the American Diabetes Association guidelines of a target goal of glycosylated hemoglobin of 7% for persons with diabetes (80). However, data from the WESDR (81) and the NHANES III (82) suggest that few persons with diabetes achieve this targeted level of glycemic control.

HYPERTENSION

In 1934, Wagener et al., in a case-series of 1,052 diabetic persons seen at the Joslin clinic, reported that retinopathy was more likely to be manifest when patients had hypertension in addition to diabetes than just diabetes alone (83). Damage to small retinal blood vessels has been shown to result from higher blood flow in eyes of hypertensive diabetic patients and thought to result in increased risk of retinopathy (84). In a small randomized clinical trial, Patel et al. showed that the use of angiotensin converting enzyme (ACE) inhibitors in patients with diabetes reduced retinal blood flow as measured by laser Doppler velocimetry compared to an increase in retinal blood flow in controls (85). They concluded that such treatment might protect against the progression of diabetic retinopathy.

However, blood pressure has inconsistently been shown to be associated with diabetic retinopathy, due, in part, to selective drop-out of patients and small sample sizes in some of these epidemiological studies (13, 14, 18, 32, 41, 86–98). In a recent study of normotensive normoalbuminuria type 1 diabetic patients, while controlling for age, duration of diabetes, and glycosylated hemoglobin, persons whose nighttime systolic ambulatory blood pressure was in the upper three quartiles (>103 mmHg) had a higher risk of having diabetic retinopathy than those whose nighttime systolic ambulatory blood pressure was in the first quartile (OR 3.71, 95% CI 1.50–9.16, P = 0.004) (99). There was no relation of clinical blood pressure with the severity of diabetic retinopathy in this study. These data suggest that ambulatory blood pressure may have an advantage over clinical blood pressure measurements as a marker of risk of diabetic retinopathy prior to the onset of hypertension.

In the WESDR, blood pressure was associated with the 14-year incidence of diabetic retinopathy in people with type 1 diabetes (41). In the epidemiological data from the UKPDS, for each 10 mmHg decrease in mean systolic blood pressure, there was a 13% reduction in microvascular complications, including retinopathy in persons with newly diagnosed type 2 diabetes (100). Stratton et al. assessed the interactive effects of glycemia and systolic blood pressure exposures on the risk of diabetic complications over a median of 10.4 years (101). They reported risk reductions of microvascular complications, including retinopathy of 21% per 1% glycosylated hemoglobin A1c decrement and 11% per 10 mmHg systolic blood pressure decrement and concluded that intensive treatment of both of these risk factors is needed to substantially reduce the incidence of these complications. In the WESDR, independent of glycosylated hemoglobin levels, a 10 mmHg rise in diastolic blood pressure was associated with a 230% increase in the 4-year risk of developing macular edema in those with type 1 diabetes and a 110% increase in the risk in those with type 2 diabetes (45).

While epidemiological data suggested a relationship of blood pressure to diabetic retinopathy, randomized controlled clinical trial data are necessary to show that reductions in blood pressure result in reductions in the incidence and progression of retinopathy.

The results of such trials have not been consistent. The EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID) study examined the role of the ACE inhibitor lisinopril in reducing the incidence and progression of retinopathy in a group of largely normoalbuminuric normotensive type 1 diabetic patients (102). Those taking lisinopril had a 50% reduction in the progression of retinopathy over a 2-year period. However, while controlling for other factors, the relationship was not statistically significant (P = 0.06). Progression to PDR was also reduced, although the relation was also not statistically significant.

