Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis

Abstract

Background: Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences.

Dipeptydil peptidase-4 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials

“…These results are consistent with those of a recent meta-analysis on patient-level data from trials with sitagliptin, which included only a fraction of the studies summarized in the present meta-analysis, and which showed a similar trend toward the increase of risk of nasopharyngitis with the DPP-4 inhibitor, although it failed to reach statistical significance [31]. It should be considered that DPP-4 is involved in the interaction between immune cells and that it could therefore modulate immune responses [32]; however, there is no evidence from mechanistic studies that inhibition of DPP-4 with currently available agents has an immunodepressant effect.…”

“…In fact, DPP-4 inhibitors do not induce any additional risk, in comparison with a placebo, either in monotherapy or in combination with sulphonylureas or insulin. This confirms the results of a recent meta-analysis performed on patientlevel data from randomized clinical trials with sitagliptin [31]. Interestingly, in the only trial performed in insulintreated patients, vildagliptin reduced the incidence of hypoglycemia in comparison with a placebo [20].…”

“…Notably, two of those trials [16,18], although published, did not report those events but since those trials were included in the registration data for drug approval in the US, the information on severe hypoglycemia can be retrieved from the FDA website. Furthermore, episodes of severe hypoglycemia were not considered in a recent meta-analysis of trials with sitagliptin, although a greater number of such events had occurred in comparator groups, which included sulphonylureas [31]. It should also be considered that some of the trials did not report any information on severe hypoglycemia, raising the possibility of a selective reporting bias.…”

Use of DPP-4 inhibitors in type 2 diabetes: focus on sitagliptin

“…52 A meta-analysis has been published in regard to adverse events with sitagliptin in 12 large, doubleblind studies with durations from 18 weeks to 2 years. 70 The meta-analysis comprised a total of 3415 patients treated with sitagliptin (100 mg daily) and 2724 controls, who were treated either with other antihyperglycemic agents or placebo. The overall incidence of adverse events in these studies was 63% in patients given sitagliptin versus 63% in controls, ie, the same degree of total number of events.…”

DPP‐4 inhibitors: their properties and place in treatment

“…5 It should be remembered that acute pancreatitis and biliary disease is more common in type 2 diabetic patients compared with nondiabetic subjects. 6 There are no long-term data on cardiovascular outcomes such as MI and stroke for DPP-4 inhibitors, but…”