DIABETIC RETINOPATHY
| UPDATE IN DIABETES —Carol Schwartz, MD, Assistant Professor, Department of Ophthalmology and Visual Sciences,
University of Toronto, Faculty of Medicine, Sunnybrook Health Sciences Centre, Toronto, ON
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| Epidemiology: diabetic retinopathy—leading cause of legal blindness; 6% of US population diabetic (90% type 2 diabetes);
now diagnosing type 2 diabetes in children; current epidemic of obesity and diabetes suggests future epidemic of diabetic
retinopathy; in those with 15-yr history of type 1 diabetes, almost 100% have evidence of diabetic retinopathy; in
those with 15-yr history of type 2 diabetes, almost 80% have diabetic retinopathy (slight drop-off due to cardiovascular
mortality); diabetic macular edema (DME)—most frequent cause of visual loss in diabetics; DME can occur at any level
of retinopathy (rate up to 70% in patients with severe proliferative diabetic retinopathy)
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| New definition of diabetic retinopathy: biochemical and cellular changes that cause progressive retinal ischemia,
which leads to elaboration of growth factors responsible for development of classic symptoms and progression from nonproliferative
to proliferative retinopathy; if unchecked, severe irreversible visual loss; increased retinal vascular leakage
from breakdown of blood-retinal barrier can occur at any stage, leading to macular edema; hyperglycemia leads to—
generation of reactive oxygen species; activation of protein kinase-C (PKC) pathway; increased blood flow through aldose
reductase pathway, and formation of advanced glycation end products; interventions—now possible to inhibit pathways
pharmacologically to prevent characteristic lesions of diabetic retinopathy (in particular, loss of pericytes in small
capillaries that leads to microaneurysm, breakdown of blood-retinal barrier, and expression of ischemia [neovascularization])
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| Treatment approaches: improving retinal metabolism and oxygenation; reducing inflammation; inhibiting PKC; administration
of anti-vascular endothelial growth factor (anti-VEGF); systemic control and management of diabetic patients;
standard treatment for improving retinal oxygenation and metabolism in retina is panretinal photocoagulation (PRP), and
for managing DME, focal laser
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| Early Treatment Diabetic Retinopathy Study (ETDRS): focal laser used to seal tiny microaneurysms and dry
DME threatening center of fovea; even with focal laser treatment, 12% of patients still lost vision (24% had persistent retinal
thickening; only 10% improved); efficacy of focal laser “terrible” for diffuse macular edema associated with foveal
ischemia and for cystoid macular edema
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| Steroid therapy: useful in some patients with poor result after focal laser treatment of macula; reduces inflammation;
intravitreal triamcinolone has anti-VEGF properties (off-label use); unfortunately, repeat injections often necessary as
treatment wears off
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 | Side effects: elevated intraocular pressure and cataract formation; monthly intravitreal injections well tolerated, but onerous
as long-term regimen
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| Implantable devices: avoid inconvenience of monthly intravitreal injections; Retisert (Bausch & Lomb); Posurdex (Allergan);
Medidur (Alimera)—tiny (approximately one-eighth inch long) fluocinolone implant; implanted through 25-
gauge injector; preliminary trials suggest dose capacity of 15 mo; study currently randomizing patients with clinically
significant DME and persistent retinal thickening >250 µm
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| VEGF: primary angiogenic growth factor in most retinal diseases (including diabetic retinopathy and wet age-related macular
degeneration [AMD]); inhibition of VEGF—activation of PKC results in biochemical pathways that contribute to
development of diabetic retinopathy; one approach to block formation of VEGF by inhibiting PKC
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| Ruboxistaurin: inhibits PKC- β in phase 1 studies, drug well tolerated with no serious adverse effects; normalizes mean
retinal circulation time and retinal blood flow; phase 3 study—almost 700 patients; treated patients had reduced risk for
visual loss, need for laser, and progression of macular edema, and increased incidence of visual improvement; research
ongoing
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| Lucentis (ranibizumab; RhuFab V2) in DME (study): criteria—persistent DME after laser treatment in patients
with type 1 or type 2 diabetes; outcome variables—primary (safety and tolerability of repeated injections); secondary (effect
on vision); speaker’s patient in trial—starting visual acuity ≈20/80 (with monthly injections, improvement to ≈20/25);
corresponding decrease in macular thickness after injection; when trial ended, visual acuity dropped from 20/20 to 20/30;
other eye had no light perception, due to tractional complications of proliferative diabetic retinopathy; intravitreal injection
of bevacizumab (Avastin) administered; visual acuity improved from 20/30 to 20/20; resolution of central foveal
edema; since December 2005, patient has needed only one additional injection (result attributed to pretreatment with Lucentis)
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| Avastin injection before PRP: “fantastic” treatment for patient who, despite extensive PRP, presents with resistant
