Diabetic retinopathy (DR) was first PROCEEDINGS DIABETIC RETINOPATHY * Ronald Klein, MD, MPH ABSTRACT

DIABETIC RETINOPATHY * Ronald Klein, MD, MPH ABSTRACT Diabetic retinopathy (DR) is characterized by the development of retinal microaneurysms, hemorrhages, deposits of leaked lipoproteins (hard exudates), microinfarction of the nerve fiber layer (cotton-wool spots or soft exudates), development of collateral vessels in ischemic areas (intraretinal microvascular abnormalities), and the proliferation of new blood vessels. Patients with type 2 diabetes and mild nonproliferative DR at baseline are at high risk of a number of undesirable clinical outcomes over a 5- to 15-year period, including progression to clinically significant macular edema or proliferative DR, decline in visual acuity, lower-extremity amputation, and death. Epidemiological studies suggest that the progression of DR is strongly related to glycemic control, and randomized clinical trials have shown that intensive therapy to lower blood glucose reduces the proportion of patients with progressing DR. The relationship between hypertension and the progression of DR is less clear, perhaps because patients with diabetes and hypertension in whom DR progresses are less likely to be seen in epidemiological studies due to death. However, most clinical trial evidence suggests that lowering blood pressure also reduces the progression of retinopathy in patients with diabetes. The role of lipid lowering in the progression of DR is currently being evaluated in large randomized *Based on a presentation given by Dr Klein at a CME dinner symposium for family physicians. Professor, Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin. Address correspondence to: Ronald Klein, MD, MPH, 610 Walnut St, Room 504 WARF, Madison, WI 53705. E-mail: kleinr@epi.ophth.wisc.edu. clinical trials. Despite the effectiveness of glycemic control and blood pressure management for reducing the risk of DR, many patients have difficulty achieving glycemic or blood pressure targets established by the American Diabetes Association. New treatments to reduce the progression of DR are currently being evaluated, but none as yet has been shown to improve the course of DR. Comprehensive eye examinations at regular intervals, including examination of the retina by ophthalmoscopy through a dilated pupil, is essential in detection and treatment of retinopathy and the prevention of visual loss in patients with diabetes. (Adv Stud Med. 2005;5(4A):S270-S275) Diabetic retinopathy (DR) was first described shortly after the invention of the ophthalmoscope by Helmholtz in 1851, 1 but it was not until the discovery of insulin by Banting and Best in 1921 that patients with type 1 diabetes began to live long enough to manifest DR in large numbers. 2 As early as 1934, studies by Wagener and coworkers had described the high rate of blindness in patients with DR. 3 Beginning in the 1970s, a series of clinical trials began to systematically evaluate various pharmacological and surgical treatments for DR. 4-7 These studies, which included the Diabetic Retinopathy Study, the Early Treatment of Diabetic Retinopathy Study, the Diabetes Control and Complications Trial (DCCT), and the United Kingdom Prospective Diabetes Study (UKPDS), have demonstrated the importance of S270 Vol. 5 (4A) April 2005

achieving tight control of hyperglycemia and blood pressure to prevention progression of DR. EYE EXAMINATION IN PATIENTS WITH DR A thorough dilated eye examination provides important information about the DR severity, which has prognostic implications for the likelihood of developing vision loss and systemic complications. For many years DR was assessed using several severity scales that required grading of fundus photographs. The American Academy of Ophthalmology has recently introduced a simplified rating scale to assess DR severity. 8 In this new classification, DR is divided into 5 levels, as shown in Table 1. Mild nonproliferative DR (NPDR) refers to the presence of microaneurysms only. Moderate NPDR is defined as the presence of microaneurysms and either hard exudates or blot hemorrhages, which are due to the deposition of lipoproteins and the exudation of red blood cells, respectively, from retinal capillaries and microaneurysms. Severe NPDR is characterized by a large number of retinal hemorrhages or the presence of cotton-wool spots (microinfarctions of the nerve fiber layer of the retina), and the development of intraretinal microvascular abnormalities (collateral vessels) in the resulting ischemic areas of retina. The progression of DR through these stages may be associated with leakage of fluids into the macular area that results in thickening (macular edema) and the gradual loss of visual acuity. Proliferative DR (PDR) is associated with the development of abnormal new retinal blood vessels. These vessels may bleed into the vitreous cavity, become fibrotic, and result in traction on the macular area that leads to loss of vision. APPLICATION OF EPIDEMIOLOGICAL STUDY FINDINGS TO A PATIENT WITH DR Epidemiologic studies have characterized the risk of DR progression in patients with diabetes. For the purposes of illustration, clinical features of a representative patient with type 2 diabetes are shown in Table 2. The risk of progression to clinically significant macular edema (CSME) or PDR has been determined in a long-term epidemiological study of clinical outcomes among patients with DR who have type 1 or type 2 diabetes. This study, the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), begun in 1979, enrolled patients with diabetes and has followed them since. 