Pioglitazone, rosiglitazone, and rosiglitazone + metformin: new drugs. Glitazone + oral antidiabetic combination: inadequately evaluated.

(1) When single-agent therapy provides inadequate glycaemic control for patients with type 2 diabetes, most guidelines recommend metformin in combination with a glucose-lowering sulphonylurea as standard treatment, despite the lack of any proven impact on morbidity or mortality. Other options include switching to insulin or abandoning the target of strict glycaemic control. (2) Pioglitazone and rosiglitazone are approved for use in combination with a glucose-lowering sulphonylurea when metformin is poorly tolerated or contraindicated, and in combination with metformin in overweight patients. (3) A fixed-dose combination containing 1 or 2 mg of rosiglitazone plus 500 mg of metformin (hydrochloride) was launched onto the French market in October 2004. (4) The indication for rosiglitazone was extended to include its use as triple-agent therapy in combination with metformin and a glucose-lowering sulphonylurea. (5) No clinical trials assessing effects on mortality or morbidity have evaluated rosiglitazone or pioglitazone in combination with other oral antidiabetic drugs. (6) Several trials have compared the glucose-lowering effects of dual-agent therapy using rosiglitazone or pioglitazone plus a glucose-lowering sulphonylurea or metformin versus dual-agent therapy with metformin and a glucose-lowering sulphonylurea. (7) These clinical trials indicate that in terms of HbA1c level, dual-agent therapy based on rosiglitazone or pioglitazone is about as effective as combination therapy with metformin plus a glucose-lowering sulphonylurea. (8) The main known adverse effect of pioglitazone and rosiglitazone is water-sodium retention, which can provoke oedema and haemodilution anaemia, and can aggravate or reveal heart failure. (9) Pioglitazone has a positive effect on the lipid profile, whereas rosiglitazone increases the LDL-cholesterol level. (10) Dual-agent therapy with pioglitazone and a sulphonylurea causes more weight gain than metformin plus a sulphonylurea. (11) Several trials have assessed triple-agent regimens containing a glitazone. Three placebo-controlled double-blind trials have tested pioglitazone (one trial, nearly 300 patients) or rosiglitazone (two trials, about 1200 patients) for 12 to 26 weeks in patients whose glycaemia was poorly controlled by dual-agent therapy with a sulphonylurea plus metformin. The glycated haemoglobin level fell by 0.3% to 1.1% (in absolute values), depending on the trial and the dosage, but at a cost of the usual adverse effects such as weight gain, anaemia and oedema. Three unblinded trials have compared oral triple-agent regimens containing glitazone versus insulin plus metformin, alone or in combination with a glucose-lowering sulphonylurea; the treatment including glitazone was no more effective in terms of the glycated haemoglobin level, but was associated with an increase in adverse effects and dropouts. (12) Given the limited clinical data available in early 2005, pioglitazone and rosiglitazone have no place in the management of type 2 diabetes.