Systemic and Ocular Factors Influencing Diabetic Retinopathy

4.1 Introduction

Epidemiologic studies have established that certain systemic factors have associations with incidence and progression of diabetic retinopathy (DR). These provide a foundation for treating the manifestations of diabetic retinopathy. Before an ophthalmologist considers using laser treatment, intravitreal injections, and surgery, optimizing the systemic factors that influence diabetic retinopathy is prudent.1 In general these factors apply to both genders and all races, although the strengths of the associations may vary across subgroups.2–4 Many more associations are present with univariate testing than with multivariate testing, suggesting that the information carried by these associations may be redundant across more than one factor.5 For example, hyperglycemia is associated with dyslipidemia. Thus in a study with the goal of determining the importance of dyslipidemia as a predictor of DR, it is important to analyze the data adjusting for baseline glycemic control (HbA1c) to determine if dyslipidemia is independently important as a predictive variable.6 Accordingly predictive variables found on multivariate testing are more important than those found by univariate testing. In addition, predictive factors are not always the same for different end points. For example, those factors that predict proliferative diabetic retinopathy (PDR), any diabetic retinopathy, and diabetic macular edema (DME) may be different.6,7

D.J. Browning (*)

Charlotte Eye Ear Nose & Throat Associates, Charlotte, NC 28210, USA

e-mail: dbrowning@ceenta.com

In addition to systemic factors, there are ocular factors that have been hypothesized to impact diabetic retinopathy, such as high myopia and preexisting chorioretinal scarring. Although less important than systemic factors, these have historical significance. It was awareness of the protective effect of pre-existing chorioretinal scarring that led Meyer-Schwickerath to think of purposefully inducing scarring with the xenon photocoagulator in diabetic retinopathy.8 Socioeconomic factors also have importance and are often overlooked or ignored as inaccessible to change by clinicians. Nevertheless, the effects of these factors are evident in daily practice and therefore they will also be covered in this chapter.

The methods used in determining systemic and ocular associations with DR are the same as those used in epidemiologic studies of demographic variables. The important terms and concepts in these types of studies are defined in Chapter 3 (Epidemiology) and the reader in need of a review is referred there before proceeding further.

4.2 Systemic Factors

4.2.1 Glycemic Control

Glycemic control has a strong influence on many indices of diabetic retinopathy such as prevalence of retinopathy, incidence of retinopathy progression of retinopathy, need for focal and scatter photocoagulation, and loss of visual acuity.9–18 The influence of glycemic control is apparent in both type 1 and type 2 diabetes. Thresholds for blood glucose used

in making the diagnosis of diabetes mellitus are chosen, in part, because of the sharp increase in prevalence of retinopathy manifested by patients when glucose rise above these levels.19 The concept of a laboratory cutpoint for blood glucose normality is vague, however, and 5–9.8% of patients over age 40 in developed countries have typical lesions of

diabetic retinopathy even though they do not meet criteria for diabetes.14,19,20 Retinopathy consistent

with diabetic retinopathy can develop in certain

patients whose blood glucoses range in the normal range for the population; in adults over the age of 49, the 5-year incidence of such an event is 10%.17 This may in part reflect increased genetic susceptibility to the effects of hyperglycemia (see Chapter 2). Responsiveness to treatments for manifestations of diabetic retinopathy may also depend on glycemic control. Failure of DME to respond to focal/grid laser photocoagulation has been associated with higher glycosylated hemoglobin.21

Fig. 4.1 Red-free fundus photograph (a) and fluorescein angiogram frame (b) of the right eye of a 74-year-old man with no history of diabetes mellitus, a current glycosylated hemoglobin of 5.5% (normal, and indicative of a mean blood glucose of

97 mg/dl), no hemoglobinopathy, and treated hypertension. There are typical lesions of diabetic retinopathy including microaneurysms, lipid exudates, intraretinal microvascular abnormalities, and neovascularization

4.2.1.1 Type 1 Diabetes Mellitus

Epidemiologic studies strongly associate glycemic control with severity of retinopathy in type 1 diabetes

mellitus (DM).16 In multivariate analyses from the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), the 10-year and 25-year incidences of DME were related to higher baseline glycosylated

hemoglobin.23 The hazard ratio per 1% increase in glycosylated hemoglobin was 1.17 (95% confidence interval [CI] 1.10–1.25, P < 0.001).24 Higher baseline glycosylated hemoglobin was also associated with2-step progression of DR severity.4 Higher baseline HbA1c was a predictor of progression to PDR in type 1 DM in a Norwegian study and with an

increased 6-year incidence of doubling of the visual angle in African Americans with type 1 DM.25,7

