Jenny Han

Bristol-Myers Squibb, New York City, New York, United States

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Publications (18)58.28 Total impact

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    ABSTRACT: The recent type 2 diabetes ADA/EASD position statement suggested insulin is the most effective glucose-lowering therapy, especially when HbA1c is very high. However, randomized studies comparing glucagon-like peptide-1 receptor agonists (GLP-1RAs) exenatide once-weekly (OW; DURATION-3) and liraglutide once-daily (OD; LEAD-5) with insulin glargine documented greater HbA1c reduction with GLP-1RAs, from baseline HbA1c ~8.3% [67 mmol/mol]. This post-hoc analysis of DURATION-3 and LEAD-5 examined changes in HbA1c , fasting glucose and weight with exenatide OW or liraglutide and glargine, by baseline HbA1c quartile.
    Diabetes Obesity and Metabolism 10/2014; · 5.18 Impact Factor
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    ABSTRACT: When patients with type 2 diabetes start their first injectable therapy, clinicians can choose between glucagon-like peptide-1 (GLP-1) receptor agonists and basal insulins. In DURATION-3, exenatide once weekly was compared with insulin glargine (henceforth, glargine) as first injectable therapy. Here, we report the results of the final 3-year follow-up. DURATION-3 was an open-label randomised trial done between May 13, 2008, and Jan 30, 2012. Patients with type 2 diabetes aged 18 years or older were enrolled at 72 sites worldwide. They were eligible when they had suboptimum glycaemic control (HbA1c 7·1-11·0% [54-97 mmol/mol]) despite maximum tolerated doses of metformin alone or with a sulfonylurea for at least 3 months, a stable bodyweight for at least 3 months, and a BMI of 25-45 kg/m(2) (23-45 kg/m(2) in South Korea and Taiwan). Patients were randomly assigned (1:1) by computer-generated random sequence with an interactive voice-response system (block size four, stratified by country and concomitant therapy) to once-weekly exenatide (2 mg subcutaneous injection) or once-daily glargine (titrated to target) to be given in addition to their existing oral glucose-lowering regimens. The primary efficacy measure at 3 years was change in HbA1c from baseline in patients given at least one dose of the assigned drug (ie, analyses by modified intention to treat). Patients, investigators, and data analysts were not masked to treatment assignment. This trial is registered with ClinicalTrials.gov, number NCT00641056. 456 patients underwent randomisation and received at least one dose of the assigned drug (233 given exenatide, 223 glargine). At 3 years, least-squares mean HbA1c change was -1·01% (SE 0·07) in the exenatide group versus -0·81% (0·07) in the glargine group (least-squares mean difference -0·20%, SE 0·10, 95% CI -0·39 to -0·02; p=0·03). Transient gastrointestinal adverse events characteristic of GLP-1 receptor agonists were more frequent with exenatide than glargine (nausea: 36 [15%] of 233 patients vs five [2%] of 223; vomiting: 15 [6%] vs six [3%]; diarrhoea: 32 [14%] vs 15 [7%]), although frequency of these events did decrease after week 26 in the exenatide group. The proportion of patients who reported serious adverse events in the exenatide group (36 patients [15%]) was the same as that in the glargine group (33 [15%]). The exposure-adjusted rate of overall hypoglycaemia was three times higher in patients given glargine (0·9 events per patient per year) than in those given exenatide (0·3 events per patient per year). Efficacy of once-weekly exenatide is sustained for 3 years. GLP-1 receptor agonists could be a viable long-term injectable treatment option in patients with type 2 diabetes who have not yet started taking insulin. Amylin Pharmaceuticals and Eli Lilly.
