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R Brodows - One of the best experts on this subject based on the ideXlab platform.

  • The effect of Exenatide re-exposure on safety and efficacy.
    Peptides, 2009
    Co-Authors: Peter Faludi, R Brodows, Jude Burger, Tibor Ivanyi, Daniel K. Braun
    Abstract:

    Abstract Exenatide, a synthetic peptide originally isolated from salivary secretions of Heloderma suspectum , like other subcutaneously injected peptides, can cause antibody formation. Despite that antibody formation has been observed in some patients, results from previous clinical trials have not shown safety and efficacy concerns in Exenatide-naive patients. The objective of this multicenter, open-label study was to investigate the response of anti-Exenatide antibody formation and the incidence of immune-related and hypersensitivity reactions after Exenatide re-exposure. Fifty-eight patients (57% male; 59 ± 10 years; weight 85 ± 19 kg; HbA1c 8.1 ± 0.9%; duration of diabetes 10 ± 5 years) were enrolled. At study initiation, 98.3% of patients were taking 1 or more antidiabetes drugs, including oral medication and various types of insulin. Treatment-emergent adverse events (TEAEs) at any time during the study were observed in 40 and 47% of patients with positive and negative treatment-emergent antibodies, respectively. Immune-related AEs were observed in 6 patients (4 were antibody positive). These AEs had not been reported in their previous exposure to Exenatide. Re-exposure to Exenatide did not result in increased hypersensitivity reactions. Overall, 72% of patients had a baseline to endpoint reduction in HbA1c (range −0.1 to −2.8%), and 87% of antibody negative versus 62% of antibody positive patients had an HbA1c endpoint reduction. The study design and the patients’ baseline characteristics, including diabetes treatment at study initiation, are confounding factors limiting clinical conclusions on Exenatide's glycemic effect in this patient population. The study results indicate that anti-Exenatide antibody formation did not increase the incidence of TEAEs in patients re-exposed to Exenatide.

  • efficacy and tolerability of Exenatide monotherapy over 24 weeks in antidiabetic drug naive patients with type 2 diabetes a randomized double blind placebo controlled parallel group study
    Clinical Therapeutics, 2008
    Co-Authors: Thomas J Moretto, Leigh Macconell, Denai R Milton, Terry D Ridge, Ted Okerson, Anne M Wolka, R Brodows
    Abstract:

    Background: Evaluation of Exenatide monotherapy in patients with type 2 diabetes may be of clinical interest based on improvements in glycemic control and weight that have been reported with the use of Exenatide in combination with oral antidiabetic agents. Objective: The aim of this study was to evaluate the efficacy and tolerability of Exenatide monotherapy in patients with type 2 diabetes naive to antidiabetic agents and whose disease was inadequately controlled with diet and exercise alone. Methods: This 24-week, double-blind, placebo-controlled, parallel-group study was conducted at 23 centers across the United States, Puerto Rico, Romania, Russia, and India. Patients aged ≥18 years with type 2 diabetes were randomly assigned to receive Exenatide 5 µg, Exenatide 10 µg, or placebo administered SC BID. Patients were instructed by investigators to maintain their individualized prestudy diet and exercise regimens throughout the study. Efficacy measures included: glycosylated hemoglobin (HbA1c); fasting serum glucose (FSG); 6-point self-monitored blood glucose; percentages of patients achieving HbA1c values ≤6.5% and ≤7.0%; weight; and homeostasis model of β-cell function (HOMA-B, a clinical measure of pancreatic β-cell function). Tolerability measures included patient-reported adverse events, hypoglycemia, and blood pressure. Results: A total of 232 patients were included in the intent-to-treat population (130 men, 102 women; 68% white; mean [SD] age, 54 [10] years; duration of type 2 diabetes, 2 [3] years; weight, 86 [16] kg; body mass index, 31 [5] kg/m2; HbA1c, 7.8% [0.9%]). At end point, least-squares mean (SE) HbA1c reductions (%) from baseline were significantly greater with Exenatide 5 and 10 µg than placebo (-0.7 [0.1] and -0.9 [0.1] vs -0.2 [0.1]; P = 0.003 and P < 0.001, respectively), as were FSG reductions (mg/dL) (-17.5 [4.0] and -18.7 [4.0] vs -5.2 [4.0]; P = 0.029 and P = 0.016, respectively). Changes in daily mean postprandial glucose excursions (mg/dL) from baseline to end point were significantly greater with Exenatide 5 and 10 µg than placebo (-21.3 [2.7] and -24.7 [2.7] vs -8.3 [2.5]; both, P < 0.001). With Exenatide 5 and 10 µg, 31% and 35% of patients achieved HbA1c ≤6.5% at end point versus 19% with placebo (P = NS and P = 0.026, respectively), while 48% and 46% versus 29% achieved HbA1c ≤7.0% (P = 0.024 and P = 0.036, respectively). Changes in weight (kg) at 24 weeks were greater with Exenatide 5 and 10 ²g than placebo (-2.8 [0.3] and -3.1 [0.3] vs -1.4 [0.3]; P = 0.004 and P < 0.001, respectively). HOMA-B values increased from baseline to end point by 32% and 28% in the Exenatide 5- and 10-µg groups, respectively, versus 6% for placebo. Improvements from baseline to end point in HOMA-B were significantly greater with Exenatide 5 and 10 µg than placebo (P = 0.002 and P = 0.010, respectively). Significant improvements in mean systolic and diastolic blood pressure (mm Hg) from baseline to end point were also observed with Exenatide (systolic, both 5 and 10 µg, -3.7 [1.2] [P = 0.037]; diastolic, 10 µg, -2.3 [0.7] [P = 0.046]) versus placebo (systolic, -0.3 [1.2]; diastolic, -0.3 [0.7]). Overall, 25% of patients reported ≥1 treatment-emergent adverse event. Nausea was reported with the greatest incidence (5 µg, 3%; 10 µg, 13%; placebo, 0%; P = 0.010 for the combined Exenatide group vs placebo). Most (88%) treatment-emergent adverse events were mild or moderate in intensity. Hypoglycemia was reported in 5%, 4%, and 1% of patients in the Exenatide 5- and 10-µg and placebo groups, respectively (P = NS), with no incidents of severe hypoglycemia reported. Conclusions: In these patients with type 2 diabetes naive to treatment with antidiabetic agents, Exenatide monotherapy was associated with improved HbA1c, improved fasting and postprandial glucose control, reduced weight, improved β-cell function (HOMA-B), and improved blood pressure, and was well tolerated. These results suggest that Exenatide monotherapy may provide a viable treatment option beyond diet and exercise and support further study of Exenatide monotherapy in antidiabetic drug-naive patients with type 2 diabetes.