4 Data from this study have been useful in estimating the risk of developing more severe complications associated with diabetes. Table 3 shows the 4-year and 10-year probabilities of several clinical outcomes for a patient with type 2 diabetes, mild NPDR at baseline, and a hemoglobin A 1c (HbA 1c ) value of 8.5% to 9%.The Table 1. Diabetic Retinopathy Disease Severity Scale No apparent retinopathy Mild NPDR (microaneurysms only) Moderate NPDR Severe NPDR Proliferative DR NPDR = nonproliferative diabetic retinopathy; DR = diabetic retinopathy. Table 2. Representative Patient with Type 2 Diabetes Referred for Ophthalmic Evaluation History: 56 years of age, 12-year history of type 2 diabetes treated with metformin Poorly controlled (HbA 1c = 9.3%) Overweight, hypertensive (144/92 mm Hg) Diabetic nephropathy (2+ proteinuria), diabetic peripheral neuropathy Peripheral atherosclerotic vascular disease with high triglycerides and low HDL cholesterol Asymptomatic Daughter with type 1 diabetes and DR requiring laser photocoagulation Father with open-angle glaucoma Visual examination: Best corrected visual acuity 20/20 each eye Slit lamp examination: Early cortical and nuclear sclerotic cataracts IOP 20 mm Hg each eye Ophthalmoscopy through dilated pupils HbA 1c = glycosylated hemoglobin; HDL = high-density lipoprotein; DR = diabetic retinopathy; IOP = intraocular pressure. Advanced Studies in Medicine S271

probability of death is 19% during the 10-year period following the initial examination, which is approximately 3 to 4 times greater than would be expected for a person in this age range without diabetes. The risk of progression is also influenced by the patient s family history. In the DCCT, the risk of progression of retinopathy was approximately 3 times higher among relatives of retinopathy-positive patients than relatives of retinopathy-negative patients. 9 PREVENTION OF DR PROGRESSION Several clinical trials have demonstrated the efficacy of a number of interventions in preventing vision loss in patients with diabetes. In the WESDR described above, the progression of retinopathy was related to the level of hyperglycemia, as measured using HbA 1c values. 10 The study population was divided into patients who were first diagnosed with diabetes at age 30 years or younger, and patients who were first diagnosed after age 30. The olderonset group was further subdivided into those who were or were not using insulin at baseline. For all 3 groups of patients, those who had HbA 1c values in the lowest quartile (5.4%- 8.5%) had the lowest probability of DR progression over 10 years of follow-up. Regardless of the type of diabetes, patients with HbA 1c values in the highest 2 quartiles (10.1%-11.5% and 11.6%-20.8%, respectively) had a risk of DR progression of approximately 70% over 10 years (Figure). 10 These findings suggests that the likelihood of progression is more closely related to the degree of hyperglycemia than to the specific type of diabetes. Similar findings were noted when the data were analyzed for follow-up durations of less than 5 years, 5 to 9 years, 10 to 15 years, or more than 15 years. A generally linear relationship between glycemic control and DR progression was observed for patients with diabetes and any degree of DR at baseline, and across the entire range of HbA 1c values (which varied from 7% to more than 18% in this study). Although these data suggested that improved glycemic control might reduce the risk of progression of DR, this was an observational study and not a randomized controlled clinical trial. A significant relationship between glycemic control and DR progression has Table 3. Long-term Prognosis of a Patient with Type 2 Diabetes, Mild NPDR, and Baseline HbA 1c Value of 8.5% to 9% Events per 1000 patients Clinical Outcome 4-year 10-year Progression to CSME 20 96 Progression to PDR 0 125 Doubling of visual angle 73 373 Amputation 30 84 Dying (45-59 years of age) 45 190 NPDR = nonproliferative diabetic retinopathy; HbA 1c = glycosylated hemoglobin; CSME = clinically significant macular edema; PDR = proliferative diabetic retinopathy. Figure.Ten-Year Progression of Retinopathy by Quartile of Glycosylated Hemoglobin Progression % 100 80 60 40 20 0 P <.0001* Younger 5.4 8.5 8.6 10.0 P <.0001 *Mantel- Haenszel Test of Trend Older, Insulin 10.1 11.5 11.6 20.8 P <.0001 Older, No Insulin The relationship of the progression to proliferative retinopathy to HbA 1c concentration in patients with younger-onset diabetes, patients with adult-onset diabetes who were using insulin at baseline, and patients with adult-onset diabetes were not using insulin at baseline. Over a 10-year period, the incidence of progression was lowest among patients in all 3 groups with HbA 1c values in the lowest quartile. HbA 1c = glycosylated hemoglobin. Reprinted with permission from Klein et al. Relationship of hyperglycemia to the longterm incidence and progression of diabetic retinopathy. Arch Intern Med. 1994; 154(19):2169-2178. 10 S272 Vol. 5 (4A) April 2005

