Comparison of fixed-dose rosiglitazone/metformin combination therapy with sulphonylurea plus metformin in overweight individuals with type 2 diabetes inadequately controlled on metformin alone

Aim: This 52-week, randomized, double-blind, parallel-group study was designed to compare rosiglitazone/metformin fixed-dose combination therapy with combination sulphonylurea plus metformin therapy in overweight individuals with inadequately controlled type 2 diabetes mellitus. Method: Individuals with inadequate glycaemic control (HbA(1c) >= 7%) while on metformin monotherapy ( >= 0.85g/day) entered a 4-week run-in period during which they received metformin 2 g/day. At the end of the run-in, individuals with fasting plasma glucose >= 7.0 mmol/l were randomized to treatment with metformin (2 g/day) and either rosiglitazone (4mg/day; RSG+MET [N=294]) or a sulphonylurea (glibenclamide 5mg/day or gliclazide 80mg/day; SU + MET [N = 302]). Medications were up-titrated to maximum tolerated doses (rosiglitazone 8 mg, glibenclamide 15mg or gliclazide 320mg plus metformin 2g/day) during the first 12 weeks of double-blind treatment. The primary efficacy end point was the change in HbA(1c) from baseline after 52 weeks of treatment. Results: RSG+MET was non-inferior to SU + MET with respect to changes in HbA(1c) after one year of treatment (Delta HbA(1c)= -0.78% and -0.86%, respectively; treatment difference =0.09%, 95% CI = -0.08, 0.25). The HbA(1c) reductions with RSG + MET, but not SU + MET, were accompanied by significant improvements in measures of P-cell function including proinsulin:insulin ratio. The degree of beta-cell failure was significantly greater with SU + MET compared to RSG +MET as measured by the coefficient of failure (0.543 vs. 0.055 HbA(1c)%/year, respectively, p=0.0002). The proportion of individuals who experienced hypoglycaemic events was significantly (p<0.0001) lower with RSG + MET (6%) than with SU + MET (30%). Diastolic ambulatory blood pressure and cardiovascular biomarkers (high-sensitivity C-reactive protein and plasminogen activator inhibitor-1) were also reduced following one year of treatment with RSG +MET but not SU + MET. Both treatments were generally well tolerated. Conclusion: Fixed-dose combination therapy with rosiglitazone/metformin is non-inferior to sulphonylurea plus metformin combination therapy in reducing HbA(1c) over one year of treatment. Improvements in measures of beta-cell function suggest that the improvements in glycaemic control may be better maintained in long-term therapy with the rosiglitazone/metformin combination.