DCCT: study design

1. Slide No. 1 • • DCCT: study design DCCT was the largest study ever conducted to investigate the effect of intensive insulin treatment on the development and progression of complications in type 1 diabetes. At baseline, all patients had type 1 diabetes with either no retinopathy (primary prevention group) or mild retinopathy (secondary intervention group). During the study, patients received conventional treatment with once or twice daily insulin injections or intensive treatment with an insulin pump or at least three daily insulin injections guided by frequent blood glucose monitoring. DCCT was the largest study ever conducted to investigate the effect of intensive insulin treatment on the development and progression of complications in type 1 diabetes. At baseline, all patients had type 1 diabetes with either no retinopathy (primary prevention group) or mild retinopathy (secondary intervention group). During the study, patients received conventional treatment with once or twice daily insulin injections or intensive treatment with an insulin pump or at least three daily insulin injections guided by frequent blood glucose monitoring.

2. Slide No. 2 • • DCCT: treatment conditions Intensive group (n = 711): Aim: symptom-free + plasma glucose: -3.9-6.7 mmol/l before meals; - < 10 mmol/l after meals; - > 4.0 mmol/l at 03.00 a.m.; - HbA1c < 6.5% ? 3 insulin injections / day or insulin pump ? 4 daily blood glucose tests Hospitalisation for initiation Comprehensive education programme Frequent dietary instructions Monthly clinic visits Conventional group (n = 730): Aim: to avoid symptoms of hyper / hypoglycaemia 1 or 2 insulin injections per day Daily self-monitoring Initial diet and exercise education Quarterly visits

3. Slide No. 3 • • DCCT: intensive therapy significantly reduces and maintains HbA1c During DCCT, intensive insulin therapy in people with type 1 diabetes significantly reduced HbA1c relative to those receiving conventional treatment. The intensively-treated group achieved a mean HbA1c of 7.1%, while the conventionally-treated patients had HbA1c of approximately 9.0%. During the EDIC (Epidemiology of Diabetes Intervention and Complications research group) follow-up of the DCCT cohort, all patients were encouraged to adopt intensive insulin therapy. During this time, HbA1c stablised to a similar level (just over 8%) in both treatment groups. During DCCT, intensive insulin therapy in people with type 1 diabetes significantly reduced HbA1c relative to those receiving conventional treatment. The intensively-treated group achieved a mean HbA1c of 7.1%, while the conventionally-treated patients had HbA1c of approximately 9.0%. During the EDIC (Epidemiology of Diabetes Intervention and Complications research group) follow-up of the DCCT cohort, all patients were encouraged to adopt intensive insulin therapy. During this time, HbA1c stablised to a similar level (just over 8%) in both treatment groups.

4. Slide No. 4 • • DCCT: intensive therapy reduces microvascular complications In patients with no retinopathy at baseline (primary prevention cohort), intensive treatment reduced the risk of the development of retinopathy by 76% and microalbuminuria by 34% compared with conventional therapy (p < 0.001 and 0.04 respectively). In the secondary prevention cohort (patients with retinopathy at baseline, data not shown), intensive treatment slowed the progression of retinopathy by 54% and reduced the onset of microalbuminuria by 43% relative to conventional treatment (p < 0.001 and = 0.001 respectively)In patients with no retinopathy at baseline (primary prevention cohort), intensive treatment reduced the risk of the development of retinopathy by 76% and microalbuminuria by 34% compared with conventional therapy (p < 0.001 and 0.04 respectively). In the secondary prevention cohort (patients with retinopathy at baseline, data not shown), intensive treatment slowed the progression of retinopathy by 54% and reduced the onset of microalbuminuria by 43% relative to conventional treatment (p < 0.001 and = 0.001 respectively)

5. DCCT: microvascular complications increase as HbA1c increases DCCT provided evidence that improved HbA1c was associated with a reduction in microvascular complications DCCT provided evidence that improved HbA1c was associated with a reduction in microvascular complications

6. Slide No. 6 • • Retinopathy 7 years after the DCCT Despite similar HbA1c (around 8%) during the 7-year EDIC follow-up period, the cumulative incidence of retinopathy remained much lower in the intensively-treated DCCT patients. These findings show that the benefit of 6.5 years of intensive treatment during the DCCT extends well beyond the trial period. This fact allows to talk about the presence of a ”metabolic memory”, which extends the benefits of intensive insulin treatment beyond the time of achievement of good glycaemic control. Despite similar HbA1c (around 8%) during the 7-year EDIC follow-up period, the cumulative incidence of retinopathy remained much lower in the intensively-treated DCCT patients. These findings show that the benefit of 6.5 years of intensive treatment during the DCCT extends well beyond the trial period. This fact allows to talk about the presence of a ”metabolic memory”, which extends the benefits of intensive insulin treatment beyond the time of achievement of good glycaemic control.

7. Slide No. 7 • • DCCT: the price of improved diabetic control – hypoglycaemia During DCCT, the risk of retinopathy increased with worsening glycaemic control (as measured by HbA1c). Conversely, as glycaemic control improved, the risk of severe hypoglycaemia increased. Consequently, improved glycaemic control reduced the risk of retinopathy but was accompanied by a three-fold increased risk of hypoglycaemia in the intensively-treated group. During DCCT, the risk of retinopathy increased with worsening glycaemic control (as measured by HbA1c). Conversely, as glycaemic control improved, the risk of severe hypoglycaemia increased. Consequently, improved glycaemic control reduced the risk of retinopathy but was accompanied by a three-fold increased risk of hypoglycaemia in the intensively-treated group.

8. Slide No. 8 • • Economic analysis - DCCT “From a health care system perspective, intensive therapy represents a good monetary value for the investment”1 “Although intensive therapy is expensive, when the costs of complications are factored in, it becomes cost-effective for the treatment of type 1 diabetes”2