Long-term microvascular and neurologic complications cause considerable morbidity and mortality in patients with insulin-dependent diabetes mellitus. These complications develop over a period of years, and in the 1960s, there was evidence to suggest that the underlying cause is chronic elevation of blood glucose. Subsequently, there was controversy as to whether improved control of blood glucose would reduce the chronic complications of diabetes, including diabetic retinopathy.^{1,2,3,4,5,6,7} If such a relationship existed, and if improved control of blood glucose could be achieved, then there was potential benefit in pursuing effective treatment strategies to reduce blood glucose levels. However, the effects of such intervention might not become apparent for years, and maintaining blood glucose concentrations as close to the normal range as possible (normoglycemia) had associated costs and potential complications. To address these questions of considerable public health importance, a prospective, multicenter, randomized, controlled clinical trial was needed.

The Diabetes Control and Complications Trial (DCCT) was established in the 1980s to determine whether improved control of blood glucose levels would reduce the frequency and severity of diabetic retinopathy and other chronic complications of diabetes.⁸ Improved control of blood glucose was termed intensive control, with the goal of achieving normoglycemia.

A total of 1,441 patients with type 1 diabetes, aged between 13 and 39, with no retinopathy and a duration of diabetes of 1 to 5 years (the primary-prevention cohort, 726 patients) or mild to moderate nonproliferative retinopathy and a duration of diabetes of 1 to 15 years (the secondary-intervention cohort, 715 patients) were enrolled.

Patients were randomly assigned to intensive or conventional insulin therapy. Intensive therapy consisted of the use of an external insulin pump (continuous subcutaneous insulin infusion) or three or more daily insulin injections and guided by four or more blood glucose tests daily (doses adjusted on the basis of self-monitoring). Conventional therapy involved one or two daily insulin injections and once-daily monitoring. Outcome measures included the appearance and progression of retinopathy using the Early Treatment Diabetic Retinopathy Study (ETDRS) retinopathy severity scale and systemic findings related to nephropathy and neuropathy.

At a mean follow-up of 6.5 years (range 3.5 to 9 years) in the primary-prevention cohort,
intensive therapy reduced the risk of developing retinopathy by 76% compared with conventional therapy. In the secondary-intervention cohort, intensive therapy slowed the progression of retinopathy by 54% and reduced the development of severe nonproliferative or proliferative retinopathy by 47%. In both cohorts, intensive therapy reduced the occurrence of microalbuminuria and albuminuria, and clinical neuropathy.^9,10,11

Cumulative 8.5-year rates of progression of retinopathy by three or more steps at two consecutive visits were 12% with intensive treatment as compared to 54% with conventional treatment in the primary-prevention cohort and 17% as compared to 49% in the secondary-intervention cohort. Once progression occurred, subsequent recovery was at least two times more likely with intensive treatment than with conventional treatment.¹²

The level of glycemic exposure (HbA_1c) measured at eligibility screening and the duration of insulin-dependent diabetes were the dominant baseline predictors of the risk of progression.¹³ The intensive treatment group achieved a median HbA_1c of 7.2% versus 9.1% in the conventional treatment group. Mean blood glucose was 155 mg/dl in the intensive treatment group and 230 mg/dl in the conventional group.

The major adverse event associated with intensive therapy was a two- to three-fold increase in severe hypoglycemia.⁹ At the 6- and 12-month visits, a small adverse effect of intensive treatment occurred, termed early worsening of retinopathy. Worsening was defined as any of the following: progression of retinopathy ≥3 steps, the development of soft exudates and/or intraretinal microvascular abnormalities, or the development of clinically important retinopathy (clinically significant diabetic macular edema [CSDME], severe nonproliferative diabetic retinopathy [NPDR], retinal neovascularization elsewhere [NVE], or neovascularization of the optic disc [NVD]). Worsening was considered early if it occurred between baseline and the 12-month follow-up visit. Early worsening was noted in 13% of patients undergoing intensive treatment and in 8% undergoing conventional treatment. Risk factors were higher HbA_1c level at screening, and reduction in this level during the first 6 months of the study (but not related to rate of reduction).¹⁴ Early worsening was followed by a beneficial effect that increased with follow-up duration,¹² and the long-term benefits of intensive treatment greatly outweighed the risks of early worsening.

