title: Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus.
abstract: BACKGROUND
  Some conventional therapies for type 2 diabetes mellitus (T2DM) fail to address the progressive nature of the disease, and as a result, they may become ineffective in maintaining normoglycemia. Antihyperglycemic agents have been developed to target incretin hormones, specifically glucagon-like peptide (GLP)-1. Incretin analogues and agents that delay GLP-1 degradation, the dipeptidyl peptidase (DPP)-4 inhibitors, offer mechanisms of action that may improve T2DM management. Saxagliptin was approved by the US Food and Drug Administration in July 2009 and by the European Medicines Evaluation Agency in October 2009 for use as monotherapy or in combination regimens for the treatment of T2DM.
  
  
  OBJECTIVE
  The aim of this article was to review the mechanism of action, pharmacology, clinical efficacy, and tolerability associated with the use of saxagliptin in patients with T2DM.
  
  
  METHODS
  MEDLINE, BIOSIS, International Pharmaceutical Abstracts, and Google Scholar were searched for English-only clinical trials and therapeutic reviews published between 1966 and June 15, 2011 (search term: saxagliptin). Additional trials and reviews were identified from the reference lists of published articles.
  
  
  RESULTS
  Findings on efficacy and tolerability were obtained from 11 completed Phase III clinical trials. In trials in saxagliptin-naive patients, changes from baseline in glycosylated hemoglobin (HbA(1c)) ranged from -0.72% to -0.90% in the saxagliptin treatment arms compared with -0.27% with placebo (all, P < 0.007). When saxagliptin was used in combination with metformin for 24 weeks, the adjusted mean reductions from baseline in HbA(1c) and the proportions of patients achieving target HbA(1c) (<7.0%) were significantly greater with saxagliptin + metformin compared with monotherapy with either drug (all, P ≤ 0.0001). When saxagliptin was used in combination with a sulfonylurea or a thiazolidinedione, the changes in HbA(1c) ranged from -0.54% to -0.64% and -0.66% to -0.94%, respectively, in a dose-dependent manner (P ≤ 0.0007 vs monotherapies). Based on changes in HbA(1c), saxagliptin + metformin was reported to be noninferior to sitagliptin + metformin (-0.52% and -0.62%, respectively; difference, 0.09% [95% CI, -0.01% to 0.20%]). Saxagliptin was reported to have been well tolerated, with the most common adverse events being upper respiratory infection, urinary tract infection, headache, and nasopharyngitis. A systematic review of cardiovascular events in pooled trial results of saxagliptin use reported no increased cardiovascular risk compared with metformin, glyburide, or placebo (relative risk, 0.24 [0.09-0.63]).
  
  
  CONCLUSIONS
  Saxagliptin, used as monotherapy and in combination regimens, has been associated with significant reductions in HbA(1c) and significant increases in the rate of achieving target HbA(1c) in patients with T2DM. It has been reported to be well tolerated compared with other oral antihyperglycemic agents. Based on the findings from the studies in this review, the primary role of saxagliptin is expected to be in combination therapy with other antihyperglycemic agents.
authors.affiliation: Purdue University, College of Pharmacy, Indianapolis, Indiana, USA. deanna.kania@va.gov
authors.forename: Deanna S
authors.initials: DS
authors.lastname: Kania
authors.forename: Jasmine D
authors.initials: JD
authors.lastname: Gonzalvo
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Weber
mesh_terms: D000218:Adamantane / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004151:Dipeptides / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006442:Glycated Hemoglobin / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000218:Adamantane; D004151:Dipeptides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; C502994:saxagliptin