the placebo group over 5 years was calculated to be 27.8%. In people taking antioxidants and zinc, this risk dropped to 20.2%. This means the supplement gave a relative risk reduction of 27%, or an absolute risk reduction of 7.6%. More simply, thirteen patients at moderate to high risk of AMD need to be treated for five years to prevent one person from developing advanced AMD. [5] Importantly, patients with no AMD, or early AMD, showed no benefit from the supplement.

The AREDS trial was published in 2001, and research has continued since then.  The AREDS2 study is a follow-up trial to the AREDS trial and is still recruiting patients. The formula that is being studied includes combinations of omega-3 fatty acids, along with vitamins C and E, lutein and zeaxanthin, beta carotene and zinc.

Since the publication of the AREDS trial, we’ve learned more about supplements and AMD. It guided what’s being studied in the AREDS2 trial. For example, we know now that the zinc dose was probably too high, as the body may not absorb more than about 25mg at a time (the AREDS dose was 80mg). We’ve also learned that vitamin E on its own doesn’t seem to offer any benefit, [6] and it might increase one’s risk of heart failure, too. [7] Not only is beta carotene bad for smokers, it might increase the risk of heart disease in non-smokers and smokers. [7] Let’s look at the current evidence for some other common supplements.

Carotenoid pigments (lutein and zeaxanthin) are found in leafy green vegetables (like  spinach) and are thought to possibly offer some protection to the retina from AMD. There’s interest in using lutein and zeaxantin as a substitute for beta carotene, which seems to raises the risk of lung cancer in smokers. [6] The evidence to demonstrate that lutein and zeaxantin are effective, however, remains weak. The current advice for those without AMD is to ensure that they are a part of your regular diet (for this and a number of other reasons). [8] But if you don’t have AMD, there’s no reason to take a special supplement. The AREDS2 trial is evaluating lutein and zeaxantin, so we should have an answer within the next several years. If you have AMD and want to take either, they do appear reasonably safe.

Omega-3 fatty acids are another food product thought to offer some benefit to eye health. Some studies suggest that those that consume fatty fish at least twice weekly are at lower risk of macular degeneration. [9] But it’s difficult to say if this is due to the fish, or if the fish consumption is just coincidental to another aspect of what is an overall healthy lifestyle. Just because the two are correlated, does not mean that one is caused by another. While the value of omega-3 fats in helping prevent AMD remains unproven, there are good reasons to consume omega-3 fats for a number of other health reasons. Fatty fish is an excellent source of DHA, and vegetarian alternatives exist. The role of omega-3’s are also being studied in the AREDS-2 trial, so we should have definitive information in a few years. If you don’t consume fish regularly, and want to supplement with Omega-3’s, the consumption of fish oil appears to be safe.

Other evaluation of vitamins and minerals

There’s little information to support broad supplementation to prevent AMD, particularly the general population (at low risk of AMD). The Cochrane Collaboration, in a review published in 2008, concluded that there is no justification for the general population to take antioxidant vitamins or minerals to delay the onset of AMD. [10]

Current recommendations by vision experts like the Canadian Ophthalmological Society support supplementation with the AREDS formula in patients with moderately advanced dry AMD.

The TOZAL Study: A Critical Review

There’s new interest in supplements for AMD with the arrival of the TOZAL (Taurine, Omega-3 Fatty Acids, Zinc, Antioxidant, Lutein) supplement. Recently launched in Canada, it’s distributed by the multi-level-marketing company Amerisciences. The TOZAL formula is summarized in the table below, and you can compare it with the AREDS formula. TOZAL has been evaluated in a single, small clinical trial – so let’s look at the science behind the hype.

The only study of this formulation appeared in BMC Opththamology in 2007. [11]There is only a single author, Francis Cangemi. To review the trial, we’ll use a standard series of questions to evaluate the quality of the study, and determine if TOZAL is all it’s claimed to be.

Is the study’s research question relevant?

The first question challenges you to find out exactly what the researcher set out to study, and if it’s applicable to the question at hand. The title of the paper describes the study as “An open case control study”, but in the text, it’s called “prospective, double-blind, 6-month trial”. So which is it? Whether or not the patients know if they’re receiving treatment can have a big impact on the credibility of the results. And while the abstract states that the primary objective was to evaluate a targeted nutritional supplement, the description of the methods shows this is not the case. If we wanted to evaluate if TOZAL helps AMD, or is superior to the AREDS formula, we would give one group of patients the TOZAL formula, and give a similar group a placebo (or the AREDS formula), and measure the effects. But the researchers actually didn’t do this. They actually set out to compare whether “microcurrent stimulation” would be an effective treatment option. (Microcurrent is a dubious “alternative” treatment for AMD which has not been demonstrated to have any meaningful effects. The American Association of Ophthalmology does not support its use.) Both groups were given the TOZAL formulation, one with real “microcurrent stimulation,” and one with fake “microcurrent stimulation.” No patients were given AREDS, and no patients received a placebo.

