The shape of the metabolic memory of HbA_1c: re-analysing the DCCT with respect to time-dependent effects

We determined the shape of the metabolic memory of HbA_1c and its contribution to retinopathy, as well as the importance of reducing HbA_1c to prevent progression of retinopathy.

The relative risk contribution of HbA_1c values at different points in time to current progression of retinopathy was determined in the DCCT patients.

HbA_1c 2 to 3 years earlier had the greatest relative risk contribution to current progression of retinopathy. HbA_1c up to 5 years earlier made a greater contribution than current values, while values from 8 years earlier still had an important impact. When HbA_1c had been at 8% for a long period and was subsequently lowered to 7%, the salutary effects did not begin to appear until 2 to 3 years after lowering. The hazard function for a constant level of HbA_1c increased with time. The numbers needed to treat when reducing HbA_1c from 8.3% to 8% from diagnosis was estimated to be 1,688 for the first 3 years and 13 for the period 9 to 12 years. Survival functions when reducing HbA_1c from 8% to 7% show that pre-study glycaemic control dominates the effect on progression of retinopathy during the first years of a trial.

The most harmful effect of hyperglycaemia on progression of retinopathy in type 1 diabetes initially increases, but declines after roughly 5 years. The salutary effect of reducing HbA_1c accelerates with time and becomes greater in clinical practice than has been previously understood. Clinical trials should preferably be designed for long periods or include patients with low previous glycaemic exposure to distinguish trial effects from those of the metabolic memory.