    The lancet. Diabetes & endocrinology. 04/2014;
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    ABSTRACT: Abstract Background and Objective: In a 30-week, double-blind, randomized, controlled Phase 3 study in patients with type 2 diabetes, the addition of fixed-dose exenatide BID to titrated insulin glargine resulted in significant HbA1c lowering and weight loss without increased hypoglycemia risk versus titrated insulin glargine alone. Because individualized insulin titration contributed to these results, this post-hoc analysis examined the results in context of the degree of insulin titration that occurred. Methods: Subjects on pre-existing insulin glargine (with or without oral antidiabetes agents) were randomized to placebo (n=123) or exenatide BID (n=138; 5 µg for 4 weeks, then 10 µg ongoing). Insulin glargine was titrated in both arms per the Treat-to-Target algorithm. Tertiles (T1, T2, T3) were based on change in insulin dose from baseline to endpoint. Change in HbA1c, hypoglycemia risk, and weight gain were assessed per insulin dose tertile. Results: The population comprised adult patients (mean age = 59 y) with type 2 diabetes and an HbA1c level between 7% and 10.5% (mean HbA1c = 8.4%). Insulin titration ranged from modest reductions in T1 to substantial increases in T3. Greater improvements in HbA1c were demonstrated with exenatide BID versus placebo in all tertiles (statistically significant in T2 and T3). With exenatide BID, more subjects achieved HbA1c <7% vs. placebo: T1, 44% vs. 29% (P=not significant [NS]); T2, 65% vs. 26%; T3, 54% vs. 29% (P<0.05 for T2 and T3). Incidence of hypoglycemia was numerically lower with exenatide BID in all tertiles. Adjunctive exenatide BID was associated with statistically significantly greater weight loss (T1, T2) or mitigation of weight gain (T3) compared with placebo. Rates of nausea (42% vs. 8%), diarrhea (18% vs. 7%) and vomiting (18% vs. 4%) were higher with exenatide BID than with placebo and did not vary by tertile. Conclusions: Addition of fixed-dose exenatide BID to optimized insulin glargine, regardless of the extent of insulin titration, significantly improved glycemia without increasing hypoglycemia risk, while mitigating insulin-induced weight gain in this post-hoc analysis.
    Current Medical Research and Opinion 03/2014; · 2.37 Impact Factor
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    ABSTRACT: Background and Aim: Exenatide is a glucagon-like peptide-1 receptor agonist demonstrated to improve glycemic control with low hypoglycemia risk in patients with type 2 diabetes mellitus. The Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention With Exenatide Once Weekly (DURATION) program comprised 6 randomized, comparator-controlled, 24- to 30-week trials of exenatide once weekly (EQW), an extended-release formulation. This post hoc analysis pooled data from patients taking EQW across 6 trials to assess efficacy and safety in a large, varied patient population. Materials and Methods: The intent-to-treat (ITT) population contained 1379 patients (baseline mean ± standard deviation glycated hemoglobin [HbA1c] levels of 8.4% ± 1.1%) who were treated with EQW over the course of 24 to 30 weeks. Changes from baseline in efficacy parameters for the ITT population and a completer population (1195 patients with ≥ 22 weeks of exposure) were evaluated. Results: The ITT population experienced significant reductions from baseline (least-squares mean [95% CI]) in HbA1c levels (-1.4% [-1.5% to -1.4%]), fasting blood glucose levels (-36 mg/dL [-38.4 mg/dL to -33.8 mg/dL]), and body weight (-2.5 kg [-2.8 kg to -2.3 kg]) after 24 to 30 weeks of EQW treatment. Reductions in HbA1c and fasting blood glucose levels were observed across baseline HbA1c level strata; patients with higher baseline HbA1c levels experienced greater reductions. Treatment with EQW was associated with modest, significant reductions in blood pressure (systolic blood pressure, -2.8 mm Hg [-3.5 mm Hg to -2.1 mm Hg]; diastolic blood pressure, -0.8 mm Hg [-1.2 mm Hg to -0.4 mm Hg]), and fasting lipid levels (total cholesterol, -6.5 mg/dL [-8.2 mg/dL to -4.7 mg/dL]; low-density lipoprotein cholesterol, -3.9 mg/dL [5.3 mg/dL to -2.5 mg/dL]; and triglyceride [geometric least-squares mean percent change (95% CI)], -6% [-8% to -4%] levels). Similar reductions were observed in the completer population. Exenatide once weekly was generally well tolerated. Transient, mild-to-moderate gastrointestinal treatment-emergent adverse events and injection-site treatment-emergent adverse events were reported most frequently, but were seldom treatment limiting. No major hypoglycemic events were observed; minor hypoglycemic events occurred infrequently in patients not using a sulfonylurea. Conclusion: This post hoc analysis of > 1300 patients demonstrated that EQW was associated with significant reductions in HbA1c levels, body weight, blood pressure, and fasting lipid levels, with minimal hypoglycemia risk. Consistent with established safety profiles, EQW therapy was generally well tolerated. Trial registration: www.ClinicalTrials.gov identifiers: NCT00308139, NCT00637273, NCT00641056, NCT00676338, NCT00877890, NCT01029886.