  • the effect of adding Exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes a randomized trial
    Annals of Internal Medicine, 2007
    Co-Authors: Bernard Zinman, Michael E. Trautmann, Byron J Hoogwerf, Dennis Dong Hwan Kim, Santiago Duran Garcia, Denai R Milton, Joseph M Giaconia, R Brodows
    Abstract:

    Background Exenatide therapy is effective in combination with metformin or sulfonylureas for treating type 2 diabetes. Thiazolidinediones (TZDs) also are commonly used, but the efficacy of Exenatide with a TZD has not been reported. Objective To compare the effects of Exenatide versus placebo on glycemic control. Design Placebo run-in, randomized, double-blind, placebo-controlled trial conducted from May 2004 to August 2005. Setting 49 sites in Canada, Spain, and the United States. Patients 233 (Exenatide group, n = 121; placebo group, n = 112) patients with type 2 diabetes that was suboptimally controlled with TZD treatment (with or without metformin). Mean (+/-SE) baseline glycated hemoglobin A1c level was 7.9% +/- 0.1%. Interventions Subcutaneous abdominal injections of 10 microg of Exenatide or placebo twice daily, added to a TZD (with or without metformin) for 16 weeks. Measurements The primary outcome was change from baseline in hemoglobin A1c level. Other outcomes were fasting serum glucose level, body weight, self-monitored blood glucose level, and any adverse events. Results Exenatide treatment reduced hemoglobin A(1c) level (mean difference, -0.98% [95% CI, -1.21% to -0.74%]), serum fasting glucose level (mean difference, -1.69 mmol/L [-30.5 mg/dL] [CI, -2.22 to -1.17 mmol/L {-40.0 to -21.1 mg/dL}]), and body weight (mean difference, -1.51 kg [CI, -2.15 to -0.88 kg]). Sixteen percent of patients in the Exenatide group and 2% of patients in the placebo group discontinued treatment because of adverse events. In the Exenatide group, 40% (n = 48) of patients experienced nausea (mostly mild [n = 21] or moderate [n = 19]), 13% experienced vomiting, and 11% experienced hypoglycemia. In the placebo group, 15% of patients experienced nausea, 1% experienced vomiting, and 7% experienced hypoglycemia. Limitations Combinations with TZDs and sulfonylureas were not tested. Trial duration was relatively short. Only 71% and 86% of patients in the Exenatide and placebo groups, respectively, completed the study. Conclusions Exenatide therapy improved glycemic control, reduced body weight, and caused gastrointestinal symptoms more than placebo in patients with type 2 diabetes that was suboptimally controlled with TZD therapy. ClinicalTrials.gov registration number: NCT00099320. For more information on Exenatide click here.

  • long term effects of Exenatide therapy over 82 weeks on glycaemic control and weight in over weight metformin treated patients with type 2 diabetes mellitus
    Diabetes Obesity and Metabolism, 2006
    Co-Authors: R E Ratner, Loretta L Nielsen, David G Maggs, R Brodows, Anthony H Stonehouse, T Poon, B Zhang, Thomas A Bicsak, Dennis Kim
    Abstract:

