The main and early trial and his legacy

Abstract

The 3 main trials who established which are the cut off levels of fasting/postprandial glycemia and HbA1c concentration in order to avoid and/or delay the onset and progression of micro and macrovascular complications introducing the novel concept of “metabolic legacy/memory” were the Control and Complications Trial (DCCT: 1983-1993) with his Epidemiology of Diabetes Interventions and Complications (EDIC) follow up for 40 years, The Kumamoto Trial (1990-2000) and the UKPDS (1977-1997) and his post-trial monitoring in T2D. In the DCCT 1,441 participants with T1D were followed under intensive therapy (HbA1c 7%) vs. conventional therapy (HbA1c 9%) reducing the risk of development/progression of microvascular complications by 35%–76% showing early beneficial effects of intensive vs. conventional therapy on complications (micro and macrovascular) persisted for 10 years after the convergence of HbA1c levels in the two groups during EDIC (“metabolic memory”). In Kumammoto study 110 patients with no retinopathy (primary prevention cohort) and 55 with simple retinopathy (secondary intervention) were assigned to multiple insulin injection therapy or conventional 2 intermediate acting insulin. Both primary and secondary cohorts showed worsening of retinopathy, nephropathy and neuropathy if they were above the preventive threshold of HbA1c <6.5% fasting glucose < 110 mg/dl and 2 hs. postprandial blood glucose < 180 mg/dl. The UKPS enroled 5102 patients between 1977 and 1991, randomly allocated to intensive control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the trial, intensive blood glucose significantly reduced microvascular complications and had a legacy effect in macrovascular complications as well as blood pressure control. Early intensive glycaemic control (sulfonylurea, insulin, metformin, compared with conventional control, confer a near-lifelong reduced risk of death and myocardial infarction.

In conclusión, HbA1c <7% was adopted worldwide as the therapeutic target for T1D and T2D patients. DCCT/EDIC has generated guided treatment priorities in T1D improving survival/quality of life for millions of people. The threshold to prevent the onset and progression of these complications should be an HbA1c < 6.5% fasting glucose < 110 mg/dl and 2 hs. postprandial glucose < 180 mg/dl. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the risk of diabetes-related complications.