This change in the study design, without adequate disclosure of information, is a huge warning to the reader that the results are likely questionable. The only way the author could evaluate the microcurrent stimulation to be meaningless would be to compare it to the other group – and they don’t report any results. And if the patients demonstrated that microcurrent stimulation offered no benefit, then we must conclude that the supplement offered no benefit to these patients, too. Why? Each patient was tested at the beginning and the end of the study. If patients benefited from the supplement, both groups should have benefited. For the results to be credible, the author cannot simply make half of the patients disappear without reporting any results – especially in a trial as tiny as this one.

Did the authors do the right type of study?

As described above, the TOZAL study gave everyone the supplements. Half (36 patients) were then assigned to get microcurrent stimulation, and half (37 patients) a placebo microcurrent stimulation. So 73 patients were enrolled. Then the author notes the following:

The IRB (institutional review board, an independent ethics committee) for this study determined that standard of care for age-related macular degeneration must include an Age-Related Eye Disease Study (AREDS)-type nutritional supplement and that no true placebo arm would be permissible. A placebo arm was constructed from a review of the literature.

What? There was no group receiving a placebo. They were all receiving the supplement. If they wanted to test TOZAL against AREDS, the study should have been designed this way, and half of the patients should have been given the AREDS formula. But rather than do this, they looked at another published study, and copied the results for 15 patients – boom! – he made up an instant placebo group! This might be acceptable if patients were closely matched for risk factors for AMD. But in this case the author failed to demonstrate that the “constructed” placebo group was similar to the TOZAL group. Importantly, there’s no information given to show that the risk factors for AMD are the same between the groups. Without this information we cannot accept a comparison between the TOZAL group and the “placebo” group– the author has not demonstrated that they are similar enough.

Unfortunately, this did not appear to occur. Even more problematic, the trial that the author copied DID NOT use the AREDS formula – the amount of zinc and beta-carotene were different. Plus, the over 50% difference in the group size (37 versus 15) is problematic for the trial. No explanation is given.

So of the 73 patients that were enrolled in the study, and given the TOZAL formulation, the results only mention 34 patients. Having 39 patients omitted from the results is another big warning sign that this is low-quality study. Without disclosure of what happened to the other 39 patients, the reader should be suspicious of the results.

All of the concerns I have document suggest the potential for significant bias in the results. After two simple questions, we can confidently stop reading the trial, and reject the conclusion – this study was not designed to tell us if TOZAL helps prevent macular degeneration, and too many questions remain about how the study was developed.

But for the sake of completion, I will summarize the remainder of the study.

Patients received eye exams at the beginning of the study and again over a 6-month period. Patients were compared to themselves (beginning eye exam versus final eye exam). The author reported that overall, patients taking the supplement experienced vision improvement by half a line on an eye exam chart. (While the author reports this to be statistically significant, there appears to be no difference in the average visual acuity:

The dots are the estimates, and the bars are the 95% confidence intervals. As the bars between baseline and follow-up overlap, the change appears to be indistinguishable from random chance.

Most importantly for our purposes, the supplement had no effect on any measure of macular degeneration. This is not a surprise, as six months in insufficient to measure this. (The AREDS trial lasted 5 years.) So there is no basis to the claim that this product is an effective treatment for AMD. There is zero evidence to demonstrate that the TOZAL formula will have any impact on the progression of AMD.

We cannot draw any conclusions from the TOZAL study based on the significant, serious flaws in the design and reporting. (Clarifying questions to the study’s author went unanswered).

TABLE 1: FORMULATIONS OF DIFFERENT SUPPLEMENTS

Ingredient	AREDS FormulaSource	TOZAL – American VersionSource	TOZAL – Canadian Version Source
Vitamin C	452 mg	452 mg	452 mg
Vitamin E	400 IU	202 IU	200 IU
Beta carotene	15 mg (28,640 IU)	18,640 IU	–
Zinc	69.6 mg	69.6 mg	50 mg
Copper	1.6 mg	1.6 mg	2 mg
Vitamin A	–	10,000 IU	9925 IU (3000mg RAE)
Lutein	–	10 mg	10 mg
Zeaxanthin		0.5 mg	0.5 mg
DHA (from fish oil)		240 mg	240 mg
Taurine		Not specified	400 mg
EPA (from fish oil)		360 mg	360 mg
Grape skin extract     (30% anthocyanocides)		Not specified	41.6 mg

It’s important to note that the TOZAL formula differs slightly based on country – the Canadian version has different amounts of beta carotene,  zinc, and copper. The amounts of taurine and grape skin extract are not specified in the American version, but both are noted as being included in the formulation.  There is no published evidence that the Canadian version has been evaluated, so we cannot form conclusions about its efficacy, compared to the version that was studied.  And as we know about AMD, the particular combination of supplements appears to be important – that’s why we need the AREDS2 study data to draw firm conclusions.

