Ординатура / Офтальмология / Английские материалы / Diabetes and Ocular Disease Past, Present, and Future Therapies 2nd edition_Scott, Flynn, Smiddy_2009

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28.Kaiser PK, Riemann CD, Sears JE, Lewis H. Macular traction detachment and diabetic macular edema associated with posterior hyaloidal traction. Am J Ophthalmol. January 2001;131(1):44–49.

29.Hartley KL, Smiddy WE, Flynn HW Jr, Murray TG. Pars plana vitrectomy with internal limiting membrane peeling for diabetic macular edema. Retina. March 2008;28(3):410–419.

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Control for these risk factors can reduce the incidence of diabetic retinopathy (primary prevention), while laser photocoagulation may prevent further progression of diabetic retinopathy and vision loss (secondary interventions). While there are many new interventions, the evidence to support their use is uncertain. This chapter provides a systematic review of the literature to determine the best evidence for primary and secondary interventions for diabetic retinopathy.

METHODOLOGY AND DATA SOURCES

A systematic literature search to identify English-language randomized controlled trials or meta-analyses evaluating interventions for diabetic retinopathy was conducted. Articles were retrieved using MEDLINE (1966 through August 2007), EMBASE, Cochrane Collaboration and NIH Clinical Trials Database through August 2007. Search terms included variations of keywords for retinopathy, diabetes, diabetic retinopathy, diabetic macular edema, retinal neovascularization, controlled clinical trial, and randomized clinical trial. This was supplemented by hand searching the reference lists of major review articles. Because the primary interest was in longer-term outcomes, studies with less than 12 months of followup and studies failing to separate data of different retinal conditions (e.g., macular edema from diabetes vs. retinal vein occlusion) were excluded. Where duplicate results were published, the most recent or complete source was used. Secondary complications of proliferative diabetic retinopathy such as neovascular glaucoma and tractional detachments were excluded as they were beyond the scope of this review. A total of 831 citations were accessed, of which 45 studies (including three meta-analyses) on interventions for diabetic retinopathy met our inclusion criteria. Additional references up to 31st December 2008 were included in the current review.

The quality of studies was assessed via the Delphi consensus criteria list [5]. Studies were evaluated on a standardized data extraction form for (1) valid method of randomization, (2) concealed allocation of treatment, (3) similarity of groups at baseline regarding the most important prognostic indicators, (4) clearly specified eligibility criteria, (5) blinding of the outcome assessor, (6) care provider,

(7) patient, (8) reporting of point estimates and measures of variability for outcomes, (9) intention-to-treat analysis, and (10) acceptable loss to follow-up rate unlikely to cause bias. Studies were scored out of a maximum of 10, and studies with a score >5 were considered as higher quality studies. The overall strength of evidence (levels I, II, and III) and ratings for clinical recommendations (levels A, B, and C) were based on previously reported criteria [6].

For primary interventions, measures included incidence of diabetic retinopathy in patients with diabetes with no retinopathy at baseline, and rate of adverse effects of intervention. For secondary interventions, outcome measures included progression of diabetic retinopathy, changes in visual acuity and macular thickness, and rates of legal blindness and adverse effects. Emphasis was given to studies where best-corrected visual acuity was measured in a masked fashion using Early Treatment Diabetic Retinopathy Study (ETDRS) protocol. For some randomized

controlled trials (RCTs), both primary (incidence of diabetic retinopathy) and secondary (progression of diabetic retinopathy) interventions were evaluated.

There were significant variations between studies. For example, studies used different methods to ascertain retinopathy, including clinical ophthalmoscopy, retinal photography, and/or fluorescein angiography [7]. Studies also classified diabetic retinopathy differently, with most using the Airlie House classification with some modifications [8,9]; diabetic macular edema was usually classified as absent or present. Definitions for progression of diabetic retinopathy also varied. The Diabetes Control and Complications Trial (DCCT) [10,11] defined progression as at least three steps worsening from baseline, while the United Kingdom Prospective Diabetes Study (UKPDS) [12] defined progression as a two-step change from baseline. Other studies used increases in number of microaneurysms or the need for laser photocoagulation as indicators of progression.

