medical treatment of diabetic retinopathy approaches and considerations.pdf

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Medical Treatment of Diabetic Retinopathy: Approaches and

Considerations

Zachary T. Bloomgarden, MD, MACE Vision impairment is a common complication of diabetes, estimated to affect between 11% and 19%

of adults with diabetes in the United States.1,2 Diabetic retinopathy (DR) is the leading cause of new

blindness in the working-age population in North America.3 Several studies reported comparative

prevalence of DR among population subgroups, including a recent report that included 9 community-

based studies from the United States.4 The prevalence of DR in persons with type 2 diabetes ranged

from 18.2% to 27.4% in nonHispanic White Americans, from 26.5% to 38.8% in African Americans,

and from 33.4% to 45.8% in Hispanics. Proliferative diabetic retinopathy (PDR) ranged from 0.9%

(White Americans) to 6.3% (Hispanics), and diabetic macular edema (DME) from 2.0% (White

Americans) to 7.5% (African Americans).

The prevalence of DR increases as the duration of diabetes increases. The META-EYE Study Group

acquired individual participant data from 35 population-based studies that included patients with type

1 or 2 diabetes reported from 1980 to 2008 in Europe, the United States, Asia, and Australia. 5 Any

DR increased almost 4-fold as the duration of diabetes increased, from 21.1% with a diabetes

duration of <10 years, to 76.3% for those with >20 years diabetes duration (Figure 1). Diabetic

macular edema underwent a more than 6-fold increase from 3.2% to 20.0% as diabetes duration

increased from <10 years to >20 years, while PDR increased 30-fold from 1.2% to 31.7%.



Progression to Macular Edema

In a longitudinal, population-based study, 447,407 persons in a managed-care network with diabetes

but without macular edema at baseline were followed for a mean of 5.3 years to explore risk factors

for developing DME.6During follow-up, 1.5% developed DME. After adjusting for possible

confounders, several factors remained as independent predictors of DME, including race, presence

of other diabetic complications and comorbidities, type of diabetes, and higher baseline A1C level.

Conversely, hyperlipidemia was associated with a 19% reduced risk of DME in this study,

conceivably a beneficial effect of lipid-lowering treatments.

A retrospective cohort analysis of 4617 managed-care enrollees with incident nonproliferative DR

(NPDR) explored possible risk factors associated with progression to proliferative DR

(PDR).7 During a median follow-up of 1.7 years from the date of NPDR diagnosis, 6.6% developed

PDR. After adjusting for confounders, each 1-point increase in A1C was associated with a 14%

increased hazard of developing PDR (adjusted hazard ratio [aHR] 1.14; 95% confidence interval



[CI]: 1.07, 1.21). In this cohort, hypertension and dyslipidemia were not associated with increased

risk of retinopathy progression by either univariate or multivariate analysis, and none of the

medications assessed were significantly associated with DR progression risk after multivariate

analysis. However, an increased risk of DR progression was associated with nonhealing ulcers (aHR

1.54; 95% CI: 1.15, 2.07) and nephropathy (aHR 1.29; 95% CI: 0.99, 1.67).

The potential value of common measures of kidney function for predicting retinopathy and

cardiovascular disease outcomes was explored in a study in Taiwan that included 487 patients who

had type 2 diabetes for a mean duration of 9.4 years at enrollment. 8 The comparative predictive

values of microalbuminuria and moderately decreased estimated glomerular filtration rate (eGFR) on

retinopathy and cardiovascular disease outcomes were analyzed. During a median follow-up of 7.6

years, 16.5% of patients had development or progression of diabetic retinopathy, 5.4% developed

advanced DR, and 12.9% experienced cardiovascular events. Regardless of the eGFR, patients with

microalbuminuria had a higher risk for the composite DR outcome of development or progression

compared with those with normoalbuminuria. After multivariable adjustment, this risk remained

significant (HR 4.18; 95% CI: 1.85, 9.43; P =.001). However, eGFR was not associated with DR in

univariate or multivariate analysis. Cardiovascular event rates were not significantly associated with

microalbuminuria or eGFR. The authors concluded that microalbuminuria is a more useful predictor

of retinal outcome in patients with type 2 diabetes compared with eGFR.

Diabetic Retinopathy: Pathogenesis and Relationship to Cardiovascular Risk Factors

Cardiovascular disease is a well-known major macrovascular complication of diabetes, with an

etiology that appears to be, at least in part, independent of atherosclerosis.9 Retinopathy,

nephropathy, and neuropathy are the major microvascular complications of diabetes. Chronically

abnormal metabolic (eg, glucose, lipids) and hemodynamic (blood pressure) factors are shared risks

for unfavorable outcomes in both diabetes and cardiovascular disease, which are involved in

overlapping and interrelated pathogenic pathways.10,11 Successful management of diabetes

includes controlling these shared risk factors, including those associated with the development of DR

(Figure 2).



Glycemia

In META-EYE pooled data from 18 studies that had similar methodologies and rigorous outcome

definitions, the age-standardized prevalence of DR in 12,620 subjects with diabetes, aged 20 to 79

years was 35.4%.5 Any DR, PDR, and DME increased with increasing A1C levels (Figure 3). The

DME prevalence increased more than 3-fold from an A1C of ≤7% (3.6%) to an A1C of >9.0%(12.5%).



The DETECT-2 collaboration analyzed pooled data from 44,623 patients in 9 studies in 5 countries(United States, Australia, India, Japan, and Singapore) that had retinopathy grading data

available.12 In the entire cohort, the prevalence of any retinopathy and diabetes-specific retinopathy

was 6.7% and 1.5%. Compared with a fasting plasma glucose (FPG) from 4.0 to 4.4 mmol/L (72 to

79 mg/dL), the odds ratio (OR) for diabetesspecific moderate or more severe retinopathy was

significantly increased when FPG reached from 6.5 to 6.9 mmol/L (117 to 124 mg/dL) (OR 6.0; 95%

CI: 2.1, 17.1; P<.01). The A1C results indicated a significant risk for retinopathy when they increased

from 6.5% to 6.9% (OR vs 4.0% to 4.4%: 16.8; 95% CI: 2.3, 123.7; P =.01).

