Tolerability of saxagliptin in patients with inadequately controlled type 2 diabetes: results from 6 phase III studies.
BACKGROUND
Oral antihyperglycemic drugs used to treat type 2 diabetes mellitus (T2DM) vary in safety and tolerability. Treatment-related hypoglycemia and weight gain can exacerbate underlying disease.


OBJECTIVE
To evaluate the tolerability of saxagliptin using data from phase III clinical trials.


METHODS
Six 24-week randomized studies in 4,214 patients with T2DM were assessed. Saxagliptin 2.5 mg or 5 mg was compared with placebo in 2 trials of monotherapy in treatment-naïve patients and in 3 trials of add-on therapy to metformin, glyburide, or a thiazolidinedione; initial combination therapy with saxagliptin 5 mg plus metformin was compared with metformin monotherapy in treatment-naïve patients. Data from the monotherapy and add-on studies were pooled; data from the initial combination study were analyzed separately. No statistical analyses of between-group comparisons across studies were conducted for these safety analyses because of multiplicity of end points and relative lack of statistical power and because small differences not reaching statistical significance have the potential to be clinically relevant.


RESULTS
In the pooled analysis, incidence rates for adverse events (AEs) with saxagliptin 2.5 mg, 5 mg, and placebo were 72.0% (635/882), 72.2% (637/882), and 70.6% (564/799), respectively; rates for serious AEs (SAEs) were 3.5% (31/882), 3.4% (30/882), and 3.4% (27/799); rates of discontinuation due to AEs were 2.2% (19/882), 3.3% (29/882), and 1.8% (14/799). AEs reported in ≥ 2% of patients receiving saxagliptin and occurring ≥ 1% more frequently with saxagliptin than with placebo were sinusitis, gastroenteritis, abdominal pain, and vomiting. In the initial combination study, AE incidence rates with saxagliptin 5 mg plus metformin and metformin monotherapy were 55.3% (177/320) and 58.5% (192/328), respectively; incidence rates for SAEs were 2.5% (8/320) and 2.4% (8/328); and rates of discontinuation due to AEs were 2.5% (8/320) and 3.4% (11/328).


CONCLUSIONS
Saxagliptin 2.5 mg or 5 mg was generally well tolerated as monotherapy, add-on combination therapy with other oral antihyperglycemic drugs, and initial combination with metformin.
The University of Texas Southwestern Medical Center, 323 Harry Hines Blvd., K5.246, Dallas, TX 75390-4854, USA. jaime.davidson@UTSouthwestern.edu.
Jaime A
JA
Davidson
D000218:Adamantane / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D017326:Clinical Trials, Phase III as Topic; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D004151:Dipeptides / Q000008:administration & dosage / Q000009:adverse effects* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced / Q000453:epidemiology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
D004151:Dipeptides; D007004:Hypoglycemic Agents; C502994:saxagliptin; D000218:Adamantane