Macular Degeneration and Nutritional Supplementation J. Daniel Friederich, OD, FAAO

Transcription

1 Macular Degeneration and Nutritional Supplementation J. Daniel Friederich, OD, FAAO Disclosure Statement I do not have any relevant financial relationships with any commercial interests Please Silence All Mobile Devices Learning Objectives Decsribe macular degeneration s (AMD S) signs, symptoms, and pathogenesis Examine research on nutritional supplementation as it relates to the prevention and progression of macular degeneration Review commonly-prescribed ocular nutritional supplements Outline the treatment of exudative AMD 1

2 Age-Related Macular Degeneration (AMD/ARMD) #1 cause of blindness in US among pts > 65 years of age Disease of the elderly Present in 10% > age 52 up to 33% > 75 As Many as 13 million Americans > 65 have suffered some loss of vision from advanced ARMD Number expected to double by 2020 As many as 200,000 new cases of wet ARMD diagnosed every year AMD is Broadly Classified into two Categories: Dry (Non-Exudative) Dry generally precedes wet Accounts for the majority of diagnosed AMD cases Wet (Exudative) Responsible for the vast majority of significant visual disability with the disease 2

3 The Macula 3

4 AMD Progression Top/Innermost Layer - RPE Middle Layer - Bruch s Membrane Bottom/Outermost Layer Choroidal Vasculature Case 84 y/o Caucasian male - SM Black spot in center of vision of left eye Started 4 days ago VA is 20/20 right eye and 20/30 left eye Had been 20/20 at last annual exam Dilated fundus examination performed 4

5 Right Retina Left Retina 5

6 Fluorescein Angiography Pathogenesis Top/Innermost Layer - RPE Middle Layer - Bruch s Membrane Bottom/Outermost Layer Choroidal Vasculature 6

7 Risk Factors Which of the following are AMD risk factors? A. Genetics B. Dietary Habits C. Cardiovascular Health D. Smoking E. Fair Skin F. Light Eyes G. All of the Above Risk Factors Which of the following are AMD risk factors? A. Genetics B. Dietary Habits C. Cardiovascular Health D. Smoking E. Fair Skin F. Macular Pigment Density G. All of the Above AMD s pathogenesis is likely multifactorial, involving a complex interaction of metabolic, functional, genetic, and environmental factors 7

8 Dry AMD Currently mainstay treatment for Dry AMD revolves around prevention of progression Vitamins, nutrition, and lifestyle changes Numerous studies have shown that a high intake of supplements with antioxidants, such as vitamin C, E, beta-carotene, zinc, omega-3 FA s, lutein, and zeaxanthin, slows the advancement of AMD Age-Related Eye Disease Study (AREDS) Sponsored by the Federal Government s National Eye Institute Randomized, placebo-controlled, double-masked clinical trial Followed 3,640 patients ages for a minimum of 5 years, monitoring them for progression to wet AMD 8

9 Ocular Inclusion/Exclusion Criteria Patients had to have: Visual acuity of 20/32 or better Media clear enough to see retina Pupils that dilate larger than 5 mm Patients could not have: Diabetic retinopathy in either eye Active uveitis Any other sight-threatening eye diseases: optic atrophy, epiretinal membrane, macular hole, retinal vein occlusion, etc. Ocular Exclusion Criteria Patients could not have (continued): Uncontrolled intraocular pressure Previous ocular surgery (except uncomplicated cataract surgery > 6 months earlier) Systemic or ocular medications known to be toxic to the lens, retina, or optic nerve (i.e. hydroxychloroquine, tamoxifen) Cancer, uncontrolled cardiovascular disease, chronic alcoholism or drug abuse 9

10 AREDS Patients Severity Categories Category 1: A few small or no drusen Category 2: Several small drusen or a few medium-sized drusen in one or both eyes, or pigment abnormalities Category 3: Many medium-sized drusen or one or more large drusen in one or both eyes, or noncentral geographic atrophy Category 4: Advanced AMD in one eye only, or vision loss due to AMD in one eye (choroidal neovascularization, geographic atrophy involving center of macula, nondrusenoid retinal pigment epithelial detachment, retinal detachment, subretinal hemorrhage, or subretinal fibrosis) AREDS Treatments Patients received one of four treatments: 1) zinc alone (80 mg of zinc as zinc oxide) 2) antioxidants alone (500 mg vitamin C, 400 IU vitamin E, 15 mg beta-carotene, 2 mg of copper as cupric oxide) 3) combination of zinc and antioxidants 4) Placebo 10

