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It is nearly 25 years since the Diabetic Retinopathy Study, a multicentred controlled clinical trial, first reported the efficacy of treatment by photocoagulation of proliferative diabetic retinopathy with high risk characteristics for visual loss.1 In 1985, the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated the beneficial effects of focal laser treatment for clinically significant macular oedema in patients with diabetes.2 Based on data from these studies, it was estimated that timely detection and photocoagulation treatment of vision threatening retinopathy could prevent nearly 95% of severe visual loss in patients with diabetes.3 Despite the resulting development of guidelines and education and screening programmes for early detection and treatment of these problems, diabetic retinopathy still remains an important cause of visual loss.4–6 More recently, the Diabetes Control and Complications Trial (DCCT)7–12 and the United Kingdom Prospective Diabetes Study (UKPDS)13–15 have demonstrated the efficacy and cost effectiveness of glycaemic control in reducing the incidence and progression of retinopathy. However, data from these and other studies12,16,17 have confirmed how difficult it is to achieve and maintain good glycaemic control over a long period. For this reason, intervention on other risk factors such as hypertension have been studied in an effort to decrease the risk of visual loss due to diabetic retinopathy. The purpose of this commentary is to briefly describe new findings regarding the role of blood pressure control in the prevention of visual loss in people with diabetes and to review whether specific classes of antihypertensive medications are associated with reduced incidence and progression of retinopathy even in normotensive people with diabetes.
IS BLOOD PRESSURE ASSOCIATED WITH DIABETIC RETINOPATHY AND MACULAR OEDEMA?
Increased blood pressure has been hypothesised, through the effects of increased blood flow, to damage the retinal capillary endothelial cells in eyes of people with diabetes.18 This hypothesis has been supported by observations from clinical studies which showed an association between hypertension and the presence and severity of retinopathy in people with diabetes.19–22
While cross sectional data suggest that hypertension is associated with diabetic retinopathy, longitudinal data have been inconsistent.23–30 The UKPDS showed that the incidence of retinopathy was associated with systolic blood pressure.30 Of the 1919 patients with older onset (type 2) diabetes from that study with retinal photographs taken at diagnosis and 6 years later, systolic blood pressure was significantly associated with retinopathy incidence (type 2). Those in the top tertile range at baseline (systolic blood pressure ≥140 mm Hg) were 2.8 times (95% confidence interval) as likely to develop retinopathy as people in the lowest tertile range (systolic blood pressure <125 mm Hg). There was no relation of systolic blood pressure at baseline with retinopathy progression. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), diastolic blood pressure was a significant predictor of progression of diabetic retinopathy to proliferative diabetic retinopathy over 14 years of follow up in patients with younger onset (type 1) diabetes mellitus, independent of glycosylated haemoglobin and the presence of gross proteinuria.31 However, neither systolic or diastolic blood pressure nor hypertension at baseline were associated with the incidence and progression of retinopathy in people with type 2 diabetes mellitus.32 In the WESDR, patients with older onset diabetes with high blood pressure and retinopathy were at a higher risk of death than people with high blood pressure without retinopathy, and the inability to find a relation between progression of retinopathy and blood pressure may have been due, in part, to this selective mortality. However, diastolic blood pressure in the fourth quartile range was found to be associated with a 330% increased 4 year risk of developing macular oedema compared to the first quartile range in those with younger onset diabetes mellitus and a 210% increased risk in those with older onset diabetes in that study.33
DOES CONTROL OF BLOOD PRESSURE REDUCE THE RISK OF INCIDENCE AND PROGRESSION OF RETINOPATHY? IF SO, IS THE TYPE OF MEDICATION USED TO CONTROL BLOOD PRESSURE IMPORTANT?
Results from three clinical trials have recently been published regarding the association of blood pressure control and type of antihypertensive medication used with the incidence and progression of retinopathy.34–38 The EURODIAB Controlled Trial of Lisinopril in Insulin Dependent Diabetes Mellitus (EUCLID) Study sought to examine the role of an angiotensin converting enzyme (ACE) inhibitor in reducing the incidence and progression of retinopathy.34 The subjects included a group of largely normotensive younger onset diabetic patients of whom 85% did not have microalbuminuria at baseline. The study showed a statistically significant 50% reduction in the progression of retinopathy in those taking lisinopril over a 2 year period compared to those not on blood pressure medication, after adjustment for glycaemic control. Progression to proliferative retinopathy was also reduced by 82% in the group taking lisinopril compared to the group treated with the placebo. After controlling for study site, the difference between treatment groups was no longer statistically significant (p=0.06). There was no significant interaction with blood glucose control. It has been postulated that ACE inhibitors, such as lisinopril, might have an effect independent of blood pressure lowering through a number of possible mechanisms which included a beneficial haemodynamic effect, enhancement of nitric oxide resulting in a reduction of endothelial dysfunction, blockage of induction of vascular endothelial growth factor receptors, and reduction of metalloproteinase activity improving the blood-retinal barrier.39 It may also be true that higher blood pressure, even in the “normal range,” is still associated with risk, and thus lowering blood pressure at all levels might be beneficial to the retina. This is consistent with observations from the UKPDS which reported that there was no evidence of a threshold effect of systolic blood pressure for the incidence of microvascular complications in people with type 2 diabetes mellitus.36
The UKPDS also sought to determine whether lower blood pressure achieved with either a β blocker or an ACE inhibitor was beneficial in reducing macrovascular and microvascular complications associated with type 2 diabetes mellitus.37 A total of 1048 patients with hypertension (mean blood pressure 160/94 mm Hg) were randomised to a regimen of tight control of blood pressure with either captopril or atenolol and another 390 patients to less tight control. The aim in the group randomised to tight control was to achieve blood pressure values <150/<85 mm Hg. If these goals were not met with maximal doses of a β blocker or ACE inhibitor, additional medications were prescribed, including a loop diuretic, a calcium channel blocker, and a vasodilator. The aim in the “control” or conventionally treated group was to achieve blood pressure values <180/<105 mm Hg. Tight blood pressure control resulted in a 35% reduction in retinal photocoagulation compared to conventional control. After 7.5 years of follow up, there was a 34% reduction in the rate of progression of retinopathy by two or more steps using the modified ETDRS severity scale and a 47% reduction in the incidence of deterioration of visual acuity by three lines or more using the ETDRS charts (for example, a reduction in vision from 20/30 to 20/60 or worse on a Snellen chart). It is assumed that the effect was largely due to a reduction in the incidence of diabetic macular oedema. Atenolol and captopril were equally effective in reducing the risk of developing these retinal microvascular complications. The effects of blood pressure control were independent of those of glycaemic control. These findings support the recommendations for tight blood pressure control in patients with type 2 diabetes mellitus as a means of preventing visual loss from diabetic retinopathy.