Data from these recent population-based studies support observations made 20 years ago in major

randomized clinical trials, such as the Diabetes Control and Complications Trial (DCCT), Kumamoto,

and the United Kingdom Prospective Diabetes Study (UKPDS).13 –16 In these studies, risk reduction

for complications including retinopathy, neuropathy, nephropathy, and cardiovascular disease

associated with each 1% decrease in A1C ranged from 28% to 38% (Table 1).



The risk of retinopathy progression remained low in patients with a mean A1C of 7%, but was

considerably elevated with increasing mean A1C levels, as shown during 9 years of follow-up in the

DCCT study.13 Intensive glycemic control compared with conventional therapy in the UKPDS study

resulted in a substantially decreased risk of microvascular complications, including significant

relative risk reductions for retinopathy progression at 6 (17%), 9 (17%), and 12 (21%) years(P ≤.05).16

The observational Epidemiology of Diabetes Interventions and Complications (EDIC) study enrolled

1375 patients from the initial DCCT trial, and obtained annual self-reported history of ocular surgical

procedures.17During a median follow-up of 23 years, significantly fewer ocular operations were

performed in patients assigned to intensive therapy compared with conventional therapy (8.9% vs

13.4%; P<.001). After adjusting for baseline factors, intensive therapy was associated with a 48%

(95% CI: 29, 63; P<.001) risk reduction for any diabetes-related ocular surgery, and a 37% (95% CI

12, 55; P =.01) reduction in all ocular surgeries. Vitrectomy and/or retinal detachment surgery and

cataract extraction were significantly reduced from 45% to 48%, respectively, by intensive therapy,

and surgical costs were 32% lower in that group. The beneficial effects of intensive therapy werecompletely attenuated after adjusting for A1C levels over the entire follow-up interval.

The ACCORD study was a multicenter randomized controlled trial in the United States and Canada

of cardiovascular events in more than 10,000 participants with type 2 diabetes who had either

established cardiovascular disease or known cardiovascular risk factors and an A1C level

≥7.5%.18 Three interventions included intensive glycemic therapy, the addition of fenofibrate to a

statin to manage serum lipids, and intensive blood pressure therapy. Intensive glycemic control



targeted an A1C of <6.0%, while standard therapy targeted an A1C from 7.0% to 7.9%. A subgroup

of 2856 patients was enrolled in the ACCORD Eye study, which examined progression of DR and

development of PDR requiring photocoagulation or vitrectomy. The progression of DR in 4 years of

follow-up was significantly greater in standard (10.4%) compared with intensive (7.3%) glycemic

therapy patients (P =.003). Vision loss was similar between groups in all comparisons.

The ADVANCE study followed a 2×2 factorial design to compare blood pressure lowering with

perindopril-indapamide versus placebo, and intensive with standard glycemic control in patients with

type 2 diabetes.19 Low retinopathy rates were observed in the entire cohort, with retinopathy

developing in 10.3% and progressing in 4.8% of patients during 4.1 years of follow-up. In a 1602

patient retinopathy substudy, incidence and progression of retinopathy occurred similarly between

standard and intensive glucose control groups (P =.27). Adjusting for baseline retinal hemorrhages

revealed significantly lower risks of microaneurysms (P =.025) and hard exudates (P =.019), and

borderline significantly reduced macular edema (P =.065) in the intensive glucose control group.

Blood Pressure

The META-EYE analysis showed elevated prevalence of DR in hypertensive compared with

normotensive patients (Table 2).5 The progression of DME and PDR were approximately 2- and 3-

fold more common in patients with hypertension.

Results have varied among studies comparing intensive versus standard blood pressure control;

however, comparing studies is complicated by considerable heterogeneity among trials. A Cochrane

review reporting intervention to reduce blood pressure was beneficial for preventing DR for 4 to 5

years (estimated risk ratio [eRR] 0.80; 95% CI: 0.71, 0.92) and for the combined outcome of

incidence and progression (eRR 0.78; 95% CI: 0.63, 0.97).20 However, DR progression and visual

outcomes were not affected by blood pressure control interventions.



In the ACCORD Blood-Pressure Trial, patients receiving intensive antihypertensive therapy had a

nonsignificantly greater rate of progression (10.4%) compared with those on standard therapy

(8.8%; P =.29).18In the ADVANCE study, patients in the antihypertensive treatment group had a

nonsignificant 22% decreased risk of incident retinopathy or progression of existing DR compared

with placebo (OR 0.78; 95% CI: 0.57, 1.06; P =.12), with significantly less macular edema (OR 0.50;95% CI: 0.29, 0.88; P =.016). The ADVANCE authors concluded that although intensive glucose and

blood pressure control did not significantly reduce the incidence and progression of retinopathy,

consistent beneficial trends were observed, and the effects were independent and additive.

