Two pivotal randomised controlled trials (RCTs) demonstrated the importance of good glycaemic control in reducing the incidence and progression of retinopathy in diabetes: the Diabetes Complications and Control Trial (DCCT) in type 1 diabetes and the United Kingdom Prospective Diabetes Study (UKPDS) in type 2 diabetes.
DCCT
The DCCT was conducted in 29 centres in the United States and Canada between 1983 and 1989. 1441 subjects with type 1 diabetes of greater than 1 and less than 15 years duration (726 with no retinopathy and 715 with background DR at
baseline) were randomised to either intensive or conventional glycaemic control (mean HbA1c achieved 7.2% and 9.1%, respectively). Mean duration of follow-up was 6.5 years [12,124,125,126].
For subjects with no DR at baseline the incidence of retinopathy (defined as a change of three steps on the ETDRS scale that was sustained over a six month period) was 76% (95% CI 62-85) lower in the intensive therapy arm than the conventional arm [12]. For subjects with background retinopathy at baseline intensive therapy reduced the risk of retinopathy progression by 3 steps (or more) by 54% (95% CI 39-66). Intensive therapy reduced the risk of severe non-
proliferative DR or proliferative retinopathy (PDR) by 47% and that of treatment with laser photocoagulation by 56% [12]. Figure 3.1 shows cumulative incidence of DR progression in subjects with and without retinopathy at baseline. The authors concluded that intensive control was most effective when started before
46 Figure 3.1 Cumulative incidence of sustained 3 step progression of retinopathy in subjects with type 1 diabetes receiving intensive or conventional therapy. A: subjects with no retinopathy at baseline. B: subjects with background DR at
baseline. Numbers of subjects in each therapy group who were evaluated at years 3,5,7 and 9 are shown below the graphs. Taken from the DCCT [12].
In the DCCT, intensive therapy reduced the incidence of microalbuminuria by 39%, albuminuria by 54% and neuropathy on clinical examination by 60% [12]. The absolute risks of nephropathy and retinopathy were proportional to the mean HbA1c level over the follow-up period preceding each event. Mortality did not differ significantly between the intensive and conventional therapy arms. However, the incidence of severe hypoglycaemia was 3 times higher in the intensive arm. A person not involved in the trial was killed in a road traffic accident after being hit by a motorbike ridden by a subject in the intensive arm who had an episode of
hypoglycaemia. More weight gain was observed in the intensive therapy arm.
Follow-up of the DCCT cohort continued annually as part of the Epidemiology of Diabetes Interventions and Complications (EDIC) study [127,128]. During this study glycaemic control no longer differed substantially between the original 2 treatment arms of the trial: at one year the difference was 0.4% (HbA1c 8.3% in the former conventional therapy arm and 7.9% in the former intensive arm, p<.001) and by 5 years the difference was non-significant. In analyses using the DCCT final
retinopathy grade as a new baseline, at 4 years of EDIC further progression of DR was between 66 to 77% less (depending on the measure used) in the former
47 intensive arm than the former conventional arm [127]. This phenomenon has been termed ‘metabolic memory’. Cumulative incidence of 3 step progression was still significantly less at 7 years [127] and 10 years [128]. Significantly fewer former intensive subjects than former conventional subjects required laser treatment during EDIC [128]. The EDIC study demonstrated a reduction in cardiovascular disease in the former intensive group which had not been apparent in the DCCT [129].
The overall results of the DCCT/EDIC were interpreted by the authors to show that the benefits of intensive glycaemic control take some years to manifest but
subsequently persist beyond the period of intervention. The authors hypothesised that the predictive association of risk of DR with preceding mean HbA1c was a causal relationship and that total glycaemic exposure determines the degree of retinopathy observed at any one time. A HbA1c target level of 7.0% or less was suggested [127] although the authors acknowledged the risks of increased hypoglycaemic events and excess weight gain with intensive therapy regimes [130,131].
The DCCT did not define the optimum methods to achieve good glycaemic control while minimising adverse events; subsequent studies would explore the benefits and risks of treatment regimens aimed at reducing mean HbA1c further. While the DCCT/EDIC analyses were adjusted for a number of baseline physiological
parameters there was no adjustment for use of medications other than
hypoglycaemic agents (e.g. aspirin and angiotensin-converting enzyme inhibitors) which is a potential confounder. The DCCT/EDIC studies commenced over 30 years ago and results are increasingly difficult to apply to current practice. Many aspects of diabetes care have changed markedly over this time. In particular management of blood pressure was generally much worse than at present. These caveats notwithstanding concepts such as metabolic memory are still highly relevant.