    Postgraduate Medicine 05/2013; 125(3):47-57. · 1.97 Impact Factor
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    ABSTRACT: Aim: Therapies for type 2 diabetes mellitus that leverage the glucagon-like peptide-1 (GLP-1) receptor signaling pathway have been shown to reduce rates of hyperglycemia and have beneficial effects on body weight. This post hoc analysis compared the effects of 2 GLP-1 receptor- based therapies, exenatide once weekly (EQW), a GLP-1 receptor agonist, and sitagliptin (sita), a dipeptidyl peptidase-4 inhibitor, on glucose control across the range of baseline glycated hemoglobin (HbA1c) levels specified in the American Association of Clinical Endocrinologists and American College of Endocrinology treatment algorithm. Materials and Methods: Data from patients treated with either EQW or sita for 26 weeks in 2 randomized, double-blind, comparator-controlled clinical trials were pooled and analyzed. Glycemic endpoints and cardiovascular risk factors were evaluated in subgroups and the overall population. Results: Analysis included 737 patients on background therapies of diet and exercise and/or metformin. While both agents reduced HbA1c and fasting blood glucose (FBG) levels from baseline, significantly greater reductions in HbA1c and FBG levels occurred with EQW compared with sita across all baseline HbA1c level strata, and significantly more patients in the EQW group achieved goal HbA1c levels compared with the sita group. Patients treated with EQW also experienced significantly greater reductions in body weight and cholesterol levels compared with patients treated with sita. The incidences of the most common adverse events of nausea and diarrhea were higher in the EQW group compared with the sita group, and incidences of these adverse events decreased over time. Both groups experienced a low incidence of minor hypoglycemic events.Conclusion:Significantly greater improvements in HbA1c and FBG levels were observed in EQW- compared with sita-treated patients across all baseline HbA1c level strata. Additionally, greater reductions in body weight and some cardiovascular risk factors were observed with EQW treatment compared with sita treatment. Both EQW and sita were generally well tolerated; sita-treated patients experienced fewer adverse events than EQW-treated patients. Trial registration: www.ClinicalTrials.gov identifiers: NCT00637273, NCT00676338.
    Postgraduate Medicine 05/2013; 125(3):58-67. · 1.97 Impact Factor
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    ABSTRACT: BACKGROUND: Diabetes is associated with a higher risk for adverse cardiovascular outcomes. To improve the health outcomes of patients with type 2 diabetes (T2DM), the American Diabetes Association (ADA) recommended target goals for the improvement of glycemic control and the reduction of cardiovascular risk factors associated with the disease. This retrospective analysis calculated the absolute benefit increase (ABI) of using exenatide once weekly (QW), a glucagon-like peptide-1 (GLP-1) receptor agonist, vs an oral glucose-lowering medication or insulin glargine to achieve ADA-recommended goals. The number needed to treat (NNT) to achieve these goals was also calculated and provides a useful clinical metric for comparing potential therapies from different drug classes. METHODS: Patient data from three double-blind or open label, 26-week, randomized, controlled trials were retrospectively analyzed separately. ABI and NNT were calculated by comparing the percentage of patients treated with exenatide QW (N = 641) vs metformin (N = 246), sitagliptin (N = 329), pioglitazone (N = 328), or insulin glargine (N = 223), who achieved a single glycemic, weight, blood pressure, or lipid goal or a composite of these recommended goals, during the DURATION-2, -3, and -4 clinical trials. RESULTS: Significant ABIs favoring exenatide QW over all four glucose-lowering medications were observed for at least one HbA1c glycemic goal. NNTs of 4 and 5 were calculated when exenatide QW was compared to sitagliptin for attaining HbA1c goals of <7.0% and <=6.5%, respectively. Additionally, significantly more patients using exenatide QW compared to sitagliptin, pioglitazone, or insulin glargine attained the composite goal of HbA1c <7% or <=6.5%, without weight gain or hypoglycemia. Exenatide QW was also favored over sitagliptin and insulin glargine for the achievement of the composite goals of HbA1c <7% (or <=6.5%), systolic blood pressure <130 mm Hg, and low-density lipoprotein <2.59 mmol/L. For most goals, exenatide QW and metformin had similar effects in treatment naive patients. CONCLUSIONS: This analysis assessed the between-therapy differences in achieving therapeutic goals with therapies commonly used for glycemic control in patients with T2DM. In clinical trials, exenatide QW assisted more patients in reaching the majority of ADA-recommended therapeutic goals than treatment with sitagliptin, pioglitazone, or insulin glargine.Trial registration: NCT00637273, NCT00641056, NCT00676338.