The DCCT demonstrated the powerful impact of glycemic control on the microvascular complications of diabetes mellitus. In patients with insulin-dependent diabetes who met the inclusion criteria, intensive insulin therapy as administered in this trial effectively delayed the onset and slowed the progression of diabetic retinopathy, nephropathy, and neuropathy.

The DCCT concluded that the beneficial effect of intensive treatment in slowing the progression of retinopathy was very substantial, increased with time, was consistent across all outcome measures assessed, and was present across the spectrum of retinopathy severity included in the study.

However, intensive therapy did not prevent retinopathy completely, and it was associated with early worsening in some patients with long-standing poor glycemic control (elevated HbA_1c), especially if retinopathy was at or beyond the moderate nonproliferative stage. In such patients, examination prior to initiation of intensive treatment and at frequent (3- to 4-month) intervals for the first year was recommended. In patients with elevated HbA_1c whose retinopathy was approaching high risk, prompt photocoagulation was recommended if intensive treatment was to be initiated.¹⁴ The magnitude, but not the rapidity, of the reduction in HbA_1c during the first 6 months of intensive treatment was an important risk factor for early worsening.

Despite this, intensive treatment had a remarkable beneficial effect that began after 3 years of therapy on all levels of retinopathy that were studied.¹⁵ The reduction in risk observed in the DCCT translated into reduced need for laser treatment and reduced risk of visual loss, and the DCCT
recommendation was to implement intensive treatment as early as possible in as many insulin-dependent diabetic patients as was safely possible.

The Epidemiology of Diabetes Interventions and Complications (EDIC) study assessed whether the benefits demonstrated in the DCCT persisted after the end of the DCCT. This study concluded that the benefits associated with intensive treatment extended well beyond the period of intensive implementation. The recommendation was that once intensive treatment is initiated in patients with insulin-dependent diabetes, it should be maintained thereafter, aiming for a target HbA_1c level of 7.0% or less (normal 3.0% to 6.0%) and a fasting blood glucose level of 110 mg/dl or less.¹⁶

The DCCT demonstrated a substantial beneficial effect of intensive insulin therapy in slowing the progression of retinopathy. Although this treatment effect increased during the follow-up period, its relation to long-term functional outcome can only be estimated.

Inclusion criteria for the DCCT were the absence of retinopathy or the presence of mild to moderate nonproliferative retinopathy, while patients with more advanced levels of retinopathy were excluded from the study. When early worsening occurred in the study patients, it was not associated with any cases of serious visual loss. It is possible, however, that patients with severe nonproliferative or proliferative diabetic retinopathy may experience early worsening that is clinically relevant when intensive treatment is initiated. Although increased surveillance and a lower threshold for photocoagulation are recommended for these patients when intensive treatment is initiated, the early effects of intensive treatment are unknown.¹²

Furthermore, the disease process appears to have considerable momentum, as evidenced by the number of years of intensive therapy required before a treatment effect manifests. In patients with advanced retinopathy, although the long-term effects are unknown, it is unlikely that intensive treatment alone can halt the progression.¹⁵

Type 2 diabetes accounts for approximately 90% of all cases of diabetes worldwide.^17,18 We are currently in the midst of a global epidemic of type 2 diabetes, although the burden is felt disproportionately by non-European populations. It is a multifactorial disease with complex interactions between genetic and environmental factors that result in the common endpoints of insulin resistance, defective insulin secretion, and increased hepatic production of glucose.¹⁹ Older age, nonwhite race, obesity, physical inactivity, poor diet, stress, Westernization, and urbanization are all risk factors.¹⁷ Type 2 diabetes is one of the world’s most important public health issues, and ophthalmologists play an integral role in diagnosing the disease, and preventing and treating retinal microvascular complications.

