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INTRODUCTION: Ertugliflozin is a sodium-glucose cotransporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The safety and efficacy of ertugliflozin were evaluated over 52 weeks in patients with chronic kidney disease (CKD). METHODS: In this double-blind randomized study (NCT01986855), patients with glycated hemoglobin (A1C) 7.0-10.5% and stage 3 CKD [estimated glomerular filtration rate (eGFR) ≥ 30 to < 60 mL/min/1.73 m2] who were undergoing treatment with standard diabetes therapy (or therapies) including insulin and/or sulfonylureas were randomized to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Patients on metformin underwent a pre-randomization ≥ 10-week wash-off period. The primary endpoint was change from baseline in A1C at week 26 in the overall cohort. Secondary efficacy endpoints were assessed in the stage 3A CKD cohort (eGFR ≥ 45 to < 60 mL/min/1.73 m2) at weeks 26 and 52. Safety was assessed in the overall cohort. RESULTS: 468 patients were randomized (baseline mean A1C 8.2%). At week 26, reductions from baseline in A1C were observed across groups in the overall cohort [least squares mean changes (95% confidence interval) - 0.3% (- 0.4, - 0.1), - 0.3% (- 0.4, - 0.1), and - 0.4% (- 0.6, - 0.3) for placebo and for ertugliflozin 5 mg and 15 mg, respectively]. Prohibited use of metformin was identified in ~ 17% of patients and impacted evaluation of the primary endpoint. Greater reductions from baseline in body weight, fasting plasma glucose, and systolic blood pressure were observed with ertugliflozin versus placebo at week 26 (stage 3A CKD cohort). The incidences of urinary tract infections, genital mycotic infections, and hypoglycemia adverse events were not meaningfully different between groups. The incidence of hypovolemia-related adverse events was higher with ertugliflozin relative to placebo. CONCLUSION: Although surreptitious metformin use impacted the primary analysis, reductions in blood glucose and body weight were observed with ertugliflozin in patients with T2DM and stage 3 CKD; ertugliflozin had an acceptable safety profile. FUNDING: Merck Sharp & Dohme Corp. a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Pfizer Inc. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT01986855.
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INTRODUCTION: In a previous pooled analysis of 19 double-blind clinical studies conducted by Merck, which included data available as of July 2009 on 10,246 patients with type 2 diabetes (T2DM), treatment with sitagliptin was shown to be generally well tolerated compared with treatment with control agents. As the sitagliptin clinical development program continues, additional studies with sitagliptin have been completed. The present analysis updates the safety and tolerability assessment of sitagliptin by examining pooled data from 25 double-blind clinical studies. METHODS: The present analysis included data from 14,611 patients in 25 studies with T2DM who received either sitagliptin 100 mg/day (n = 7,726; sitagliptin group) or a comparator agent (n = 6,885; non-exposed group). These studies represent all randomized, double-blind trials conducted by Merck that included patients treated with the usual clinical dose of sitagliptin (100 mg/day) for between 12 weeks and 2 years, and for which results were available as of December 2011. These studies assessed sitagliptin, versus comparator agents, taken as monotherapy, initial combination therapy with metformin or pioglitazone, or as add-on combination therapy with other antihyperglycemic agents (metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or metformin + pioglitazone or rosiglitazone). Patient-level data from each study were used to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events (AEs). RESULTS: Overall incidence rates of AEs and drug-related AEs were higher in the non-exposed group compared with the sitagliptin group. Incidence rates of specific AEs were generally similar between the two groups, except for higher incidence rates of hypoglycemia related to the greater use of a sulfonylurea and diarrhea related to the greater use of metformin in the non-exposed group, and of constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events, malignancy, or pancreatitis. CONCLUSION: In this updated pooled safety analysis of data from 14,611 patients with T2DM, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.