48
UKPDS
The UKPDS was conducted between 1977 and 1997. 3867 subjects with newly diagnosed type 2 diabetes (median age 54 years; IQR 48-60 years) who, after 3 months diet treatment had a fasting plasma glucose concentration of 6.1-15.0 mmol/L, were randomly assigned to intensive glycaemic control with a
sulphonylurea or insulin, or conventional therapy with diet [132,133,134,135]. Mean HbA1c levels achieved were 7.0% (6.2–8.2) and 7.9% (6.9–8.8), respectively. Median follow-up was 10.0 years (IQR 7.7–12.4). Subjects in the intensive
treatment arm had a significant 25% risk reduction in microvascular endpoints. Most of this reduction was due to fewer subjects requiring retinal laser treatment. The UKPDS investigated surrogate endpoints, including 2 step progression of DR, at visits at 3 year intervals. Subjects in the intensive treatment arm demonstrated a 34% reduction in incidence of DR and 17% lower rate of 2 step progression (a
difference which was significant even when subjects who received retinal laser were excluded). Each 1% reduction in HbA1c gave a 31% reduced risk of incidence or 2 step progression of DR.
Relatively few subjects in the UKPDS developed late complications of DR such as vitreous haemorrhage or blindness. This may be because the follow-up period was not long enough. A more likely explanation is that subjects were examined
regularly and received laser photocoagulation as necessary. Despite this the intensive arm showed a 16% reduction in legal blindness. With regard to
macrovascular endpoints the UKPDS showed evidence of a 16% risk reduction for myocardial infarction, which included non-fatal and fatal myocardial infarction and sudden death. This difference was not statistically significant by conventional criteria: p=0·052. It is possible that this difference may have been greater given a longer duration of follow-up. Interpretation of this outcome is complicated by the multifactorial nature of cardiovascular disease. Diabetes-related mortality and all- cause mortality did not differ between the intensive and conventional groups. However, the study was not sufficiently powered to exclude a beneficial effect on mortality.
49 The number needed to treat to prevent one subject developing any of the single trial endpoints (either micro or macrovascular) over 10 years was 19.6 subjects (95% CI 10–500). The ‘complication free interval’ (defined as the time at which 50% of subjects had at least one diabetes related trial endpoint) was 14.0 years in the intensive arm and 12.7 years in the conventional arm (p=0.029). As in the DCCT the proportion of subjects experiencing hypoglycaemic episodes was significantly higher in the intensive arm. In subjects treated with insulin each year, 3% had a major episode and 40% a minor or major hypoglycaemic episode. Subjects in the intensive arm also demonstrated significantly increased weight: mean 3.1 kg (99% CI –0.9 to 7.0, p<0·0001) at 10 years.
Importantly the UKPDS showed that clinical benefit could be gained at lower HbA1c values than DCCT. The UKPDS compared a difference in HbA1c between intensive and conventional arms of 0.9% (7.0 vs 7.9%) over 10 years. This is smaller than the difference compared in the DCCT: 1.9% (7.2 vs 9.1%). The DCCT studied younger subjects with type 1 diabetes and used slightly different (mainly surrogate) outcome measures. With this caveat, comparison of DCCT and UKPDS results suggests that the benefits of HbA1c reduction on risk of progression of microvascular disease are proportional: 21% for retinopathy in UKPDS and 63% in the DCCT, and, for
albuminuria, 34% and 54% respectively.
ACCORD and ADVANCE
The DCCT and UKPDS demonstrated unequivocal reductions in ocular morbidity with improved glycaemic control. However, the potential benefits of tighter control remain controversial. The Action to Control Cardiovascular Risk in Diabetes
(ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) were large RCTs of glycaemic control to levels lower than the DCCT and UKPDS. In the ACCORD study 10,251 subjects with type 2 diabetes who were at high risk for cardiovascular disease were randomised to either intensive or standard glycaemic control (target <6.0% or 7.0 to 7.9%; at one year achieved mean HbA1c were 6.4% and 7.5%, respectively). Of these
50 standard therapy: 160 mg daily of fenofibrate plus simvastatin or placebo plus simvastatin. The remaining 4733 subjects were randomised to either intensive or standard therapy for systolic blood-pressure control: target <120 or <140 mm Hg [136,137]. A sub-group of 2856 subjects was evaluated at 4 years for the effects of these interventions on the progression of DR by 3 (or more) steps on the ETDRS scale or development of DR necessitating laser photocoagulation or vitrectomy.
At 4 years follow-up, progression of DR was seen in 7.3% of the intensive group and 10.4% of the standard group (adjusted odds ratio 0.67; 95% CI 0.51 - 0.87; p=0.003). In the ACCORD Eye study there was a non-significant trend towards reduced MVL (23.8% vs 26.3%; hazard ratio 0.88; 95% CI 0.77-1.01; p=0.06). However, in the entire ACCORD population there was a significant reduction in MVL in the intensive group (19.1% vs 20.7% with standard therapy; hazard ratio, 0.91; 95% CI, 0.83 to 1.00; P = 0.047)[138]. The authors concluded that intensive glycaemic control reduced the rate of progression of DR and reduced visual loss (even in a population receiving regular eye examination and with access to treatment for DR).
Unfortunately the ACCORD trial showed a significantly increased risk of having a hypoglycaemic event that necessitated assistance in the intensive arm. Most worryingly the intensive regime was associated with an increase in all-cause
mortality after mean 3.5 years follow-up. This led to the premature cessation of the glycaemic trial. The study may therefore have underestimated the reported effect of glycaemic treatment on DR. More importantly though ACCORD demonstrates real risks associated with intensive treatment strategies. The ACCORD population were older than those of the DCCT and UKPDS and pre-selected to be at high risk of cardiovascular disease. Results from the trial regarding risks should be generalised to all patients with type 2 diabetes with caution.