Type 1 and type 2 diabetes are clinically and pathogenically distinct entities. Therefore, data from clinical trials examining type 1 diabetes cannot be fully extrapolated to patients with type 2 diabetes. The DCCT was arguably the most important clinical trial in diabetes research, but it only examined patients with type 1 diabetes. The United Kingdom Prospective Diabetes Study (UKPDS) was organized in order to fulfill the need to examine the effects of intensive glycemic control in patients with type 2 diabetes. Three prior trials existed at the time, but they were limited in sample size, and results were equivocal.^20,21,22

The UKPDS recruited over 7,600 potential subjects and included 5,102 patients with newly diagnosed type 2 diabetes from
23 medical centers in the United Kingdom between 1977 and 1991. All patients were white. Patients were followed for an average of 10 years, and over 20 million data items were collected to produce one of the largest epidemiologic databases for diabetes research.

Subjects were either randomized to intensive glycemic control defined as fasting plasma glucose <108 mg/dl using a combination of chlorpropamide, glyburide, metformin, and insulin, or to diet modification with the goal of fasting plasma glucose <270 mg/dl. When subjects in the diet-modification group could not attain the goal glycemic levels, they were crossed over to the intensive treatment group. When single agents failed, combinations were used, and metformin was used only in obese patients. Numerous substudies were embedded within the trial.²³ The retinopathy component of UKPDS relied on fundus photographs graded according to a modified Early Treatment of Diabetic Retinopathy Study (ETDRS) Severity Scale.²⁴ The UKPDS used four photographic fields (central macula, nasal macula, temporal macula, and optic disc), rather than the standard seven ETDRS fields.

The final results of the UKPDS were published in 1998.^25,26 Baseline examination of 2,964 patients revealed that the prevalence of any level of retinopathy at the time of diagnosis was 39% in men and 37% in women.²⁶ The overall degree of retinopathy was mild, with approximately one of five subjects having only isolated microaneurysms in one eye, with 97% of these patients having three or fewer microaneurysms. The few cases of severe retinopathy were seen more commonly in men. Male sex, elevated fasting plasma glucose, and systolic blood pressure (SBP) were independent risk factors for increasing retinopathy severity.

The median glycosylated hemoglobin levels over the subsequent 10 years were 7.0% in the intensive treatment group, compared to 7.9% in the conventional group (this 0.9% difference was half that seen in the DCCT, where the difference was 1.9%).²⁵ There was an overall 25% risk reduction of microvascular complications in the intensive treatment group. Most of the risk reduction was attributed to the decreased requirement of photocoagulation. Other endpoints such as amputation, renal failure, and unilateral blindness did not reach statistical significance. Cataract extraction occurred less frequently in the intensive treatment group. There were no differences in microvascular endpoints between the different diabetic medications.

Surrogate endpoints were measured every 3 years, and included two-step progression of diabetic retinopathy and visual acuity. After 6 years of follow-up, fewer subjects in the intensive group had a two-step deterioration in retinopathy, even after controlling for the need for photocoagulation. At 12 years, the risk reduction of two-step deterioration in retinopathy was 21%. In comparison, the DCCT had a 63% risk reduction.⁹

The UKPDS examined whether the presence of microaneurysms, in the absence of other lesions, has predictive value in the progression of diabetic retinopathy.²⁷ Of the 5,102 patients enrolled in the UKPDS, 3,569 had fundus photographs at the time of entry into the study. Of these patients, 2,424 also had fundus photographs at 6 years, and 1,809 of these had either no retinopathy or isolated microaneurysms at baseline. Spontaneous resolution of microaneurysms occurred at rates of 47.5%, 30.8%, and 16.7%, for eyes with 1, 3, or 5 or more microaneurysms, respectively, at 6 years. There was a correlation between the number of microaneurysms at the time of entry and subsequent worsening of retinopathy at 6 and 12 years. This would seem intuitive since longer duration of disease is likely to cause more severe retinopathy. However, the authors argue that the number of microaneurysms alone had predictive value, because the rate of progression between entry and 6 years is “very similar” to that between 3 and 9 years. Regression analysis was not performed.

