Search

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

The article discusses the necessity of conducting a definite go/no-go study before making a major investment (phase 3) on a newly developed drug. Topics covered include conducting a study or review of a probable occurrence of an adverse event from previous studies, checking if a dose-limiting adverse event may have occurred that could affect patient tolerance to the drug, and validating a delivery medical device that may have an unacceptable failure rate.

Aims Exenatide has been demonstrated to improve glycaemic 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 the 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 ± SEM 253 ± 8.5 pg ml−1, 399 ± 11.9 pg ml−1 and 627 ± 21.2 pg ml−1). 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 two-sided 90% confidence interval for placebo-corrected, baseline-adjusted QTcP (ΔΔ QTcP) was <10 ms at all time points and exenatide concentrations. The mean of three measures assessed at the highest steady-state plasma exenatide concentration of ∼500 pg ml−1 (ΔΔ QTcPavg) was −1.13 [−2.11, −0.15). No correlation was observed between ΔΔ QTcP and exenatide concentration. Assay sensitivity was confirmed with moxifloxacin. Conclusions These results demonstrated that exenatide, at supratherapeutic concentrations, does not prolong QTc and provide an example of methodology for QT assessment of drugs with an inherent heart rate effect. [ABSTRACT FROM AUTHOR]

Background Exenatide (exendin-4) exhibits dose-dependent glucoregulatory activity, but causes dose-limiting nausea and vomiting. This study was designed to formally assess the possibility of inducing tolerance to the side effects of nausea and vomiting at therapeutic doses of exenatide, using a dose-escalation methodology. Methods In this two-arm, triple-blind, multicenter study, 123 subjects with type 2 diabetes were enrolled and randomized; 99 (80.5%) of them completed the study. Subjects in the exenatide-primed arm received subcutaneous exenatide, starting at 0.02 µg/kg three times a day (TID) and increasing in 0.02 µg/kg per dose increments every 3 days for 35 days. Subjects in the exenatide-naive arm received placebo TID for 35 days. At the end of this 35-day regimen, subjects in both arms received the same highest dose of exenatide (0.24 µg/kg TID) for 3 days. Thus, the exenatide-naive arm received exenatide for the first time on Day 35. Results The exenatide-primed arm had a lower proportion of subjects experiencing nausea and vomiting in response to exposure to the highest dose of exenatide (27 vs 56% in the exenatide-naive arm; p = 0.0018). Kaplan-Meier estimates of cumulative incidence were 0.28 in the exenatide-primed arm, compared with 0.68 in the exenatide-naive arm ( p ≤ 0.001). As predicted by the study design, fewer subjects in the exenatide-primed arm reported severe nausea (29%) and vomiting (10%) than those in the exenatide-naive arm (48 and 31%, respectively). In the exenatide-primed arm, fasting serum glucose progressively declined over the first 35 days of dosing, but was unchanged in the exenatide-naive arm (placebo phase) during the same interval. Conclusion Gradual dose-escalation of exenatide successfully reduced the proportion of subjects experiencing dose-limiting nausea and vomiting, with no loss of glucoregulatory activity, thus demonstrating the value of gradual dose-escalation in mitigating the gastrointestinal side effects of exenatide. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Purpose: Infertile couples undergoing in vitro fertilization-embryo transfer (IVF-ET) program were included to study the relationship of pronuclear stage morphology and chromosome status at cleavage stage. Methods: Eighteen to twenty-one hours after fertilization, zygotes were checked for pronuclear morphology with modified Scott Z-score system. After embryo transfer on day 3, arrested or non-transferred 2 PN embryos were spread for fluorescence in sim hybridization (FISH) staining of probes to chromosomes 18, X and Y. Results: Ninety-eight embryos were successfully fixed and stained. The chromosome status were recorded in each 2 PN score group: 7 (54%) of 13 embryos in Z2 group, 14 (35%) of 40 in Z3 group and 10 (36%) of 28 in Z4 group being normal diploid. Z1 group has 12 (71%) of 17 embryos being normal diploid, which is significantly more than Z3 (p = 0.020) and Z4 group (p = 0.033). Conclusion: Our results demonstrated a high probability to get normal diploid embryos if good morphology at pronuclear stage was used as selection criteria, especially for Z1 score embryos. [ABSTRACT FROM AUTHOR]