Abstract
BackgroundIn a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. As clinical development of sitagliptin continues, additional studies have been completed, and more patients have been exposed to sitagliptin. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies.MethodsThe present analysis included data from 10,246 patients with type 2 diabetes who received either sitagliptin 100 mg/day (N = 5,429; sitagliptin group) or a comparator agent (placebo or an active comparator) (N = 4,817; non-exposed group). The 19 studies from which this pooled population was drawn represent the double-blind, randomized studies 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 July 2009. These 19 studies assessed sitagliptin 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 rosiglitazone + metformin). Patients in the non-exposed group were taking placebo, metformin, pioglitazone, a sulfonylurea ± metformin, insulin ± metformin, or rosiglitazone + metformin. The analysis used patient-level data from each study to evaluate between-group differences in the exposure-adjusted incidence rates of adverse events.ResultsSummary measures of overall adverse events were similar in the sitagliptin and non-exposed groups, except for an increased incidence of drug-related adverse events in the non-exposed group. Incidence rates of specific adverse events were also generally similar between the two groups, except for increased 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 constipation in the sitagliptin group. Treatment with sitagliptin was not associated with an increased risk of major adverse cardiovascular events.ConclusionsIn this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration.
Highlights
In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents
Endpoints of particular interest regarding the safety of medications used in patients with type 2 diabetes were evaluated in greater detail, as were adverse events potentially related to the mechanism of action of specific antihyperglycemic agents (AHAs), and events postulated to be potentially related to inhibition of the DPP-4 enzyme [8,9,10]
To further explore the small between-group difference in the incidence rate for the residual, non-malignant adverse events overall within the Neoplasms System Organ Class (SOC), analyses were conducted in the following additional populations: (1) a broader patient population (N = 6748 and 4855 patients in the sitagliptin and non-exposed groups, respectively) consisting of the primary population plus patients dosed with sitagliptin other than 100 mg daily (i.e., 12.5, 50, and 200 mg daily) or comparator, including patients with renal insufficiency who were randomized to receive dose-adjusted sitagliptin or comparator, and (2) the subset of this broader patient population randomized to receive the higher dose of sitagliptin (200 mg once daily; N = 456) or comparator (N = 363) for up to 1 year. These analyses showed results similar to those observed in the primary analysis, with between-group differences in the overall incidence rate for the residual non-malignant adverse events within the Neoplasms SOC of 0.7 (0.3, 1.2) and 0.6 (-2.6, 3.4) for the broader population and the sitagliptin 200-mg population, respectively
Summary
In a previous pooled analysis of 12 double-blind clinical studies that included data on 6,139 patients with type 2 diabetes, treatment with sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, was shown to be generally well tolerated compared with treatment with control agents. The purpose of the present analysis is to update the safety and tolerability assessment of sitagliptin by pooling data from 19 double-blind clinical studies. The safety and tolerability of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, were found to be generally comparable to non-sitagliptin treatments in a pooled analysis of 12 double-blind, randomized, controlled studies comprising data on 6,139 patients with type 2 diabetes. Studies that included 10,246 patients with type 2 diabetes. Endpoints of particular interest regarding the safety of medications used in patients with type 2 diabetes (e.g., cardiovascular adverse events [2] and adverse events of malignancy [3]) were evaluated in greater detail, as were adverse events potentially related to the mechanism of action of specific antihyperglycemic agents (AHAs) (e.g., hypoglycemia, gastrointestinal intolerance, bone fractures [4,5,6,7]), and events postulated to be potentially related to inhibition of the DPP-4 enzyme [8,9,10]
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