Risk factors for the 6-year progression of diabetic retinopathy were examined in
1,919 patients with fundus photographs and complete clinical data at 6 years.²⁸ At baseline, 1,216 (63.4%) had no retinopathy. At 6 years, 22% of these patients had developed some level of retinopathy. The independent risk factors for the incidence of retinopathy were elevated glycosylated hemoglobin, elevated SBP, and interestingly, not smoking. In patients with existing retinopathy at baseline, 37% had a two-step or more progression of retinopathy according to a modified ETDRS retinopathy severity scale. The independent risk factors for progression of existing retinopathy were elevated glycosylated hemoglobin level, male sex, older age, and again, not smoking.

The Hypertension in Diabetes Study was an important component of the UKPDS that was introduced in 1987 to examine the effects of blood pressure control in the UKPDS cohort²⁹; 1,148 patients with type 2 diabetes and hypertension, defined as SBP > 160 mmHg and/or diastolic blood pressure (DBP) > 90 mmHg if treatment naive for hypertension, or SBP > 150 mmHg and/or DBP > 85 mmHg if already receiving treatment, were enrolled. Patients were randomized to tight blood pressure control (SBP < 150 mmHg and DBP < 85 mmHg), or less tight control (SBP < 180 mmHg and DBP < 105 mmHg), using either an angiotensin-converting enzyme (ACE) inhibitor or a beta blocker.

Median follow-up in the Hypertension in Diabetes Study was 9.3 years. The mean blood pressure of the tight control group over the 9 years was 144/82 and 154/87 for the less tightly controlled group (P < 0.0001). The tightly controlled group had fewer microaneurysms, hard exudates, and cotton-wool spots at 4.5 and 7.5 years. There was also a 34% risk reduction for a two-step or more deterioration in the ETDRS retinopathy severity scale (P = 0.0004), 35% risk reduction for requiring photocoagulation (P = 0.023), and a 47% risk reduction in losing 3 lines or more of visual acuity (P = 0.004). These effects were seen in both patients with no retinopathy at baseline (primary prevention), and those with existing retinopathy (secondary prevention). However, the differences in blood pressure between the two groups disappeared within 2 years of termination of the trial, and the risk reductions for all major endpoints were lost. This indicated that benefits of previous blood pressure control are not sustained unless tight control is maintained.³⁰

The UKPDS showed that tight glycemic control and blood pressure control are both essential in preventing the incidence and progression of diabetic retinopathy in patients with type 2 diabetes. Glycemic control was by then a well-established means to prevent microvascular complications, but the UKPDS had a significant role in establishing blood pressure control as an effective co-strategy.

The exact mechanisms of how hypertension worsens the course of diabetic retinopathy are still in investigation. However, it appears that the shear force applied by elevated blood pressures against retinal vasculature with impaired autoregulation appears to play a role in exacerbating the microvascular insults caused by hyperglycemia.²⁹

The UKPDS was one of the largest clinical trials in medicine and provided many insights into diabetes care, but there were several limitations to its design. It was noted after the trial commenced that achieving intensive treatment with monotherapies was difficult. One of the initial goals of the study was to compare the efficacies of the different medications, but this was not possible due to most patients requiring more than one medication. Furthermore, approximately 80% of the patients in the control group could not maintain fasting plasma glucose levels <270 mg/dl, and were crossed over into the treatment arm.³¹ Such crossovers diluted the treatment and control groups, resulting in only modest reductions in glycosylated hemoglobin levels.

The methodologies and endpoints regarding diabetic retinopathy in the UKPDS also had several differences with other major population-based studies described in this chapter. For example, the UKPDS used four-field fundus photography for grading purposes, rather
than the standard seven-field ETDRS retinal photography. This may have decreased the sensitivity in grading retinopathy.

The emphasis on the number of microaneurysms was a unique but likely relevant endpoint, since all of the patients were newly diagnosed patients with minimal retinopathy. However, it remains unclear whether the number of microaneurysms can truly predict the progression of disease, independent of other risk factors such as glycemic indices and as this study showed, hypertension.

The presentation of visual acuity and anatomic outcomes was also less comprehensive compared to other studies. For example, the UKPDS provided limited data regarding the prevalence and progressive incidence of visual impairment and blindness. Also, data specific to macular edema, the most common cause of visual loss in diabetic retinopathy, was often lost in the general category of subjects who required photocoagulation (lumped together with panretinal photocoagulation for neovascular disease).