been demonstrated in 2 prospective randomized clinical trials: the DCCT in patients with type 1 diabetes and the UKPDS in patients with type 2 diabetes. In the latter study, patients were randomized to one of 2 glycemic control strategies and were monitored for up to 12 years. Patients in the intensive blood glucose control group received aggressive glucose control therapy with either sulfonylureas or insulin, whereas patients in the conventional treatment group received conventional treatment. 7 After 12 years, the mean HbA 1c value of the intensive treatment group was 0.9% lower than that of the conventional treatment group. This was associated with a 21% relative risk reduction for the progression of DR (P =.015). These investigators also found that more intensive treatment was associated with a 24% reduction in the risk of cataract extraction (P =.05), a 33% reduction in the risk of albuminuria (P =.00005), and a 16% reduction in the risk of myocardial infarction (P =.052). In addition, the investigators concluded that for overweight patients with type 2 diabetes, metformin was preferred as the first-line pharmacological therapy over insulin or sulfonylurea. Some epidemiological studies have also suggested that controlling hypertension may reduce the progression of DR in patients with type 2 diabetes, although this benefit has not been established as clearly as the value of glucose control. The relatively limited clinical data on the effect of hypertension management on DR progression may be due to the high mortality rate among patients with diabetes who have hypertension and other vascular complications. For example, in the WESDR, we found that patients with type 2 diabetes who had high blood pressure (systolic blood pressure of 160 mm Hg or diastolic blood pressure of 90 mm Hg) and who had moderate DR at baseline had a high mortality rate. Thus, in that study, many of these hypertensive patients at risk for progression of their retinopathy were not seen at follow-up. 11 However, data from the WESDR showed that, after controlling for HbA 1c and severity of retinopathy at baseline, each increase in diastolic blood pressure of 10 mm Hg was associated with a 35% increase in the odds of developing macular edema over a 10-year period. 11 The UKPDS investigators also examined the effects of tight blood pressure control on morbidity and mortality in patients with type 2 diabetes, and determined whether angiotensin-converting enzyme (ACE) inhibitors are superior to beta blockers for the prevention of diabetes-related complications. Patients with type 2 diabetes and hypertension were randomized to treatment with an ACE inhibitor (captopril) or a beta blocker (atenolol) with a blood pressure goal of less than 150 mm Hg systolic and less than 85 mm Hg diastolic. Although this may not be considered aggressive blood pressure control by current standards, this study was performed in the 1990s, before the benefits of aggressive blood pressure lowering were clearly established. 12 After 9 years of follow-up, the investigators demonstrated a highly significant 34% relative reduction in the risk of progression of retinopathy in the tight blood pressure control group, compared with less-tight blood pressure control. This magnitude of risk reduction for DR progression associated with blood pressure control appears to be at least as large as the 21% decrease in retinopathy progression with improved glycemic control, as described previously. In addition, tight blood pressure control was also associated with significant reductions in a number of other endpoints, including retinal photocoagulation (35% relative risk reduction compared with less-tight control, P =.023); photocoagulation for CSME (42%, P =.016); a 3-line decrease in visual acuity (47%, P =.004); legal blindness in one eye (24%, P =.046); and also incidence of microalbuminuria of greater than 50 mg/l (29% reduction after 6 years; P =.009). No differences in outcomes were observed between ACE inhibitor and beta blocker therapy. The investigators also concluded that the cost effectiveness of blood pressure control compared favorably with other preventive medicine programs. Conflicting results were reported from a second large clinical trial, the Appropriate Blood Pressure Control in Diabetes (ABCD) study. 13 In this clinical trial, patients with type 2 diabetes and high blood pressure were randomized to intensive blood pressure control (with a target diastolic blood pressure 75 mm Hg) or to moderate blood pressure control (target diastolic blood pressure of 80-89 mm Hg). No difference was observed in DR progression over a 5-year period between the 2 treatment groups. These authors noted several potential reasons for the discrepant findings between this study and the UKPDS. The ABCD trial was conducted over a shorter period of time; the patients had poorer glycemic control at baseline; and lower blood pressure levels were achieved than in the UKPDS. In a subsequent study, these investigators also reported the effects of blood pressure reduction in normotensive (rather than hypertensive) patients with type Advanced Studies in Medicine S273