The ADVANCE study randomly assigned 11,140 patients with type 2 diabetes to either intensive (gliclazide plus other drugs) or standard control. After median follow-up 5 years mean HbA1c achieved was 6.5% and 7.3%, respectively [139]. A subgroup of 1241 subjects in the ADVANCE Retinal Measurements (AdRem) study underwent retinal photography and ETDRS grading of DR [140]. In the main study
51 intensive control reduced the incidence of major microvascular events (hazard ratio 0.86; 95% CI, 0.77 to 0.97; p=0.01) and of combined major macrovascular and microvascular events (hazard ratio 0.90; 95% CI 0.82-0.98; p=0.01). These results were mainly due to a reduction in incidence of nephropathy.
In the main study there was no significant difference between the 2 arms in the number of subjects undergoing retinal photocoagulation. However, the absolute numbers requiring laser treatment were low thus limiting the power of the study to detect a difference. In the AdRem sub-study there was no significant reduction in development or progression of DR or maculopathy. There were no significant differences between the intensive and standard arms with regard to major macrovascular events, death from cardiovascular cause or death from any cause. Intensive control was associated with an increased risk of severe hypoglycaemia (hazard ratio 1.86; 95% CI 1.42-2.40; p<0.001) and an increased risk of
hospitalisation.
Steno 2
Trials assessing multifactorial interventions have informed understanding of the effects of glycaemic control on DR. The Danish Steno 2 study randomised 160 subjects with type 2 diabetes and persistent microalbuminuria to an intervention comprising tight glucose control, the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents and behavioural modification or standard care. The mean treatment period was 7.8 years and subsequent follow-up continued for a mean of 5.5 years. The intensive group showed reduced risk of retinal
photocoagulation (relative risk 0.45; 95% CI 0.23-0.86; p=0.02), all-cause mortality (hazard ratio 0.54; 95% CI 0.32-0.89; p = 0.02), death from cardiovascular causes (hazard ratio, 0.43; 95% CI 0.19-0.94; p=0.04) and of cardiovascular events (hazard ratio, 0.41; 95% CI 0.25-0.67; p<0.001) [141]. Few major side effects were reported. This study showed large relative and absolute improvements in microvascular and macrovascular outcomes. It was not designed to identify the relative contributions of the individual elements in the intervention package. The Steno 2 study is one of the most important studies on which modern diabetes management is based. Box
52 3.1 lists the targets for modifiable risk factors and behavioural changes that were set in the study.
Therapeutic issues in glycaemic control
A goal of HbA1c <7% is suitable for the majority of persons with diabetes [142]. Certain patients may benefit from lower HbA1c targets (≤ 6.5%) but the beneficial effects for DR progression are limited. For some patients, including those with cardiovascular disease or a record of severe hypoglycaemia, the risks in terms of mortality of a HbA1c target <7% may outweigh the benefits. A phenomenon observed in both the DCCT and UKPDS was rapid DR progression in a minority of subjects (13% in DCCT) within the first 18 months of the initiation of intensive therapy [143]. A similar observation was made in patients achieving excellent glycaemic control following combined renal and pancreas transplants [144]. Patients with poor glycaemic control, with diabetes of long duration and moderate
Box 3.1 Targets for modifiable risk factors and lifestyle changes set by the Steno 2 study [141]
• Glycosylated haemoglobin (HbA1c) < 6.5% • Blood pressure < 130/80 mmHg
• Total cholesterol < 175 mg/dl • Triglycerides < 150 mg/dl
• Angiotensin-converting enzyme (ACE) inhibitor (regardless of blood pressure): equivalent to captopril 50mg twice daily
• Aspirin 150 mg daily to patients with a history of cardiovascular disease
• Reduction in intake of dietary fat: total daily intake of fat less than 30% of total daily energy intake, and intake of saturated fatty acids of less than 10% of total daily energy intake
• Regular exercise: at least 30 min three to five times a week • Smoking cessation
• A dietary supplement consisting of vitamins C (250 mg daily) and E (100 mg daily), folic acid and chromium picolinate
53 or severe non-proliferative DR require careful monitoring by an ophthalmologist for at least 12 months before and following initiation of intensive therapy.
Thiazolidinediones (glitazones) are hypoglycaemic agents used in type 2 diabetes. There is evidence of a beneficial effect of these agents on DR progression beyond their hypoglycaemic effects [145]. However, some studies have identified an increased risk of maculopathy with glitazone use [146]. A large prospective study of 170,000 subjects using the Diabetes Case Identification Database at Kaiser
Permanente, Southern California, 9.9% of whom were taking glitazones, identified a 2.6-fold increased risk of developing diabetic maculopathy (95% CI 2.4–3.0) [147]. Other studies [145] including ACCORD [148] have not identified an increased risk of DMO. Current practice is to avoid glitazones in patients who develop maculopathy, particularly when peripheral oedema is also present.