Improvement in glycaemic control with rosiglitazone/metformin fixed-dose combination therapy in patients with type 2 diabetes with very poor glycaemic control

Objective: Traditional first-line intervention in patients with type 2 diabetes and very poor glycaemic control is insulin therapy or high doses of sulfonylureas if there is no evidence of volume depletion. This study explored the safety and efficacy of open-label treatment with rosiglitazone and metformin (RSG/MET) fixed-dose combination therapy (AVANDAMET) in patients with type 2 diabetes with very poor glycaemic control, to better characterize the magnitude of glycated haemoglobin (A1c) reduction after 24 weeks of therapy. Methods: In this multicentre, open-label trial, 190 patients with an A1c greater than 11% or fasting plasma glucose (FPG) greater than 15 mmol/l were included after failing to meet glycaemic entry criteria for a primary double-blind, controlled, randomized study. Unless tolerability issues arose, eligible patients initiated RSG/MET 4 mg/1000 mg fixed-dose combination therapy and were up-titrated in increments of 2 mg/500 mg at 4-week intervals to a daily dose of 8 mg/2000 mg or the maximum tolerated dose. Patients were assessed for efficacy and safety at five visits over a 24-week period. The primary efficacy end point was change from baseline in A1c at week 24. Secondary efficacy end points included the proportion of patients achieving defined A1c targets, change from baseline to week 24 in FPG and insulin sensitivity. Results: The majority of patients (78%) completed 24 weeks of open-label treatment. At week 24, clinically significant mean reduction in A1c from 11.8 to 7.8% (mean reduction, 4.0 +/- 2.2%; p < 0.0001) and mean FPG reduction from 16.9 to 9.2 mmol/l (mean reduction, 7.7 +/- 4.4 mmol/l; p < 0.0001) were observed. A clinically significant reduction in FPG (5.2 mmol/l) was observed after 4 weeks of treatment with RSG/MET fixed-dose combination therapy. Despite a high mean baseline A1c of 11.8%, 33% of patients achieved treatment goal of A1c less than or equal to 6.5% at week 24, and 44% achieved an A1c less than 7% at week 24. RSG/MET fixed-dose combination was well tolerated, with a low incidence of hypoglycaemia (2%) and mean increase in weight from baseline of 2.6 +/- 5.2 kg, and few patients withdrew (2.6%) because of an adverse event. Conclusions: RSG/MET fixed-dose combination therapy was effective as initial therapy in patients with type 2 diabetes and very high levels of A1c and/or FPG, as demonstrated by robust and relatively rapid improvements in glycaemic control. RSG/MET fixed-dose combination was well tolerated as first-line therapy with no new tolerability issues identified.