Clinical Medicine Reviews in Vascular Health

Background: Combination oral glucose-lowering drug therapy is often required to maintain glycemic control in patients with type 2 diabetes. Single-tablet fixed-dose combinations of oral glucose-lowering agents provide one means to increase adherence, which may improve metabolic and clinical outcomes. A new fixed-dose combination of pioglitazone and extended-release metformin has recently been approved in the US in dosage strengths of 15 mg/1000 mg and 30 mg/1000 mg.

Aims: To review the clinical pharmacokinetics, efficacy and safety of the fixed-dose combination of pioglitazone and extended-release metformin, and to discuss the rationale behind its development.

Data Sources: English-language articles from PubMed (without date restriction) using key words pioglitazone, metformin, extended- release and fixed-dose combination. Additional sources included published conference abstracts and US prescribing information.

Results: The efficacy and safety/tolerability of pioglitazone and immediate-release metformin as dual therapy have been established in randomized controlled trials. This combination provides durable glycemic control over 2 years and is associated with a low risk of hypoglycemia. Individually, both drugs have evidence for macrovascular benefits. Potential drawbacks include weight gain and edema with pioglitazone and gastrointestinal disturbances with metformin. Published clinical data regarding the specific combination of pioglitazone and extended-release metformin (either as fixed-dose combination or dual therapy) remain scarce. However, bioequivalence between fixed-dose combination and dual therapy has been demonstrated, and studies have confirmed equivalence between extended-release metformin and immediate-release metformin in terms of drug exposure and efficacy/safety. The clinical efficacy/safety profile of the fixed-dose combination of pioglitazone and extended-release metformin can thus be extrapolated from dual therapy studies using immediate-release metformin.

Conclusion: The fixed-dose combination of pioglitazone and extended-release metformin provides a new option when implementing therapy with a well-characterized oral agent combination. As it requires only once-daily dosing with one or two tablets, it may be particularly appropriate for patients in whom adherence is a concern.