diabetic macular edema:management in the era of ever- … · 2018-10-26 · regular eye exams ....
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Diabetic Macular Edema:Management in
the Era of Ever-Increasing Treatment
Options Paul F. Torrisi,M.D.
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Diabetic Macular Edema(DME)
Diabetes, DR, and DME Newer approved treatment modalities Preferred “first line” treatment and shift in paradigm away from laser photocoagulation Combination treatment Surgery
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Incidence of Diabetes in U.S.
2010 11.3% of adults 26 million
2020 15% 39 million
2050 33% ???
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Retinal Microvascular Disease
DME results from damage to retinal blood vessels from angiogenesis and inflammation leading to vascular permeability and increase central macular thickening
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DME accounts for 75% of vision loss from diabetic retinopathy
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Important for Patients to be Engaged in their
Health! Better management of blood glucose diminishes likelihood of blindness (DCCT, UKPDS) Insulin pumps and modern biphasic insulin units help with tight control Diet and exercise to maintain a healthy weight No smoking HemoglobinA1c Control blood pressure Regular eye exams
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Hyperglycemia, hypertension, and hyperlipidemia-all common
features of poorly controlled diabetes
Major Risk Factors for DME
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Other Potential Risk Factors for DME
• Diabetic nephropathy
• Anemia
• Sleep apnea
• Glitazone usage (Actos, Avandia)
• Pregnancy
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Treatment of DME for decades:
Encouraging optimal metabolic control
Focal/grid laser photocoagulation according to the guidelines established by (ETDRS) in 1985 –Laser reduced moderate vision loss by 50% in patients with CSME ETDRS- only 15% gained 3 lines of vision with Laser
Pre-laser Rx
Post-laser Rx
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ETDRS definition of CSME no longer the “gold standard” for
DME
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DME Center involved
Not center involved
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Laser
Focal laser treating non-foveal involved macular edema
Effective, initial treatment for DME that does not have foveal involvement, i.e., non-center involving DME
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Paradigm Shift Increasing evidence of the effectiveness of pharmacologic therapies.
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Pharmacologic treatment:
Anti-VEGF (vascular endothelial growth factor)
Corticosteroids
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Anti-VEGF Therapy
Ranibizumab (Lucentis) + prompt or deferred laser superior to laser alone with center-involved DME
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Ranibizumab
Antibody fragment-all isoforms of VEGF-A RISE & RIDE Trials RISE 44.8% “3 line gainers” RIDE 33.6% “ 3 line gainers”
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Ranibizumab
RISE & RIDE Ranibizumab first line Rx for center involved DME-improved vision through 36 months 40% gained 3 lines of vision
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Ranibizumab vs Laser
RISE/RIDE
40% of patients gained 3 lines with Ranibizumab
ETDRS
15% of patients gained 3 lines with Laser
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20/400 20/40
Avastin/focal laser/Lucentis/focal laser/Lucentis
Ranibizumab
SS 60yo 20/400
21 months
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Bevacizumab
Full length antibody-all isoforms of VEGF-A Off label for DME -widespread availability and low cost BOLT study small number of patients with center-involved DME 32% gain 3 lines in 2 years
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Aflibercept
Recombinant fusion protein- activity against VEGF-A, VEGF-B, and placental growth factor August 2014
VIVID/VISTA trials 33-40% gain 3 lines of vision in 2 years
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“Head to head” Comparisons
Ranibizumab (Lucentis) RISE/RIDE 40% gain in 3 lines in 2 years Aflibercept (Eylea) VIVID/VISTA q4wks then q8wks 33-40% gain in 3 lines in 2 years Bevacizumab (Avastin) BOLT trial ( small study-80 patients) 32% gain in 3 lines in 2 years
DRCR.net Protocol T
Pivotal Trial for DME
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Good News! REDUCTION in treatment burden with injections over time (DRCR.net)...data through year 3-only 2-4 injections out of possible 13 were required! Anticipated that data through year 5 will demonstrate similar low treatment burden.
BONUS of decreasing the overall DR over time! (RISE/RIDE studies) …time of progression to PDR in treated eyes compared to sham(1%vs12% to PDR) and 25% required no injections after 36 months (maybe related to DR improving over time!).
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Anti-VEGF Agents
Safe in diabetics with no significant increase in BP, hemorrhagic events, or CVA. May modify long term outlook for our patients with DME, hopefully resulting in fewer injections once we have controlled the disease.
