4.3.5 Statins

Hydroxymethylglutaryl coenzyme A reductase inhibitors (HMGCaA reductase inhibitors, or statins) have been associated with a reduction in recurrence rates of diabetic vitreous hemorrhage and reduction in rates of retinopathy progression in small clinical studies.88,128 In a case–control chart review, use of statins was not associated with reduced development of diabetic retinopathy.89 Statins may have beneficial effects on diabetic retinopathy by reduction of serum cholesterol levels, by direct anti-apop- tosis effects on retinal endothelial cells, and by protection of the blood–retinal barrier through antiinflammatory effects.72,131 Statins may also change the response to focal/grid laser for DME. In a small randomized trial, atorvastatin increased the resolution in macular hard exudates at 18 weeks following laser treatment compared to patients with similar severity of DME not receiving drug.86

been found to raise plasma vascular endothelial growth factor and to be associated with peripheral

edema in 3–7.5% of patients taking them, especially when used in combination with insulin.136–138 Ret-

rospective case reports and case series have sug-

gested that use of these drugs may be associated with induction or exacerbation of DME.139,131,141

Cessation of thiazolidinedione use led to reduction of DME in 73% and resolution of DME in 36% of patient, respectively.140 A case–control study did not show a higher incidence of DME in diabetics taking thiazolidinediones as might have been expected from the anecdotal reports, but did show a delay in progression of severe NPDR to PDR in patients taking these drugs.142 A prospective cohort study from a managed care organization with 170,000 diabetic patients showed that thiazolidinedione use was associated with DME with an odds ratio of 2.6 (95% CI 2.4–3.0).143

4.3.6 Protein Kinase C Inhibitors

Protein kinase C b (PKC b) is activated in diabetes with multiple effects linked to development and progression of DR including thickening of basement membranes, increased leukocyte vascular adhesion,

increased vascular permeability, and prolongation of retinal circulation time (see Chapter 1).132,133 Rubox-

istaurin is a PKC b inhibitor that has been shown to reduce the progression of DME > 100 mm from the center of the macula to DME <100 mm from the center of the macula in a randomized clinical trial over 3 years.134 In addition, the drug reduced the frequency of sustained moderate visual acuity loss, the rate of decrease of visual acuity associated with

severe DME, and the need for focal/grid laser treatment.134,135 Ruboxistaurin is in continued phase 3

randomized trials and is not available for clinical use.

4.3.7 Thiazolidinediones (Glitazones)

Thiazolidinediones are oral antidiabetic drugs that bind to peroxisome proliferator–activator receptor gamma and act as insulin sensitizers. They have

4.3.8 Miscellaneous Drugs

Use of oral hypoglycemic drugs has been associated with an increased 4-year incidence of DR compared to management of diabetes by diet.18 The atypical antipsychotic drug risperidone has been reported to exacerbate diabetes and has been associated with lipemia retinalis.144

4.4Ocular Factors Influencing Diabetic Retinopathy

Diabetic retinopathy severity is affected by certain ocular factors.58 In a multivariate model incorporating demographic variables (age, gender, race, duration of diabetes, stroke history, coronary artery disease history, drinking history, smoking history) and systemic variables (fasting blood glucose, diabetes medications, serum lipids, blood pressure, hypertension medication use, diuretic use, and certain laboratory tests), the following ocular variables were associated with increasing severity of DR: smaller retinal arteriole/venule ratio, presence of retinal A/V nicking, and focal arteriolar narrowing.58 In black type

1 diabetics, greater baseline retinopathy severity is an independent risk factor for 6-year incidence of doubling of the visual angle.25

In WESDR, greater baseline retinopathy severity was associated with a higher incidence rate of DME in both younger and older onset diabetics (Figs. 4.7 and 4.8).23 Other studies have confirmed the association in type 1 diabetics.24 Using the state of no DR as the reference level, and a modification of the ETDRS adaptation of the modified Airlie House classification of DR (see Chapter 5), the hazard

ratios for incidence of DME for retinopathy severity levels 21 (minimal NPDR), 31–37 (mild NPDR), 43–53 (moderate–severe NPDR), and 60+ (PDR) were 1.52, 2.71, 3.26, and 3.40, respectively.24

In addition to systemic factors associated with progression of retinopathy, certain ocular factors are predictive. The main ocular factor associated with progression to PDR in type 1 DM is presence of NPDR.7 In WESDR, multivariate analyses showed that less severe retinopathy at baseline was associated with 2-step progression of DR severity.4

Fig. 4.7 Graph of the 10-year incidence of DME in younger onset diabetics in WESDR by baseline DR severity. Data from Klein et al.23 The definitions of the retinopathy severity

Fig. 4.8 Graph of the 10year incidence of DME in older onset diabetics regardless of insulin use in WESDR by baseline DR severity. Data from Klein et al.23 The definitions of the retinopathy severity levels follow: 10 ¼ no diabetic retinopathy; 21, 31, 37, 43, 47, and

53 ¼ nonproliferative diabetic retinopathy of increasing severity; and 60+ ¼ proliferative diabetic retinopathy

levels follow: 10 ¼ no diabetic retinopathy; 21, 31, 37, 43, 47, and 53 ¼ nonproliferative diabetic retinopathy of increasing severity; and 60+ ¼ proliferative diabetic retinopathy

