Epidemiological evidence supports a strong relationship between plasma glucose levels and morbidity and mortality. This association has represented the ground for intervention trails, designed to ascertain whether and to which extent intensive glycemic control can reduce the risk of chronic complications in Type 2 diabetes (T2DM) patients. Initial support to this hypothesis came from the UKPDS. The trial, however, pointed out the progressive nature of the disease underscoring the need of treatment intensification over the time. By using multiple treatment and more intensive therapeutic approach subsequent trials (ACCORD, ADVANCE, VADT) manage to achieve and maintain strict glycemic control in large cohorts of T2DM patients. Nonetheless, effect on cardiovascular outcomes was, at its best, limited. Multiple reasons have been claimed to account for this disappointing result, including the need to earlier and more appropriate therapeutic intervention capable at ensuring good glycemic control since the time of the diagnosis. Achieving such a goal, however, requires proper appreciation of the pathophysiologic mechanisms accounting for the progressive nature of T2DM and in particular of the critical role played by continuous loss of functional beta-cell mass. Treatment aiming at preserving beta-cell mass while reducing side effects (hypoglycemia, body weight gain….) could results in better durability of glycemic outcomes. Introduction of new forms of treatments must, therefore, carefully evaluated with respect of their safety:efficacy ratio and possibility to improve early attainment of good glycemic control. Yet, short-term surrogate measures of success must be followed by long-term clinical risk/benefit outcomes.