Diabetic Retinopathy

American Diabetes Symposium

Reported by Joelle Escoffery

Somatostatin Analogs in the Treatment of Diabetic Retinopathy

The hormone somatostatin opposes the actions of both growth hormone (GH) and insulin-like growth factor 1 (IGF-1). It is currently being examimned for the treatment of diabetic retinopathy (DR). The somatostatin analog octreocotide is being examined for its ability to delay progression to proliferative diabetic retinopathy (PDR) among patients with nonproliferative diabetic retinopathy (NPDR). Octreocide (200-500 mcg/day sq for 15 months) has been shown retard DR progression or delay time to laser surgery. Furthermore, treatment with octreocide was associated with suppression of IGF-1, suggesting a role for this growth factor in the progression of diabetic retinopathy.Octreocide has also been shown to reduce the risk of vitreous hemorrhage in patients with PDR and prior laser photocoagulation. When 100 mcg octreocide was given tid for 36 months, a marked reduction in vitreous hemorrhage and improvements in VA compared with controls was demonstrated.

More recently, a long-acting form of octreotide has been undergoing clinical study. Using the long-acting formulation, octreotide levels can be maintained over a month, and GH levels are suppressed. Two randomized, controlled phase 3 trials using long-acting octreocide have been conducted testing its efficacy for the treatment of DR. One clinical trail was conducted in Europe, and one was conducted in the Americas (US, Canada, and Brazil). The primary endpoint in these studies progression of DR, and progression to diabetic macular edema (DME) was a secondary endpoint. In both studies, patients had moderate NPDR (47 to 61 on ETDRS severity scale). They were primarily insulin-requiring white males with type 2, long standing diabetes, and albuminuria. The 2 samples were comparable in most characteristics, with the exception higher body mass index (BMI) in the American study.

In the American study, there was a significant reduction in time to progression to PDR, but no differences in DME progression were observed. Visual acuity (VA) results showed a trend for visual improvements, but it did not reach statistical significance. IGF-1 levels suppressed. No change in urinary albumin was observed. In the European study, there was no significant effect of octreocide on progression to PDR or DME. As was the case with the American study, there was a trend toward improved VA that did not reach statistical significance, possibly due to inadequate statistical power. In this study, IGF-1 was also suppressed, and no significant change in urinary albumin was detected. The most frequent adverse effects were gastrointestinal in nature, and they did not affect study participation. More patients with hypertension in placebo than in the octreocide group, and vitreous hemorrhage occurred at a lower frequency in patients receiving octreocide. Although the primary study objective was achieved in the American study, progression of DR was not delayed in the European study. Current efforts are focusing on the examination of variables that may explain the difference in findings.

Statins and Diabetic Retinopathy

There are clearly established targets for glycemic, blood pressure, and lipid control among patients with diabetes, as these strategies can prevent diabetic complications. Recent work has examined the possible role of lipid abnormalities in the progression of diabetic retinopathy. Combined hyperlipidemia is associated with peripheral ischemia, cotton wool spots, and hard exudates. Satins have been shown to have protective effects against glaucoma, and their use is associated with lower intraocular pressure. Fibrates may also play a protective role in terms of diabetic retinopathy progression. In 4 studies on examining the efficacy of fibrates for the treatment of diabetic retinopathy, no change in VA was observed despite a reduction in exudation. However, these patients evidenced very poor VA at study entry and may have had limited prospect of recovery. There is a significant linear trend of worsening diabetic retinopathy was total and LDL cholesterol increase.

In the Atherosclerosis Risk in Community (ARIC) study,  intima media thickness is associated with DR, but the association is weak. Tight carotid stenosis leads to ocular ischemia. In spite of the suggestive evidence, no intervention data testing the efficacy of statins on DR are currently available. There is some evidence to suggest that statin use is beneficial in DR. Patients on statin therapy evidenced a delay in time to first hemorrhage and recurrence. Statin use may also improve or stable vision, decrease exudation, and decrease DME. The Collaborative Atorvastatin Diabetes Study (CARDS) demonstrated that10 mg of atorvastatin reduced incidence of new photocoagulation reduced by 21% and maintained the reduction throughout the study, although this trend wa not significant, possibly due to the large amount of missing data.  In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study, the need for laser therapy in patients with no history of retinopathy was reduced by about 40%.

In summary, more photographic studies with adequate statistical power are needed. Based on available evidence, the best results may be achieved with combination statin-fibrate therapy.

The Eye as a Risk Marker for Cardiovascular Morbidity and Mortality

Cardiovascular disease (CVD) is a cause of significant morbidity and mortality, and a substantial proportion of the variance for CVD is not explained by traditional risk factors. Retinal microvascular abnormalities have been shown to predict CVD mortality. Retinal vascular signs, both focal and diffuse, may be important for the predicting future CVD. In terms of measuring retinal vascular signs, ophthalmologic exam is not an adequately sensitive test, and photographic images should be used. A system of retinal vascular grading has been developed, and the development of the Singapore Vessel Assessment software (SIVA) has improved grading.

In terms of target population, approximately 3-14% of general population haa retinal vascular signs, and these signs are strongly related to mean arterial blood pressure.Retinal arteriolars narrow in a linear fashion with increasing blood pressure, and patients with diabetes have a smaller arteriovenous (AV) ratio. Conversely, lower AV ration among healthy individuals is associated with risk of diabetes. Retinal vascular signs have been shown to predict gross proteinurea and are associated with increased risk of stroke and CHF. 

In short, a retinal exam may add independent information about the risk of CVD outcomes, and strategies for measuring retinal vascular signs are improving. Patients with a history of hypertension, diabetes, or elevated CVD risk may benefit from assessment of retinal vascular signs.

They Eye Is not a Risk Marker for Cardiovascular Morbidity and Mortality

Ocular factors are related to survival in type 2 diabetes, but there is limited and conflicting evidence about the relationship of the retinal microvasculature and macrovascular disease. Retinal arteriolar narrowing and AV nicking were not associated with CVD in the ARIC Study. Severity of DR is not associated with stroke or CHD. Additionally, DR is not associated with subclinical markers of CVD. In the Beaver Dam Eye Study, generalized arteriolar narrowing was not associated with increased mortality risk. In the EURODIAB study, NPDR not associated with mortality. PDR was associated with all-cause mortality; however, after adjusting for other CVD risk factors, the relationship attenuated.  Retinopathy is not an independent risk marker, but reflects the detrimental effect of CVD risk factors.