Primary Interventions

Glycemic Control. A consistent relationship between glycated hemoglobin (HbA1c) levels and the incidence of diabetic retinopathy has been demonstrated in epidemiological studies [13,14]. This key observation has been confirmed in large randomized clinical trials demonstrating that tight glycemic control reduces both the incidence and progression of diabetic retinopathy (Table 14.1). For type 1 diabetes, the DCCT [10,11,15,16] conducted between 1983 and 1993, randomized 1441 patients with type 1 diabetes to receive intensive glycemic or conventional therapy. Over 6 years of follow-up, intensive treatment (median HbA1c, of 7.2%) reduced the incidence of diabetic retinopathy by 76% (95% confidence interval [CI], 62–85%) and progression of diabetic retinopathy by 54% (95% CI, 39–66%), as compared with conventional treatment (median HbA1c, of 9.1%) [10,11,15,16].

For type 2 diabetes, similar findings were reported in the UKPDS [18]. The UKPDS randomized 3867 newly diagnosed persons with type 2 diabetes to intensive or conventional therapy. Intensive therapy reduced microvascular endpoints by 25% (95% CI, 7–40%) and the need for laser photocoagulation by 29%. Data from a subgroup of participants’ retinal photographic grading showed a similar association [32]. These findings have been replicated in other studies [20,33], including a meta-analysis prior to the DCCT [21] (Table 14.1).

Long-term observational data from the DCCT, with participants followed up in the Epidemiology of Diabetes Intervention and Complications study (EDIC), showed that despite gradual equalization of HbA1c values after study termination, the rate of diabetic retinopathy progression in the former intensively treated group in DCCT remained significantly lower than the former conventional group [11,17], emphasizing the importance of instituting tight glycemic control early in the course of diabetes. This concept is supported in another randomized clinical trial [34] in which participants initially assigned to intensive glucose control had lower 10-year incidence of severe retinopathy as compared to conventional treatment [35].

While the benefits of tight glycemic control are apparent, this intervention has two clinically important adverse effects. First, there is risk of early worsening of diabetic retinopathy. In the DCCT, this occurred in 13.1% of the intensive as compared to 7.6% of the conventional treatment group [36]. However, this effect was

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reversed by 18 months and no case of early worsening resulted in serious visual loss. Similar adverse event rates were reported in a meta-analysis [22]. Participants at risk of this early worsening had higher HbA1c levels at baseline and a more rapid reduction of HbA1c levels in the first 6 months, suggesting that physicians should avoid rapid reductions of HbA1c levels where possible. Second, tight glycemic control is a known risk factor for hypoglycemic episodes and diabetic ketoacidosis [21]. A meta-analysis of 14 randomized clinical trials, including the DCCT [37], indicated that intensive treatment is associated with a three-fold increased risk of hypoglycemia and 70% higher risk of ketoacidosis as compared with conventional treatment. The risk of ketoacidosis was seven-fold higher among patients exclusively using insulin pumps [37], suggesting that multiple daily insulin injections might be a safer strategy.

Blood Pressure Control. Blood pressure has not been shown to be a consistent risk factor for diabetic retinopathy incidence and progression in epidemiological studies [38–41]. However, evidence from randomized clinical trials indicates that tight blood pressure control is a major modifiable factor for the incidence and progression of diabetic retinopathy (Table 14.2). The UKPDS [12] randomized 1048 patients with hypertension to tight control (target blood pressure <150/<85 mmHg) or conventional control (target blood pressure <180/<105 mmHg). After 9 years of follow-up, patients having tight control had a 34% reduction (99% CI, 11–50%) in diabetic retinopathy progression, 47% reduction (99% CI, 7–70%) in visual acuity deterioration, and 35% reduction in laser photocoagulation therapies (primarily due to a reduction in the incidence of diabetic macular edema) compared with those having conventional control. In fact, the magnitude of benefit with tighter blood pressure control outweighed the magnitude of the benefits seen with tight glucose control in the UKPDS.

