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A fixed-dose combination of pioglitazone and metformin:a promising alternative in metabolic control

ABSTRACT Background: When type 2 diabetes is managed with glucose-lowering monotherapy, glycemic control ultimately deteriorates due to the inability of the β-cell to overcome insulin resistance. Combining drugs with different complementary mechanisms of action improves long-term glycemic control and may lower the risk of vascular complications. A fixed-dose combination of pioglitazone (a thiazolidinedione) and metformin has been approved for use in the US (Actoplus met*) and in Europe (Competact†). * ACTOplus met is a registered trademark of Takeda Pharmaceutical Company Limited, Osaka, Japan and used under license by Takeda Pharmaceuticals North America, Inc, Lincolnshire, Illinois, USA † Competact is a registered trademark of Takeda Pharmaceutical Company Limited, Osaka, Japan and marketing authorization has been filed by Takeda Global R&D Centre (Europe) Scope: This review (based upon MEDLINE and EMBASE searches from January 1990 to April 2006) discusses the potential benefits of co-formulating metformin and pioglitazone with respect to compliance and targeting glycemia, as well as other metabolic parameters. Findings: Pioglitazone increases insulin sensitivity, while metformin reduces hepatic gluconeogenesis and improves peripheral glucose uptake. Both agents reduce hyperglycemia and hyperinsulinemia, and appear to protect β‐cell function. Their similar pharmacokinetic time profiles have facilitated a co-formulation bioequivalent to their separate administration. In randomized studies, pioglitazone and metformin administered separately provided significantly better glycemic control than metformin monotherapy or metformin plus gliclazide. Pioglitazone and metformin have complimentary benefits on diabetic dyslipidemia; pioglitazone primarily improves high-density lipoprotein cholesterol and triglyceride levels (to a greater extent than rosiglitazone does), while metformin mainly improves total cholesterol. Pioglitazone and metformin also modulate other atherosclerosis biomarkers, including inflammatory mediators, coagulation thrombosis components, and carotid intima media thickness. Together, these pleiotropic effects have the potential to confer a reduced risk of cardiovascular disease in patients with type 2 diabetes. Pioglitazone and metformin are well tolerated in combination, with low rates of hypoglycemia, and the convenience of a single tablet may be expected to aid dosing compliance. Conclusion: The co-formulation of pioglitazone and metformin is a rational approach that maximizes the established, complimentary benefits of these agents, while potentially improving compliance.