Recent developments in the management of dry age-related macular degeneration

Figures & data

Table 1 Characteristics of AREDS 1 and AREDS 2^33,34

	AREDS 1		AREDS 2
Period	1992–2001		2006–2012
Design	Multicenter, phase 3, randomized controlled clinical trial		Multicenter, phase 3, randomized controlled clinical trial
Participants	3,609 eligible*		4,186 eligible
Average follow-up	6.3 years		5 years
Enrollment criteria	– Extensive small drusen, intermediate drusen, large drusen, noncentral GA, or pigment abnormalities in one or both eyes – Advanced AMD or vision loss due to AMD in one eye – At least one eye had best-corrected visual acuity of 20/32 or better		– Bilateral large drusen or nonfoveal GA – Large drusen or nonfoveal GA in one eye and advanced AMD in the fellow eye
Randomization	Supplementation		Primary		Secondary
	1. Antioxidants: vitamin C, 500 mg; vitamin E, 400 IU; beta-carotene, 15 mg 2. Zinc, 80 mg; and copper, 2 mg; 3. Antioxidants plus zinc 4. Placebo		1. Lutein, 10 mg; zeaxanthin, 2 mg 2. ω-3 LCPUFAs: DHA, 350 mg; EPA, 650 mg 3. Combination of 1 and 2 4. Placebo		1. AREDS 1 formulation unchanged 2. AREDS 1 formulation with zinc, 25 mg 3. AREDS 1 formulation without beta-carotene 4. Combination of 2 and 3
Primary outcomes	1. Photographic assessment of progression to or treatment for advanced AMD 2. At least moderate visual acuity loss from baseline (≥15 letters)		1. Photographic assessment of progression to advanced AMD
Secondary outcomes	1. Visual acuity loss attributable to AMD 2. Marked visual acuity loss 3. Visual acuity loss in eyes with advanced AMD at baseline 4. Development of neovascular AMD 5. Development of GA in the center of the macula** 6. Progression of AMD in category 2 participants		1. Effect of the primary randomization supplements on progression to moderate vision loss 2. Effect of the primary randomization supplements on progression of lens opacity 3. Effect of the primary randomization supplements on vision 4. Effect of the variations of the AREDS 1 supplements on progression to advanced AMD 5. Effect of the variations of the AREDS supplements on progression to moderate vision loss
Results	AMD progression			AMD progression in primary randomization
	Groups	Risk reduction in AMD categories 2, 3 and 4	Risk reduction in AMD categories 3 and 4	Groups	Risk reduction
	Antioxidants vs no antioxidants	Nonsignificant	Nonsignificant	Lutein + zeaxanthin vs placebo	Nonsignificant
	Zinc vs no zinc	Suggestive	Significant	DHA + EPA vs placebo	Nonsignificant
	Antioxidants vs placebo	Nonsignificant	Nonsignificant	Lutein + zeaxanthin + DHA + EPA vs placebo	Nonsignificant
	Zinc vs placebo	Suggestive	Significant
	Antioxidants + zinc vs placebo	Significant	Significant
	Visual acuity loss			AMD progression in secondary randomization
	Groups	Risk reduction in AMD categories 2, 3 and 4	Risk reduction in AMD categories 3 and 4	AREDS 1 supplement groups	Effect
	Antioxidants vs no antioxidants	Nonsignificant	Nonsignificant	Low-dose zinc vs original	Nonsignificant effect
	Zinc vs no zinc	Nonsignificant	Nonsignificant	No beta-carotene vs original	Nonsignificant effect
	Antioxidants vs placebo	Nonsignificant	Nonsignificant	Low-dose zinc and no beta-carotene vs original	Nonsignificant effect
	Zinc vs placebo	Nonsignificant	Nonsignificant
	Antioxidants + zinc vs placebo	Suggestive	Significant

Notes:

* Study participants enrolled in the AMD clinical trial;

** From point 1 to 5, the analysis of secondary outcomes was restricted to AREDS categories 3 and 4.

Abbreviations: AREDS, Age-Related Eye Disease Study; AMD, age-related macular degeneration; DHA, docosahexaenoic acid, EPA, eicosapentaenoic acid; GA, geographic atrophy; IU, international units; LCPUFA, long-chain polyunsaturated fatty acids.

Table 2 New antioxidants in dry AMD therapy

Nutrients and elements	Effect	Efficacy
Crocetin	Reduces apoptosis Increases oxygen diffusion through plasma Reduces lipid peroxidation Upregulates trophic factors	Animal models^Citation41 Humans (uncertain)^Citation42
Curcumin	Reduces lipid peroxidation and formation of reactive oxygen species, modulating the expression of many oxidative stress-regulating genes, such as PDGF, VEGF, HO1, and others	In vitro models^Citation43,Citation44
Resveratrol	Modulates cell proliferation, apopotosis, and angiogenesis	In vitro models^Citation46,Citation47
Vitamins B9, B12, and B6	Decrease serum homocysteine level	Humans (uncertain)^Citation45

Abbreviations: AMD, age-related macular degeneration; PDGF, platelet-derived growth factor; VEGF, vascular endothelial growth factor; HO1, heme oxygenase 1.

Table 3 Summary of current trials on dry AMD therapy based on drusen components

Type of drug	Name of the drug	Way of administration	Reference
Anti-β-amyloid antibodies	RN6G GSK933776 Glatiramer acetate	Intravenous Intravenous Weekly injection Subcutaneous	ClinicalTrials.gov NCT01577381 (suspended) ClinicalTrials.gov. NCT01342926 (ongoing) ClinicalTrials.gov. NCT00466076 (status unknown) ClinicalTrials.gov. NCT00541333 (suspended)
Anti-C5 antibodies	LFG316 ARC1905 Eculizumab	Intravitreal Intravitreal Intravitreal Intravenous	ClinicalTrials.gov. NCT01255462 (completed, no results available) ClinicalTrials.gov. NCT01527500 (recruiting patients) ClinicalTrials.gov. NCT00950638 (completed, no results available) Results found in “The COMPLETE study” (Yehoshua et al)^Citation86
Anti-factor D antibody	Lampalizumab	Intravitreal	Results found in “The MAHALO study” (Mones)^Citation64
Anti-inflammatory agents	Fluocinolone acetonide Rapamycin	Intravitreal Intravitreal Subconjuntival Intravitreal	ClinicalTrials.gov. NCT00695318 (ongoing) ClinicalTrials.gov. NCT01675947 (completed, no results available) Results in “The SIRGA study” (Wong et al)^Citation65 ClinicalTrials.gov. NCT01445548 (completed, results available online)
Lipids	Statins	Oral	Cochrane review (Gehlbach et al)^Citation72

Abbreviations: AMD, age-related macular degeneration; COMPLETE, COMPLement Inhibition with Eculizumab for the Treatment of NonExudative Age-Related Macular Degeneration; GA, geographic atrophy; SIRGA, Sirolimus in the Treatment of Bilateral GA Associated With AMD.

Table 4 Summary of current and future targets of dry AMD therapy based on drusen components

Targets	Strategy	Reference
Complement components	Prevention of activation/accumulation	Anderson et al^Citation21
Proteins of acute phase response to inflammation	Modulation/inhibition	Bowes et al^Citation66
Microglia and macrophages	Modulation of recruitment to the site of injury	Combadiere et al^Citation67
Mast cells	Prevention of degranulation	Lutty et al^Citation68

Abbreviation: AMD, age-related macular degeneration.

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