-
[show abstract]
[hide abstract]
ABSTRACT: Abstract
Background
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. 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.
Methods
The 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.
Results
Summary 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.
Conclusions
In 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.
BMC Endocrine Disorders. 01/2010;
-
Mai A Elobeid,
Miguel A Padilla,
Theresa McVie,
Olivia Thomas,
David W Brock, Bret Musser,
Kaifeng Lu,
Christopher S Coffey,
Renee A Desmond,
Marie-Pierre St-Onge,
Kishore M Gadde,
Steven B Heymsfield,
David B Allison
[show abstract]
[hide abstract]
ABSTRACT: Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods.
We searched PubMed and Cochrane databases (2000-2006) for articles published in English and manually searched bibliographic references. Articles of pharmaceutical randomized controlled trials with weight loss or weight gain prevention as major endpoints were included. Two authors independently reviewed each publication for inclusion. 121 articles met the inclusion criteria. Two authors independently extracted treatment, sample size, drop-out rates, study duration, and statistical method used to handle missing data from all articles and resolved disagreements by consensus. In the meta-analysis, drop-out rates were substantial with the survival (non-dropout) rates being approximated by an exponential decay curve (e(-lambdat)) where lambda was estimated to be .0088 (95% bootstrap confidence interval: .0076 to .0100) and t represents time in weeks. The estimated drop-out rate at 1 year was 37%. Most studies used last observation carried forward as the primary analytic method to handle missing data. We also obtained 12 raw obesity randomized controlled trial datasets for empirical analyses. Analyses of raw randomized controlled trial data suggested that both mixed models and multiple imputation performed well, but that multiple imputation may be more robust when missing data are extensive.
Our analysis offers an equation for predictions of dropout rates useful for future study planning. Our raw data analyses suggests that multiple imputation is better than other methods for handling missing data in obesity randomized controlled trials, followed closely by mixed models. We suggest these methods supplant last observation carried forward as the primary method of analysis.
PLoS ONE 02/2009; 4(8):e6624. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
For 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.
In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.
BMC Endocrine Disorders 11/2008; 8:14. · 2.16 Impact Factor
-
Ngozi Erondu,
Carol Addy,
Kaifeng Lu,
Madhuja Mallick, Bret Musser,
Ira Gantz,
Joseph Proietto,
Arne Astrup,
Søren Toubro,
Aila M Rissannen,
Serena Tonstad,
William G Haynes,
Keith M Gottesdiener,
Keith D Kaufman,
John M Amatruda,
Steven B Heymsfield
[show abstract]
[hide abstract]
ABSTRACT: Central counter-regulatory mechanisms, including those related to the orexigenic hormone neuropeptide Y (NPY), may limit the weight loss observed with conventional pharmacological monotherapy. This study evaluated whether blockade of the NPY Y5 receptor (NPY5R) with the selective antagonist MK-0557 potentiates sibutramine and orlistat weight loss effects.
Obese patients (497, BMI 30 to 43 kg/m2) were randomized to 1 of 5 treatment arms [placebo, n = 101; sibutramine 10 mg/d, n = 100; MK-0557 1 mg/d plus sibutramine 10 mg/d, n = 98; orlistat 120 mg TID, n = 99; MK-0557 1 mg/d plus orlistat 120 mg TID, n = 99] in conjunction with a hypocaloric diet for 24 weeks. The all-patients-treated population, imputing missing data using last observation carried forward, was used to assess weight loss from baseline.
The study was completed by 71% of patients in placebo, 76% in sibutramine alone, 79% in MK-0557 + sibutramine, 69% in orlistat alone, and 76% in MK-0557 + orlistat groups. Least squares (LS) mean difference [95% confidence interval (CI)] in weight change from baseline between MK-0557 + sibutramine and sibutramine alone was -0.1 (-1.6, 1.4) kg (p = 0.892) and between MK-0557 + orlistat and orlistat alone was -0.9 (-2.4, 0.6) kg (p = 0.250). Sibutramine alone induced a LS mean weight loss of -5.9 (-6.9, -4.9) kg vs. -4.6 (-5.7, -3.6) kg for orlistat (p = 0.097). There were no serious drug-related adverse events and MK-0557 was well tolerated.
Blockade of the NPY5R with the potent antagonist MK-0557 did not significantly increase the weight loss efficacy of either orlistat or sibutramine monotherapy.
Obesity 09/2007; 15(8):2027-42. · 4.28 Impact Factor
-
Ira Gantz,
Ngozi Erondu,
Madhuja Mallick, Bret Musser,
Rajesh Krishna,
Wesley K Tanaka,
Karen Snyder,
Cathy Stevens,
Mark A Stroh,
Haiyuan Zhu,
John A Wagner,
Douglas J Macneil,
Steven B Heymsfield,
John M Amatruda
[show abstract]
[hide abstract]
ABSTRACT: The gastrointestinal peptide hormone, peptide YY(3-36) (PYY(3-36)), is implicated to be a postprandial satiety factor.
The aim of this study is to assess the safety, tolerability, and efficacy of intranasal PYY(3-36) to induce weight loss in obese patients.
The study was designed as a randomized, 2-wk, single-blind placebo run-in followed by a 12-wk double-blind, placebo-controlled treatment period.
The study was set within a private and institutional practice.
A total of 133 obese patients (body mass index, 30-43 kg/m(2); age, 18-65 yr) participated in the study.