11 AREDS Results Patients with no AMD or early AMD (Category 1 and 2) showed a rate of progression to advanced AMD that was too low to assess treatment effects The AREDS results demonstrated no benefits for this group This low-risk group constitutes the majority of patients under the age of 70 years AREDS Results Patients with intermediate AMD (Category 3) and advanced AMD (Category 4) taking both high-dose antioxidants and zinc had a 20% chance of developing advanced AMD compared with a 28% chance for placebo patients (more than a 25% reduction of risk) The reduction in risk for advanced AMD for those taking zinc alone was 21%, and for those taking antioxidants alone was 17% 11

12 Percentage of Category 3 and 4 Patients that Progressed to Wet AMD 5 0 A + Z Zinc Alone Antioxidants Alone Placebo AREDS Adverse Effects No statistically significant serious adverse effects from nutritional supplements were reported Hospitalizations for genitourinary disorders were more frequent for male and female participants receiving zinc 12

13 AREDS Treatment Recommendations Patients with intermediate or advanced AMD (category 3 or 4) should consider taking high-dose antioxidants with zinc on a daily basis No benefit displayed for category 1 and 2 patients does this mean that we don t prescribe for them? Case SM was not taking ocular supplementation, though he had been educated about its benefits and it had been recommended 84 y/o with a fixed income Supplements cost $$$ Not covered under Rx drug plans Not worth it to many of the elderly and their families figure they ll be dead before blind 13

14 Prevention with Supplementation What percentage of non-supplemented patients with intermediate or advanced AMD will NOT progress to wet AMD over the next 5 years? A. Over 80% B. Over 70% C. Over 60% D. Over Half Percentage of Category 3 and 4 Patients that Progressed to Wet AMD 10 0 A + Z Zinc Alone Antioxidants Alone Placebo 14

15 Limitations of Supplementation Nutritional supplements can help some patients, but won t protect all patients from advanced AMD, because AMD is multifactorial in nature Some patients receiving the study medication continued to progress to advanced AMD and lose vision over time Supplement Ingredients Which ingredient should be avoided in smokers? A. Vitamin C B. Beta-carotene C. Lutein D. Vitamin E 15

16 Beta-Carotene and AREDS CARET Study (The beta-carotene And Retinol Efficacy Trial) Began in early 1980 s Thought was that vitamin A could be protective against development of cancer 18,000 participants chosen because of increased risk of lung cancer either from smoking or significant exposure to asbestos Given 30mg beta-carotene and 25,000 IU retinyl palmitate per day Study looked at development of lung cancer, cardiovascular mortality and all cause mortality Study was stopped before the scheduled completion date because those receiving supplements were found to be at significantly increased risk. Compared with placebo, the supplement group had: Lung Cancer: 28% increase incidence Cardiovascular Disease Mortality: increased All Cause Mortality: 17% increase Beta-Carotene and AREDS ATBC (Alpha-Tocopherol, Beta-Carotene) Cancer Prevention Trial 29,000 male smokers followed for 6 years in Finland Took vitamin E and beta-carotene (20mg per day) Physician s Health Study 11,000 male physicians followed for 12 years Half were current or former smokers Took beta-carotene (50mg on alternate days) Women s Health Study 40,000 health professionals followed for 2 years Took beta-carotene (50mg on alternate days) 16

17 Beta-Carotene and AREDS Data from all four of these studies was combined and analyzed for risk; published in Cancer July 2008 Combined total of 110,000 participants Half received beta-carotene supplement, half as control The risk of lung cancer in current smokers increases 24% with supplemental beta-carotene No statistically significant increase in risk for former smokers The increased risk of lung cancer returned to baseline after stopping the Beta-Carotene supplement AREDS2 Primary objective is to evaluate the effect of lutein and zeaxanthin, and/or omega-3 fatty acids (including DHA and EPA) on progression to advanced AMD Lutein, zeaxanthin and meso-zeaxanthin represent the majority of all retinal carotenoids Lutein and zeaxanthin are garnered from dietary intake Evidence suggests that meso-zeaxanthin is primarily formed during chemical reactions within the retina Enrollment for AREDS2 concluded in June 2008 Over 4,000 study participants enrolled All participants are of Category 3 or 4 AMD severity Participants will be followed for 5-6 years The first official reports from AREDS2 are anticipated in