    Aim:  The ability of the incretin mimetic Exenatide to improve glycaemic control and reduce body weight was assessed over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with maximally effective doses of metformin. Methods:  In this interim 82-week analysis, 150 (total cohort) of an eligible population of 183 patients opted to continue Exenatide treatment in an uncontrolled open-label extension of a 30-week double-blind, placebo-controlled trial. Of these, 92 patients (completer cohort) achieved 82 weeks of Exenatide therapy. Patients continued metformin throughout the study. Results:  At the end of the placebo-controlled trial, Exenatide resulted in an haemoglobin A1c (HbA1c) reduction from baseline of −1.0 ± 0.1% (mean ± SE) (Exenatide treatment arms), with durable HbA1c reductions after 82 weeks of −1.3 ± 0.1%. The percent of patients who achieved HbA1c≤7% at weeks 30 and 82 was 46 and 59% respectively. After 30 weeks, Exenatide caused a reduction in weight from baseline of −3.0 ± 0.6 kg, with a progressive reduction in weight of −5.3 ± 0.8 kg after 82 weeks. In addition, Exenatide treatment produced clinically significant improvements in cardiovascular risk factors after 82 weeks. The most frequent adverse event after 30 and 82 weeks of Exenatide was nausea, which was generally of mild-or-moderate intensity. It decreased in incidence after initiation in the controlled trial and the uncontrolled open-label extension. Hypoglycaemia was rare, with no severe events. Conclusion:  Exenatide was generally well tolerated, producing a durable reduction in HbA1c and a progressive reduction in weight over 82 weeks in patients with type 2 diabetes failing to achieve glycaemic control with metformin.

  • Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes a randomized trial
    Annals of Internal Medicine, 2005
    Co-Authors: Robert J Heine, Luc F Van Gaal, Don Johns, Michael J Mihm, Mario Widel, R Brodows
    Abstract:

    Background: Physicians may use either insulin or Exenatide injections for patients with type 2 diabetes mellitus who have poor glycemic control despite taking oral blood glucose-lowering drugs. Objective: To compare effects of Exenatide and insulin glargine on glycemic control in patients with type 2 diabetes mellitus that is suboptimally controlled with metformin and a sulfonylurea. Design: 26-week multicenter, open-label, randomized, controlled trial. Setting: 82 outpatient study centers in 13 countries. Patients: 551 patients with type 2 diabetes and inadequate glycemic control (defined as hemoglobin A 1c level ranging from 7.0% to 10.0%) despite combination metformin and sulfonylurea therapy. Intervention: Exenatide, 10 μg twice daily, or insulin glargine, 1 daily dose titrated to maintain fasting blood glucose levels of less than 5.6 mmol/L (<100 mg/dL). Measurements: Hemoglobin A 1c level, fasting plasma glucose level, body weight, 7-point self-monitored blood glucose, standardized test-meal challenge, safety, and tolerability. Results: Baseline mean hemoglobin A 1c level was 8.2% for patients receiving Exenatide and 8.3% for those receiving insulin glargine. At week 26, both Exenatide and insulin glargine reduced hemoglobin A 1c levels by 1.11% (difference, 0.017 percentage point [95% Cl, -0.123 to 0.157 percentage point]). Exenatide reduced postprandial glucose excursions more than insulin glargine, while insulin glargine reduced fasting glucose concentrations more than Exenatide. Body weight decreased 2.3 kg with Exenatide and increased 1.8 kg with insulin glargine (difference, -4.1 kg [Cl, -4.6 to -3.5 kg]). Rates of symptomatic hypoglycemia were similar, but nocturnal hypoglycemia occurred less frequently with Exenatide (0.9 event/patient-year versus 2.4 events/ patient-year; difference, -1.6 events/patient-year [Cl, -2.3 to -0.9 event/patient year]). Gastrointestinal symptoms were more common in the Exenatide group than in the insulin glargine group, including nausea (57.1% vs. 8.6%), vomiting (17.4% vs. 3.7%) and diarrhea (8.5% vs. 3.0%). Limitations: The trial was open-label and did not assess clinical complications related to diabetes. Of the 551 participants, 19.4% of those receiving Exenatide and 9.7% of those receiving insulin glargine withdrew from the study. Only 21.6% of the insulin glargine group and 8.6% of the Exenatide group achieved the target level for fasting plasma glucose of less than 5.6 mmol/L (<100 mg/dL). Conclusions: Exenatide and insulin glargine achieved similar improvements in overall glycemic control in patients with type 2 diabetes that was suboptimally controlled with oral combination therapy. Exenatide was associated with weight reduction and had a higher incidence of gastrointestinal adverse effects than insulin glargine.

Michael E. Trautmann - One of the best experts on this subject based on the ideXlab platform.

  • five year efficacy and safety data of Exenatide once weekly long term results from the duration 1 randomized clinical trial
    Mayo Clinic Proceedings, 2015
    Co-Authors: Carol Wysham, David G Maggs, Leigh Macconell, Ming Zhou, Peter S Griffin, Michael E. Trautmann
    Abstract:

    Abstract Objective To evaluate the 5-year efficacy and safety of once weekly Exenatide. Patients and Methods The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of Exenatide once weekly vs 10 μg of Exenatide twice daily) with an open-ended uncontrolled extension (once weekly Exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 μg of Exenatide twice daily switched to 2 mg of Exenatide once weekly. Study end points included changes from baseline in hemoglobin A 1c , fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate. Results Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A 1c levels were significantly and durably reduced from baseline (least-squares mean, –1.6%; 95% CI, –1.8% to –1.4%; vs –1.9% for Exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A 1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (–28.8 mg/dL; 95% CI, −36.2 to −21.5 mg/dL), weight (–3.0 kg; 95% CI, –4.6 to –1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed. Conclusion Long-term once weekly Exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes. Trial Registration clinicaltrials.gov Identifier: NCT00308139