neovascular tissue at 6 wk; in past, PRP repeated, often resulting in posterior vitreous detachment, traction, and hemorrhage;
new approach may eliminate cascade reaction; case—severe ischemia, poor circulation, massive neovascularization;
patient at high risk for visual loss, even with focal laser and vitrectomy; prelaser injection of Avastin followed by
long-term VEGF suppression may eliminate tractional complications; Avastin effective treatment for neovascular glaucoma
(in case above, ectropia in uvea and neovascularization of iris disappeared within 5 days after treatment); as adjuvant
therapy, Avastin 1 wk before vitrectomy reduces bleeding intraoperatively and makes surgery easier
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| ADVANCES IN MEDICAL THERAPY FOR DIABETIC RETINOPATHY —Lloyd P. Aiello, MD, PhD, Associate Professor
of Ophthalmology, Harvard Medical School, Head, Joslin Diabetes Center Section on Eye Research, and Director,
Beetham Eye Institute, Boston, MA
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| Compounds evaluated: pegaptanib (phase 2 study completed; phase 3 ongoing); ranibizumab (three phase 3 trials ongoing);
Avastin (phase 2 study completed by Diabetic Retinopathy Clinical Research Network [Web site, DRCR.net]); in
all studies—limited adverse effects; limited duration of action (downside high burden of repetitive injections); improvement
in visual acuity; regression of retinal neovascularization, proliferative diabetic retinopathy, and iris neovascularization
from diabetes; reduced retinal thickening, but response variable
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| Phase 2 randomized clinical trial of intravitreal bevacizumab for DME (DRCR.net): 109 eyes with
baseline visual acuities 20/32 to 20/320; all had DME; patients randomized to 5 groups, including intravitreal injection of
bevacizumab alone, photocoagulation alone, and combination therapy; main outcome measures central subepithelial
thickness (CST) and best-corrected visual acuity; at baseline, median CST 411 µg and median Snellen visual acuity 20/
50; at 3 wk, 2 doses of bevacizumab associated with greater reduction in retinal thickening, and at 12 wk, 1 line better visual
acuity, compared to photocoagulation alone; at 3 wk, decrease in CST above reliability limit (ie, >11%) achieved in
43% of bevacizumab-treated patients, compared to 28% of laser-treated patients; at 6 wk, only 37% of bevacizumab patients
maintained reduction (compared to 50% of laser-treated patients); combining focal photocoagulation with bevacizumab
resulted in no apparent short-term benefit or adverse outcomes; no specific drug side effects noted; conclusions—
not clear; intravitreal bevacizumab can reduce DME in some eyes; phase 3 trial needed to determine whether treatment
fully beneficial
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| VEGF-independent pathways that produce macular edema in diabetic setting (Gao et al, 2007):
through kallikrein pathway, activation of carbonic anhydrase within eye in turn activates bradykinin receptor and VEGF-
independent increase in permeability
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| NUTRITION IN AGE-RELATED MACULAR DEGENERATION AND DIABETES —Michael J. Cooney, MD, MBA,
Vitreous Retina Macula Consultants of New York, New York, NY
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Age-Related Macular Degeneration
| Pharmacologic treatments for wet AMD: verteporfin (Visudyne), pegaptanib (Macugen), Lucentis, Avastin (off-
label), and combination therapy; as disease advances, vision loss and cost of care for patients with end-stage disease increases
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| Natural history of AMD progression: ≥10% rate of conversion from dry (non-neovascular) to wet (neovascular)
AMD (in Age-Related Eye Disease Study [AREDS], nutritional supplementation decreased statistical risk for conversion);
oxidation hypothesis—breakdown of antioxidant systems and generation of free radicals damages lipid membranes;
antioxidant deficiency may predispose patient to disease; nutritional supplementation may slow process
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| AMD and cardiovascular disease: shared risk factors—elevated lipids, cholesterol, C-reactive protein (CRP); arteriosclerosis;
cigarette smoking; inflammation; hypertension
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| Can antioxidant vitamins and minerals slow progression of AMD and rate of vision loss? AREDS
(sponsored by National Eye Institute [NEI]) gold standard clinical trial on issue
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| Categories of AMD progression: 1) little-to-no AMD; 2) few small drusen; 3) large intermediate-size drusen or nonfoveal
geographic atrophy; 4) at least 1 eye has neovascular AMD or foveal geographic atrophy; issue whether nutrition
can modify progression to wet AMD; natural history of progression—of patients with early AMD (category 1 or 2),
risk of developing wet AMD at 5 yr <1.5%; for category 3, risk almost 20% (if wet AMD present in 1 eye, risk to fellow
eye ≥45%)
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| Study parameters: 5000 participants randomized to receive placebo, antioxidant alone, zinc alone, or antioxidant plus
zinc; pharmacologic doses high
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| Risk for vision loss at 5 yr: antioxidant plus zinc associated with almost 20% reduction in risk for vision loss ≥3 lines; no
other groups (placebo, antioxidant, or zinc) had statistically significant benefit
