We assessed the effect of the addition of pioglitazone on metabolic control and heart function of patients with type 2 diabetes already receiving sulfonylurea plus metformin. Forty-four patients were given 30 mg of pioglitazone for 3 months. Physical examination, laboratory tests including N-terminal pro-brain natriuretic peptide (NT-proBNP), and echocardiography, were performed at baseline and at study completion. Target HbA(1c) levels were achieved by 44.2% of the patients. Pioglitazone ameliorated lipid profile and lowered liver enzymes and C-reactive protein. Significant increases in NT-proBNP by 39% (P < 0.005) were noticed, but echocardiographic parameters were not altered, even in high-risk subgroups (patients older than 60 years, with diabetes for more than 10 years, with hypertension, with elevated baseline NT-proBNP levels, with left ventricular hypertrophy). In patients with a greater than 60% increase in NT-proBNP levels, a significant increase in left ventricular ejection fraction (P < 0.05) and in fractional shortening (P < 0.05) was found. None of the patients developed edema or signs or symptoms of heart failure. Triple oral combination antidiabetic treatment is an effective therapeutic strategy and weight gain does not abrogate its beneficial actions. Pioglitazone does not affect heart function and even though it increases NT-proBNP, this appears to represent a reaction to volume overload.