    Cardiovascular Diabetology 03/2013; 12(1):48. · 4.21 Impact Factor
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    ABSTRACT: AIMS: Exenatide has been demonstrated to improve glycemic control in patients with type 2 diabetes, with no effect on heart-rate corrected QT (QTc) at therapeutic concentrations. This randomized, placebo- and positive-controlled, crossover, thorough QT study evaluated effects of therapeutic and supratherapeutic exenatide concentrations on QTc. METHODS: Intravenous infusion was employed to achieve steady-state supratherapeutic concentrations in healthy subjects within a reasonable duration (i.e., days). Subjects received exenatide, placebo, and moxifloxacin, with ECGs recorded pre-therapy and during treatment. Intravenous exenatide was expected to increase heart rate to a greater extent than subcutaneous twice-daily or once-weekly formulations. To assure proper heart-rate correction, a wide range of baseline heart rates was assessed and prospectively defined methodology was applied to determine the optimal QT correction. RESULTS: Targeted steady-state plasma exenatide concentrations were exceeded (geometric mean±standard error of 253±8.5 pg/mL, 399±11.9 pg/mL, and 627±21.2 pg/mL). QTcP, a population-based method, was identified as the most appropriate heart-rate correction and was prespecified for primary analysis. The upper bound of the 2-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTcP (ΔΔQTcP) was <10 ms at all time points and exenatide concentrations. The mean of 3 measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg/mL (ΔΔQTcP ( avg) ) was -1.13 [-2.11, -0.15). No correlation was observed between ΔΔQTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. CONCLUSIONS: These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provided an example of methodology for QT assessment of drugs with an inherent heart rate effect.
    British Journal of Clinical Pharmacology 08/2012; · 3.69 Impact Factor
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    ABSTRACT: Considerable clinical data on the treatment of type 2 diabetes with incretin-based therapies (glucagon-like peptide 1 receptor agonists [GLP-1RAs] and dipeptidyl-peptidase IV [DPP-4] inhibitors) are available. This meta-analysis was performed to support the understanding of the overall evidence by summarizing the findings from studies of the incretin-based therapies. The MEDLINE, EMBASE, BIOSIS, and BIOSIS trial databases were searched for relevant literature published between January 1, 1990, and June 30, 2011. Search terms included GLP-1, DPP-4, the names of drugs that have been approved by the US Food and Drug Administration for the treatment of diabetes, and the names of drugs that have not been approved but are in late-stage research. Studies were included if they were randomized controlled trials of 12 to 52 weeks' duration and having change from baseline in hemoglobin (Hb) A(1c) as the primary end point. The random effects meta-analyses models examined HbA(1c), fasting plasma glucose (FPG), and body weight for individual therapies, but did not compare effects between therapies. The reviewers identified 362 unique clinical studies, of which 80 were eligible for inclusion in the present meta-analysis. Mean baseline HbA(1c) values ranged from 7.4% to 10.3% (GLP-1RA studies) and 7.2% to 9.3% (DPP-4 inhibitor studies). The highest maintenance doses of the GLP-1RAs and the DPP-4 inhibitors were associated with changes from baseline in mean HbA(1c) of -1.1% to -1.6% and -0.6% to -1.1%, respectively. Mean reductions in FPG with exenatide once weekly (QW) or liraglutide once daily were apparently greater than those with exenatide twice daily (BID) and the DPP-4 inhibitors, with the exception of vildagliptin. Mean weight losses with the GLP-1RAs and the DPP-4 inhibitors were >-2.0 and -0.2 to -0.6 kg, respectively. The limitations of the present analysis included a lack of adjustment for placebo use and interstudy heterogeneity associated with differences in methodology (eg, management of concurrent medications, blinding, criteria for treatment discontinuation). All of the incretin-based therapies in the present meta-analysis were associated with significant reductions from baseline in HbA(1c) and FPG. Further direct comparative studies between the GLP-1RAs and the DPP-4 inhibitors and within the GLP-1RA class are justified.
