Dataset Information

Pathophysiological and pharmacological rationale for the use of exenatide once weekly in patients with type 2 diabetes.

ABSTRACT:

Introduction

A new formulation of exenatide has become available recently that is the first antidiabetic medication for type 2 diabetes mellitus (T2DM) dosed on a weekly schedule. This review summarizes the pharmacology, efficacy, and safety of exenatide once weekly (exenatide QW). The results are interpreted in terms of the pathophysiology of T2DM, as well as the pharmacology of the new formulation.

Methods

Relevant literature on exenatide QW and diabetes was identified through PubMed database searches from inception until September 2013.

Discussion

In the new once-weekly formulation of exenatide, the exenatide molecule is dispersed in microspheres. Following subcutaneous injection, these microspheres degrade in situ and slowly release active agent. In clinical trials, therapy with exenatide QW as monotherapy or in combination with other antidiabetic treatments was associated with reductions in glycated hemoglobin (-1.3% to -1.9%), fasting plasma glucose (-32 to -41 mg/dL), and body weight (-2.0 to -3.7 kg). These outcomes were achieved without an associated increase in the rate of hypoglycemic episodes, except when exenatide QW was used in combination with sulfonylureas. The primary tolerability issues in the trials were gastrointestinal adverse events, particularly during the first weeks of use, although the rate of nausea during startup with exenatide QW was lower than that with the related agents, exenatide twice daily and liraglutide once daily.

Conclusions

Exenatide QW may be particularly well suited to patients who desire the benefits associated with glucagon-like peptide-1 receptor agonists, including significant glycemic control, low risk of hypoglycemia, and moderate weight loss, but prefer the convenience of once-weekly dosing.

SUBMITTER: Grossman SS

PROVIDER: S-EPMC3961598 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Exenatide once weekly (QW) is a glucagon-like peptide-1 receptor agonist (GLP-1RA) for the treatment of type 2 diabetes. Safety and tolerability are key considerations in treatment selection. This analysis examines the safety and tolerability profile of exenatide QW, other approved GLP-1RAs (exenatide twice daily and liraglutide once daily), and a pooled population of commonly used non-GLP-1RA treatments. METHODS:Intent-to-treat populations from eight randomized Phase III trials with 24-week and 30-week comparator-controlled periods were analyzed. Data were pooled for exenatide QW, exenatide twice daily, and non-GLP-1RA comparator groups; comparisons between exenatide QW and liraglutide were analyzed separately to better match study groups. The incidence of treatment-emergent adverse events with 95% confidence intervals and exposure-adjusted incidence were calculated. Duration and recurrence were analyzed for gastrointestinal adverse events and adverse events of special interest. RESULTS:Incidences of serious adverse events did not differ between treatments. Discontinuations due to adverse events occurred numerically less frequently with exenatide QW than with other GLP-1RAs but numerically more frequently than with non-GLP-1RA comparators. The most frequent adverse events in the GLP-1RA groups were gastrointestinal and generally mild, with decreasing incidence over time. Gastrointestinal adverse event incidences appeared lower with exenatide QW versus other GLP-1RAs and greater than with non-GLP-1RA comparators. Injection site-related adverse events seemed highest with exenatide QW, but generally did not lead to withdrawal and abated over time. Hypoglycemia was infrequent overall, but occurred numerically more frequently in the non-GLP-1RA comparator group and increased with concomitant sulfonylurea use. Pancreatitis, thyroid cancer, renal failure, and gallbladder disease were rarely reported. CONCLUSION:The overall safety and tolerability profile of exenatide QW was similar to that of other GLP-1RAs, with improved gastrointestinal tolerability. The safety and tolerability profile of exenatide QW compared with non-GLP-1RA comparators was similar overall, with the exception of a lower incidence of hypoglycemia and anticipated differences in gastrointestinal and injection site-related adverse events.