The Appropriate Blood Pressure Control in Diabetes (ABCD) trial [43,47], which randomized 470 people with type 2 diabetes and hypertension to receive intensive control (target diastolic blood pressure of 75 mmHg) or moderate blood pressure control (target diastolic blood pressure of 80–89 mmHg), found somewhat different findings as compared to the UKPDS. In the ABCD, over 5 years, there was no difference in diabetic retinopathy progression between the groups. The lack of efficacy in this study may be related to poorer glycemic control, shorter follow-up and lower blood pressure levels at baseline as compared to the UKPDS. It is unclear if there is a threshold effect beyond which further blood pressure lowering no longer influences diabetic retinopathy progression.

The effects of therapy with antihypertensive agents are also apparent among people with diabetes who are normotensive. In another arm of the ABCD trial [47], among 480 patients with type 2 diabetes without hypertension, intensive blood pressure control (10 mmHg below the baseline diastolic) significantly reduced diabetic retinopathy progression over 5 years as compared to moderate blood pressure control. The EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus (EUCLID) [45] evaluated the effects of the angiotensin-converting enzyme (ACE) inhibitor lisinopril on diabetic retinopathy progression in normotensive, normoalbuminuric patients with type 1 diabetes. Lisinopril reduced the

progression of diabetic retinopathy by 50% (95% CI, 0.28–0.89) and progression to proliferative diabetic retinopathy by 80% over 2 years [45]. EUCLID was limited by differences in baseline glycemic levels between groups (treatment group had lower HbA1c) and a short follow-up of 2 years. This study, along with another smaller randomized clinical trial [48] suggested that ACE inhibitors may have an additional benefit on diabetic retinopathy progression independent of blood pressure lowering. However, data from the UKPDS [42] and the ABCD study [43,47] did not find ACE inhibitors to be superior to other blood pressure medications.

The Action in Diabetes and Vascular Disease (ADVANCE) [49] study evaluated a low dose perindopril-indapamide combination in 11,140 hypertensive and normotensive persons with type 2 diabetes. Although additional treatment with perindopril-indapamide reduced mean blood pressure (140.3/77 mmHg compared to 134.7/74.8 mmHg with placebo) and macrovascular events, there was no significant reduction in eye events or visual deterioration with treatment [46]. Whether newer blood pressure medications have additional beneficial effects is unclear. A recent small randomized clinical trial (n = 24) with short follow-up (4 months) reported a worsening of diabetic macular edema among patients treated with angiotensin-II receptor blocker losartan compared with controls [50].

The Diabetic Retinopathy Candesartan Trial (DIRECT) randomized 5231 normotensive or mildly hypertensive patients with type 1 or type 2 diabetes to daily placebo or 32 mg candesartan, an angiotensin II receptor blocker [51,52] After 6 years’ follow-up, use of candesartan in patients with type 1 diabetes modestly reduced the incidence of retinopathy by 18% but had no effect on the progression of existing retinopathy. In patients with type 2 diabetes, candesartan significantly increased the regression of existing retinopathy by 34% and reduced its progression by 13%, although the latter finding was not statistically significant. In both DIRECT studies, these modest effects were achieved in participants with early retinopathy only and could be related to the blood pressure lowering effects of candesartan. Thus, although DIRECT indicates that candesartan reduces retinopathy in both type 1 and 2 diabetes, whether this effect is independent of tight blood pressure control and whether it translates into significant prevention of vision loss is still unclear.

Finally, the Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD-EYE), which is evaluating development and progression of diabetic retinopathy with target systolic blood pressure of <120 and <140 mmHg, respectively, will be reporting results in 2010 [53].

Lipid-Lowering Therapy. There are several epidemiological studies suggesting that dyslipidemia increases the risk of diabetic retinopathy, particularly diabetic macular edema [38,54]. Observational data from the DCCT and ETDRS both linked higher LDL cholesterol levels with increased risk of hard exudates [55]. A small randomized clinical trial in 50 patients with diabetic retinopathy and short follow up found a nonsignificant trend in visual acuity improvement in patients on simvastatin treatment [56], while another study reported a reduction in hard exudates but no improvement in visual acuity in clinically significant diabetic macular edema treated with clobifrate [57].