Greater baseline severity of diabetic retinopathy was associated with a higher rate of progression to proliferative retinopathy in the ETDRS. Of eyes with levels 35 (mild NPDR), 43, and 47 (moderate NPDR), and 53 (severe NPDR) retinopathy at baseline, 15.2, 21, 27, and 57.8%, respectively, progressed to high-risk proliferative diabetic retinopathy after 5- year follow-up.145 A similar result was found in the UKPDS in patients with type 2 diabetes. In patients with no retinopathy at baseline, 0.2 and 2.6% required photocoagulation at 3 and 9 years of fol- low-up, respectively.146 In patients with microaneurysms or more severe retinopathy in both eyes at baseline, 15.3 and 31.9% required laser photocoagulation at 3 and 9 years, respectively. The commonest indication for laser treatment was diabetic macular edema.146 In adult patients with type 1 diabetes, there was an association of larger arteriolar and venular caliber with progression of retinopathy severity from mild to severe and with development of proliferative diabetic retinopathy.147

Diabetic retinopathy is generally symmetric between the two eyes. The Spearman correlation coefficient between the two eyes for diabetic retinopathy severity at 10-year follow-up in WESDR was 0.90, 0.82, and 0.82 for the younger onset, older onset taking insulin, and older onset not taking insulin groups, respectively.148 Thus, asymmetry of retinopathy provides clues regarding protective or predisposing ocular risk factors for retinopathy. Some factors associated with protection from PDR are optic atrophy, higher intraocular pressure,

unilateral glaucoma, and chorioretinal scar- ring.149–152 Bilateral glaucoma has not been found

to influence prevalence of DR.13 Myopia has been inconsistently associated with protection from diabetic retinopathy; higher degrees of myopia seem to provide more protection when an association has been discerned.13,153 Although ipsilateral carotid occlusive disease was raised as a possible protective factor against development of PDR in a study based on ophthalmodynamometry, a later prospective study using fluorescein angiography to document neovascularization found no association.154,155 There are also regionally protective factors for diabetic retinopathy within the same eye. For example, diabetic eyes with tilted disk syndrome and inferior staphylomas may have sparing from diabetic retinopathy in the area of the thinner retina inferiorly.156

4.5Diabetic Retinopathy

and Associated Comorbidity

Systemic factors influence not only diabetic retinopathy but also aspects of diabetic retinopathy can be warning signs regarding systemic health. In a population-based study of adults aged 40 and above in Beijing, diabetic-like retinopathy was an independent predictor of all cause mortality.157 In population-based studies from the Australia and the United States, baseline presence of retinopathy was associated with increased mortality from cor-

onary heart disease and cardiovascular disease (coronary heart disease and stroke), respectively.158,159

Presence of CSME was significantly associated with all cause mortality and ischemic heart disease mortality in patients with type 2 diabetes, but not with type 1 diabetes.160 In two independent Finnish

population-based studies, PDR in type 2 DM was associated with coronary heart disease death.161,162

In the Atherosclerosis Risk in Communities Study, presence of DR at baseline was associated with a higher rate of congestive heart failure after 9 years of follow-up.163 Such broad-based evidence across multiple countries suggests that patients with diabetic retinopathy need heightened surveillance for the detection of cardiovascular disease.160,163 DME may be an indicator of generalized vascular hyperpermeability as reflected in urinary albumin excretion and transcapillary escape of albumin.164

4.6 Economic Consequences

Glycemic control has economic consequences. In a modeling study based on existing epidemiologic studies, a change in the average HbA1c level for the population from 7.25 to 9.6 was associated with an increase in 30-year average direct medical cost to manage the diabetic complications from $35,000 to $49,000, other variables being held constant.165 Conversion from conventional to intensive glucose control has been predicted to cost $19,987 per quality adjusted life year gained, a number well

within the range considered to represent a good value.31,166

Systemic associations with diabetic retinopathy are often overlooked. Their recognition offers approaches to treatment that may help ocular outcomes and other aspects of health as well.

Retinopathy identical to that associated with diabetes is seen in 5–10% of persons over age 40 who do not have diabetes mellitus as conventionally defined.

In type 1 diabetes mellitus, there is no glycemic threshold below which further reduction in HbA1c toward normal does not result in further improvement in retinopathy end points, but the risk of hypoglycemia correspondingly goes up as well. A HbA1c goal is therefore an individualized decision for each patient. In general, a goal of 7.0% strikes a balance between benefits and risks.

Metabolic memory is a term indicating that glycemic control has consequences for retinopathy progression that persist for years. Tight control early in the course of diabetes is thus a goal.

Rapid improvement in glycemic control can cause short-term worsening of retinopathy, but is still associated with long-term better outcomes than continued conventional control.

Lowering blood pressure benefits multiple aspects of DR in all subtypes of the disease.

Awareness of the potential for pregnancy to be associated with rapid progression of DR, of the need for a screening examination early in the course of pregnancy, and of the need for fol- low-up examinations calibrated according to the severity of retinopathy will prevent unnecessary visual loss.

Patients with renal insufficiency can manifest DME that is better managed at the systemic level first before considering specific ocular intervention such as laser photocoagulation. Control of blood pressure, systemic fluid retention, and anemia can lead to resolution of edema in such cases.

Patients with more advanced diabetic retinopathy need systemic monitoring for coronary artery disease and peripheral vascular disease as their risk is higher compared to patients without retinopathy.

Continuous improvement in glucose monitoring techniques with the possibility of eliminating fingersticks and more widespread use of insulin pumps may help more diabetics achieve intensive glycemic control with beneficial effects on retinopathy and other complications. Improved communication between internists, who manage the important systemic risk factors, and ophthalmologists, who monitor the retinopathy, may be expected in an era of increasing use of the electronic medical record with benefits for outcomes. The relationship of many drugs with potential effects on the retina and the course of DR is largely unexplored and will probably increase in the future. Because of possible interactions of multiple drugs, large databases will be advantageous in such investigations, again aided by the increasing adoption of the electronic medical record.

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