2 diabetes. 14 In this analysis, 34% of patients in the intensive blood pressure control group exhibited progression of DR over 5 years, compared with 46% of patients in the moderate blood pressure control group (P <.05). No difference in the progression of retinopathy was noted between patients who received the calciumchannel blocker nislodipine or the ACE inhibitor enalapril. In addition, lowering blood pressure in normotensive individuals with type 2 diabetes resulted in a decrease in the progression from normoalbuminuria to microalbuminuria and in the progression of microalbuminuria to overt albuminuria, as well as a reduction in the incidence of stroke by 70%. Dyslipidemia may also be related to the incidence and progression of diabetic retinopathy. One of the manifestations of CSME is the development of hard exudates in the macular area. It has long been suspected that controlling serum lipids might reduce the deposition of lipids in hard exudates in the retina. Data from the Early Treatment Diabetic Retinopathy Study suggested that lowering lipids before the development of hard exudates may reduce vision loss due to macular edema in patients with diabetes. 15 In the 1960s and 1970s, a number of clinical trials attempted to reduce the development of hard exudates and the loss of visual acuity in patients with diabetes by lowering blood lipids with pharmacological therapy or diet modification. In several early studies the drug clofibrate or a corn-oil diet reduced hard exudate deposits in the retina, although none of these studies demonstrated significant effects on visual acuity. 6-18 Two clinical trials are currently evaluating the effects of lipid modification on exudative retinopathy in patients with diabetes. The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non Insulin Dependent Diabetes Mellitus (ASPEN) clinical trial has enrolled 2421 patients with diabetes. 19 The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is being conducted by the National Heart, Lung, and Blood Institute to evaluate the effects of normalization of blood pressure, glucose, and lipids in patients with type 2 diabetes, with a planned enrollment of 10 000 patients. 19 RECOMMENDATIONS FOR PATIENT MANAGEMENT Patients with diabetes and very early stages of DR, such as having only a few retinal microaneurysms, should be told that they have the earliest stage of retinopathy and even though it has not affected their vision, they are at risk of progression. This risk is greater in a patient with family history of DR is present. On the basis of the WESDR study, it may be anticipated that the risk of progression of retinopathy is approximately 70% over 10 years among patients with these early stages at baseline. A dilated eye examination is important for such patients in the early, presymptomatic stages of DR. In addition, better control of blood glucose and blood pressure has been shown to significantly reduce the risk of progression of vision-threatening DR. Because different types of antihypertensive medications appear to be similar in the degree of risk reduction, the selection of a blood pressure medication may depend on the presence of other complications associated with diabetes, such as diabetic nephropathy or congestive heart failure. Lowering the serum cholesterol clearly reduces the risk of cardiovascular disease, and may also reduce the development of retinal lipid deposits and macular edema. Based on data from the UKPDS, good glycemic control may reduce the progression of cataracts and the need for cataract surgery. The risk of glaucoma is elevated in patients with diabetes, especially in those who also have a family history of glaucoma. It is important to regularly check the intraocular pressure; however, approximately 50% of patients with glaucoma have normal intraocular pressure, 20 and regular evaluation for optic nerve head changes (eg, increase in the cup-to-disc ratio) is therefore required. Finally, the timely detection of severe retinopathy is essential because the use of photocoagulation in patients with progressing DR can prevent 90% or more of severe visual loss. 21 Including an ophthalmologist in the management of a patient with microvascular complications of diabetes may provide important long-term benefits for patient care. These patients are at high risk for a number of ophthalmologic conditions, including DR, glaucoma, and other complications. The ability of the ophthalmologist to communicate the findings of the eye examination to the patient, and the opportunity for interaction between the ophthalmologist and the primary care physician, may lead to an increased ability to detect and manage vision problems before extensive vision loss occurs. NEW DEVELOPMENTS IN THE TREATMENT OF DR Although good control of blood glucose and blood pressure has been shown to slow the progression of DR and reduce the risk of vision loss, many patients find it difficult to achieve recommended therapeutic goals S274 Vol. 5 (4A) April 2005