Lastly, the UKPDS was carried out in white populations in the United Kingdom, where the access to and delivery of medical care differs greatly from the United States. The data from the UKPDS provides insightful information regarding the epidemiology and risk factors for diabetic retinopathy in patients with type 2 diabetes, but care should be taken when applying the results to other populations and individual patients.

In the 1970s, there was limited data concerning the epidemiology of diabetic retinopathy. Information on the prevalence and severity of retinopathy in a large cohort of diabetic patients was needed to plan a well-coordinated approach to this important public health problem. To recommend the guidelines for ophthalmologic care, patients with a broad distribution of retinopathy severity needed to be examined and followed up, and patients with risk factors for developing visual loss from diabetic retinopathy needed to be identified. Such data would also be helpful in planning future clinical trials to better define etiologic relationships and to assess the effects of new treatments.

The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) was established to address these issues. The WESDR was a cross-sectional and longitudinal study designed to provide data on the prevalence, severity, incidence, and progression of diabetic retinopathy in a geographically defined population of diabetic patients. It was the largest and most comprehensive epidemiologic study of diabetic retinopathy.

Established in the late 1970s, the WESDR sought (a) to describe the prevalence and severity of diabetic retinopathy and its component lesions, and to determine the frequency of visual impairment in a total population of patients with diabetes who were under physicians’ care in a defined geographic region, and (b) to determine the relationships between risk factors, prevalence, and severity of diabetic retinopathy in these patients.

The patient population described in the WESDR was obtained in the following manner: in an 11-county area in southern Wisconsin, 452 primary care physicians (99% of total) provided charts of all diabetic patients they had seen over a 1-year period. Approximately 10,000 charts were identified and reviewed, and a sample of approximately 3,000 patients was selected for examination.

Patients were examined in the early 1980s to determine the prevalence and severity of diabetic retinopathy and associated risk variables. The WESDR cohort was reexamined periodically thereafter to determine the
incidence and progression of visual impairment and retinopathy. Both the younger- and older-onset groups were reexamined 4 and 10 years later, but only the younger-onset group was reexamined at the 14-year follow-up due to the high death rate among older-onset patients.

Outcome measures included visual acuity using the ETDRS protocol: visual impairment, grouped into four levels (no impairment: >20/40; mild impairment: 20/40 to 20/63; moderate impairment: 20/80 to 20/160; blind: ≤20/200); the relative contribution of diabetic retinopathy in eyes with impaired vision; the severity and progression of diabetic retinopathy using a modification of the Airlie House classification scheme that specifies nine levels³²; the presence of macular edema; and metabolic control as determined by glycosylated hemoglobin and protein levels in the urine.

Fifteen percent of patients were diagnosed with diabetes before 30 years of age and were taking insulin (younger-onset group), while 85% were diagnosed at 30 years of age or older (older-onset group). The older-onset patients had their diagnosis confirmed by a random or postprandial serum glucose level of at least 200 mg/dl or a fasting level of at least 140 mg/dl, and approximately 50% of these patients were taking insulin.

Visual impairment (visual acuity in the better eye ≤ 20/40) increased with increasing age. Legal blindness (visual acuity in the better eye ≤ 20/200) was related to the duration of diabetes in both the younger- and older-onset groups. In the younger-onset group, legal blindness was present in 3.6% of patients, and diabetes was at least partly responsible in 86% of such patients. In the older-onset group, legal blindness was present in 1.6%, and diabetes was a cause in 33%.³³

In the younger-onset group, the prevalence of diabetic retinopathy was 17% in patients with diabetes <5 years and 98% for those with diabetes for ≥15 years. Proliferative retinopathy was present in 23%. Retinopathy severity was related to longer duration of diabetes and higher levels of glycosylated hemoglobin.³⁴ In the older-onset group, the prevalence of retinopathy was 29% in patients with diabetes for <5 years and 78% in those with diabetes ≥15 years. Proliferative disease was present in 9%. Retinopathy severity was related to longer duration of diabetes, younger age at diagnosis, higher glycosylated hemoglobin levels, higher SBP, and the use of insulin.³⁵