The Diabetes Control and Complications Trial (DCCT) was a randomized trial that investigated the effect of tight blood glucose control compared to conventional control in patients with type 1 diabetes mellitus ranging in age from 13 to 39 years at the time of enrollment (Table 4.1). There were two cohorts studied. The primary-prevention cohort consisted of 726 patients with no baseline diabetic retinopathy. The secondary-intervention cohort consisted of 715 patients with mild-to–moderate nonproliferative diabetic retinopathy (NPDR) at baseline. The intensive control patients received three to four injections of short-acting insulin per day or subcutaneous insulin infusions. Fingerstick blood glucose checks were done four times daily. The conventional control group received one to two injections of insulin daily and checked blood glucose once daily. Median HbA1cs were 9.1 and 7.3% for the conventional and intensive control groups, respectively, over a mean duration of follow-up of 6.5 years. Over 9 years of follow-up, a 3-step progression of retinopathy on the ETDRS retinopathy severity scale was decreased 76% with tight glucose control.26,27 For the primary-prevention cohort, the risk of any retinopathy was reduced by 27% over a mean follow-up of 6.5 years (from 90 to 70% for the conventional versus intensive treatment groups).9 For this cohort, the cumulative 8.5 year rates of 3- step or more retinopathy progression were 54.1 and 11.5% for the conventional and intensive therapy groups, respectively. For the secondary-intervention cohort, the cumulative 8.5 year rates of 3-step or more retinopathy progression were 49.2 and 17.1%, respectively (Fig. 4.2). The beneficial effects became apparent after approximately 2–3 years of therapy and were evident for all levels of baseline retinopathy, but were greatest when intensive therapy was initiated earlier in the course of type 1 diabetes and with less severe levels of baseline retinopathy.9 The risks of receiving any laser therapy over 9 years of

follow-up were 30 and 7.9% for the conventional and intensive treatment groups, respectively (P ¼ 0.001).9 There was a strong exponential relationship between the risk of retinopathy progression and the duration of follow-up for any given level mean glycosylated hemoglobin during the study (Fig. 4.3). As the mean glycosylated hemoglobin during the study increased, the steepness of the relationship between retinopathy progression risk and duration in the study increased. Thus, risk of retinopathy progression depends on both duration of retinopathy and level of glycemic control.29 The risk relationships were similar in the primary-prevention and secondary-intervention cohorts. There was no threshold glycosylated hemoglobin value below which further normalization of

glucose failed to provide additional benefit.27,30

The potential impact that tighter glycemic control could have on ocular and other microvascular complications was shown from modeling of DCCT outcomes and US epidemiologic data regarding type 1 diabetes. Cumulative incidence of PDR and DME would be reduced by approximately one-half and one-third, respectively, with tighter control compared to conventional control.31 The predicted average number of years free of proliferative retinopathy, DME, and blindness would increase by 14.7, 8.2, and 7.7 years, respectively, if tighter control were achieved.31

The Epidemiology of Diabetes Interventions and Complications Study (EDIC) was an extension study involving 1,375 (95%) of the participants in the DCCT study. The goal of this study was to determine the later effects of the interventions tested in the DCCT. Upon advice, most patients in both treatment groups were on an intensive regimen of glucose control for the EDIC study and had convergence of group mean glycosylated hemoglobin values during the course of EDIC (8.07% versus 7.98% overall mean glycosylated hemoglobin values for the former conventional and intensive control groups, respectively, over 10 years follow-up).32 The benefit from the difference in glycosylated hemoglobin in the former intensively controlled group during the years of the DCCT waned slightly. The cumulative incidence of a 3-step progression of retinopathy was 53% as much in the former intensive control group as in the former conventional control group throughout the 10 years of the EDIC study (Fig. 4.4). Over the first 4 years of EDIC, the risk reduction for 3-step progression of retinopathy was 70%. Over years 4–10

Fig. 4.2 The cumulative incidence of a 3-step retinopathy progression on the ETDRS retinopathy severity scale in the DCCT for the conventional and intensive blood glucose control groups for the secondary-intervention cohort (patients with some baseline diabetic retinopathy). The numbers in the table at the bottom refer to participants evaluated in the two groups at each of the time points. Reproduced with permission from DCCT27

Cumulative Incidence of Retinopathy Progression

Rate per 100 Patient-years

Fig. 4.3 Family of curves representing the relationship of risk of retinopathy progression versus time in the DCCT study for any given mean HbA1c level during the study for the conventional treatment group. The y-axis is rate of 3-step progression of retinopathy severity per 100 patient years of follow-up. For any given mean glycosylated hemoglobin

level, the relationship of risk of retinopathy progression to duration is exponential. The steepness of the exponential relationship increases as the mean glycosylated hemoglobin increases. A similar family of curves, but much less steep, was found for the intensive treatment group. Reprinted with permission from DCCT27

the risk reduction was 38%. Thus, some waning of the protective effect of former intensive glycemic control was noted.32 Other end points were consonant with the retinopathy progression end point. At 4

years into the EDIC study, laser therapy (either focal or scatter) had been given to 6% of the former conventional control group, but 1% in the former intensive control group (P ¼ 0.002).27