Fig. 4.4 Cumulative incidence of a 3-step progression in retinopathy severity on the ETDRS retinopathy severity scale for the former conventional and former intensive glucose control groups of the DCCT study for 10 years of followup during the EDIC study. Reproduced with permission from Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group32

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The beneficial effects of intensive glucose control on retinopathy progression do not become apparent for approximately 2–3 years. In fact, there is an early paradoxical early worsening of retinopathy experienced in the first 6 months of intensive retinopathy control.33 Once the benefits of intensive control accrue, however, they persist even if the intensity of control is relaxed. The relationship of glycemic control to retinopathy, therefore, has a characteristic of

momentum and has been termed metabolic memory.27,32 In the EDIC study, metabolic memory was

noted to wane faster in patients with more severe retinopathy at the baseline of the period of intensive control, thus the goal should be to institute intensive control as early in the course of type 1 diabetes as possible.32 Metabolic memory works in the reverse direction as well. A period of poor glycemic control has adverse effects on retinopathy progression that persist beyond the period of poor control.32

The beneficial effects of more intensive glycemic control are not without risks, such as a higher rate of severe hypoglycemia and increased weight gain.34,35 The two adverse effects may be linked, as subjects on intensive regimens may eat more to prevent hypoglycemia.35 Behaviors associated with increased risk of hypoglycemic episodes include taking excess insulin, increasing exercise without other adjustments, delaying or missing meals, and drinking alcohol.

4.2.1.2 Type 2 Diabetes Mellitus

As with type 1 diabetes, epidemiologic evidence supports the importance of glycemic control with multiple aspects of diabetic retinopathy in type 2 DM.

Increasing HbA1c is associated with higher risk of any DR, PDR, and DME.15,36,37 Incidence of diabetic

retinopathy over 9.4 years of follow-up increased with increasing glycosylated hemoglobin.19 The odds ratio for the group with the highest tertile of glycosylated hemoglobin was 3.29 (95% CI 1.85–40.60) compared with the lowest tertile.19 In a cross-sectional study of type 2 diabetics, more severe retinopathy was associated with higher glycosylated hemoglobin.38

The United Kingdom Prospective Diabetes Study (UKPDS) was a randomized trial that examined the effect of tight glycemic control in patients with type 2 diabetes mellitus. In this study of 3,867 patients randomized to intensive therapy with a sulfonylurea or insulin at the outset or to conventional therapy based on diet, the intensive glycemic control and conventional glycemic control groups had median glycosylated hemoglobins of 7.0 and 7.9%, respectively, over a median follow-up of 10 years (Table 4.2).10 Over this interval, the rates of laser photocoagulation and progression of retinopathy were 27% lower in patients with tighter glycemic control compared to those with conventional control

(P < 0.05).10 The relative risk of any retinal photocoagulation (most of which was focal) in the intensive glycemic control group was 0.71 (95% CI 0.53–0.96, P = 0.0031).10 More recently, the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial randomized 11,140 patients with type 2 DM to intensive or standard glucose control. After a median of 5 years of follow-up the median glycosylated hemoglobins were 6.5 and 7.3% for the intensive and standard control groups, respectively. The rates of new or worsening DR were 6.0 and 6.3%, respectively. The relative risk reduction with intensive treatment was 5% (95% CI 10– 18%).39 In type 2 diabetics, once glycemic control

approaches a target glycosylated hemoglobin of 7.0%, the evidence suggests that at least with regard to retinopathy end points, further efforts at intensifying control may produce little benefit.

As with type 1 diabetes, tighter glycemic control in type 2 diabetics carries a risk of hypoglycemic epi-

sodes and the gravity of the risk may be greater in type 2 than in type 1 patients.10,34 The Action to

Control Cardiovascular Risk in Diabetes (ACCORD) study was terminated early because of an excess rate of fatal myocardial infarction in the intensive control group (1.41% versus 1.14% per year for the intensive and standard glycemic control groups, respectively).40 Therefore, less stringent

glycosylated hemoglobin goals may be preferable in patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions.40 Once glycosylated hemoglobin levels reach 7.0%, efforts to tighten glucose control have been successful, and further tightening may be ill advised.41 Tighter glycemic control requires great effort by patients, and in the large majority of patients for whom intensive control is appropriate, reinforcement and encouragement should be part of the clinical encounter with the ophthalmologist.

4.2.1.3Rapidity of Improvement in Glycemic Control

In general, improved metabolic control of diabetes mellitus is associated with less rapid progression of retinopathy over extended follow-up periods, however, if metabolic control is greatly improved over a short period, there can be paradoxical worsening in retinopathy thought to be mediated by

concomitant increases in insulin-like growth factor 1 (Fig. 4.5).41–44 In the DCCT, using a variety of

definitions of early worsening of retinopathy, intensive glycemic control was associated with early worsening in 13.1% of patients at the 6- or 12-month

follow-up visits compared to 7.6% of patients in the conventional treatment group (P < 0.001).42 Despite this early worsening, and despite the fact that such early worsening is associated with higher cumulative incidence in 3-step retinopathy progression at all subsequent follow-up times, the beneficial long-term effects of intensive glycemic control outweigh the negative effects of early worsening, such that intensive control is still recommended. In certain subsets of patients, for example, those approaching proliferative retinopathy with highrisk characteristics, institution of intensive control may be delayed until completion of scatter laser, especially if the baseline glycosylated is high. Although some have intentionally treated individual patients with reversion to poor control because of deterioration of diabetic retinopathy despite laser treatment, this approach is controversial.41 Accelerated retinopathy with sudden tightening of control has been put forth as an explanation for findings of decreased NPDR but not PDR in some more recent epidemiologic studies compared to WESDR, but this explanation has been discounted.36 Instead, methodological differences in studies over time have been suggested, including detection bias with nonexamination of patients with less severe disease, as more likely explanations for the apparently paradoxical data.45

Fig. 4.5 Fundus photographs and OCT images of a 48-year-old patient with 28 years of type 1 diabetes mellitus. When first examined, his best corrected visual acuity was 20/20 in both eyes, subclinical diabetic macular edema was present in the right fundus (a, c), and clinically significant diabetic macular edema was present in the left fundus (b, d). Focal/grid laser photocoagulation was recommended for the left eye, but he desired to try to improve the left eye by working on systemic factors alone. He abruptly and markedly improved his blood glucose and blood pressure and over 4 months lost 20 pounds of body weight. His retinopathy deteriorated bilaterally. His subclinical DME in the right eye evolved to clinically significant macular edema (e, g) and his clinically significant macular edema in the left eye worsened (f, h)

a

c

e

g

b

d

f

h