The Absence of a Glycemic Threshold for the Development of Long-Term Complications: The Perspective of the Diabetes Control and Complications Trial

Abstract

The Diabetes Control and Complications Trial (DCCT) demonstrated a reduction in the development and progression of the long-term complications of IDDM with intensive therapy aimed at achieving glycemic control as close to the nondiabetic range as possible. The DCCT subsequently showed that the total lifetime exposure to glycemia was the principal determinant of the risk of retinopathy and that there was a continuous nonlinear relationship between this risk and the mean level of HbA1c (DCCT Research Group, Diabetes 44:968–993, 1995). In contrast, other authors, based on a retrospective study (Krolewski et al., N Engl J Med 332:1251–1255, 1995), have suggested that a glycemic threshold for microabuminuria and for retinopathy exists at an HbA1c level of ∼ 8%, below which there is no further appreciable reduction in risk. In this perspective, we examine whether the DCCT data demonstrate such a glycemic threshold for the development of retinopathy, nephropathy, or neuropathy. In the DCCT, 1,441 patients with IDDM were randomly assigned to intensive (n = 711) or conventional (n = 730) therapy and followed for a mean of 6.5 years. Retinopathy was assessed every 6 months by stereoscopic fundus photography; albumin excretion was measured annually in a 4-h collection; and neuropathy was assessed with a standardized protocol performed at baseline and at 5 years. Glycosylated hemoglobin was measured quarterly. Episodes of severe hypoglycemia were ascertained using standardized procedures. The risks (hazard rates) of retinopathy progression and of developing microalbuminuria and neuropathy were found to be continuous but nonlinear over the entire range of glycosylated hemoglobin values in the intensive, conventional, and combined treatment groups. These nonlinear relationships describe a constant relative risk gradient in which proportional reductions in HbA1c are accompanied by proportional reductions in the risk of complications. Although the magnitude of the absolute risk reduction declines with continuing proportional reductions in HbA1c, there are still meaningful further reductions in risk as the HbA1c is reduced toward the normal range. When the instantaneous risks for different complications associated with different HbA1c values are compounded over time, there are substantial differences in the cumulative incidence of patients experiencing a complication for patients with HbA1c values of 6 vs. 7 vs. 8% or higher. In fact, no HbA1c threshold could be identified, short of normal glycemia, below which there was no risk of the development or progression of these complications. Furthermore, as the HbA1c was reduced proportionately, the proportional rate of decline in the relative risk for each of these complications was similar for HbA1c levels ≤ 8.0% and for levels > 8%. In contrast, although the absolute risk of severe hypoglycemia in the intensive treatment group increased as the HbA1c decreased, the relative risk gradients were significantly less for HbA1c levels ≤ 8.0% than for levels > 8%. These extensive prospective DCCT data do not support the conjecture that a glycemic threshold for the development of complications exists at an HbA1c of 8% or that an HbA1c goal of 8% is maximally beneficial. In the DCCT, as HbA1c was reduced below 8% there were continuing relative reductions in the risk of complications, whereas there was a slower rate of increase in the risk of hypoglycemia. Therefore, the DCCT continues to recommend implementation of intensive therapy with the goal of achieving normal glycemia as early as possible in as many IDDM patients as is safely possible.