    Clinical Therapeutics 05/2012; 34(6):1247-1258.e22. · 2.23 Impact Factor
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    ABSTRACT: Studies of the glucagon-like peptide-1 receptor agonists (GLP-1RAs) are needed to determine the durability of metabolic response and tolerability associated with long-term treatment. The present study was conducted to provide long-term data on glycemic control, weight changes, and tolerability of exenatide 10 μg BID treatment in patients with type 2 diabetes mellitus who have failed to achieve glycemic targets with oral antihyperglycemic medication. In this uncontrolled, open-label trial with treatment up to 156 weeks, patients received exenatide 10 μg BID while continuing treatment with metformin and/or a sulfonylurea (SFU). Intent-to-treat (ITT), 52-, 100-, and 132-week completer populations were defined. Metabolic changes were analyzed in the completer and ITT populations; adverse events (AEs) were summarized in the ITT population. Descriptive statistics were used for absolute and change-from-baseline data. Within-treatment comparisons were conducted using the paired t test. Of 155 patients in the ITT population (mean [SD]: age, 59 [9] years; 56% female; duration of diabetes, 9.1 [5.9] years; weight, 88.8 [16.5] kg; body mass index, 31.9 [4.7] kg/m(2); hemoglobin [Hb] A(1c), 8.7% [1.2%]), 133, 111, and 103 patients completed 52, 100, and 132 weeks of treatment, respectively. In the ITT population, the mean (SE) change in HbA(1c) from baseline to week 132 was -1.0% (0.10%) (P < 0.0001). In patients completing 52, 100, and 132 weeks, HbA(1c) changes from baseline to end point were -1.3% (0.10%), -1.0% (0.12%), and -1.0 (0.13%) (P < 0.0001), with 40% of patients achieving HbA(1c) <7% at 132 weeks. Patients in the ITT and completer populations experienced mean (SE) weight changes of -3.7 (0.39) kg and -3.9 (0.51) kg (P < 0.0001) at week 132. Improved glycemic control and weight loss occurred in 63% of patients in the completer population at week 132. In addition, 38% of completers at week 132 achieved HbA(1c) <7% without weight gain. No relationship was found between the development of antiexenatide antibodies and change in HbA(1c). The most common AEs were gastrointestinal in nature, reported in 46% of patients and leading to discontinuation in 7 cases. Serious AEs were reported in 26% of patients, and 18% withdrew due to a treatment-emergent AE. Of 24% of patients in whom hypoglycemia was reported, 22% were on SFU or metformin + SFU combination, and 2% were on metformin. The findings from this open-label, single-arm study characterized the response to exenatide 10 μg BID for up to 132 weeks. Significant, persistent improvements in HbA(1c) and weight were observed in patients receiving exenatide BID, with reported AEs consistent with those from studies of shorter duration. ClinicalTrials.gov identifier: NCT00044668.
    Clinical Therapeutics 05/2012; 34(6):1301-13. · 2.23 Impact Factor
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    ABSTRACT: Patients with type 2 diabetes (T2DM) are at risk of long-term vascular complications. In trials, exenatide once weekly (ExQW), a GLP-1R agonist, improved glycemia, weight, blood pressure (BP), and lipids in patients with T2DM. We simulated potential effects of ExQW on vascular complications, survival, and medical costs over 20 years versus standard therapies. The Archimedes model was used to assess outcomes for ~25,000 virtual patients with T2DM (NHANES 1999-2006 [metformin ± sulfonylureas, age 57 years, body mass index 33 kg/m(2), weight 94 kg, duration T2DM 9 years, hemoglobin A1c [A1C] 8.1%]). The effects of three treatment strategies were modeled and compared to moderate-adherence insulin therapy: advancement to high-adherence insulin at A1C ≥ 8% (treat to target A1C < 7%) and addition of pioglitazone (PIO) or ExQW from simulation start. ExQW effects on A1C, weight, BP, and lipids were modeled from clinical trial data. Costs, inflated to represent 2010 $US, were derived from Medicare data, Drugstore.com, and publications. As ExQW was investigational, we omitted ExQW, PIO, and insulin pharmacy costs. By year 1, ExQW treatment decreased A1C (~1.5%), weight (~2 kg), and systolic BP (~5 mmHg). PIO and high-adherence insulin decreased A1C by ~1%, increased weight, and did not affect systolic BP. After 20 years, A1C was ~7% with all strategies. ExQW decreased rates of cardiovascular and microvascular complications more than PIO or high-adherence insulin versus moderate-adherence insulin. Over 20 years, ExQW treatment resulted in increased quality-adjusted life-years (QALYs) of ~0.3 years/person and cost savings of $469/life-year versus moderate adherence insulin. For PIO or high-adherence insulin, QALYs were virtually unchanged, and costs/life-year versus moderate-adherence insulin increased by $69 and $87, respectively. This long-term simulation demonstrated that ExQW treatment may decrease rates of cardiovascular and some microvascular complications of T2DM. Increased QALYs, and decreased costs were also projected.
    Vascular Health and Risk Management 01/2012; 8:255-64.
