Saxagliptin: the evidence for its place in the treatment of type 2 diabetes mellitus

Abstract

Introduction: The worldwide prevalence of type 2 diabetes mellitus (T2DM) is high, and the chronically poor metabolic control that can result from T2DM is associated with a high risk for microvascular and macrovascular complications. Because of the progressive pathophysiology of T2DM, oral antidiabetic agents often fail to provide sustained glycemic control, indicating the need for new therapies. Saxagliptin (Onglyza™; Bristol-Myers Squibb Company, Princeton, NJ, USA; AstraZeneca Pharmaceuticals LP, Wilmington, DE, USA) is an oral dipeptidyl peptidase-4 inhibitor, recently approved for the treatment of T2DM.

Evidence review: Saxagliptin significantly improves glycemic control vs placebo, as demonstrated by decreasing glycated hemoglobin, fasting plasma glucose, and postprandial plasma glucose levels when used as monotherapy; in initial combination with metformin; and as add-on therapy with metformin, sulfonylurea (SU), or thiazolidinedione (TZD). Saxagliptin also significantly improves β-cell function, is weight neutral, has a low risk for hypoglycemia, and has been shown to have cardiovascular safety.

Place in therapy: The clinical profile for saxagliptin indicates that it is useful as an adjunct to diet and exercise as first-line monotherapy and in combination with metformin; or as add-on treatment for patients who cannot achieve glycemic control with a combination of diet and lifestyle changes and metformin, SU, or TZD.

Keywords: GLP-1; HbA1c; dipeptidyl peptidase-4 (DPP-4) inhibitor; incretin; saxagliptin.

Figure 1

Evidence base included in the saxagliptin review. Notes: ^aIncludes nonsystematic reviews, letters, editorials, news items, notes, comments, corrections, articles pertaining to other drugs or treatments, and articles on pharmacokinetics and drug interactions. Abbreviation: RCT, randomized-controlled trial.

Figure 2

Mechanism of action of DPP-4 inhibitors. A) action of incretins.– B) action of DPP-4 inhibitors.– Reprinted from Cell Metabolism, Volume 3, Daniel J. Drucker, The biology of incretin hormones, 153–165, March 2006, with permission from Elsevier. Abbreviations: DPP-4, dipeptidyl peptidase-4; GI, gastrointestinal; GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1.

Figure 3

Saxagliptin 5 mg effects on HbA_1c in placebo-controlled and active-controlled comparative studies.–,,, Notes: ^aStatistical significance vs placebo. ^bStatistical significance vs comparator. Abbreviations: HbA_1c, glycated hemoglobin; MET, metformin; QAM, daily before noon; QPM, daily after noon; SU, sulfonylurea; TZD, thiazolidinedione.

Figure 4

Postprandial concentrations during the 3-hour oral glucose tolerance test. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Volume 25 by Rosenstock, et al. © 2009 by Current Medical Research and Opinion. Notes: ^aSample size at 120-minute time point. ^bAdjusted mean change in 120 minute (PPG). ^cP = 0.007 vs PBO. ^dP = 0.0009 vs PBO. ^eP < 0.0001 vs PBO. Abbreviations: PBO, placebo; PPG, postprandial glucose; SAXA, saxagliptin.