18 AREDS2 Treatments Patients are receiving one of four treatments: 1) Placebo for both lutein/zeaxanthin and EPA/DHA 2) 10mg lutein/2mg zeaxanthin and EPA/DHA placebo 3) Placebo for lutein/zeaxanthin and 350mg DHA/650mg EPA 4) 10mg lutein/2mg zeaxanthin and 350mg DHA/650mg EPA AREDS2 All participants were also offered original AREDS formulation Those who agree to take the AREDS formulation and consent to a second randomization are being given one of four alternative AREDS 18

19 Supplement Usage What percentage of patients that would benefit take an AMD supplement? A) 91% B) 76% C) 61% D) 43% Supplement Usage What percentage of patients that would benefit take an AREDS supplement appropriately? A) 91% B) 76% C) 61% D) 43% Charkoudian LD, et al. Vitamin usage patterns in the prevention of advanced age-related macular degeneration. Ophthalmology Jun;115(6): (61%) Hochstetler BS, et al. Adherence to recommendations of the age-related eye disease study in patients with age-related macular degeneration. Retina Sep;30(8): (43%) 19

20 AREDS 2 Formula Based on Original AREDS formula plus new evidence 452 mg vitamin C 400 IU vitamin E 70 mg Zinc, 2 mg Copper No Beta-carotene 1000 mg omega DHA, 650 EPA 10 mg lutein 2 mg zeaxanthin 2 soft gels BID $ a year ICAPS Lutein and Omega-3 One Softgel Daily 10 mg of Lutein 2 mg of Zeaxanthin 280 mg Omega-3 B Vitamins No Beta-carotene Best for early, or at risk patients $ a year 20

21 Patient Prescribing Considerations No disease but at high risk to develop Early, prevent further drusen formation? Intermediate Extensive, high-risk AMD? Supplement Lifestyle changes, carotenoids Carotenoids with or without lower antioxidants; no AREDS AREDS, consider carotenoids and omega- 3 AREDS 1 or AREDS 2 plus omega-3 Case SM was again educated about ocular supplements Started on AREDS 2, two softgels BID Annual cost of ~$350 Worth it? What about his wet AMD? 21

22 Wet AMD Treatment What is the current treatment of choice for wet AMD? A. Laser photocoagulation B. Intravitreal Injection of Avastin C. Photodynamic Therapy D. Intravitreal Injection of Lucentis Wet AMD Treatment Thermal Laser, Photodynamic Therapy Recurrence is common Outcome almost always delayed severe visual loss No visual improvement Anti-VEGF Agents (Avastin and Lucentis) Vascular endothelial growth factor (VEGF) plays key role in wet AMD pathogenesis Injected intravitreally Effectively control vision loss in 95% of wet AMD In over a third of patients, they improve vision! 22

23 Intravitreal Injection Avastin vs. Lucentis Lucentis (Ranibizumab) approved by FDA in June 2006 Bevacizumab (Avastin) is a lung and colon cancer drug not FDA-approved for wet AMD Global acceptance and widespread clinical use since 2006 Patient must be informed of its off-label use Both dosed every 4 weeks for 3 months to start Complications of Age-Related Macular Degeneration Treatment Trial (CATT) has put them head-to-head 2 nd year results released May 1, 2012 Similar effects on visual acuity, similar rate of adverse events Cost Avastin - $15-$50 per 0.3 ml injection Lucentis - $2500 per 0.3 ml injection 23

24 Case Continued SM informed of FDA status of bevacizumab (Avastin) vs. ranibizumab (Lucentis) SM elected to use therapy with Avastin, and it was injected intravitreally into the left eye without complication Gatifloxacin (Zymar) was prescribed for use qid OS for four days, and a follow-up visit was scheduled for one month Follow-up #1 Vision the same; leakage still present A second dose of bevacizumab was injected intravitreally into the left eye without complication RTC 1 month Follow-up #2 Case Continued Vision the same, submacular fluid still present SM received a third injection RTC 1 month Follow-up #3 His vision had returned to 20/20, and no submacular fluid present Instructed to F/U in 2 months No-show for Follow-up #4 Reached wife by phone and she stated SM in hospital for bone cancer SM died 3 months later 24

25 Summary AMD most common cause of blindness in elderly has devastating impact on vision, quality of life Nutritional supplementation is the only proven medical intervention to slow the progression of dry AMD to wet AMD If patient converts to wet AMD, there is still hope 25