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    ABSTRACT: Exenatide twice daily is a first-in-class glucagon-like peptide receptor agonist approved for the treatment of type 2 diabetes. The objective of this analysis was to evaluate the safety profile of exenatide twice daily and to compare its profile with that of a pooled comparator (placebo and insulin) in patients with type 2 diabetes. Data from 19 completed, randomized, controlled clinical trials of exenatide twice daily (5 μg and 10 μg) were pooled and analyzed; the pooled data included 5594 intent-to-treat patients who were followed for 12-52 weeks. Incidence rates, exposure-adjusted incidence rates, and 95% confidence intervals around risk differences between groups were calculated. Baseline demographics and exposure time were comparable between groups (exenatide, N = 3261; pooled comparator, N = 2333; mean exposure time 166-171 days). Transient, mild- to-moderate nausea was the most frequent adverse event with exenatide (36.9% versus 8.3% in the pooled comparator). The incidence of hypoglycemia (minor or major) with concomitant sulfonylurea (exenatide 26.5%, pooled comparator 20.7%) was higher than that without sulfonylurea (exenatide 3.1%, pooled comparator 2.7%) in all groups. Serious adverse events, discontinuations due to serious adverse events, and deaths were reported with similar frequency in the exenatide and pooled comparator groups. Composite exposure-adjusted incidence rates were not statistically different between groups for pancreatitis, renal impairment, or major adverse cardiac events; there was a difference in incidence rates for benign thyroid neoplasm (0.3% versus 0%). Overall, this analysis, representing over 1500 patient-years of exposure, demonstrated that exenatide twice daily was safe and generally well tolerated in patients with type 2 diabetes. The incidence of most adverse events, including serious adverse events, was similar in both exenatide-treated and comparator-treated patients. The most distinct differences between groups were in gastrointestinal-related adverse events, which is consistent with other therapies within the glucagon-like peptide class.
    Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy 01/2012; 5:29-41.
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    ABSTRACT: It is important for patients that treatments for diabetes not increase cardiovascular (CV) risk. The objective of this analysis was to examine retrospectively the CV safety of exenatide BID, a GLP-1 receptor agonist approved for treating hyperglycemia in patients with type 2 diabetes not adequately controlled with diet and exercise. Individual participant data was pooled to assess the relative risk (RR) of CV events with exenatide BID versus a pooled comparator (PC) group treated with either placebo or insulin from 12 controlled, randomized, clinical trials ranging from 12-52 weeks. Mean baseline values for HbA1c (8.33-8.38%), BMI (31.3-31.5 kg/m2), and duration of diabetes (8 y) were similar between groups. Trials included patients with histories of microvascular and/or macrovascular disease. Customized primary major adverse CV events (MACE) included stroke, myocardial infarction, cardiac mortality, acute coronary syndrome, and revascularization procedures. The Primary MACE RR (0.7; 95% CI 0.38, 1.31), calculated by the Mantel-Haenszel method (stratified by study), suggested that exenatide use (vs. PC) did not increase CV risk; this result was consistent across multiple analytic methods. Because the trials were not designed to assess CV outcomes, events were identified retrospectively from a list of preferred terms by physicians blinded to treatment. Other limitations included the low number of CV events, the short duration of trials (≤1 y), and a single active comparator (insulin). The results of these analyses are consistent with those of a recent retrospective analysis of a large insurance database that found that patients treated with exenatide twice daily were less likely to have a CV event than were patients treated with other glucose-lowering therapies.Keywords: GLP-1 receptor agonist, diabetes, cardiovascular safety.
    Cardiovascular Diabetology 03/2011; 10:22. · 4.21 Impact Factor
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    ABSTRACT: The once-weekly (QW) formulation of the glucagon-like peptide-1 receptor agonist exenatide has been demonstrated to improve A1C, fasting plasma glucose (FPG), body weight, serum lipid profiles, and blood pressure in patients with type 2 diabetes through 52 weeks of treatment. In this report, we describe the 2-year results of the open-label, open-ended extension to the DURATION-1 trial of exenatide QW for type 2 diabetes. A 2-stage protocol was used: patients received either exenatide QW (2 mg) or exenatide twice daily for 30 weeks (5 μg for the first 4 weeks and 10 μg thereafter), followed by 1.5 years of treatment with exenatide QW (2 mg), for a total of 2 years (104 weeks) of exenatide treatment. Of the 295 (intent-to-treat [ITT]) patients who entered the trial, 73% (n = 216) completed 2 years of treatment (completer population). Baseline characteristics (mean ± SE) for these patients were: A1C, 8.2 ± 0.1%; FPG, 168.4 ± 43.0 mg/dL; body weight, 101.1 ± 18.7 kg; and diabetes duration, 7 ± 5 years. In the completer population, significant improvements (LS mean ± SE [95% CI]) were maintained after 2 years of treatment in A1C (-1.71 ± 0.08% [-1.86 to -1.55%]), FPG (-40.1 ± 2.9 mg/dL [-45.7 to -34.5 mg/dL]), and body weight (-2.61 ± 0.52 kg [-3.64 to -1.58 kg]) compared with baseline. The percentages of patients who achieved an A1C of <7.0% and ≤6.5% at 2 years were 60% and 39%, respectively. A significant reduction in systolic blood pressure (SBP; -3.0 ± 1.0 mmHg [-4.9 to -1.1 mmHg]) was maintained through 2 years of treatment. Serum lipid profiles were also significantly improved, including triglycerides (geometric LS mean change from baseline, -15 ± 2.7% [-21% to -10%]), total cholesterol (-8.6 ± 2.8 mg/dL [-14.0 to -3.1 mg/dL]), and low-density lipoproteins (-4.5 ± 2.2 mg/dL [-8.9 to -0.01 mg/dL]). Changes in A1C, body weight, FPG, SBP, and lipids in the ITT population were similar to those seen in the completer population. Nausea (predominantly mild in intensity) was the most common adverse event, although the frequency and intensity of nausea decreased over time. No severe hypoglycemia was observed. Exenatide QW was well tolerated during the 2-year treatment period. This study demonstrated sustained glucose control and weight loss throughout 2 years of treatment with exenatide QW. ClinicalTrials.gov NCT00308139.