After 9 years of follow-up in the UKPDS study, the tight blood pressure control group had a 37%

reduction (95% CI: 11%, 56%) in the risk of microvascular disease compared with the less-tight

group (P =.0092), which was attributed primarily to reduced retinal photocoagulation required in that

group.21 This was associated with a 34% reduction in risk of deterioration of retinopathy by 2 steps

(99% CI: 11%, 50%; P =.0004) after a median of 7.5 years, and a 47% reduced risk of visual acuity

deterioration of ≥3 lines (99% CI: 7%, 70%; P =.0004) after 9 years of follow-up. The relative risk of

≥5 microaneurysms, hard exudates, and ≥2-step deterioration in DR decreased significantly in

patients randomized to tight blood pressure control compared with those in the less-tight control

group starting at the 4.5-year follow-up.22

Studies of Anti-hypertension Drugs in Normotensive Patients

A study of patients with type 1 diabetes explored the potential benefits of renin-angiotensin system

(RAS) blocking drugs on progression of retinopathy and nephropathy.23 Normotensive patients

(N=285) were randomly assigned to losartan, enalapril, or placebo. After 5 years of follow-up,

although there were no nephropathy benefits in the treatment groups, the odds of ≥2 step

retinopathy progression were reduced 65% (P =.02) in the enalapril and 70% (P =.008) in the losartan

groups compared with the placebo group.

The DIRECT trials were global studies of the angiotensin-receptor antagonist candesartan in

normotensive patients to determine a possible benefit in reducing the incidence (DIRECT-Prevent 1)

and progression (DIRECT-Protect 1) of retinopathy in 1421 participants with type 1 diabetes.24 The

incidence of retinopathy was defined as a ≥2-step increase on the Early Treatment of Diabetic

Retinopathy Study (ETDRS) scale (Table 3); that is, it could represent at least 1 step in both eyes, or

2 steps in 1 eye. Although DR incidence was reduced in patients treated with candesartan compared

to those treated with placebo patients during a median 4.7 years of follow-up (HR 0.82; 95% CI:

0.67, 1.00; P =.0508), results were similar after adjusting for baseline characteristics (P =0.192), and

when further adjusted by systolic blood pressure during the trial (P =.413). When a post hoc analysis

explored incidence as a ≥3-step ETDRS scale increase, treatment was beneficial in unadjusted

analysis (HR 0.65; 95% CI: 0.48, 0.87; P =.0034), when adjusted for baseline characteristics

(P =.023), and when adjustment for SBP during the trial was added (P =.046). However, retinopathy

progression (≥3-step change in EDRS from baseline) during a median 4.8 years of follow-up in the

Protect 1 study was similar in both groups (HR 1.02; 95% CI: 0.80, 1.31, P =.85).



DIRECT-Protect 2 explored the effect of candesartan on progression and regression of retinopathy

in 1905 normotensive or treated hypertensive patients with type 2 diabetes and mild-to-moderately

severe NPDR.25Similar to the Protect 1 study, retinopathy progression (≥3 ETDRS steps) in

candesartan patients (17%) was not significantly different from that in the placebo group (19%)

during a median follow-up of 4.7 years (HR 0.87; 95% CI: 0.70, 1.08; P =.20). Retinopathy



regression, a secondary endpoint defined as a reduction of ≥3 steps on the ETDRS scale from

baseline to any follow-up visit, was significantly more likely in the candesartan group (HR 1.34; 95%

CI: 1.08, 1.68; P =.009). Accordingly, there was an overall trend toward less severe retinopathy at the

end of the study in patients in the candesartan compared with placebo group (OR 1.17; 95% CI:

1.05, 1.30; P =.003). Risks were not attenuated by adjusting for baseline variables or blood pressure

changes during the study.

Lipids

Hyperglycemia is a known risk factor for chronic hyperlipidemia, which can have several adverse

effects on both the systemic and retinal vasculature.26 However, data linking dyslipidemia to DR are

not as robust as those for hyperglycemia and hypertension.

Lipids were measured annually for 1441 patients with type 1 diabetes in the DCCT study.27 After

controlling for study group, A1C, and other risk factors, total-to-HDL cholesterol and LDL predicted

development of clinically significant macular edema (P for trend for both = 0.03) and hard exudate

(P ≤.002). Progression of DR and incidence of PDR were not associated with serum lipids after

adjusting for A1C or in other multivariate analysis.

An epidemiologic study of 1736 persons with type 2 diabetes in India reported that serum

cholesterol, triglycerides, and non-HDL cholesterol were higher in subjects with DR compared with

those without (P ≤.025).28 After adjusting for A1C and BMI, triglyceride level was significantly

associated with DR, and LDL-cholesterol with macular edema.

In the Australian population-based AusDiab study of 11,247 adults with type 2 diabetes, serum lipids

were not associated with retinopathy, while data supported other reports that duration of diabetes,

A1C levels, and systolic blood pressure are independent risk factors for DR.29 A cross-sectional

multi-ethnic study of 778 persons with diabetes in the MESA study in the United States also failed to

observe an association between plasma lipids and either DR or DME.30

The META-EYE study reported data on total cholesterol and prevalence of DR (Table 4).5 Any DR

and PDR were similar in the high- and low-cholesterol subgroups, while patients with elevated

cholesterol were more likely to have DME.



The FIELD study investigated macrovascular and microvascular outcomes, including need for laser

treatment for retinopathy, in 9795 patients with type 2 diabetes receiving long-term lipid-lowering

therapy with fenofibrate or placebo.31 An ophthalmology substudy enrolled 1012 patients to assess

retinopathy progression (≥2-steps). In the entire study cohort, the need for laser treatment over 5

years was not affected by plasma lipid concentrations; however, laser treatment was needed more

frequently in the setting of poor glycemic or blood pressure control, and in the presence of a greater

clinical microvascular disease burden. A 1.5% absolute risk reduction of first laser requirement was

observed in the fenofibrate compared with placebo group (3.4% vs. 4.9%; P =.0002). Similar absolute

risk reductions were observed whether the indication for laser treatment was maculopathy (1.1%) or

proliferative retinopathy (0.7%).