  • clinical relevance of anti Exenatide antibodies safety efficacy and cross reactivity with long term treatment
    Diabetes Obesity and Metabolism, 2012
    Co-Authors: Mark Fineman, Kenneth F. Mace, Michaela Diamant, T Darsow, Brenda B. Cirincione, L A Kinninger, T Booker K Porter, Michael E. Trautmann
    Abstract:

    Aims: Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-Exenatide antibodies and potential effects on efficacy and safety. Methods: Data from intent-to-treat patients in 12 controlled (n = 2225,12-52weeks) and 5 uncontrolled (n = 1538, up to 3 years) Exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30weeks) Exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52weeks) were analysed. Results: Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of Exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of Exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-Exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, Exenatide BID; -1.6% and -1.3% Exenatide QW). No correlation between change in HbA1c and titre was observed for Exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for Exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres. Conclusions: Low-titre anti-Exenatide antibodies were common with Exenatide treatment (32% Exenatide BID, 45% Exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% Exenatide BID, 12% Exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for Exenatide QW. Other than injection-site reactions, anti-Exenatide antibodies did not impact the safety of Exenatide. © 2012 Blackwell Publishing Ltd.

  • Clinical relevance of anti‐Exenatide antibodies: safety, efficacy and cross‐reactivity with long‐term treatment
    Diabetes obesity & metabolism, 2012
    Co-Authors: Mark Fineman, Kenneth F. Mace, Michaela Diamant, T Darsow, Brenda B. Cirincione, T. K. Booker Porter, L A Kinninger, Michael E. Trautmann
    Abstract:

    Aims: Antibody formation to therapeutic peptides is common. This analysis characterizes the time-course and cross-reactivity of anti-Exenatide antibodies and potential effects on efficacy and safety. Methods: Data from intent-to-treat patients in 12 controlled (n = 2225,12-52weeks) and 5 uncontrolled (n = 1538, up to 3 years) Exenatide twice-daily (BID) trials and 4 controlled (n = 653,24-30weeks) Exenatide once weekly (QW) trials with 1 uncontrolled period (n = 128,52weeks) were analysed. Results: Mean titres peaked early (6-22 weeks) and subsequently declined. At 30 weeks, 36.7% of Exenatide BID patients were antibody-positive; 31.7% exhibited low titres (≤125) and 5.0% had higher titres (≥625). Antibody incidence declined to 16.9% (1.4% higher titre) at 3 years. Similarly, 56.8% of Exenatide QW patients were antibody-positive (45.0% low/11.8% higher titre) at 24-30 weeks, declining to 45.4% positive (9.2% higher titre) at 52 weeks. Treatment-emergent anti-Exenatide antibodies from a subset of patients tested did not cross-react with human GLP-1 or glucagon. Other than injection-site reactions, adverse event rates in antibody-positive and antibody-negative patients were similar. Efficacy was robust in both antibody-negative and antibody-positive patients (mean HbA1c change: -1.0 and -0.9%, respectively, Exenatide BID; -1.6% and -1.3% Exenatide QW). No correlation between change in HbA1c and titre was observed for Exenatide BID, although mean reductions were attenuated in the small subset of patients (5%) with higher titres. A significant correlation was observed for Exenatide QW with no difference between antibody-negative and low-titre patients, but an attenuated mean reduction in the subset of patients (12%) with higher titres. Conclusions: Low-titre anti-Exenatide antibodies were common with Exenatide treatment (32% Exenatide BID, 45% Exenatide QW patients), but had no apparent effect on efficacy. Higher-titre antibodies were less common (5% Exenatide BID, 12% Exenatide QW) and within that titre group, increasing antibody titre was associated with reduced average efficacy that was statistically significant for Exenatide QW. Other than injection-site reactions, anti-Exenatide antibodies did not impact the safety of Exenatide. © 2012 Blackwell Publishing Ltd.

  • DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with Exenatide twice daily in patients with type 2 diabetes.
    The Journal of clinical endocrinology and metabolism, 2011
    Co-Authors: Thomas Blevins, Kristin Taylor, Michael E. Trautmann, John Pullman, Jaret Malloy, Ping Yan, Christine Schulteis, Lisa Porter
    Abstract:

    DURATION-5 demonstrates that continuous Exenatide exposure with Exenatide once weekly produces superior glycemic control, measured by HbA1c, with less nausea compared to Exenatide twice daily.

  • duration 1 Exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks
    Diabetes Care, 2010
    Co-Authors: John B Buse, Larry Z Shen, Kristin Taylor, Michael E. Trautmann, Ken Wilhelm, Daniel J Drucker, Terri Kim, Brandon Walsh, Lisa Porter
    Abstract:

    Abstract Objective: In the DURATION-1 study, the safety and efficacy of 30 weeks of treatment with the GLP-1 receptor agonist Exenatide once weekly (Exenatide QW; 2mg) was compared to Exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of Exenatide QW in a) patients who continued treatment for an additional 22 weeks (52 weeks total), and b) patients who switched from Exenatide BID to Exenatide QW after 30 weeks. Research Design and Methods: In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n=128 QW-only; n=130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. Results: Patients continuing Exenatide QW maintained A1C improvements through 52 weeks (−2.0% [−2.1 to −1.8%]; LS mean [95% CI]). Patients switching from Exenatide BID to Exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71% and 54% of all patients achieved an A1C 40 mg/dL and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed. Conclusion: Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment; patients switching to Exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss. ClinicalTrials.gov identifier: NCT00308139

Kristin Taylor - One of the best experts on this subject based on the ideXlab platform.