The UKPDS also included a randomized controlled clinical trial to determine whether lowering blood pressure was beneficial in reducing macrovascular and microvascular complications associated with type 2 diabetes (5, 103). One thousand fortyeight patients with hypertension (mean blood pressure 160/94 mmHg) were randomized to a regimen of tight control with either captopril (an ACE-inhibitor) or atenolol (a beta blocker) and another 390 patients to less tight control of their blood pressure. The aim in the group randomized to the tight control treatment group (by the standards at the beginning of the clinical trial) was to achieve blood pressure values <150/<85 mmHg, while the aim in the group randomized to less tight control was to achieve blood pressure values <180/<105mmHg. By 4.5 years after randomization, there was a highly significant difference in number of retinal microaneurysms with 23% in the tight blood pressure control group and 33.5% in the less tight blood pressure control group having five or more microaneurysms (relative risk (RR) 0.70; P = 0.003). The effect continued to 7.5 years (RR, 0.66; P < 0.001). Similarly, there was a 47% reduction in hard exudates and cotton wool spots in the tight blood pressure control group (RR, 0.53; P < 0.001) compared to the less tight blood pressure control group. There was a 25% reduction in progression of retinopathy and a 42% reduction in photocoagulation for diabetic macular edema in the tightly controlled group compared to the less tightly controlled group. The cumulative incidence of the end point of legal blindness (Snellen visual acuity, ≤ 20/200) in 1 eye was 2.4% (18/758) for the tightly controlled blood pressure group compared with 3.1% (12/390) for less tightly controlled blood pressure equating to a 24% reduction in risk. They found no detectable differences in outcome between the two randomized therapies of ACE-inhibition and beta-blockade suggesting that blood pressure reduction itself was more important than the type of medication used to reduce it. The effects of blood pressure control were independent of those of glycemic control. These findings support the recommendations for blood pressure control in patients with type 2 diabetes as a means of preventing visual loss from diabetic retinopathy.

The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial consisted of two randomized masked clinical trials comparing the effects of intensive and moderate blood pressure control in persons with type 2 diabetes. The first trial included a diastolic blood pressure goal of 75 mmHg in the intensive group and a diastolic blood pressure of 80–89 mmHg in the moderate group in 470 hypertensive subjects (baseline diastolic blood pressure of > 90 mmHg) with type 2 diabetes (6,104). The mean blood pressure achieved was 132/78 mmHg in the intensive group and 138/86 mmHg in the moderate control group. Over a 5-year follow-up period, there was no difference between the intensive and moderate groups with regard to progression of diabetic retinopathy. There was no difference in nisoldipine vs. enalapril in progression of retinopathy. The authors concluded that the lack of efficacy in their study compared to the UKPDS might

have resulted from the lower average blood pressure control in the ABCD Trial (144/82 mmHg vs. 154/87 mmHg in the UKPDS), the shorter time period of the ABCD Trial (5 years vs. 9 years on average for the UKPDS), and poorer glycemic control in the ABCD Trial than the UKPDS (5, 104). These data may also be interpreted as showing a threshold effect below which there is minimal reduction in the risk of progression of retinopathy by further reduction of blood pressure.

However, results from a second clinical trial from the same ABCD group suggested otherwise (6). In the second ABCD Trial, the question was whether lowering blood pressure in normotensive (BP < 140/90 mmHg) patients with type 2 diabetes offered any beneficial results on vascular complications. The effect of intensive vs. moderate diastolic blood pressure control on diabetic vascular complications in 480 normotensive type 2 diabetic patients was examined in a prospective, randomized controlled trial. Over the 5-year period, the intensive blood pressure control group showed less progression of diabetic retinopathy (34% vs. 46%, P = 0.019) than the moderate therapy group with no difference whether enalapril or nisoldipine was used as the initial antihypertensive agent. There was no difference in the incidence of retinopathy between the moderate and the intensive groups (39% vs. 42%, respectively). The authors concluded that “over a five-year follow-up period, intensive (approximately 128/75 mmHg) control of blood pressure in normotensive type 2 diabetic patients decreased the progression of diabetic retinopathy.” They concluded that the specific initial agent used (calcium channel blocker vs. ACE inhibitor) appears to be less important than the achievement of the lower blood pressure values in normotensive type 2 diabetic patients.

In an open parallel trial, patients with diabetes at the Steno clinic in Denmark were allocated to standard treatment (Danish guidelines, n = 80) or intensive treatment (stepwise implementation of behavior modification, pharmacological therapy targeting hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, n = 80) (105). After 3 years of follow-up, patients in the intensive group had significant (55%) reduction in odds of progression of retinopathy compared to those in the standard group.

The ACCORD trial is also examining whether in the context of good glycemic control, a “therapeutic strategy that targets a systolic blood pressure of < 120 mmHg will reduce the rate of cardiovascular disease events compared to a strategy that targets a systolic blood pressure of < 140 mmHg” in persons with type 2 diabetes. In that trial, the effect of blood pressure control on the incidence and progression of retinopathy will be examined. The aim of another clinical trial that is underway, the Diabetic Retinopathy Candesartan Trials (DIRECT), consisting of three randomized double-masked, parallel, placebo-controlled studies, is to determine the impact of treatment with candesartan, an angiotensin II type 1 receptor blockade, on the incidence and progression of diabetic retinopathy (106).