In the ophthalmology substudy, retinopathy progression was not significantly different betweenfenofibrate and placebo groups overall (9.6% vs 12.3%; P =.19), or in the subset of patients without

pre-existing retinopathy (11.4% vs 11.7%; P =.87). However, significantly fewer patients in the

fenofibrate group with pre-existing retinopathy had retinopathy progression compared with the

placebo group (3.1% vs 14.6%; P =.004).

In 1593 participants in both the ACCORD Eye and ACCORD Lipid studies, retinopathy progression

≥3 steps at 4 years was significantly less in the simvastatin plus fenofibrate compared with

simvastatin plus placebo group (6.5% vs 10.2%; adjusted OR [aOR] 0.60; 95% CI: 0.43,

0.87; P =.006).18

Fenofibrate: Theories for Mechanism of Action

Although the results of the FIELD and ACCORD-Eye studies suggest that fenofibrate treatment may

prevent DR progression in patients with pre-existing disease, the beneficial effect does not appear to

be mediated through an effect on lipid concentrations.11,32 Fenofibrate is a peroxisome proliferator-

activator receptor (PPAR) agonist, with pleiotropic effects beyond lipid lowering. Three PPAR

isoforms have been identified, all of which are expressed in the retina.33 A beneficial effect of

PPARα activation was first reported almost 50 years ago. PPARγ is proposed to have a role in



abrogating neurodegeneration and microangiopathy, and its suppression may be involved in the

pathogenesis of DR.

An in vivo study in a rodent type 1 diabetes model reported that fenofibrate decreased retinal

vascular leakage and leukostasis after both oral and intravitreal administration.34 In addition, rats

with oxygen-induced-retinopathy (OIR) had decreased neovascularization in fenofibrate-injectedeyes compared with the contralateral vehicle-injected eye. Animals fed fenofibrate chow had

decreased levels of inflammatory factors that promote leukostasis and leukocyte infiltration.

Similarly, OIR rats had significantly decreased retinal VEGF and hypoxia-inducible factor-1α, which

activates VEGF in ischemic conditions.

The beneficial effects of fenofibrate may be associated with these other mechanisms of action,

including direct effects on retinal inflammation and angiogenesis. Additional research is warranted to

further explore the potential of fenofibrate as an adjunct therapy in patients with diabetes.35

Diabetic Retinopathy Clinical Practice Guidelines

Multidisciplinary involvement is important for optimizing efforts to prevent the development andinhibit the progression of DR. Accordingly, management guidelines provide recommendations to

related clinical specialties; for example, the comprehensive American Diabetes Association (ADA)

Standards of Care devote a section to DR,36 and the American Academy of Ophthalmology has a

Diabetic Retinopathy Preferred Practice Pattern (PPP).37

American Diabetes Association Standards of Care

The ADA's Standards of Care include recommendations based on graded evidence related to

screening, diagnostic, and therapeutic options that are known or believed to favorably affect the

health outcomes of persons with diabetes.36 Recommendations are graded among 4 levels that

reflect the source and robustness of the evidence. The 2014 ADA Standard of Care updatecontinues to emphasize that optimizing both glycemic and blood pressure control can reduce the risk

or slow the progression of retinopathy (A level).

AAO Preferred Practice Pattern

The AAO PPP provides additional detailed guidance for eye care professionals and emphasizes the

importance of involving patients and their physicians in the management of the systemic disorder,

and acknowledges that eye care professionals must not only identify patients at risk for developing

diabetic retinopathy, but must encourage and provide lifelong evaluation of retinopathy

progression.37

Retinopathy Screening

The ADA recommends that an initial dilated and comprehensive eye examination should be provided

for adults with type 1 diabetes within 5 years after diabetes onset, and for patients with type 2

diabetes, it should be provided shortly after diagnosis. If no retinopathy is observed for ≥1 eye exam,

repeat exams can be scheduled at 2-year intervals. Patients with retinopathy should have annual

exams, which should be more frequent if retinopathy is progressing or sight threatening. High-quality



fundus photographs can be used as a screening tool, but they are not a substitute for a

comprehensive eye exam.

The AAO recommends performing the first examination for patients with type 1 diabetes within 3 to 5

years after diagnosis, and recommends an examination for patients with type 2 diabetes at the time

of diagnosis. Follow-up for both types of diabetes is recommended at yearly intervals, compared withthe 2-year ADA-recommended intervals. The AAO also notes that abnormal findings may warrant

more frequent follow-up.

Both the ADA and AAO recommend that women with diabetes who are pregnant or planning to

become pregnant should have a comprehensive eye exam prior to conception and early in the first

trimester. The ADA emphasizes that patients should be counseled on the risk for development

and/or progression of DR, with close follow-up during pregnancy and 1-year postpartum. The AAO

recommends following women with no retinopathy or mild-to-moderate NPDR every 3 to 12 months;

while if they have severe NPDR or worse a 1 –3 month follow-up interval is warranted.

Screening Interval Assessments

A recent retrospective study of Medicare beneficiaries showed that vision care recommendations are

not being met, even by populations who have vision care insurance coverage.38 In a group of 1150

persons with diabetes in a Medicare database, over 60 months, nearly 1000 did not have a retinal

exam, but 7% of those having exam had retinopathy, of whom 2% had PDR.

A study in England assessed the incidence and progression of DR in a population-based screening

program that included annual retinal photography.39 The cohort included 20,686 persons with type 2

diabetes who had up to 14 annual examinations between 1990 and 2006. At baseline, 79.5% had no

retinopathy, 17.5% had NPR, and 3.0% had PDR. Subsequent screening intervals were <12 months

(7.0%), 12 to 18 months (49%), 18 to 24 months (23%), and >24 months (21%). Patients without

retinopathy at baseline were at low risk of progressing to preproliferative retinopathy (requiring

specialist referral; cumulative 5- and 10-year incidences 4% and 16%), and at very low risk of

progressing to treatment-requiring PDR (cumulative 5- and 10-year cumulative incidences 0.68%

and 1.5%) or maculopathy (cumulative 5- and 10-year incidences 0.59% and 1.2%). The authors

concluded that DR screening intervals over 1-year for persons without retinopathy at their first

examination may be appropriate.

