Evolving metformin treatment strategies in type-2 diabetes: from immediate-release metformin monotherapy to extended-release combination therapy.

Over the last 40 years, metformin has revolutionized the treatment of type-2 diabetes worldwide and is still the most influential oral antidiabetic drug today. International guidelines now recommend that patients with type-2 diabetes are started on metformin therapy as soon as they are diagnosed, as it has been shown to improve long-term clinical outcomes compared with initial management with diet alone, without increasing the risk of developing hypoglycemia or weight gain. The older, immediate-release formulation of metformin does have some limitations, with incidence of gastrointestinal adverse effects restricting the dose in some patients, forming a barrier to treatment adherence, and subsequent glycemic control. However, the second-generation extended-release formulation (met XR) has the potential to overcome these challenges. In this review, we provide an overview of the evidence supporting the use of metformin as the first-line gold standard for type-2 diabetes management and the expansion of its potential roles for the future. We also consider the advantages of met XR, in terms of its tolerability and convenient dose regimen, and review therapeutic options for when disease progression inevitably leads to inadequate control with monotherapy. These therapy options include the synergistic potential of combination strategies with met XR and dipeptidyl peptidase 4 inhibitors, a combination that has also been indicated for early-stage use (at diagnosis) as a potential method for preserving β-cell function.