Project description:This analysis assessed whether responses with exenatide once weekly plus dapagliflozin (n?=?231), exenatide once weekly alone (n?=?230), or dapagliflozin alone (n?=?233) differed in key patient subpopulations of the DURATION-8 trial. Potential treatment-by-subgroup interactions for changes in glycated haemoglobin (HbA1c) and body weight after 28?weeks were evaluated among subgroups determined by baseline HbA1c, age, sex, body mass index, type 2 diabetes duration, race, ethnicity and estimated glomerular filtration rate (eGFR). Exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all subgroups: least-squares mean reductions ranged from -8.4 to -26.1?mmol/mol (-0.77% to -2.39%) for HbA1c and from -2.07 to -4.55?kg for body weight. Potential treatment-by-subgroup interactions (P?<?.10) were found for HbA1c change by age (P?= .016) and eGFR (P?= .097). Age subgroup analysis findings were not consistent with expected mechanistic effects, with the small number of patients aged ?65?years (n?=?74 vs n?=?499 for patients aged <65?years) limiting the interpretability of the interaction term. In the exenatide once weekly plus dapagliflozin and dapagliflozin groups, but not the exenatide once weekly group, HbA1c reductions were greater among patients with eGFR ?90 vs ?60 to <90?mL/min/1.73?m2 (least-squares mean reductions of -23.6 vs -19.0?mmol/mol [-2.16% vs -1.74%], -17.3 vs -12.0?mmol/mol [-1.58% vs -1.10%], and -17.7 vs -16.9?mmol/mol [-1.62% vs -1.55%] for the respective treatments); this was consistent with the mechanism of action of dapagliflozin. A potential treatment-by-subgroup interaction was observed for change in body weight by sex (P?= .099), with greater weight loss for women vs men across all treatments (range?-2.56 to -3.98?kg vs -0.56 to -2.99?kg). In conclusion, treatment with exenatide once weekly plus dapagliflozin reduced HbA1c and body weight across all patient subgroups and was more effective than exenatide once weekly or dapagliflozin alone in all adequately sized subgroups.

Project description:INTRODUCTION:Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycemia in patients with type 2 diabetes, but heart rate increases have been observed. METHODS:A pooled post hoc analysis of 11 randomized clinical trials (N = 4595) of 10-30 weeks' duration from the exenatide once-weekly (QW) development program evaluated heart rate with exenatide QW (intervention group) and exenatide twice daily (BID), liraglutide, and non-GLP-1RAs (insulin, metformin, pioglitazone, and sitagliptin) (comparison groups). The time course and size of heart rate changes from baseline and the relationship of heart rate change with baseline heart rate were studied. A multivariate analysis (9 studies; N = 3903) examined associations between patient characteristics or treatments and heart rate increases. RESULTS:Mean baseline heart rate ± standard deviation was 75.0 ± 8.5 beats per minute (bpm) with exenatide QW (n = 2096), 75.8 ± 8.7 bpm with exenatide BID (n = 606), 75.2 ± 8.9 bpm with liraglutide (n = 450), and 74.5 ± 8.6 bpm with non-GLP-1RAs (n = 1443). Least-squares mean ± standard error changes from baseline to final heart rate were + 2.7 ± 0.2, + 1.0 ± 0.3, and + 3.0 ± 0.4 bpm with exenatide QW, exenatide BID, and liraglutide, respectively, and - 0.8 ± 0.2 bpm with non-GLP-1RAs. The size and direction of heart rate changes in individual patients varied within each treatment group at all time points. At posttreatment follow-up, heart rate reverted to the baseline level after GLP-1RA discontinuation. Heart rate changes correlated negatively with baseline heart rate for all therapies (r = - 0.3 to - 0.4). Baseline heart rate was the strongest predictor of increased heart rate. CONCLUSIONS:Small increases in heart rate were associated with exenatide QW, exenatide BID, and liraglutide treatments but reverted to baseline after discontinuation. Increases were more likely in patients with a low baseline heart rate. The clinical relevance of these heart rate increases is unknown but will be clarified by several ongoing and recently completed cardiovascular outcome studies.