Treatment

The ADA emphasizes that patients with any level of macular edema, severe NPDR, or any PDR

should be promptly referred to an ophthalmologist who is knowledgeable and experienced in the

management and treatment of diabetic retinopathy.36 Laser photocoagulation therapy is indicated in

patients with high-risk PDR, clinically significant macular edema, and in some cases of severe

NPDR to reduce the risk of vision loss. Antivascular endothelial growth factor (VEGF) treatment is

indicated for DME. Aspirin therapy does not increase the risk of retinal hemorrhage; therefore,

retinopathy is not a contraindication for cardioprotective aspirin therapy.

As a guidance document for eye care specialists, the AAO PPP provides details on the

characteristics and components of quality eye care for patients with DR.37 The AAO reminds that the



recommendations are guidelines and not medical standards to be followed for all individual patient

situations.

Summary

Diabetes is a systemic disease, and control of modifiable risk factors, in particular glucose levels and

blood pressure, has an important role in preventing the development and progression of DR and

DME.

References

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3. Thomas B, et al. Can J Ophthalmol. 2013;48:22 –30.

4. Ruta L, et al. Diabet Med. 2013;30:387 –398.

5. Yau J, et al. Diabetes Care. 2012;35:556 –564.

6. Talwar N, et al. Inv Ophthalmol Vis Sci . 2013;54:Abs. 1540.

7. Nwanyanwu K, et al. Diabetes Care. 2013;36:1562 –1568.

8. Chen Y-H, et al. Diabetes Car e. 2012;35:803 –808.

9. Forbes J, et al. Physiol Rev . 2013;93:137 –188.

10. Cheung N, et al. Lancet. 2010;376:124 –136.

11. Safi S, et al. BioMed Res Intl . 2014;2014:801269.

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13. DCCT. Diabetes. 1995;44:968 –983.

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16. UKPDS. Lancet . 1998;352:837 –853.

17. DCCT/EDIC. N Eng J Med . 2015;372:1722 –1733.

18. ACCORD. N Eng J Med. 2010;363:233 –244.

19. Beulens J, et al. Diabetologia. 2009;52:2027 –2036.

20. Do D, et al. Cochrane Database Syst Rev . 2015; 1:CD006127.

21. UKPDS. BMJ . 1998;317:703 –713.

22. UKPDS. Arch Ophthalmol . 2004;122:1631 –1640.

23. Mauer M, et al. N Eng J Med . 2009;361:40 –51.

24. Chaturvedi N, et al. Lancet . 2008;372:1394 –1402.

25. Sjolie A, et al. Lancet . 2008;372:1385 –1393.

26. Diep T, et al. Diab Res Clin Pract . 2013;100:298 –305.

27. Miljanovic B, et al. Diabetes. 2004;53:2883 –2892.



28. Rema M, et al. Diabet Med. 2006;23:1029 –1036.

29. Tapp R, et al. Diabetes Care. 2003;26:1731 –1737.

30. Wong T, et al. Am J Ophthalmol. 2006;141:446 –455.

31. Keech A, et al. Lancet . 2007.32. Simo R, et al. Prog Retin Eye Res. 2015;DOI:10.1016/j.preteyeres.2015.1004.1003.

33. Ciudin A, et al. PPAR Research. 2013;2013:686525.

34. Chen Y, et al. Diabetes. 2013;62:261 –272.

35. Abcouwer S. Diabetes. 2013;62:36 –36.

36. ADA. Diabetes Care. 2014;37:S14 –S80.

37. AAO. 2012; http://www.aao.org/ppp. Accessed May 10, 2015.

38. Sloan F, et al. Ophthalmology . 2014;121:2452 –2460.

39. Jones C, et al. Diabetes Care. 2012;35:592 –596.

40. UKPDS. BMJ. 1998;317.

41. Wang B, et al. Lancet Diabetes Endocrinol . 2015;3:263 –274.

Almost 10% of the US population has diabetes.1 Of these approximately 30 million persons, more

than 8 million are estimated to be undiagnosed, and therefore are not receiving proper care.

Hospitalization for heart attack and stroke, and cardiovascular disease death rates were

approximately 1.5 to 1.7 times higher in adults with diagnosed diabetes compared with those without

diabetes. Diabetes is the primary cause of almost half (44%) of new kidney failure cases.

More than one-fourth (28.5%) of adults aged ≥40 years with diabetes have diabetic retinopathy (DR),

with 4.4% having diabetic macular edema (DME) or proliferative DR (PDR), which are significant

causes of vision loss in adults.2 However, during recent decades, despite the increasing prevalence

of diabetes, improved management of glycemia, blood pressure, and lipid levels have contributed to

much lower risks of PDR, DME, and visual impairment in persons who are recently diagnosed with

type 1 or 2 diabetes (Figure 1).3

http://www.aao.org/ppp






Managing DME

Grid laser treatments to reverse aneurysm leakage provided the DME standard of care for more than

20 years. Laser treatment can be appropriate for eyes with a single microaneurysm that has minimalleakage (Figure 2).4,5The exact mechanism of action of laser treatment is not completely

understood; theories include the possibility that increased retinal oxygen concentrations may occur

over the laser scars, which may induce more efficient elimination of excess fluid and relieve

hypoxia.4,6



Newer therapies, including intravitreal corticosteroids and anti-VEGF agents, expanded the available

DME treatments after randomized controlled trials showed significant visual and anatomic

benefits.7 With these increased treatment options, the eye care provider should ensure appropriate

treatments are selected for individual patients.

