It is still a much debated question whether antidiabetic therapy to target normal glycated hemoglobin levels would reduce cardiovascular events in patients with advanced type 2 diabetes. New findings result from ACCORD, ADVANCE and VADT. These trials reveal that microvascular and macrovascular effects of intensive glucose lowering have to be considered separately: Glycemic control convincingly demonstrated to have a protective impact on microvascular complications, especially nephropathy. However, macrovascular benefits remain doubtful in these megatrials and have to be considered in connection with the individual global risk. On the other hand, the Diabetes Intervention Study (DIS) and UKpharmacodynamicsS 10-year follow-up results yielded better cardiovascular outcomes for those patients who received intensive glucose-lowering therapy very early after diabetes diagnosis, but the favourable influences did not manifest until a time period of 1 – 2 decades.

For the first time, the cardiovascular benefit of an antidiabetic substance (pioglitazone) could be verified in the large-scale outcome-trial PROactive for patients with advanced diabetes and multiple manifestations of macroangiopathy. The results provide strong support for a beneficial influence on macrovascular complications just under 3 years of treatment. Nevertheless, the positive findings did not result from better glycemic control, but from the complexity of effects of PPARgamma agonist pioglitazone on insulin resistance, lipoprotein spectrum, blood pressure, endothelial function and biomarkers of subclinical inflammation. It is obvious that we need to integrate such pleiotropic effects on metabolic syndrome and cardiovascular disease to improve the quality of drug-therapy decisions. This, in turn, requires a growing body of evidence from large, long-term outcome trials – but appropriate data are still unavailable for the vast majority of antidiabetic drugs.