D. Williams-Herman

Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes.

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.

Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency

Objective:  To assess the safety of sitagliptin in patients with type 2 diabetes and moderate [creatinine clearance (CrCl) ≥30 to <50 ml/min] or severe renal insufficiency [CrCl <30 ml/min including patients with end‐stage renal disease (ESRD) on dialysis]. The efficacy of sitagliptin in this patient population was also assessed.

Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis

Recent case reports of acute pancreatitis in patients with type 2 diabetes (T2DM) treated with incretin‐based therapies have triggered interest regarding the possibility of a mechanism‐based association between pancreatitis and glucagon‐like peptide‐1 mimetics or dipeptidyl peptidase‐4 (DPP‐4) inhibitors. The objective of this review was to describe the controlled preclinical and clinical trial data regarding the incidence of pancreatitis with sitagliptin, the first DPP‐4 inhibitor approved for use in patients with T2DM. Tissue samples from multiple animal species treated with sitagliptin for up to 2 years at plasma exposures substantially in excess of human exposure were evaluated to determine whether any potential gross or histomorphological changes suggestive of pancreatitis occurred. Sections were prepared by routine methods, stained with haematoxylin and eosin and examined microscopically. A pooled analysis of 19 controlled clinical trials, comprising 10,246 patients with T2DM treated for up to 2 years, was performed using patient‐level data from each study for the evaluation of clinical and laboratory adverse events. Adverse events were encoded using the Medical Dictionary for Regulatory Activities (MedDRA) version 12.0 system. Incidences of adverse events were adjusted for patient exposure. Tissue samples from preclinical studies in multiple animal species did not reveal any evidence of treatment‐related pancreatitis. The pooled analysis of controlled clinical trials revealed similar incidence rates of pancreatitis in patients treated with sitagliptin compared with those not treated with sitagliptin (0.08 events per 100 patient‐years vs. 0.10 events per 100 patient‐years, respectively). Preclinical and clinical trial data with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with T2DM treated with sitagliptin.

Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study

ABSTRACT Objective: To assess the 54-week efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes and inadequate glycemic control (HbA1c 7.5–11%) on diet and exercise. Methods and materials: This was multinational study conducted at 140 clinical sites in 18 countries. Following an initial 24-week, double-blind, placebo-controlled period, patients entered a double-blind continuation period for an additional 30 weeks. Following the week 24 evaluation, patients remained on their previously assigned active, oral treatments: sitagliptin 50 mg b.i.d. + metformin 1000 mg b.i.d. (S100 + M2000), sitagliptin 50 mg b.i.d. + metformin 500 mg b.i.d. (S100 + M1000), metformin 1000 mg b.i.d. (M2000), metformin 500 mg b.i.d. (M1000), and sitagliptin 100 mg q.d. (S100). Patients initially randomized to placebo were switched to M2000 (designated PBO/M2000) at week 24. This report summarizes the overall safety and tolerability data for the 54-week study and presents efficacy results for patients randomized to continuous treatments who entered the 30-week continuation period. Results: Of the 1091 randomized patients, 906 completed the 24-week placebo-controlled phase and 885 patients continued into the 30-week continuation period (S100 + M2000 n = 161, S100+M1000 n = 160, M2000 n = 153, M1000 n = 147, S100 n = 141, PBO/M2000 n = 123). At baseline, patients included in the efficacy analysis had mean age of 54 years, mean BMI of 32 kg/m2, mean HbA1c of 8.7% (8.5–8.8% across groups), and mean duration of type 2 diabetes of 4 years. At week 54, in the all-patients-treated analysis of continuing patients, least-squares (LS) mean changes in HbA1c from baseline were −1.8% (S100 + M2000), −1.4% (S100 + M1000), −1.3% (M2000), −1.0% (M1000), and −0.8% (S100). The proportions of continuing patients with an HbA1c < 7% at week 54 were 67% (S100 + M2000), 48% (S100 + M1000), 44% (M2000), 25% (M1000), and 23% (S100). For the patients completing treatment through week 54, LS mean changes in HbA1c from baseline were −1.9% (S100 + M2000), −1.7% (S100 + M1000), −1.6% (M2000), −1.2% (M1000), and −1.4% (S100). Glycemic response was generally durable over time across treatments. All treatments improved measures of β-cell function (e.g., HOMA-β, proinsulin/insulin ratio). Mean body weight decreased from baseline in the combination and metformin monotherapy groups and was unchanged from baseline in the sitagliptin monotherapy group. The incidence of hypoglycemia was low (1–3%) across treatment groups. The incidence of gastrointestinal adverse experiences with the co-administration of sitagliptin and metformin was similar to that observed with metformin alone. Limitations: The patient population evaluated in the 54-week efficacy analysis was a population of patients who entered the continuation period without receiving glycemic rescue therapy in the 24-week placebo-controlled period. Because the baseline HbA1c inclusion criteria ranged from 7.5 to 11% and the glycemic rescue criterion was an HbA1c > 8% after week 24, there was a greater likelihood of glycemic rescue in the monotherapy groups; this led to more missing data in the continuation all-patients-treated population(CAPT) analysis and fewer patients contributing to the completers analysis in the monotherapy groups. Conclusions: In this study, initial treatment with sitagliptin, metformin, or the combination therapy of sitagliptin and metformin provided substantial and durable glycemic control, improved markers of β-cell function, and was generally well-tolerated over 54 weeks in patients with type 2 diabetes.

Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes.

Aim: To assess the 104‐week efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy in patients with type 2 diabetes and inadequate glycaemic control (HbA1c 7.5–11%) on diet and exercise.

Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: a randomized, double-blind, non-inferiority trial

Aim: To evaluate the efficacy and safety of adding sitagliptin or glimepiride to the treatment regimen of patients with type 2 diabetes mellitus and inadequate glycaemic control on metformin monotherapy.

Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes

Aim: To compare the efficacy and safety of monotherapy with sitagliptin and metformin in treatment‐naïve patients with type 2 diabetes.

Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes.

Aim: The aetiology of acute pancreatitis (AP) is complex, and many risk factors for AP are shared by patients with type 2 diabetes mellitus (T2DM). However, few have assessed risk factors for AP specifically in T2DM patients.

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

BackgroundSitagliptin, 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.ResultsFor clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed.ConclusionIn patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.

Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial

Abstract Objective: Type 2 diabetes in the elderly is an important and insufficiently studied public health problem. This study evaluated sitagliptin monotherapy in patients with type 2 diabetes aged ≥65 years. Research design and methods: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted at 52 sites in the United States. Patients were treated with once-daily sitagliptin (100 or 50 mg, depending on renal function) or placebo for 24 weeks. Key endpoints included change from baseline in glycated hemoglobin (HbA1c), 2-hour post-meal glucose (2-h PMG) and fasting plasma glucose (FPG) at week 24, and average blood glucose on treatment days 3 and 7. Clinical trial registration: NCT00305604. Results: Among randomized patients (N = 206), mean age was 72 years and mean baseline HbA1c was 7.8%. At week 24, HbA1c decreased by 0.7%, 2-h PMG by 61 mg/dL, and FPG by 27 mg/dL in sitagliptin-treated patients compared with placebo (all p < 0.001). On day 3 of treatment, mean average blood glucose was decreased from baseline by 20.4 mg/dL in sitagliptin-treated patients compared with placebo (p < 0.001). In subgroups defined by baseline HbA1c <8.0% (n = 132), ≥8.0% to <9.0% (n = 42), and ≥9.0% (n = 18), the placebo-adjusted reductions in HbA1c with sitagliptin treatment were 0.5%, 0.9%, and 1.6%, respectively. Patients in the sitagliptin and placebo groups had similar rates of adverse events overall (46.1% and 52.9%, respectively); serious adverse events were reported in 6.9% and 13.5%, respectively. No adverse events of hypoglycemia were reported. Potential study limitations include a relatively small number of patients with more severe hyperglycemia (HbA1c ≥9.0%) and the exclusion of patients with severe renal insufficiency. Conclusion: In this study, sitagliptin treatment significantly and rapidly improved glycemic measures and was well tolerated in patients aged ≥65 years with type 2 diabetes.