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| Risk for progression to wet AMD at 5 yr: zinc with antioxidant or zinc alone (risk reduced 25%)
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| Recommendations: patients with intermediate to advanced AMD (category 3 or 4) should take daily supplemental therapy
according to AREDS findings (as exception, people who smoke should avoid beta carotene due to increased risk
for lung cancer); widespread compliance could prevent ≥300,000 new cases of vision loss each year
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| AREDS II: ongoing study of lutein, zeaxanthin, and omega-3 fatty acids; lutein and zeaxanthin—natural carotenoids
found in macula; antioxidants; filters of UV light; play role in structural signal transduction; macular pigment decreases
with age (decrease predisposes patient to increased risk for AMD); oral administration of zeaxanthin can increase macular
pigment; in cadaver eyes, lower levels of lutein associated with greater likelihood of AMD; in most observational
studies, dietary lutein protective (risk of developing wet AMD reduced; contrary findings may be due to problems inherent
in questionnaires about food frequency); based on odds ratios, lutein and zeaxanthin better carotenoids than beta carotene
(odds ratio <1 protective; >1 harmful)
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| Dietary fat (studies by Seddon): modifiable risk factor for AMD; higher body mass index associated with greater
risk for AMD; with high intake of fat in processed baked goods, odds ratio for developing wet AMD 2.4; other sources of
fat, (eg, nuts) protective
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| Omega-3 fatty acids: lutein, zeaxanthin, and omega-3 fatty acids not produced by body (increased levels require increased
intake); structural components of phospholipid membranes (particularly outer segments of retina); docosahexaenoic
acid (DHA [an omega-3 fatty acid]), makes up 50% of lipids in outer photoreceptor segment (increases fluidity
so that outer segments able to move); many observational studies suggest that high intake of omega-3 fatty acids protects
against wet AMD (response almost dose-dependent); omega-3 fatty acids in broiled or baked fish—associated with almost
dose-dependent decrease in risk for AMD progression
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| More about AREDS II: ongoing investigation of lutein, zeaxanthin, and omega-3 fatty acids; 4000 participants randomized
to either placebo, lutein, zeaxanthin, or omega-3 fatty acids (then combination lutein, zeaxanthin, and omega-3 fatty
acids)
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| Speaker’s advice to patients: if avascular pathology present, consult internist or cardiologist before starting nutritional
supplementation recommended in AREDS
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Diabetes
| Epidemiology: diabetes growing public health problem (affects 1 in 20 individuals in United States, and 150 million
people worldwide); deaths from diabetes worldwide projected to rise rapidly over next 20 yr; obesity, sedentary lifestyles,
and poor eating habits contributing factors; recent advent of type 2 diabetes in obese children especially troubling
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| Genistein: isoflavone derived from soybeans; may affect areas of oxidative stress and signal transduction systems; orally
bioavailable; good safety profile; activity—antioxidant effects; inhibits protein tyrosine kinase (PTK), aldose reductase,
and matrix metalloproteinase
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| Upregulation of PKC pathway: mechanism of diabetic retinopathy; increased glucose leads to decreased retinal oxygen,
which upregulates growth factors; growth factors bind to cell surface receptor, which starts downstream signaling
cascade intracellularly; signal proteins become phosphorylated (ie, activated); hypothesis that inhibition of PTK pathways
may ameliorate end-stage developments (eg, vascular leakage or proliferative retinopathy)
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| Genistein in animal models of retinal disease
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| Activation of PTK pathways: VEGF-mediated injury response; ischemia reperfusion injury; because retina ischemic,
number of phosphorylated proteins in retina increased after reperfusion; in animal models, genistein inhibits PTK pathways;
on staining, blunting of phosphotyrosine nearly dose-dependent; neuroprotective effect—in ischemic rats lose inner
retinal layer; at various doses of genistein, inner retina preserved
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| Type 2 diabetes (Zucker diabetic fatty rat model): at baseline, significant increase in phosphotyrosine in retinal proteins
(at various doses of genistein, significant decrease); significant amount of venous beading and abnormal-looking retinal
vasculature (after treatment with genistein, diabetic rat more like those in control group); in treatment group, significant
decrease in VEGF-receptor activation
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| Type 1 diabetes (diabetic rat model): indirect sucrose typing—in diabetic rat, increased retinal leakage (at various doses of
genistein, decreased retinal leakage); retinal albumin—another marker for retinal leakage; in diabetic rat, much retinal
albumin leakage into surrounding retina (with higher doses of genistein, response blunted)
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Suggested Reading
Adamis AP et al: Changes in retinal neovascularization after pegaptanib (Macugen) therapy in diabetic individuals.