Eye Examination

A comprehensive eye examination, enhanced by imaging advancements introduced during the past

15 years, can provide essential guidance for treatment selection. Widefield angiography, first

described in 2004, has shown superior capabilities for visualization of the peripheral retina in

diabetic pathology.8 Areas of ischemic nonperfusion revealed on fluorescein angiography (FA) are

often shown to have subsequent abnormal neovascularization in response to VEGF (Figure 3).

Observations revealed on FA can be used to describe macular edema as focal or diffuse, dependingon the leakage pattern. However, leakage observed on FA does not correlate with clinical retinal

thickening or edema.4 Optical coherence tomography (OCT) is a valuable investigation that obtains

a noninvasive virtual cross-sectional scan through the retina, facilitating observation of macular

edema and subretinal fluid. OCT studies of eyes with clinically significant macular edema allow

identification of retinal swelling, cystoid macular edema, and retinal detachment.



Macular edema can often be resolved; however, the success of efforts to treat areas of nonperfusion

and reduce proliferation, whether by anti-VEGF agents, steroids, or laser therapy, is greatly

diminished in a setting of poor glycemic and blood pressure control. Discussing imaging results with

patients can be a valuable educational tool, and may motivate patients to improve adherence with

systemic disease management.

Intravitreal Therapies for DME

Intravitreal steroid treatment for DME was under investigation before the era of anti-VEGF therapies.

The rationale for using corticosteroids to treat DME is based on their known activity inhibiting the

expression of VEGF and the VEGF gene as well as their anti-inflammatory properties.9 Although

several anti-VEGF agents are now used to treat DME, ideal long-term benefits are not yet achieved

in the majority of patients.

The Diabetic Retinopathy Clinical Research Network (DRCR.net) was formed in 2002 with more

than 109 participating sites. This collaboration has played a prominent role in facilitating multicenter

clinical research focusing on DR, DME, and associated conditions. Intravitreal triamcinolone was

initially suggested as having potential for treating DME without the support of long-term clinical trial

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data; accordingly, the DRCR.net performed a randomized controlled trial to evaluate the efficacy and

safety of 2 doses of intravitreal triamcinolone compared with standard focal/grid laser

photocoagulation.10

Eyes were randomized to focal/grid laser (n=330), 1 mg intravitreal triamcinolone (n=256), or 4 mg

intravitreal triamcinolone (n=254), with retreatment provided for persistent or new edema at 4-monthintervals. The primary outcome was visual acuity at 2 years. The mean number of treatments over 2

years was 2.9, 3.5, and 3.1 in the laser, 1 mg, and 4 mg triamcinolone groups. Although mean visual

acuity was greater at 4 months in the 4 mg triamcinolone group compared with the laser ( P<.001)

and 1 mg triamcinolone group (P =.001), by 1 year there were no differences among treatment

groups. From 16 months to 2 years, mean visual acuity was better in the laser group compared with

the 1 mg (P =.02) and 4 mg (P =.002) steroid groups (1 mg vs 4 mg: P =.49). In general, OCT results

paralleled visual acuity outcomes. Intraocular pressure (IOP) was increased ≥10 mm Hg at any visit

in 4%, 16%, and 33% of patients in the 3 treatment groups, and cataract surgery was performed in

13%, 23%, and 51% of eyes. The authors concluded that focal/grid photocoagulation was more

effective and had fewer adverse effects than either dose of intravitreal triamcinolone.

A subsequent DRCR.net study compared intravitreal treatment with either triamcinolone 4 mg or an

anti-VEGF agent (ranibizumab) combined with focal/grid laser (prompt laser), and with both

treatments initiated as monotherapies (deferred laser).11 Similar to the earlier study, the steroid

group underwent initial visual acuity improvements that peaked between 20 and 24 weeks, followed

by a decrease to reach a mean change similar to that of the sham + prompt laser group after 1 year.

At the 2-year visit, visual acuity was not improved with intravitreal triamcinolone + prompt laser

compared with sham + prompt laser. In an analysis limited to pseudophakic eyes, the triamcinolone

+ prompt laser visual acuity outcome was similar to that of the 2 ranibizumab groups (prompt or

deferred laser); however, none of the active intravitreal treatment groups in this patient subset had

significantly better visual acuity changes compared with the sham + prompt laser group.12Patients inthe triamcinolone group had a median of 3 injections in the first year, compared with 8 and 9 in the 2

ranibizumab groups, which was reduced in the second year to 1, 2, and 3 injections. Therefore,

despite the rationale supporting corticosteroid use, this and several other studies failed to support

the efficacy and safety of intravitreal injection of triamcinolone suspensions for treating DME.

This DRCR.net study Protocol I now has 5 years of follow-up data available for the study extension

in qualifying patients who were randomized to ranibizumab plus either the prompt (n=124) or

deferred (≥24 weeks; n=111) laser .13 The 5-year visual acuity change from baseline was 7.2 and 9.8

letters in the prompt and deferred laser groups (−2.6 letter difference; 95% CI: −5.5, +0.4; P =.09).

During the 5-year study, 56% of the deferred laser group did not receive laser treatment. The

median number of injections was 13 and 17 in the prompt and deferred groups, while 54% and 45%

of subjects in each group did not receive an injection in year 4, increasing to 62% and 52% in year 5.

The authors concluded that initial laser treatment is not superior to deferring treatment for ≥24 weeks

in this patient population, and observed that although more than half of the deferred laser group did

not receive laser treatment, this may be associated with more injections.