    BMC Endocrine Disorders 01/2011; 11:9. · 2.65 Impact Factor
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    ABSTRACT: The objective was to compare the treatment effects between exenatide and insulin, which are 2 injectable peptide hormone-based therapy options for the treatment of type 2 diabetes mellitus. Data from 4 randomized, open-label, comparator-controlled clinical trials in 1423 patients with type 2 diabetes followed for 16 to 52 weeks were pooled and analyzed. At 26 weeks, glycemic control with exenatide (-1.2% HbA1c) was non-inferior to insulin (-1.1%; exenatide vs insulin; P = 0.09). In a tertile analysis of HbA1c reduction from baseline, exenatide induced similar reductions compared with insulin, with the greatest reductions observed in the tertile with the highest baseline HbA1c (9%-12.7%). Exenatide treatment induced weight loss (-2 kg) and reduced systolic blood pressure (SBP) from baseline (SBP, -4.9 mm Hg, exenatide vs insulin; P < 0.0001). In contrast, insulin treatment increased body weight (1.8 kg) and decreased SBP by -0.4 mm Hg. Overall, about 3-fold more exenatide-treated patients (70%) experienced weight loss compared with those treated with insulin (21%). Occurrence of nocturnal mild-to-moderate hypoglycemia was lower with exenatide (15%) treatment than with insulin (29%; difference, -14; [95% CI, -18, -9.8]). Effects of exenatide on HbA1c and weight were sustained at 52 weeks. These findings indicate that exenatide is non-inferior to insulin for glycemic control. Further studies are warranted to explore the effects of exenatide on blood pressure and body weight, and the potential for long-term effects on cardiovascular outcomes.
    Postgraduate Medicine 05/2010; 122(3):118-28. · 1.97 Impact Factor
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    ABSTRACT: This study evaluates the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing to achieve glycemic control with maximally effective metformin doses. A triple-blind, placebo-controlled, 30-week study at 82 U.S. sites was performed with 336 randomized patients. In all, 272 patients completed the study. The intent-to-treat population baseline was 53 +/- 10 years with BMI of 34.2 +/- 5.9 kg/m(2) and HbA(1c) of 8.2 +/- 1.1%. After 4 weeks of placebo, subjects self-administered 5 microg exenatide or placebo subcutaneously twice daily for 4 weeks followed by 5 or 10 microg exenatide, or placebo subcutaneously twice daily for 26 weeks. All subjects continued metformin therapy. At week 30, HbA(1c) changes from baseline +/- SE for each group were -0.78 +/- 0.10% (10 microg), -0.40 +/- 0.11% (5 microg), and +0.08 +/- 0.10% (placebo; intent to treat; adjusted P < 0.002). Of evaluable subjects, 46% (10 microg), 32% (5 microg), and 13% (placebo) achieved HbA(1c) < or =7% (P < 0.01 vs. placebo). Exenatide-treated subjects displayed progressive dose-dependent weight loss (-2.8 +/- 0.5 kg [10 microg], -1.6 +/- 0.4 kg [5 microg]; P < 0.001 vs. placebo). The most frequent adverse events were gastrointestinal in nature and generally mild to moderate. Incidence of mild to moderate hypoglycemia was low and similar across treatment arms, with no severe hypoglycemia. Exenatide was generally well tolerated and reduced HbA(1c) with no weight gain and no increased incidence of hypoglycemia in patients with type 2 diabetes failing to achieve glycemic control with metformin.