Ophthalmology 113:23, 2006; Aiello LP: Angiogenic pathways in diabetic retinopathy. N Engl J Med 353:839,
2005; Cummingham ET Jr et al: A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial
growth factor aptamer, for diabetic macular edema. Ophthalmology 112:1747, 2005; Diabetic Retinopathy
Clinical Research Network, Scott IU et al: A phase II randomized clinical trial of intravitreal bevacizumab
for diabetic macular edema. Ophthalmology 114:1860, 2007; Gao BB et al: Extracellular carbonic anhydrase mediates
hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat Med 13:181, 2007;
Haritoglou C et al: Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina
26:999, 2006; Hernandez C et al: Erythropoietin is expressed in the human retina and it is highly elevated in
the vitreous fluid of patients with diabetic macular edema. Diabetes Care 29:2028, 2006; Joy SV: Ruboxistaurin, a
protein kinase C beta inhibitor, as an emerging treatment for diabetes microvascular complications. Ann Pharmacother
39:1693, 2005; Nakajima M et al: Normalization of retinal vascular permeability in experimental diabetes with
genistein. Invest Ophthalmol Vis Sci 42:2110, 2001; PKC-DRS2 Group, Aiello LP et al: Effect of ruboxistaurin on
visual loss in patients with diabetic retinopathy. Ophthalmology 113:2221, 2006; Strom C et al: Effect of ruboxistaurn
on blood-retinal barrier permeability in relation to severity of leakage in diabetic macular edema. Invest Ophthalmol
Vis Sci 46:3855, 2005.
Educational Objectives
| The goal of this program is to improve management of diabetic retinopathy. After hearing and assimilating this program,
the clinician will be better able to:
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| 1. Describe current methods for managing diabetic retinopathy.
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| 2. Discuss new and proposed approaches to treatment of diabetic retinopathy.
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| 3. Evaluate the efficacy of intravitreal bevacizumab for diabetic macular edema.
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| 4. Describe the role of nutritional therapy in preventing progression of age-related macular degeneration.
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| 5. Discuss the role of nutrition in managing diabetic retinopathy.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee
members to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of
interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and
not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Schwartz has
been an advisory board member for Novartis and a clinical consultant to GlaxoSmithKline; Dr. Cooney has been a paid
consultant to Bausch & Lomb. Dr. Aiello and the planning committee reported nothing to disclose.
Acknowledgments
Dr. Schwartz was recorded at Update in Medicine and Ophthalmology, presented December 8-9, 2006, in Toronto, ON, by
the Departments of Ophthalmology and Vision Sciences, and Continuing Medical Education, University of Toronto, Faculty
of Medicine; Dr. Aiello was recorded at What’s New in Posterior Segment Disorders, presented October 20, 2007, in
Cambridge, MA, by the Ocular Immunology & Uveitis Foundation, Cambridge, and jointly sponsored by the Massachusetts
Eye Research, and Surgery Institute, Cambridge, and the Dulaney Foundation, Southeastern, PA; Dr. Cooney was recorded
at the Annual Clinical Conference, presented January 5-6, 2006, in Kansas City, MO, by the Kansas City Society of
Ophthalmology and Otolaryngology.
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