with the available medications. Despite all of the interventions available, few patients are able to meet glycemic or blood pressure control guidelines developed by the American Diabetes Association. Thus, there is a need for new treatments to prevent the progression of retinopathy in patients with diabetes. Several new treatments are currently in advanced stages of clinical testing. These include inhibitors of protein kinase C-β; inhibitors of vascular endothelium growth factor, which stimulates the formation of new blood vessels; and intravitreal steroid injections. None of these approaches has yet been shown to significantly reduce the progression of DR or the incidence of macular edema. At present, working to achieve better glycemic control is still probably the most important goal for reducing the progression of DR. SUMMARY AND CONCLUSIONS Even minimal retinopathy in a patient with type 2 diabetes is associated with increased risk of vision loss and of systemic complications. Although patients may understand that they are at increased risk of cardiovascular outcomes, many do not appreciate they are at significant risk of vision-threatening retinopathy. These risks can be lowered by intensive control of blood sugar, blood pressure, and possibly serum lipid levels. New treatments for diabetic retinopathy are being tested, but have not yet been shown to reduce its progression. DR is usually asymptomatic until it has begun to cause severe structural damage to the retina; it can progress despite medical intervention. Yearly comprehensive dilated eye examinations (or more frequent examinations for patients with more severe DR) are important because timely detection and photocoagulation treatment may prevent severe visual loss. REFERENCES 1. Ravin JG. Sesquicentennial of the ophthalmoscope. Arch Ophthalmol. 1999;117(12):1634-1638 2. Marble A, Krall LP, Bradley RF. Joslin s Diabetes Mellitus. Philadelphia: Lea & Febiger; 1985. 3. Wagener HP, Dry TJ, Wilder RM. Retinitis in diabetes. N Engl J Med. 1934;211:1131. 4. The Diabetic Retinopathy Study Research Group. Four risk factors for severe visual loss in diabetic retinopathy. The third report from the Diabetic Retinopathy Study. Arch Ophthalmol. 1979;97(4):654-655. 5. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986. 6. Early Treatment Diabetic Retinopathy Study Research Group. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study Report Number 1. Arch Ophthalmol. 1985;103(12):1796-1806. 7. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352(9131):837-853. Erratum in: Lancet. 1999;354(9178):602. 8. Wilkinson CP, Ferris FL 3rd, Klein RE, et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology. 2003;110(9):1677-1682. 9. The Diabetes Control and Complications Trial Research Group. Clustering of long-term complications in families with diabetes in the diabetes control and complications trial. Diabetes. 1997;46(11):1829-1839. 10. Klein R, Klein BE, Moss SE, Cruikshanks KJ. Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy. Arch Intern Med. 1994; 154(19):2169-2178. 11. Klein R, Klein BE, Moss SE, Cruikshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The longterm incidence of macular edema. Ophthalmology. 1995;102(1):7-16. 12. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998; 317(7160):703-713. Erratum in: BMJ. 1999; 318(7175):29. 13. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood pressure control on diabetic microvascular complications in patients with hypertension and type 2 diabetes. Diabetes Care. 2000;23(suppl 2):B54-B64. 14. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61(3):1086-1097. 15. Chew EY, Klein ML, Ferris FL 3rd, et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch Ophthalmol. 1996;114(9):1079-1084. 16. Harrold BP, Marmion VJ, Gough KR. A double-blind controlled trial of clofibrate in the treatment of diabetic retinopathy. Diabetes. 1969;18(5):285-291. 17. Cullen JF, Town SM, Campbell CJ. Double-blind trial of Atromid-S in exudative diabetic retinopathy. Trans Ophthalmol Soc U K. 1974;94(2):554-562. 18. King RC, Dobree JH. Exudative diabetic retinopathy treated with corn oil diet. Proc R Soc Med. 1962;55:800-801. 19. Prisant LM. Clinical trials and lipid guidelines for type II diabetes. J Clin Pharmacol. 2004;44(4):423-430. 20. Grodum K, Heijl A, Bengtsson B. A comparison of glaucoma patients identified through mass screening and in routine clinical practice. Acta Ophthalmol Scand. 2002; 80(6):627-631. 21. Porta M, Allione A. Current approaches and perspectives in the medical treatment of diabetic retinopathy. Pharmacol Ther. 2004;103(2):167-177. Advanced Studies in Medicine S275