American Diabetes Association guidelines recommend blood pressure level targets of less then 130/85 mmHg based on the above clinical trial data (107). However, a study at an academically affiliated institution found only 15% of diabetic patients in that study achieved the ADA goals (108). Similarly, in the NHANES, among U.S. adults with diabetes in 1999–2002, 49.8% had A1c < 7%; and nearly 40% met ADA blood pressure recommendations (109). Reduction of weight, increased physical activity, and other behaviors that might help reduce blood pressure beyond use of antihypertensive agents are often not achieved in people with diabetes (110). These data show the difficulty of

achieving recommendations based on findings from clinical trials in clinical practice and the need for new approaches for meeting these goals.

LIPIDS

Retinal hard exudates result from the deposition of lipoproteins in the outer layers of the retina that have leaked from retinal capillaries and microaneurysms in persons with diabetes. So, it is not surprising that epidemiological data have shown that higher levels of serum lipids are associated with a higher frequency and incidence of retinal hard exudates in persons with diabetes (53, 111–114). In the WESDR, while controlling for duration of diabetes, blood pressure, glycosylated hemoglobin, and diabetic nephropathy, higher serum total cholesterol was associated with the presence of hard exudates in both younger-onset persons (OR per 50 mg/dL 1.65, 95% CI, 1.24–2.18) and older-onset persons (OR 1.50, 95% CI, 1.01–2.22) taking insulin (111). In the ETDRS, diabetic persons with higher serum triglycerides, low-density lipoproteins (LDL), and very- low-density lipoproteins at baseline were about twice as likely to have retinal hard exudates at baseline as persons with normal levels and were more likely to develop hard exudates and visual loss during the course of the study (112). In the Hoorn study, higher serum total cholesterol (OR per 1.19 mmol/L, 1.59, 95% CI, 1.13–2.23) and LDL cholesterol (OR per 1.05 mmol/L, 1.63, 95% CI, 1.12–2.37) but not HDL cholesterol (OR per 0.36 mmol/L 1.03, 95% CI, 0.69–1.53) or triglyceride level (OR per 50 mmol/L 1.23, 95% CI, 0.93–1.63) were related to hard exudates in persons with type 2 diabetes (113). In the Atherosclerosis Risk in Communities study, while controlling for age, gender, duration of diabetes, serum glucose, and type of diabetes medications taken, the presence of retinal hard exudates was associated with plasma LDL cholesterol (OR/10 mg/dL 1.18, 95% CI, 1.09–1.29) and plasma Lp(a) (OR/10 mg/dl 1.02, 95% CI, 1.00–1.05) (53). In the DCCT, both the serum total-to-high density lipoprotein (HDL) cholesterol ratio and LDL cholesterol level predicted the incidence of CSME (RR for extreme quintiles 3.84, p-test for trend = 0.03 for serum total-to-HDL cholesterol ratio, and RR 1.95, p-test for trend = 0.03 for serum LDL cholesterol) and hard exudate (RR 2.44, p for trend = 0.0004 for total-to-HDL cholesterol ratio, and RR 2.77, p for trend = 0.002 for LDL cholesterol) in patients with type 1 diabetes (114). Lipid levels at baseline were not associated with progression of diabetic retinopathy in this study. In Mexican patients with type 2 diabetes, Santos et al. showed the frequency of severe retinal hard exudates was higher in those with 4 allele polymorphism of the apolipoprotein E gene (115).

While higher serum lipids appear associated with hard exudates in observational studies, it is not certain that intensive control of dyslipidemia with cholesterol lowering agents reduce the incidence of hard exudate, macular edema, and visual loss in persons with diabetic retinopathy. Earlier clinical trials of clofibrate showed that treatment with this medication reduced lipid levels and the incidence of hard exudate but did not restore vision to eyes when macular edema was present at the onset of the trial (116). Due to the association of clofibrate with liver toxicity, it is no longer used. Few clinical trial data are available regarding the efficacy of statins in preventing the incidence of hard exudates and macular edema. Data from small short-term pilot studies suggested that statin therapy may have a possible benefit in preventing or reducing the severity of macular edema (117–119). However, there have been no completed large clinical trials