Aim: This study assessed the efficacy and safety of rosiglitazone and metformin (RSG/MET) fixed-dose combination (AVANDAMET) as initial therapy in patients with uncontrolled type 2 diabetes compared with monotherapy with either RSG or MET after 32 weeks of treatment.
Methods: A total of 468 drug-naive patients with uncontrolled type 2 diabetes were recruited for this multicentre, double-blind trial if their glycated haemoglobin (A1c) was greater than 7.5%, but less than or equal to 11%, and their fasting plasma glucose (FPG) was less than or equal to 15 mmol/l. Patients were randomized to 32 weeks of blinded treatment with either RSG/MET fixed-dose combination (n = 155), MET (n = 154) or RSG (n = 159). The groups were comparable at baseline, with mean A1c of 8.8% and FPG of 11 mmol/l. RSG/MET was initiated with a total daily dose of 2 mg/500 mg and could be increased up to 8 mg/2000 mg; MET therapy began with a total daily dose of 500 mg and could be increased up to 2000 mg; and RSG treatment began with a total daily dose of 4 mg and could be increased up to 8 mg. Medication was uptitrated during on-therapy visits based on failure to attain glycaemic target of mean daily glucose less than or equal to 6.1 mmol/l (unless at maximum tolerated dose). Patients were assessed for efficacy and safety at nine visits over a 32-week treatment period. This was a trial designed to show greater efficacy of RSG/MET combination therapy compared with MET or RSG monotherapy. The primary end point was change in A1c from baseline to week 32. Secondary end points included the proportion of patients achieving recommended A1c and FPG targets for glycaemic control and change from baseline in FPG, free fatty acid, lipids, insulin, insulin sensitivity, C-reactive protein and adiponectin. Safety evaluations included adverse-event (AE) monitoring, changes in weight and clinical laboratory evaluations.
Results: At week 32, RSG/MET showed significant improvements in A1c from a baseline of 8.9 +/- 1.1% to 6.6 +/- 1.0% at study end, and this 2.3% reduction was significantly greater than the reductions achieved individually with MET (-1.8%; p = 0.0008) and RSG (-1.6%; p < 0.0001). The greatest mean decrease in FPG was seen with RSG/MET (-4.1 mmol/l) and was significant compared with MET (-2.8 mmol/l; p < 0.0001) and RSG (-2.6 mmol/l; p < 0.0001). Target A1c of less than or equal to 6.5% and less than 7% were achieved in more patients in the RSG/MET group (60% and 77%) than with MET (39% and 57%) or RSG (35% and 58%) respectively. Treatment was well tolerated, with nausea, vomiting and diarrhoea as the most commonly reported AEs. Oedema was comparable between RSG/MET (6%) and RSG (7%) and lower in the MET group (3%). No new safety and tolerability issues were observed in the RSG/MET group.
Conclusions: As first-line therapy in patients with uncontrolled type 2 diabetes, RSG/MET fixed-dose combination therapy achieved significant reductions in A1c and FPG compared with either RSG or MET monotherapy. RSG/MET was generally well tolerated as initial therapy, with no new tolerability issues identified with the fixed-dose combination.