    Diabetes Care 06/2005; 28(5):1092-100. · 7.74 Impact Factor
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    ABSTRACT: Exenatide (synthetic exendin-4;AC2993) is a 39-amino acid peptide in the new class of antidiabetic agents known as incretin mimetics. In clinical trials, exenatide exhibited glucoregulatory effects (glucose-dependent stimulation of insulin secretion, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying) in patients with type 2 diabetes mellitus (DM). The goal of this study was to determine the relative bioavailability of exenatide injected subcutaneously into the abdomen, arm, or thigh. Patients with type 2 DM were randomized in an open-label, crossover study to assess relative bioavailability of exenatide (10 microg) injected into the arm and thigh versus injection into the abdomen. Serial plasma exenatide concentrations were measured for 10 hours after injection. A sample size of >24 patients provided approximately 80% power to ensure that 90% CIs were within the 80% to 125% interval for the ratios (geometric least squares [LS] means) of AUC(0-infinity). Twenty-eight patients were randomized into the study (mean age, 56 [8] years; glycosylated hemoglobin, 8.0 [1.7]%; body mass index, 33 [5] kg/m2; all values given as mean [SD]). AUC(0-infinity) values (geometric LS mean SE for SC injections into the abdomen arm and thigh were 63,935 (6608), 59,573 (6157), and 62,148 (6424) pg./mL, respectively. The AUC (geometric LS mean ratio for relative bioavailability) for arm versus abdomen was 0.93 (geometric 90% CI, 0.82-1.05); for thigh versus abdomen it was 0.97 (geometric 90% CI, 0.86-1.10). Consistent with the observed data, intrasubject variability of AUC(0-infinity) was low among the 3 treatments (coefficient of variation, 26%). C(max) values (geometric LS mean [SE]) were 220 (24) pg/mL, abdomen; 218 (23) pg/mL, arm; and 193 (21) pg/mL, thigh. The C(max) (geometric LS mean ratio) for arm versus abdomen was 0.99 (geometric 90% CI, 0.85-1.15), and for thigh versus abdomen it was 0.88 (geometric 90% CI, 0.75-1.02). The most common treatment-emergent adverse events were mild to moderate nausea (36%), headache (25%), vomiting (21%), and dizziness (18%). Three patients received an inadvertent 10-fold overdose and were withdrawn from the study immediately. All experienced severe nausea and vomiting, and 1 patient experienced severe hypoglycemia requiring aid. All recovered without mishap and were excluded from statistical and tolerability results. There were no adverse events related to the injection or the injection site. In this study of patients with type 2DM, SC administration of exenatide into the abdomen, arm, or thigh resulted in comparable bioavailability.
    Clinical Therapeutics 02/2005; 27(2):210-5. · 2.23 Impact Factor
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    ABSTRACT: This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy. At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA(1c) > 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c) <or= 7% (P < 0.001). Fasting plasma glucose concentrations decreased in the 10-microg arm compared with placebo (P < 0.05). Subjects in the exenatide arms had dose-dependent progressive weight loss, with an end-of-study loss in the 10-microg exenatide arm of -1.6 +/- 0.3 kg from baseline (P < 0.05 vs. placebo). The most frequent adverse events were generally mild or moderate and gastrointestinal in nature. No severe hypoglycemia was observed. Exenatide significantly reduced HbA(1c) in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea. Exenatide was generally well tolerated and was associated with weight loss.
    Diabetes Care 12/2004; 27(11):2628-35. · 7.74 Impact Factor
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    ABSTRACT: This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol. kg(-1). min(-1)) or placebo during a 270-min stepwise hyperinsulinemic-hypoglycemic clamp (insulin infusion 0.8 mU. kg(-1). min(-1)). Plasma glucose was clamped sequentially at 5.0 (0-120 min), 4.0 (120-180 min), 3.2 (180-240 min), and 2.7 mmol/l (240-270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to approximately 3.2 mmol/l. The time to achieve plasma glucose >/=4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were approximately 3.5-fold higher than in the placebo arm (353 +/- 29 vs. 100 +/- 29 pmol/min [least-square means +/- SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (</=4 mmol/l) in both groups. Glucagon was suppressed in the exenatide arm during euglycemia and higher than placebo during hypoglycemia. Plasma glucose recovery time was equivalent for both treatments. The areas under the concentration-time curve from 270 to 360 min for cortisol, epinephrine, norepinephrine, and growth hormone were similar between treatment arms. There were no differences in adverse events. In the presence of exenatide, there was a preserved, glucose-dependent insulin secretory response and counterregulatory response during hypoglycemia.
    Diabetes 09/2004; 53(9):2397-403. · 7.90 Impact Factor

Publication Stats

2k Citations
58.28 Total Impact Points

Institutions

  • 2014
    • Bristol-Myers Squibb
      New York City, New York, United States
  • 2012–2014
    • Amylin Pharmaceuticals
      San Diego, California, United States