Research in context
Evidence before this study
We searched PubMed, ScienceDirect, and the Cochrane Library for articles published in English between Jan 1, 1997, and Dec 31, 2007, with search terms “type 2 diabetes”, “metformin”, “pioglitazone”, “sulfonylureas”, and “cardiovascular events”, or “cardiovascular disease” or “cardiovascular mortality”, or “glycated haemoglobin”, or “treatment failure” or “heart failure”. In patients with type 2 diabetes, metformin is the recommended first-line drug treatment, but there is considerable uncertainty as to the best add-on treatment in patients whose glycaemia is inadequately controlled with metformin alone. Sulfonylureas are the most widely used choice, but their cardiovascular safety is uncertain. Pioglitazone could represent a suitable alternative, in view of the evidence supporting its protective effect on ischaemic cardiovascular disease, although concerns remain about possible clinically relevant side-effects. The cardiovascular effects, glycaemic effects, and safety of these therapeutic approaches have not previously been compared in a long-term, head-to-head trial.
Added value of this study
The TOSCA.IT trial provides a direct comparison of two widely available and affordable second-line treatment regimens for patients with type 2 diabetes. The patients enrolled represent an almost primary prevention population that is usually neglected in trials done to investigate the cardiovascular effects of glucose-lowering drugs. The results showed that, if used appropriately, in terms of patient selection and dose, both pioglitazone and a sulfonylurea (glimepiride or gliclazide) as add-on to metformin are associated with similarly low rates of cardiovascular events and few clinically relevant side-effects. Our findings also suggest that pioglitazone could be advantageous compared with sulfonylureas in terms of durability of glycaemic control and frequency of hypoglycaemia.
Implications of all the available evidence
Our results lend support to current treatment guidelines for type 2 diabetes, particularly in relation to patients with a low cardiovascular risk, by suggesting that both pioglitazone and sulfonylureas (glimepiride or gliclazide) are suitable alternatives as add-on treatment when metformin alone fails to provide adequate glycaemic control.