It’s also concerning that the TOZAL formulation is being advertised to optometrists to sell directly and the reason seems to be profit, not patient care. Here is an excerpt of an online ad from easypracticprofits.com :

Let me ask you a question … how much money are you making when you recommend PreserVision, Ocuvite or ICaps to one of your patients?  I’ll tell you how much … nada, zero, zip!  Yet what most doctors are doing is pulling out their Rx pad and writing the name of an OTC eye supplement when treating a patient with or at risk for AMD.  I must admit, for many years I did the same thing.

I finally WOKE UP and said to myself  – why I’m I letting money walk out the door?

Instead of recomending PreserVision, Ocuvite or ICaps to your patients, you’ll recommend TOZAL Eye Health Formula.

Recommending TOZAL Eye Health Formula to just 2 patients a day will generate over $180,000 in your 2nd year.

So before you accept your optometrist’s advice, or anyone else’s advice to take TOZAL, consider the source – is there a conflict of interest? Genuine medical advances don’t appear by multi-level-marketing. Despite claims to the contrary, only the AREDS formulation has been shown to benefit AMD.

Conclusion

The AREDS formulation is the current “standard of care” for those at high risk of macular degeneration. There is no persuasive evidence yet to demonstrate that this has changed with the TOZAL study.

Here are some general guidelines to discuss with your health/eye care professional [12]:

Non-Smokers at Risk of AMD: Until better evidence emerges, the AREDS formulation continues to be the evidence-based supplement of choice for people at high risk of AMD. Adding omega-3 fats in the diet is unlikely to harm and may provide some benefit. There isn’t enough evidence to support supplementing with lutein yet.

Smokers: Smokers at high risk of AMD should consider taking the AREDS formula (without the beta carotene) or zinc alone. The biggest modifiable factor to reduce the risk of AMD would likely be to stop smoking.

General public (low risk of AMD): Despite extensive study, there is no persuasive evidence that antioxidant or vitamin supplements have any impact on the risk of AMD. However, dietary changes that may reduce the future risk of AMD are consistent with what we already know to be a healthy diet. Lots of fruits and vegetables, with good sources of lutein (e.g., kale, spinach, chard) as well as omega-3 fats (e.g., fish) are smart choices for everyone, regardless of your age, or risk of AMD. Maintaining a health weight, and reducing the consumption of simple carbohydrates (sugary foods, white bread, etc.) is also good advice for everyone and may reduce your risk as well. Supplementing with lutein or omega-3 fats is unlikely to be harmful, but there isn’t enough evidence to demonstrate that they will provide any benefit.

Patients with AMD: Any patient at risk of AMD should see if they are eligible to participate in the AREDS2 trial.  If not, the only supplement proven to help AMD is the AREDS formula. Because of the high doses of beta carotene and vitamin E in the TOZAL formula (US) and the AREDS formula, they’re not recommended unless advised by a health professional.

Other Useful Resources

Canadian Opthalmological Society: What is Macular Degeneration? [PDF]

National Eye Institute FAQs on AMD

Ageing Eye: The Eye Digest

UPDATE: July 17, 2009: When the article was originally posted, the manufacturer’s website, the source of the Canadian formulation, listed incorrect information. The manufacturer has updated their website to clarify the amount per serving. The table and text have been updated to reflect this revised information.

References

[1] 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(10):1417-1436.

[2]Penfold PL, Provis JM. Macular Degeneration.  Springer; 2004.

[3] Natural Medicines in the Clinical Managment of Eye Disorders: Age-Related Macular Degeneration, Cataracts, and Glaucoma [Internet]. [cited 2009 Jul 3] Available from: http://www.naturaldatabase.com

[4] Age-Related Macular Degeneration. Pharmacist’s Letter 2004; 20:200510.

[5] Kertes PJ, Johnson TM. Evidence-based eye care.  Lippincott Williams & Wilkins;  2007. pp 11-13

[6] Nutrition Action Healthletter. Centre for Science in the Public Interest 2009; May.

[7] Arroyo JG. Age-related macular degeneration: Treatment and prevention. In: UpToDate, Sokol, HN (Ed) UpToDate, Waltham MA, 2009.

[8] Nutrition Action Healthletter. Centre for Science in the Public Interest 2007; July/Aug.

[9] Nutrition Action Healthletter. Centre for Science in the Public Interest 2007; October.

[10] Evans JR, Henshaw K. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD000253. DOI: 10.1002/14651858.CD000253.pub2

[11] Cangemi, F. (2007). TOZAL Study: An open case control study of an oral antioxidant and omega-3 supplement for dry AMD BMC Ophthalmology, 7 (1) DOI: 10.1186/1471-2415-7-3

[12] Evans, J. (2008). Antioxidant supplements to prevent or slow down the progression of AMD: a systematic review and meta-analysis Eye, 22 (6), 751-760 DOI: 10.1038/eye.2008.100