The Appropriate Blood Pressure Control in Diabetes (ABCD) Trial was a prospective randomised masked clinical trial comparing the effects of intensive (diastolic blood pressure goal of 75 mm Hg) and moderate (diastolic blood pressure of 80–89 mm Hg) blood pressure control in 470 hypertensive subjects (baseline diastolic blood pressure of ≥90 mm Hg) with type 2 diabetes mellitus.38 People were randomised to nisoldipine 10 mg/day (titrated up to 60 mg/day as needed), enalapril 5 mg/day (titrated up to 40 mg/day as needed), or placebo as the initial hypertensive medication.38 If single study medication alone did not achieve the target blood pressure, then metoprolol followed by hydrochlorothiazide was added until the target blood pressure was achieved. The mean blood pressure achieved was 132/78 mm Hg in the intensive group and 138/86 mm Hg 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 versus enalapril in progression of retinopathy. The authors concluded that lack of efficacy in their study compared to the UKPDS might have resulted from the shorter time period of the ABCD trial (5 years versus 9 years on average for the UKPDS), lower average blood pressure control in the ABCD trial (144/82 mm Hg versus 154/87 mm Hg in the UKPDS), and poorer glycaemic control in the ABCD trial than the UKPDS. It is possible that there is a threshold effect below which there is no or minimal effect of reducing the risk of progression of retinopathy by further reduction of blood pressure. Results from other clinical trials that are currently under way should provide more information regarding the relative efficacy of blood pressure control and specific antihypertensive medications in reducing the progression of retinopathy in people with diabetes.
Hypertension in people with diabetes is common, affecting 30% of people with younger onset diabetes mellitus and 75% with older onset diabetes mellitus (Klein R, unpublished data). It is often poorly controlled with only about 60% of those with younger onset diabetes mellitus and 42% of those with older onset diabetes mellitus achieving normal blood pressure (Klein R, unpublished data). While observational longitudinal data show an association of blood pressure with long term incidence and progression of retinopathy, there is no clinical trial evidence that blood pressure control prevents the incidence and progression of retinopathy in those with type 1 diabetes mellitus. The data for people with type 2 diabetes mellitus are not consistent. The efficacy of blood pressure control for retinopathy in people with hypertension and diabetes may be a moot point because of the known serious systemic sequelae (for example, higher risk of cardiovascular disease, nephropathy, and amputation) of uncontrolled hypertension. For these reasons the American Diabetes Association has issued guidelines for targeted systolic blood pressure levels of <130 mm Hg and diastolic blood pressure levels of <85 mm Hg.40 Whether lowering of blood pressures already in the normal range is beneficial, is still unknown.
An important unanswered question is: do specific types of antihypertensive agents, such as ACE inhibitors, have a beneficial effect in preventing the incidence and progression of retinopathy in diabetic people who are normotensive? The EUCLID data are suggestive for people with type 1 diabetes mellitus, but the findings are not conclusive owing to the small sample size in that study.34 The UKPDS data show no difference in the efficacy of ACE inhibitors and β blockers with regard to retinopathy progression in people with type 2 diabetes mellitus, suggesting that blood pressure lowering and not the type of medication was more important in people with moderately severe hypertension.37 Thus, ophthalmologists at this point should not be recommending a specific type of antihypertensive medication, such as ACE inhibitors, be used for reducing the risk of progression of diabetic retinopathy in normotensive individuals. These medications may be costly and are not without risk. However, for diabetic people with cardiovascular disease, microalbuminuria, or nephropathy, this too may be a moot point. Data from the Heart Outcomes Prevention Evaluation (HOPE) study showed that ramipril, an ACE inhibitor, substantially lowered the risk of death from cardiovascular disease by 37%, stroke by 33%, myocardial infarction by 22% , need for revascularisation procedure by 17%, and overt nephropathy by 24% in a group of diabetic patients (n=3577, of whom 56% had known hypertension) participating in that study.41,42 These findings resulted despite a very small reduction in blood pressure. A large randomised controlled clinical trial, the DIRECT study, has just begun with its major objective to examine the efficacy of use of ACE inhibitors to prevent incidence and progression of retinopathy in people with type 1 and type 2 diabetes mellitus.
This research is supported by National Institutes of Health grants EYO3083, EY12198, and NL59259. RK is a member of the Steering Committee of the DIRECT trial sponsored by Astra-Zeneca.
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