Dietary Supplements and the Brain

A very important and interesting question is whether supplementation with vitamins or fish oil retards the process of senility which is broadly termed cognitive functioning. Some studies have shown that reduced dietary levels of betacarotene, vitamin C, or docosahexaenoic acid (DHA, an omega-3 fish oil) are associated with more rapid a decline in cognitive function in the elderly whereas other studies have found no differences.

As a physician I see all kinds of seventy-five year olds. Some exercise a lot, eat all the right things, maybe still work or volunteer, and read books or surf the internet. Others, who usually look older, mostly sit on their couches at home. Most people who are active eat a good diet. Many of the couch sitters don’t. That’s why it’s hard to tell if it really is the betacarotene, for instance, in the diet that reduced the decline in brain power or did the study just select out the healthier more active people who took the time to make a spinach salad?

It’s important that AREDS II is testing cognitive functioning. Some people in AREDS II will be randomized to beta-carotene or fish oil whereas other won’t be. The randomization process of five thousand people should result in a pretty good cross section in each group. Then if we find that the people who are getting fish oil keep their brain power, (or not), it may really be due to the fish oil. The AREDS II leadership should be commended for adding cognitive function tests to the follow-up protocol of this study.

References:

Grodstein F, Chen J, Willett WC. High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. The American Journal of Clinical Nutrition 2003; 77(4):975-984. PMID: 12663300

Maksai KH, Losonczy KG, Izmirlian G, Foley DJ, Ross GW, Petrovitch H, Havlik R, White LR. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology 2000;54(6):1265-1272. PMID: 10746596

Grodstein F, Kang JH, Glynn RJ, Cook NR, Gaziano JM. A randomized trial of beta carotene supplementation and cognitive function in men: the Physicians' Health Study II. Archives of Internal Medicine 2007;167(20):2184-90. PMID: 17998490

Dangour AD, Clemens F, Elbourne D, Fasey N, Fletcher AE, Hardy P, Holder GE, Huppert FA, Knight R, Letley L, Richards M, Truesdale A, Vickers M, Uauy R. A randomised controlled trial investigating the effect of n-3 long-chain polyunsaturated fatty acid supplementation on cognitive and retinal function in cognitively healthy older people: the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study protocol [ISRCTN72331636]. Nutrition Journal 2006;5:20. PMID: 16945130

McNeill G, Avenell A, Campbell MK, Cook JA, Hannaford PC, Kilonzo MM, Milne AC, Ramsay CR, Seymour DG, Stephen AI, Vale LD. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. Nutrition Journal 2007;6:10. PMID: 17474991.

Clear Sailing

Last March (March 1, 2007), I commented on the “Dear Dr.” letter sent from Genentech about the higher risk of stokes in patients receiving 0.5mg Lucentis® compared to those receiving 0.3mg. This risk was found in an interim analysis of the large SAILOR trial which compared the two doses. My general message in that blog was that we should withhold judgment until the one year results are known.

The one-year results have now been announced Dr. David Boyer. The stroke rates at one year in the SAILOR trial were 0.7% for the 0.3mg Lucentis group and 1.2% for the 0.5mg group. There was no significant difference between these two rates.

My blog on January 2, 2008 discussed a recent article that found the annual risk of stroke was about 3.5% in Medicare patients regardless whether they had AMD or not. Thus the stroke risks in the SAILOR trial were much lower than seen in the Medicare population as a whole. Does that mean that Lucentis protects against strokes? Probably not. The reason is probably because the SAILOR trial attracted healthier patients than found in an average Medicare population. This was no conspiracy. Doctors generally don’t offer trials to sick patients and sick patients often don’t want to participate in trials which require monthly follow-up visits and testing. So the SAILOR patients were healthier to being with. The results are still reassuring and show that Lucentis at either dose probably doesn’t increase the risk of stroke.

Reference:

1. Avery RL, Ho AC. Good News for Anti-VEGF Therapy. Retina Today 2008; 3(2):7.

Avastin versus Lucentis

A recent study from Bashshur and colleagues reported on 60 patients who were treated with Avastin® and then followed for one year. They gave their AMD patients one injection of Avastin 2.5 mg and then followed them monthly with OCTs. The injections were repeated every month until the macula was dry on OCT. If the OCT was dry, the authors didn’t give an injection but asked the patient to return in one month. The treatment paradigm was similar to the PrONTO study except in PrONTO, Lucentis® .5mg was used instead of Avastin and the patient first received three monthly injections followed by additional injections as needed. The other difference was that Bashshur and colleagues would not reinject if the eye showed persistent subretinal or intraretinal fluid after three injections. They believe that these eyes often remain stable. Therefore they would follow them and only reinject if they worsened. In the PrONTO study, any fluid on OCT was an indication for another injection.

I could criticize the paper because there were only 60 patients and nine of them were lost to follow-up. Still it struck me how similar these results were using Avastin to the results of the PrONTO study, (also a small study), which used Lucentis. The authors used 2.5mg of Avastin which is twice the 1.25mg dose usually used successfully in the US. The higher dose may be the reason however that most of their patients had a dry macula one month after the first injection. In my experience, 1.25mg of Avastin often doesn’t result in a dry macula at one month so maybe the higher dose is useful at least for the first dose.

The Comparison of AMD Treatment Trials (CATT) is starting and will be the definitive study comparing Avastin to Lucentis for the treatment of wet AMD. The results of Bashshur and colleagues however predict that at most, we’ll find only a modest difference between the two drugs.

References:

1. Bashshur, ZF AJO 2008;145:249-256.

2. Lalwani GA, Fung AE, Michels S, Dubovy SR, Feuer WJ Jr, Puliafito CA, Rosenfeld PJ. An OCT-Guided Variable-Dosing Regimen With Ranibizumab (Lucentis) in Neovascular AMD: Two Year Results of the PrONTO Study (Poster Session 247. 1834/B694) ARVO Annual Meeting: The Aging Eye. May 6-10 2007, Fort Lauderdale, FL. Available at http://tinyurl.com/yt5fwd. (you will need to enter "Pronto" in the search field and restrict it to "presentation title").