Anti-VEGF Agents

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Ranibizumab

The monoclonal antibody fragment ranibizumab was the first FDA-approved pharmacotherapy

indicated for treating DME. The RISE and RIDE studies compared 0.3 mg and 0.5 mg monthly

ranibizumab with sham injections, allowing macular laser treatment according to protocol-specified

criteria.14 These studies provided the pivotal data for receiving FDA approval in 2012, with a

recommended regimen of monthly 0.3-mg injections.15 In both studies, at 24 months 33.6% to

45.7% of ranibizumab patients achieved the primary outcome of a ≥15-letter gain in visual acuity

from baseline, compared with 19.2% and 22.0% of RISE and RIDE sham-injected groups.16From 24

to 36 months, sham patients were eligible to cross over to ranibizumab treatment. Although 20% of

crossover patients achieved the primary endpoint at 36 months, the average gains were less than

those of the ranibizumab groups after 1 year of treatment.

Aflibercept

Aflibercept is a recombinant fusion protein comprising the key binding domains of human VEGF

receptors 1 and 2.17 The VIVID and VISTA trials provided pivotal data for the 2014 FDA approval for

treating DME.18,19 Vision improvements in patients receiving 2 mg every 4 weeks or every 8 weeks

after 5 initial monthly doses were compared with those receiving macular photocoagulation.

Proportions of eyes with ≥15-letter gains at week 52 were significantly higher than the laser group in

both aflibercept groups in both studies (P<.0001). Accordingly, the recommended regimen is 2 mg

every 4 weeks for the first 5 injections, followed by dosing at 8-week intervals.18 Aflibercept has

recently received FDA approval for intravitreal use in patients with diabetic retinopathy and macular

edema.

Bevacizumab

Bevacizumab, which has FDA approval for several oncology indications, continues to play a

prominent offlabel role in treating DME. Bevacizumab was the firstline treatment of choice for a

phakic patient with DME by more than half (54%) of respondents to the 2014 American Society of

Retina Specialists Global Trends Survey.20

Anti-VEGF Agents: DRCR.net Head-to-Head Randomized Controlled Trial

DRCR.net Randomized Controlled Trial compared the efficacy and safety of intravitreal aflibercept,

bevacizumab, and ranibizumab for the treatment of DME.21 This multicenter study randomized 660

adults with DME involving the macular center to aflibercept 2.0 mg (n=224), bevacizumab 1.25 mg

(n=281), or ranibizumab 0.3 mg (n=218). A protocol-specified algorithm allowed drug administration

as frequently as every 4 weeks. The primary outcome was mean change in visual acuity at 1 year. Aflibercept patients had a 1-year improvement of 13.3 letters, compared with 9.7 for bevacizumab

(P<.001) and 11.2 for ranibizumab (P =.03) patients. The difference was driven by the eyes with

worse visual acuity at baseline (P<.001 for interaction); accordingly, the differences between groups

were not considered to be clinically meaningful. In subgroups based on initial visual acuity, there

were no differences among groups for eyes with initially mild visual acuity loss, while aflibercept was

more effective at improving vision in eyes with more extensive initial visual acuity loss. The median

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number of injections was 9, 10, and 10 in the aflibercept, bevacizumab, and ranibizumab groups,

respectively (P =.045 for overall comparison). Laser photocoagulation was performed at least once in

37%, 56%, and 46% of aflibercept-, bevacizumab-, and ranibizumab-treated eyes (P<.001 for overall

comparison). Proportions of eyes with central subfield thickness <250 μm we re 66%, 36%, and 58%

in the aflibercept, bevacizumab, and ranibizumab groups. Changes were related to initial visual

impairment; however, there was a consistent lesser effect in bevacizumab treated eyes. Adverse

events were similar among groups.

Intravitreal Steroids

Intravitreal steroid research pursued developing extended release delivery systems. This research

resulted in FDA approval of a dexamethasone biodegradable implant and a fluocinolone

nonbiodegrable insert for treating DME.22,23

Dexamethasone Implant

Dexamethasone has 5 times the potency of triamcinolone, but is limited by a short (3 h) intravitreal

half-life.6 Accordingly, a biodegradable co-lactide-co-glycolide polymer similar to that used forresorbable sutures provides a drug delivery system, with a lifespan of ≤6 months. In 2009, the

dexamethasone (DEX) implant was FDA-approved as the first-of-its-kind for treating macular edema

related to branch or central retinal vein occlusion, and the indication was extended to include uveitis

in 2010.23

The MEAD study comprised two 3-year trials of the safety and efficacy of the DEX implant in

patients with DME, who were randomized to 0.7 mg DEX implant, 0.35 mg DEX implant, or sham

procedure.24 Patients could be retreated at no less than 6-month intervals. The mean number of

treatments over 3 years was 4.1, 4.4, and 3.3 in the DEX 0.7 mg, DEX 0.35 mg, and sham groups.Proportions of patients with ≥15-letter improvement in visual acuity from baseline were significantly

greater in both DEX groups compared with the sham group (Figure 4). Cataract-related adverse

events occurred in 67.9%, 64.1%, and 20.4% of DEX 0.7 mg, DEX 0.35 mg, and sham eyes. IOP

increases usually resolved or were controlled with medication; while 2 (0.6%) and 1 (0.3%) patients

in the 0.7 mg and 0.35 mg DEX implant groups required trabeculectomy. The 0.7 mg DEX implant,

contained in a single-use applicator, was approved for treating DME in 2014.23



Dexamethasone Implant Head-to-Head versus Bevacizumab

The BEVORDEX study was a phase 2 multicenter trial that enrolled 88 eyes of 61 patients with

center-involving DME.25 Eyes were randomized between bevacizumab 1.25 mg and the 0.7 mg DEX

implant, with retreatment possible at ≥4-week and ≥16-week intervals. The primary outcome was the

proportion of eyes with a ≥10-letter improvement in visual acuity, which was achieved at 12 months

by 40% of the bevacizumab and 41% of the dexamethasone-treated eyes (P =.83). None of the

bevacizumab-treated eyes lost ≥10 letters, compared with 11% of the dexamethasone-treated eyes,

which was due to increased cataract density in 4 of the 5 affected eyes. Mean central macular

thickness decreased significantly more in the dexamethasone (187 μm) compared with bevacizumab



(122 μm) eyes (P =.015). The bevacizumab group eyes received a mean of 8.6 injections compared

with 2.7 for the dexamethasone eyes.

