Objectives Most patients eventually become hyperglycaemic on metformin monotherapy. We modelled clinical and economic consequences for such patients of switching to a single-tablet metformin-glibenclamide combination (Glucovance®) or glibenclamide, or increasing metformin dosage. Methods A validated computer simulation model of diabetes projected long-term clinical and cost outcomes for the French setting, using data from a 16-week randomised controlled trial. Results Compared with metformin, Glucovance® 500/2.5 mg or 500/5 mg was associated with increased quality-adjusted life expectancy (0.45 and 0.27 quality-adjusted life-years [QALYs] respectively; base case analysis), reduced direct medical costs (by 3,331 and 2,026) and fewer diabetes-related complications. Compared with glibenclamide, Glucovance® 500/5 mg increased quality-adjusted life expectancy by 0.28 QALYs and reduced direct medical costs by 1,793. Conclusions From a third-party healthcare payer perspective in France, Glucovance® represents a dominant treatment option versus metformin or glibenclamide for patients sub-optimally controlled on metformin monotherapy.