  • duration 2 efficacy and safety of switching from maximum daily sitagliptin or pioglitazone to once weekly Exenatide
    Diabetic Medicine, 2011
    Co-Authors: C Wysham, Richard M Bergenstal, Brandon Walsh, Jaret Malloy, Ping Yan, James Malone, Kristin Taylor
    Abstract:

    Diabet. Med. 28, 705–714 (2011) Abstract Aims  In the initial 26-week, double-blind, double-dummy assessment period of the DURATION-2 trial in patients with Type 2 diabetes on metformin, the once-weekly glucagon-like peptide 1 (GLP-1) receptor agonist Exenatide once-weekly resulted in greater HbA1c improvement and weight reduction compared with maximum approved daily doses of sitagliptin or pioglitazone. This subsequent, 26-week, open-label, uncontrolled assessment period evaluated the safety and efficacy of (i) continued Exenatide once-weekly treatment and (ii) switching from sitagliptin or pioglitazone to Exenatide once-weekly. Methods  Randomised oral medications were discontinued and all patients received Exenatide once-weekly. Of the 364 patients [original baseline HbA1c 8.5 ± 1.1% (70 mmol/mol), fasting plasma glucose 9.0 ± 2.5 mmol/l, weight 88 ± 20 kg) who continued into the open-label period, 319 patients (88%) completed 52 weeks. Results  Evaluable patients who received only Exenatide once-weekly demonstrated significant 52-week improvements (least square mean ± se) in HbA1c (−1.6 ± 0.1%), fasting plasma glucose (−1.8 ± 0.3 mmol/l) and weight (−1.8 ± 0.5 kg). Evaluable patients who switched from sitagliptin to Exenatide once-weekly demonstrated significant incremental improvements in HbA1c (−0.3 ± 0.1%), fasting plasma glucose (−0.7 ± 0.2 mmol/l) and weight (−1.1 ± 0.3 kg). Patients who switched from pioglitazone to Exenatide once-weekly maintained HbA1c and fasting plasma glucose improvements (week 52: −1.6 ± 0.1%, −1.7 ± 0.3 mmol/l), with significant weight reduction (−3.0 ± 0.3 kg). Exenatide once-weekly was generally well tolerated and adverse events were predominantly mild or moderate in intensity. Nausea was the most frequent adverse event in this assessment period (intent-to-treat: Exenatide once-weekly-only 5%; sitagliptin  Exenatide once-weekly 11%; pioglitazone  Exenatide once-weekly 10%). No major hypoglycaemia was observed. Conclusions  Patients who switched to once-weekly Exenatide from daily sitagliptin or pioglitazone had improved or sustained glycaemic control, with weight loss.

  • DURATION-5: Exenatide once weekly resulted in greater improvements in glycemic control compared with Exenatide twice daily in patients with type 2 diabetes.
    The Journal of clinical endocrinology and metabolism, 2011
    Co-Authors: Thomas Blevins, Kristin Taylor, Michael E. Trautmann, John Pullman, Jaret Malloy, Ping Yan, Christine Schulteis, Lisa Porter
    Abstract:

    DURATION-5 demonstrates that continuous Exenatide exposure with Exenatide once weekly produces superior glycemic control, measured by HbA1c, with less nausea compared to Exenatide twice daily.

  • duration 1 Exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks
    Diabetes Care, 2010
    Co-Authors: John B Buse, Larry Z Shen, Kristin Taylor, Michael E. Trautmann, Ken Wilhelm, Daniel J Drucker, Terri Kim, Brandon Walsh, Lisa Porter
    Abstract:

    Abstract Objective: In the DURATION-1 study, the safety and efficacy of 30 weeks of treatment with the GLP-1 receptor agonist Exenatide once weekly (Exenatide QW; 2mg) was compared to Exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of Exenatide QW in a) patients who continued treatment for an additional 22 weeks (52 weeks total), and b) patients who switched from Exenatide BID to Exenatide QW after 30 weeks. Research Design and Methods: In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n=128 QW-only; n=130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. Results: Patients continuing Exenatide QW maintained A1C improvements through 52 weeks (−2.0% [−2.1 to −1.8%]; LS mean [95% CI]). Patients switching from Exenatide BID to Exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71% and 54% of all patients achieved an A1C 40 mg/dL and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed. Conclusion: Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment; patients switching to Exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss. ClinicalTrials.gov identifier: NCT00308139

  • Exenatide once weekly for the treatment of type 2 diabetes.
    Expert opinion on investigational drugs, 2009
    Co-Authors: James K. Malone, Kristin Taylor, Michael E. Trautmann, Ken Wilhelm, David M. Kendall
    Abstract:

    Exenatide is the first glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). Exenatide lowers blood glucose through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, suppression of excess glucagon secretion, reduction of food intake and slowing of gastric emptying. The current formulation of Exenatide requires twice-daily dosing (Exenatide BID), and an extended-release formulation of Exenatide is now in development for use as a once-weekly injection (Exenatide QW). The purpose of this report is to review the most current clinical data on the development of Exenatide QW for the treatment of T2DM. In clinical trials, Exenatide QW significantly improved glycemic control, resulted in patient weight loss, and was well tolerated in patients with T2DM. In a head-to-head clinical trial, Exenatide QW caused greater improvements in glycemic control and was better tolerated than Exenatide BID. Given the rapidly increasing prev...

  • Exenatide once weekly versus twice daily for the treatment of type 2 diabetes a randomised open label non inferiority study
    The Lancet, 2008
    Co-Authors: Daniel J Drucker, Kristin Taylor, Michael E. Trautmann, David M. Kendall, John B Buse, Dongliang Zhuang, Lisa Porter
    Abstract:

    Summary Background Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight reductions, when administered twice a day in patients with type 2 diabetes. We compared the efficacy of a once-weekly formulation of Exenatide to that of a twice daily dose. Methods A 30-week, randomised, non-inferiority study compared a long-acting release formulation of Exenatide 2 mg administered once weekly to 10 μg Exenatide administered twice a day, in 295 patients with type 2 diabetes (haemoglobin A 1c [HbA 1c ] 8·3% [SD 1·0], mean fasting plasma glucose 9 [SD 2] mmol/L, weight 102 [SD 20] kg, diabetes duration 6·7 [SD 5·0] years). The patients were naive to drug therapy, or on one or more oral antidiabetic agents. The primary endpoint was the change in HbA 1c at 30 weeks. This study is registered with ClinicalTrials.gov, number NCT00308139. Findings At 30 weeks, the patients given Exenatide once a week had significantly greater changes in HbA 1c than those given Exenatide twice a day (−1·9 [SE 0·1%] vs −1·5 [0·1%], 95% CI −0·54% to −0·12%; p=0·0023). A significantly greater proportion of patients receiving treatment once a week versus twice a day achieved target HbA 1c levels of 7·0% or less (77% vs 61% of evaluable patients, p=0·0039). Interpretation Exenatide once weekly resulted in significantly greater improvements in glycaemic control than Exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight. Funding Amylin Pharmaceuticals Inc and Eli Lilly and Company.

John B Buse - One of the best experts on this subject based on the ideXlab platform.

  • rationale and design of the Exenatide study of cardiovascular event lowering exscel trial
    American Heart Journal, 2016
    Co-Authors: R R Holman, M A Bethel, Jyothis T George, Harald Sourij, Zoe Doran, Joanne Keenan, Nardev S Khurmi, Robert J Mentz, Abderrahim Oulhaj, John B Buse
    Abstract:

    Exenatide once-weekly is an extended release formulation of Exenatide, a glucagon-like peptide-1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding Exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes. EXSCEL is an academically led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35 countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years. Participants will be randomized (1:1) to receive Exenatide once-weekly 2 mg or matching placebo by subcutaneous injections. The trial will continue until 1,360 confirmed primary composite cardiovascular end points, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, have occurred. The primary efficacy hypothesis is that Exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular end point. EXSCEL is powered to detect a 15% relative risk reduction in the Exenatide once-weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that Exenatide once-weekly is noninferior to usual care with respect to the primary cardiovascular composite end point. Noninferiority will be concluded if the upper limit of the CI is <1.30. EXSCEL will assess whether Exenatide once-weekly can reduce cardiovascular events in patients with T2DM with a broad range of cardiovascular risk. It will also provide long-term safety information on Exenatide once-weekly in people with T2DM. ClinicalTrials.gov Identifier: NCT01144338.

  • Rationale and design of the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial
    American heart journal, 2015
    Co-Authors: R R Holman, M A Bethel, Jyothis T George, Harald Sourij, Zoe Doran, Nardev S Khurmi, Robert J Mentz, Abderrahim Oulhaj, Joanne F. Keenan, John B Buse
    Abstract:

    Exenatide once-weekly is an extended release formulation of Exenatide, a glucagon-like peptide-1 receptor agonist, which can improve glycemic control, body weight, blood pressure, and lipid levels in patients with type 2 diabetes mellitus (T2DM). The Exenatide Study of Cardiovascular Event Lowering (EXSCEL) will compare the impact of adding Exenatide once-weekly to usual care with usual care alone on major cardiovascular outcomes. EXSCEL is an academically led, phase III/IV, double-blind, pragmatic placebo-controlled, global trial conducted in 35 countries aiming to enrol 14,000 patients with T2DM and a broad range of cardiovascular risk over approximately 5 years. Participants will be randomized (1:1) to receive Exenatide once-weekly 2 mg or matching placebo by subcutaneous injections. The trial will continue until 1,360 confirmed primary composite cardiovascular end points, defined as cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, have occurred. The primary efficacy hypothesis is that Exenatide once-weekly is superior to usual care with respect to the primary composite cardiovascular end point. EXSCEL is powered to detect a 15% relative risk reduction in the Exenatide once-weekly group, with 85% power and a 2-sided 5% alpha. The primary safety hypothesis is that Exenatide once-weekly is noninferior to usual care with respect to the primary cardiovascular composite end point. Noninferiority will be concluded if the upper limit of the CI is