Placebo or 200- or 600-microg PYY(3-36) was administered as an intranasal spray 20 min before breakfast, lunch, and dinner in conjunction with a hypocaloric diet and exercise.
Body weight was the main outcome measure.
The number of patients completing 12 wk on the drug was 38 of 43 (88%), 31 of 44 (70%), and 12 of 46 (26%) for placebo, 200 microg three times a day (t.i.d.) and 600 microg t.i.d., respectively. In the 600 microg t.i.d. group, 27 of 46 (59%) patients discontinued due to nausea and vomiting. Among all randomized patients who took at least one drug dose and had a postbaseline measurement, the mean body weight change from baseline was -2.8, -3.7, and -1.4 kg for placebo, 200 and 600 microg, respectively. The least squares mean difference (95% confidence interval) between placebo and 200 microg was -0.9 (-2.6, 0.7) kg (P = 0.251). A difference of 2.11 kg was sought. No meaningful inference can be drawn from the few patients who completed the study on 600 microg.
Intranasal PYY(3-36) as administered at these intervention doses and preprandial timing is not efficacious in inducing weight loss in obese patients after 12 wk of treatment.
Journal of Clinical Endocrinology & Metabolism 06/2007; 92(5):1754-7. · 6.50 Impact Factor
-
Ngozi Erondu,
Thomas Wadden,
Ira Gantz, Bret Musser,
Allison Martin Nguyen,
Harold Bays,
George Bray,
Patrick M O'Neil,
Arnaud Basdevant,
Keith D Kaufman,
Steven B Heymsfield,
John M Amatruda
[show abstract]
[hide abstract]
ABSTRACT: To evaluate whether MK-0557, a highly selective, orally administered neuropeptide Y Y5 receptor antagonist, could limit weight regain after very-low-calorie diet (VLCD)-induced weight loss.
We enrolled 502 patients 18 to 65 years of age with a BMI of 30 to 43 kg/m2. Patients were placed on a VLCD (800 kcal/d liquid diet) for 6 weeks. Patients who lost>or=6% of initial body weight (n=359) were randomized to 52 weeks of 1 mg/d MK-0557 or placebo and maintained on a hypocaloric diet (300 kcal below weight maintenance requirements).
In randomized patients, the VLCD was associated with an average weight loss of 9.1 kg. After 12 weeks of double-blind treatment, weight began to gradually increase for both placebo- and MK-0557-treated patients. The mean weight change (95% confidence interval) from baseline at the end of the VLCD to Week 52 was +3.1 (2.1, 4.0) and +1.5 (0.5, 2.4) kg for patients treated with placebo and MK-0557, respectively. The difference of 1.6 kg between the two groups was significant (p=0.014). Secondary endpoints, such as blood pressure, lipid profile, insulin, and leptin, as well as waist circumference and quality-of-life measurements, did not show significant differences between MK-0557 and placebo treatments.
Although the difference in weight regain between placebo- and MK-0557-treated patients was statistically significant, the magnitude of the effect was small and not clinically meaningful. Antagonism of the neuropeptide Y Y5 receptor is not an efficacious treatment strategy for reducing weight regain after VLCD.
Obesity 04/2007; 15(4):895-905. · 4.28 Impact Factor
-
Ngozi Erondu,
Ira Gantz, Bret Musser,
Shailaja Suryawanshi,
Madhuja Mallick,
Carol Addy,
Josee Cote,
George Bray,
Ken Fujioka,
Harold Bays, [......],
Bengt Långström,
Richard J Hargreaves,
H Donald Burns,
Akio Kanatani,
Takehiro Fukami,
Douglas J MacNeil,
Keith M Gottesdiener,
John M Amatruda,
Keith D Kaufman,
Steven B Heymsfield
[show abstract]
[hide abstract]
ABSTRACT: Neuropeptide Y (NPY) is a potent orexigenic neuropeptide, and antagonism of NPY Y1 and NPY Y5 receptors (NPYxR) is considered a potentially important anti-obesity drug target. We tested the hypothesis that blockade of the NPY5R will lead to weight loss in humans using MK-0557, a potent, highly selective, orally active NPY5R antagonist. The initial series of experiments reported herein, including a multiple-dose positron-emission tomography study and a 12 week proof-of concept/dose-ranging study, suggested an optimal MK-0557 dose of 1 mg/day. The hypothesis was then tested in a 52 week, multicenter, randomized, double-blind, placebo-controlled trial involving 1661 overweight and obese patients. Although statistically significant at 52 weeks, the magnitude of induced weight loss was not clinically meaningful. These observations provide the first clinical insight into the human NPY-energy homeostatic pathway and suggest that solely targeting the NPY5R in future drug development programs is unlikely to produce therapeutic efficacy.
Cell Metabolism 11/2006; 4(4):275-82. · 13.67 Impact Factor
-
Mai A Elobeid,
Miguel A Padilla,
Theresa Mcvie,
Olivia Thomas,
David W Brock, Bret Musser,
Kaifeng Lu,
Christopher S Coffey,
Renee A Desmond,
Marie-Pierre St-Onge,
Kishore M Gadde,
Steven B Heymsfield,
David B Allison
[show abstract]
[hide abstract]
ABSTRACT: Background: Dropouts and missing data are nearly-ubiquitous in obesity randomized controlled trails, threatening validity and generalizability of conclusions. Herein, we meta-analytically evaluate the extent of missing data, the frequency with which various analytic methods are employed to accommodate dropouts, and the performance of multiple statistical methods.
