Linagliptin/Metformin Fixed-Dose Combination Treatment: A Dual Attack to Type 2 Diabetes Pathophysiology

Combination therapies are a widely accepted approach to type 2 diabetes treatment, considering that monotherapies fail to provide adequate glycemic control in the majority of cases. The combination of oral antidiabetic agents into a single tablet would significantly simplify the therapeutic regimen and maximize patients’ adherence to treatment. Recently, a fixed-dose, single-tablet, combined formulation of linagliptin (a dipeptidyl peptidase-4 inhibitor) and metformin has been approved for use in type 2 diabetic patients, and is indicated as an adjunct to diet and exercise for those patients who remain inadequately controlled despite maximal tolerated doses of metformin, metformin and sulfonylurea, or linagliptin and metformin monotherapies. The combination tablet is administered twice daily and can be used either alone or combined with sulfonylureas. Clinical trials suggest that this fixed-dose combination provides significantly superior glycemic control compared to linagliptin and metformin monotherapy, in terms of improving key parameters of glucose homeostasis such as glycosylated hemoglobin, fasting and postprandial glucose levels. It also exhibits an excellent tolerability profile, without promoting weight gain and hypoglycemic episodes. The compounds of this formulation do not display clinically relevant pharmacokinetic interactions with each other, and exert synergistic (complementary) pharmacodynamic effects, including an enhanced incretin effect, suppressed hepatic glucose production, and improved peripheral insulin sensitivity. As a result, a linagliptin/metformin fixeddose combination offers the potential to address multiple defects of type 2 diabetes pathophysiology (pancreatic islet dysfunction, insulin resistance, increased hepatic glucose output), and most importantly, in the context of a safe, efficacious, flexible, and convenient therapeutic regimen.