  • baseline factors associated with glycemic control and weight loss when Exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes
    Diabetes Care, 2012
    Co-Authors: Julio Rosenstock, John B Buse, Sylvia K Shenouda, Richard M Bergenstal, Leonard C Glass, Cory R Heilmann, Anita Y M Kwan, Leigh Macconell, Byron J Hoogwerf
    Abstract:

    OBJECTIVE To determine variables associated with glycemic and body weight responses when adding Exenatide to basal insulin–treated type 2 diabetes. RESEARCH DESIGN AND METHODS Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing Exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 Exenatide; 122 placebo). RESULTS Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C ( P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions ( P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI ( P < 0.05). Exenatide participants with longer diabetes duration lost the most weight ( P < 0.001). CONCLUSIONS Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration.

  • duration 1 Exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks
    Diabetes Care, 2010
    Co-Authors: John B Buse, Larry Z Shen, Kristin Taylor, Michael E. Trautmann, Ken Wilhelm, Daniel J Drucker, Terri Kim, Brandon Walsh, Lisa Porter
    Abstract:

    Abstract Objective: In the DURATION-1 study, the safety and efficacy of 30 weeks of treatment with the GLP-1 receptor agonist Exenatide once weekly (Exenatide QW; 2mg) was compared to Exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of Exenatide QW in a) patients who continued treatment for an additional 22 weeks (52 weeks total), and b) patients who switched from Exenatide BID to Exenatide QW after 30 weeks. Research Design and Methods: In this randomized, multicenter, comparator-controlled, open-label trial, 258 patients entered the 22-week open-ended assessment phase (n=128 QW-only; n=130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. Results: Patients continuing Exenatide QW maintained A1C improvements through 52 weeks (−2.0% [−2.1 to −1.8%]; LS mean [95% CI]). Patients switching from Exenatide BID to Exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71% and 54% of all patients achieved an A1C 40 mg/dL and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed. Conclusion: Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment; patients switching to Exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss. ClinicalTrials.gov identifier: NCT00308139

  • Exenatide once weekly versus twice daily for the treatment of type 2 diabetes a randomised open label non inferiority study
    The Lancet, 2008
    Co-Authors: Daniel J Drucker, Kristin Taylor, Michael E. Trautmann, David M. Kendall, John B Buse, Dongliang Zhuang, Lisa Porter
    Abstract:

    Summary Background Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight reductions, when administered twice a day in patients with type 2 diabetes. We compared the efficacy of a once-weekly formulation of Exenatide to that of a twice daily dose. Methods A 30-week, randomised, non-inferiority study compared a long-acting release formulation of Exenatide 2 mg administered once weekly to 10 μg Exenatide administered twice a day, in 295 patients with type 2 diabetes (haemoglobin A 1c [HbA 1c ] 8·3% [SD 1·0], mean fasting plasma glucose 9 [SD 2] mmol/L, weight 102 [SD 20] kg, diabetes duration 6·7 [SD 5·0] years). The patients were naive to drug therapy, or on one or more oral antidiabetic agents. The primary endpoint was the change in HbA 1c at 30 weeks. This study is registered with ClinicalTrials.gov, number NCT00308139. Findings At 30 weeks, the patients given Exenatide once a week had significantly greater changes in HbA 1c than those given Exenatide twice a day (−1·9 [SE 0·1%] vs −1·5 [0·1%], 95% CI −0·54% to −0·12%; p=0·0023). A significantly greater proportion of patients receiving treatment once a week versus twice a day achieved target HbA 1c levels of 7·0% or less (77% vs 61% of evaluable patients, p=0·0039). Interpretation Exenatide once weekly resulted in significantly greater improvements in glycaemic control than Exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight. Funding Amylin Pharmaceuticals Inc and Eli Lilly and Company.

Nayyar Iqbal - One of the best experts on this subject based on the ideXlab platform.

  • Pancreatitis Incidence in the Exenatide BID, Exenatide QW, and Exenatide QW Suspension Development Programs: Pooled Analysis of 35 Clinical Trials
    Diabetes Therapy, 2019
    Co-Authors: Marion L. Vetter, Elise Hardy, Kristina Johnsson, Hui Wang, Nayyar Iqbal
    Abstract:

    Introduction Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for treatment of type 2 diabetes mellitus; however, there have been concerns that GLP-1RA treatment may be associated with an increased incidence of pancreatitis. This study aimed to evaluate the incidence of pancreatitis in a pooled population of type 2 diabetes trials from the clinical development program of the GLP-1RA Exenatide as well as to describe patient-level data for all reported cases. Methods The primary analysis examined pooled data among patients with type 2 diabetes from the controlled arms of 35 trials (ranging from 4 to 234 weeks’ duration) in the integrated clinical databases for Exenatide twice daily, once weekly, and once-weekly suspension, excluding comparator arms with other incretin-based therapies. The exposure-adjusted incidence rate (EAIR) of pancreatitis was calculated for Exenatide and non-Exenatide (non-incretin-based therapy or placebo) treatment groups. Patient-level data were described for all pancreatitis incidences. Results The primary analysis included 5596 patients who received Exenatide and 4462 in the non-Exenatide group. The mean duration of study medication exposure for the Exenatide and non-Exenatide treatment groups was 57.0 and 47.9 weeks, respectively. Pancreatitis was diagnosed in 14 patients (Exenatide, n  = 8; non-Exenatide, n  = 6), of whom 13 recovered with or without sequelae. The pancreatitis EAIR was 0.1195 events per 100 patient-years [95% confidence interval (CI), 0.0516–0.2154] in the Exenatide group versus 0.1276 events per 100 patient-years (95% CI 0.0468–0.2482) in the non-Exenatide treatment group. The EAIR ratio for the Exenatide versus non-Exenatide treatment group was 0.761 (95% CI 0.231–2.510). Conclusion In this pooled analysis of 10,058 patients among studies comparing Exenatide with other glucose-lowering medications or placebo, pancreatitis was rare. The EAIRs of pancreatitis were low and similar between Exenatide and non-Exenatide treatment groups. No evidence of an association between Exenatide and pancreatitis was observed. Funding Bristol-Myers Squibb and AstraZeneca. Plain Language Summary Plain language summary available for this article.

  • changes in serum calcitonin concentrations incidence of medullary thyroid carcinoma and impact of routine calcitonin concentration monitoring in the Exenatide study of cardiovascular event lowering exscel
    Diabetes Care, 2019
    Co-Authors: M. Angelyn Bethel, Rishi Patel, Vivian Thompson, Peter Merrill, Shelby D Reed, Sara Ahmadi, Brian G Katona, S M Gustavson, Peter Ohman, Nayyar Iqbal
    Abstract:

    OBJECTIVE Increases in serum calcitonin, a tumor marker for medullary thyroid carcinoma (MTC), have been associated with glucagon-like peptide 1 receptor agonist use in some preclinical studies. We report calcitonin changes in Exenatide-treated and placebo-administered participants and MTC incidence in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) and consider the impact of within-trial calcitonin monitoring. RESEARCH DESIGN AND METHODS EXSCEL participants were randomized 1:1 to once-weekly Exenatide 2 mg or placebo. Serum calcitonin was measured at baseline (with trial medication discontinued if >40 ng/L) and annually thereafter (with trial medication discontinued if ≥50 ng/L). Median calcitonin concentrations were calculated at each time point, and thyroid malignancies were collected prospectively. Data regarding follow-up after an elevated calcitonin were collected retrospectively. RESULTS At baseline, 52 (30 Exenatide and 22 placebo) participants had calcitonin >40 ng/L, and during follow-up an additional 23 participants (15 Exenatide and 8 placebo) had calcitonin ≥50 ng/L in the intention-to-treat population. Median calcitonin concentrations were similar between treatment groups at baseline with no increase over time. Confirmed MTC occurred in three participants (2 Exenatide and 1 placebo), all of whom had significantly elevated baseline calcitonin values (413, 422, and 655 ng/L). CONCLUSIONS During a median 3.2 years’ follow-up, no change in serum calcitonin was seen with Exenatide therapy. The three confirmed cases of MTC all occurred in participants with markedly elevated baseline calcitonin levels, measured prior to trial medication administration. Regular calcitonin monitoring identified no additional cases of MTC, suggesting no benefit of routine calcitonin monitoring during Exenatide treatment.

  • Efficacy and tolerability of the new autoinjected suspension of Exenatide once weekly versus Exenatide twice daily in patients with type 2 diabetes.
    Diabetes obesity & metabolism, 2017
    Co-Authors: Carol Wysham, Peter Ohman, Marion L. Vetter, Julio Rosenstock, Fang Dong, Nayyar Iqbal
    Abstract:

    Aims To simplify administration of aqueous Exenatide once weekly, which requires reconstitution, the Exenatide microspheres have been reformulated in a ready-to-use autoinjector with a Miglyol diluent (Exenatide QWS-AI). This study compared the efficacy and safety of Exenatide QWS-AI with the first-in-class glucagon-like peptide-1 receptor agonist Exenatide twice daily (BID). Materials and Methods This randomized, open-label, controlled study in patients with type 2 diabetes using diet and exercise or taking stable oral glucose-lowering medication randomized patients 3:2 to either Exenatide QWS-AI (2 mg) or Exenatide BID (10 μg) for 28 weeks. The primary outcome was the 28-week change in glycated haemoglobin (HbA1c). A subset of patients completed a standardized meal test for postprandial and pharmacokinetic assessments. Results A total of 375 patients (mean HbA1c, 8.5% [69 mmol/mol]; body mass index, 33.2 kg/m2; diabetes duration, 8.5 years) received either Exenatide QWS-AI (n = 229) or Exenatide BID (n = 146); HbA1c was reduced by −1.4% and −1.0%, respectively (least-squares mean difference, −0.37%; P = .0072). More patients achieved HbA1c