Comparison of Fixed-dose Rosiglitazone/Metformin Combination Therapy with Sulphonylurea Plus Metformin in Overweight Individuals with Type 2 Diabetes Inadequately Controlled on Metformin Alone

Abstract

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 (≥0.85 g/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 (4 mg/day; RSG+MET [N=294]) or a sulphonylurea (glibenclamide 5 mg/day or gliclazide 80 mg/day; SU+MET [N=302]). Medications were up-titrated to maximum tolerated doses (rosiglitazone 8 mg, glibenclamide 15 mg or gliclazide 320 mg plus metformin 2 g/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 (ΔHbA_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 β-cell function including proinsulin:insulin ratio. The degree of β-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 β-cell function suggest that the improvements in glycaemic control may be better maintained in long-term therapy with the rosiglitazone/metformin combination.

type 2 diabetes mellitus - rosiglitazone - sulphonylureas - glycaemic control - hypoglycaemia

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