Saxagliptin and its active metabolite M2 are dipeptidyl peptidase-4 inhibitors that improve glycaemic control by preventing the inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This increases GLP-1 levels, stimulates insulin secretion and reduces postprandial glucagon and glucose levels. In well designed, 24-week trials in treatment-naive patients with type 2 diabetes mellitus, monotherapy with oral saxagliptin 2.5 or 5 mg once daily significantly improved glycaemic control, as measured by mean glycosylated haemoglobin (HbA(1c)) levels, relative to placebo. In large, well designed, 24-week trials, combination therapy with saxagliptin 5 mg once daily plus metformin significantly improved HbA(1c) levels relative to single-agent saxagliptin or metformin in treatment-naive patients; in treatment-experienced patients with inadequate glycaemic control, the addition of saxagliptin 2.5 or 5 mg once daily to metformin, glyburide or a thiazolidinedione, significantly improved HbA(1c) levels relative to continued use of existing monotherapy. Saxagliptin as monotherapy or in combination with other oral antihyperglycaemics was generally well tolerated, with most adverse events being of mild to moderate severity. In clinical trials, the incidence of hypoglycaemic events in patients receiving saxagliptin was generally similar to that in patients receiving placebo or other oral antihyperglycaemic agents. Saxagliptin therapy was not associated with an increased risk of cardiovascular events according to pooled data from eight clinical trials. Saxagliptin generally had a weight-neutral effect.
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