Fluocinolone Acetonide Insert

Fluocinolone acetonide (FA) is a corticosteroid that has also been incorporated into an intravitreal

therapy for DME. The inserts are cylindrical tubes (3.5 × 0.37 mm) composed of a nonbiodegradable

polymer loaded with FA, which can be inserted into the vitreous cavity through a 25-gauge

needle.26 The FAME study produced data for FA’s 2014 FDA approval.27 After the 2-year primary

endpoint was reached, 36-month data revealed that 28.7% and 27.8% of patients receiving 0.2 μg/d

and 0.5 μg/d FA gained ≥15-letter scores from baseline, compared with 18.9% in the sham group

(P =.018). In subgroup analysis of patients with a ≥3-year DME duration at baseline, 2.5-fold more

patients in the 0.2 μg/d group achieved a ≥15-letter improvement compared with the sham group

(34.0% vs 13.4%; P<.001); while improvement was similar in patients with non-chronic DME (22.3%

vs 27.8%; P =.275).28 Between 80% to 90% of phakic eyes in the FA insert groups developed

cataract, and the incidence of incisional glaucoma surgery at month 36 was 4.8% and 8.1%.27 The

approved dosage form is designed to release the drug for 36 months at an initial release rate of 0.25μg/day.22 The use of FA is indicated for patients who have previously been treated with a course of

corticosteroids without experiencing a clinically significant increase in intraocular pressure.

Intravitreal Steroids in Eyes That Failed Other Treatments

The availability of both anti-VEGF agents and corticosteroids expands DME treatment options based

on considerations other than treatment regimen. The 2 classes block different sites of the

pathological pathway to DME; accordingly, corticosteroids may be an option in patients who do not

respond to anti-VEGF therapy.29 Although no studies have been designed to address the treatment

success of intravitreal steroids in eyes that failed other therapies, 2 case series reported 6-month

follow-up data on the DEX implant that included patients who had previously received othertreatments. In a small prospective study, 15 of 20 eyes with persistent DME had received anti-VEGF

injections within 3 months prior to receiving the DEX implant.30 Visual acuity was significantly

increased from baseline through week 16. A 6-month retrospective case series investigated the

response of 58 patients with persistent DME that had been refractory to multiple previous

therapies.31 Mean foveal thickness and visual acuity were significantly improved at 1-month, which

persisted throughout the 6 months.

Summary

Recent advancements have increased therapies available for the treatment of DME. Successfully

managing diabetes requires a team approach among primary care physicians, endocrinologists, andophthalmologists, which includes timely communication of patient status and management

strategies. A productive partnership with the patient can promote adherence to healthcare.

References

1. CDC. National Diabetes Statistics Report. 2014; Available at

http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf . Accessed May 11,

2015.

http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf





2. CDC. 2012; Available at http://www.cdc.gov/diabetes/statistics/visual/fig2.htm . Accessed May 11,

2015.

3. Antonetti D, et al. N Eng J Med. 2012;366:1227 –1239.

4. Bhagat N, et al. Surv Ophthalmol. 2009;54:1 –32.

5. Gupta N, et al. Open Ophthalmol J. 2013;7:4 –10.

6. Stewart M. Curr Diab Rep. 2012;12:364 –375.

7. Thomas B, et al. Can J Ophthalmol. 2013;48:22 –30.

8. Wessel M, et al. Br J Ophthalmol. 2012;96:694 –698.

9. Boyer D, et al. Ther Adv Endocrinol Metab. 2013;4:151 –169.

10. DRCRN. Ophthalmology. 2008;115:1447 –1477.

11. DRCR.net. Ophthalmology. 2010;117:1064 –1077.

12. Elman M, et al. Ophthalmology. 2011;118:609 –614.

13. Elman M, et al. Ophthalmology. 2015;122:375 –381.

14. Nguyen Q, et al. Ophthalmology. 2012;119:789 –801.

15. LUCENTIS [Package insert]. South San Francisco, CA: Genentech, Inc.; 2015.

16. Brown D, et al. Ophthalmology. 2013;120:2013 –2022.

17. Do D, et al. Ophthalmology. 2012;119:1658 –1665.

18. EYLEA [Package insert]. Tarrytown, NY: Regeneron; 2014.

19. Korobelnik J, et al. Ophthalmology. 2014;121:2247 –2254.

20. Rezaei K, Stone T, eds. American Society of Retina Specialists; 2014.

21. DRCRN. N Eng J Med. 2015;372:1193 –1203.

22. ILUVIEN [Package insert]. Alpharetta, GA: Alimera Sciences, Inc.; 2014.

23. OZURDEX [Package insert]. Irvine, CA: Allergan, Inc.; 2014.

24. Boyer D, et al. Ophthalmology. 2014;121:1904 –1914.

25. Gillies M, et al. Ophthalmology. 2014;121:2473 –2481.

26. Campochiaro P, et al. Ophthalmology. 2011;118:626 –635.

27. Campochiaro P, et al. Ophthalmology. 2012;119:2125 –2132.

28. Cunha-Vaz J, et al. Ophthalmology. 2014;121:1892 –1903.

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29. Agarwal A, et al. Curr Opin Ophthalmol. 2015;26:000 –000.

30. Pacella E, et al. Clin Ophthalmol. 2013;7:1423 –1428.

31. Dutra Medeiros M, et al. Ophthalmologica. 2014;231:141 –146.

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