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Intravitreal VEGF Blockade
Most efficacious and safest treatment for center-involved DME Should be first-line treatment for center-involved DME
M.B. 63 yo DME s/p PPV OU
1/14 20/60 5/14 20/40+1 8/14 20/40+1 11/14 20/25+2
Lucentis x5, Eylea x3 OD
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8/11 20/30 8/11 20/100
1/11 20/80-2 1/11 6/400
1/11 Avastin/PRP 1/11 Avastin/PRP
Avastin/focal laser Avastin/focal laser
66y.o. DMx2yrs., struggling with VA x2 yrs., DME/PDR/marked ischemia OU
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OD 3/12 20/40+1
OS 3/12 20/80+1
Add’l Focal laser+PRP OU Avastin
OD 2/14 20/30
NO further Rx since 3/13
OS 2/14 20/80-2
NO further Rx since 8/12
OD 10/14 20/40
NO further RX
OS 10/14 20/70
NO further Rx
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Corticosteroids • Longer lasting and safer steroids with
recent advances in pharmacotherapy • Increasing role in treatment of DME • Unlikely to replace anti-VEGF Rx as a first
line agent • But may add effective weapons in our
armamentarium
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Triamcinolone acetonide(TA)
Has been used off-label for DME Use has declined as anti-VEGF Rx has increased,in part, due to risks of cataract and IOP elevation
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Bioerodible dexamethasone
intravitreal implant Ozurdex for DME ( MEAD Study) …. 22% 3 line gainer 2 yrs
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Ozurdex
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Sustained-release nonbioerodible Fluocinolone
acetonide Fame Study showing benefits over 3 years for DME but increased risks of cataract and IOP elevation –Iluvien (Alimera)
29% 3 line gainer over 2 years
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All “3 line gainers”! Statistically achieve significant
improvement of 15 letters(3 lines) vs sham
Combination Therapy for DME
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Combination Therapy for DME
3 line gainers Ranibizunab(Lucentis) 40% 2yrs. (RISE/RIDE) Aflibercept (Eylea) 33-40% 2 yrs. (VIVID/VISTA) Bevacizumab (Avastin) 32% 2 yrs. (BOLT) Dexametasone (Ozurdex) 22% 2 yrs. (MEAD)
Other side of the story
60% not 3 line gainers 60-66% not 3 line gainers 68% not 3 line gainers 78% not 3 line gainers 71% not 3 line gainers Fluocinolone acetonide(Iluvien)
29% 2 yrs. (FAME)
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Rationale for Combination Rx
Despite several medications now approved for treatment of DME more than 50% of the time 3 line gain is not achieved with any one of them!
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Next Step if Monotherapy not Optimal
Switching or Adding
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DME/Multifactorial Disease
Not purely VEGF driven Inflammatory cytokines and chemokines,e.g. interleukins 6 and 8 – not affected by anti-VEGF but susceptible to steroids
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Inflammation plays a role as well in diabetic
retinopathy and macular edema!
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Corticosteroids affect multiple mediators of
inflammation, including VEGF
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Combination Therapy
• Combination Rx may be helpful for patients who are unresponsive or have a suboptimal response to anti-VEGF agents
• Combination Rx works by targeting multiple factors in the inflammatory cascade
• Combination Rx an option for “difficult to treat” patients
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1/12 20/70
3/12 20/60+2
Avastin
8/12 20/70+2
Laser IVTA
Lucentis
12/12 20/70
3/13 20/80
12/13 20/100-2
IVTA
1/14 20/60
Lucentis
Lucentis Avastin
10/14 20/70+2
Ozurdex
11/14 20/40
PB 68y.o. 1/12 DME OD only
Avastin x11, Focal laser x1, IVTAx1, Lucentis x17, Ozurdex x1
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Vitrectomy Surgery Its role in management of DME not clear-limited evidence combining vitrectomy with intravitreal anti-VEGF agents, corticosteroids, and/or laser photocoagulation to Rx refractory DME-small non-randomized, uncontrolled case series.
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Vitrectomy Surgery Effectively reduces retinal thickness but visual outcomes less consistent!
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Summary of Current Management Strategies
• Optimal control of blood sugar, blood pressure, serum lipids, and body mass index
• Medications, e.g. oral glitazones assoc. DME • Non-center involved DME- ETDRS laser • Center-involved DME: paradigm shift from focal/
grid laser to intravitreal anti-VEGF as first-line treatment
• DME refractory to anti-VEGF Rx, intravitreal corticosteroids may be added
• PPV/membranectomy with center-involved DME and vitreomacular traction or epiretinal membrane, when pharmacoRx unsuccessful
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Finally
• Data from DRCRnet protocol T should better define differences among various anti-VEGF agents
• More data needed to better define the ideal timing of various treatments, as well as the potential for combination Rx regimens to achieve better clinical outcomes and/or reduced treatment burden compared with monotherapy