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A Review of the Long-Term Efficacy, Tolerability, and Safety of Exenatide Once Weekly for Type 2 Diabetes.

ABSTRACT: Exenatide once weekly (ExeOW, Bydureon®, Astra Zeneca), a drug belonging to the class of glucagon-like peptide-1 (GLP-1) receptor agonists, is the first agent approved for treatment of type 2 diabetes (T2D) that can be administered on a weekly basis.Data concerning treatment of T2D with ExeOW are reviewed with special reference to its long-term efficacy, tolerability, and safety. Relevant literature was identified through the PubMed database from inception to January 2015.In randomized clinical trials ExeOW, as add-on to oral antidiabetics, achieved significantly improved glycemic control compared to maximum recommended doses of exenatide twice daily, sitagliptin, pioglitazone, and insulin glargine, as measured by HbA1c. In drug-naïve patients ExeOW was superior to sitagliptin and non-inferior to metformin, whereas non-inferiority to pioglitazone and liraglutide was not proven. In different trials reductions in HbA1c ranged from -1.1% to -2.0%. ExeOW therapy over 6 months was also associated with a mean weight loss of -2 to -4 kg, improved systolic blood pressure and lipid profile, and no hypoglycemia unless associated to sulfonylurea. ExeOW long-term therapy up to 3-6 years allowed persistent glycemic control (HbA1c -1.6%), sustained decreases in blood pressure (-2 mmHg), and improvements of lipid profile. ExeOW tolerability was comparable to that of the other GLP-1 receptor agonists, with better gastrointestinal tolerability when direct comparison was done (namely liraglutide and exenatide BID), but higher incidence of injection site reactions and few treatment discontinuations mainly due to gastrointestinal events.ExeOW is a well-tolerated and convenient option for long-term treatment of T2D allowing significant and persistent glycemic control with moderate weight loss and low risk of hypoglycemia unless associated with sulfonylureas.

SUBMITTER: Genovese S

PROVIDER: S-EPMC5565650 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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A Review of the Long-Term Efficacy, Tolerability, and Safety of Exenatide Once Weekly for Type 2 Diabetes.

Genovese Stefano S Mannucci Edoardo E Ceriello Antonio A

Advances in therapy 20170703 8

<h4>Introduction</h4>Exenatide once weekly (ExeOW, Bydureon<sup>®</sup>, Astra Zeneca), a drug belonging to the class of glucagon-like peptide-1 (GLP-1) receptor agonists, is the first agent approved for treatment of type 2 diabetes (T2D) that can be administered on a weekly basis.<h4>Methods</h4>Data concerning treatment of T2D with ExeOW are reviewed with special reference to its long-term efficacy, tolerability, and safety. Relevant literature was identified through the PubMed database from i ...[more]

PMID: 28674957

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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:INTRODUCTION:The safety and efficacy of exenatide once weekly (EQW) is overall well established. EQW is primarily renally eliminated. In this study, the efficacy and renal and gastrointestinal tolerability of EQW were summarised in participants with type 2 diabetes and chronic kidney disease stage 3 (CKD3; moderate renal impairment; estimated glomerular filtration rate [eGFR] ≥ 30 to < 60 mL/min/1.73 m2) or CKD stage 2 (CKD2; mild renal impairment; eGFR ≥ 60 to < 90 mL/min/1.73 m2). METHODS:Data on participants with type 2 diabetes and baseline CKD3 or CKD2 from eight phase 3, double-blind or open-label studies with 26- or 28-week controlled treatment periods were pooled. Participants received EQW or a placebo/non-glucagon-like peptide-1 receptor agonist comparator (sitagliptin, metformin, pioglitazone, dapagliflozin and insulin). RESULTS:Participants with baseline CKD3 (N = 182) or CKD2 (N = 772) receiving EQW differed in a number of baseline characteristics, such as age < 65 years, race, mean body mass index and mean type 2 diabetes duration, whereas mean blood pressure and glycated haemoglobin (HbA1c) were similar. Mean reductions in HbA1c, body weight and systolic blood pressure from baseline to week 26/28 in participants receiving EQW were similar between the CKD subgroups. The proportions of participants (CKD3 and CKD2) with any adverse event (AE) were 81% and 72%, respectively, for EQW and 74% and 68%, respectively, for all comparators; those for serious AEs were 2.7% and 3.4%, respectively, for EQW and 6% and 5%, respectively, for all comparators. Gastrointestinal AE rates were higher in the EQW CKD3 subgroup (42.2% of participants) than in the CKD2 (32.8%) subgroup, although rates for nausea and vomiting were similar. There were no dehydration events; one participant in each treatment group had a serious AE of acute kidney injury (EQW with CKD3, n = 1; pioglitazone with CKD2, n = 1). CONCLUSION:Exenatide once weekly was well tolerated and demonstrated similar efficacy in participants with type 2 diabetes with mild and moderate renal impairment. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: NCT00637273, NCT00676338, NCT02229383, NCT02229396, NCT00641056, NCT01652729, NCT00935532, NCT01003184.

Project description:ObjectiveAmong patients with type 2 diabetes uncontrolled with metformin, exenatide once weekly (QW) plus dapagliflozin combination produced greater reductions in glycemia, weight, and systolic blood pressure (SBP) at 28 weeks than exenatide QW or dapagliflozin alone (DURATION-8). Here, we investigated the safety and maintenance of efficacy at 52 weeks, after a 24-week extension.Research design and methodsThis phase 3, multicenter, double-blind study randomized adults with type 2 diabetes (with glycated hemoglobin [HbA1c] 8.0-12.0% [64-108 mmol/mol] and on metformin ≥1,500 mg/day) to exenatide QW (2-mg subcutaneous injection) plus once-daily dapagliflozin (10-mg oral tablet), exenatide QW plus oral placebo, or dapagliflozin plus injected placebo. Extension-period P values were nominal.ResultsOf 1,375 patients screened, 695 were randomized (mean baseline HbA1c 9.3% [78 mmol/mol]); 81.2% completed the study, and 75.3% completed treatment. At 52 weeks, HbA1c reductions were greater with exenatide QW plus dapagliflozin (least squares mean change -1.75% [-19.1 mmol/mol]) versus exenatide QW (-1.38% [-15.1 mmol/mol]; P = 0.006) or dapagliflozin (-1.23% [-13.4 mmol/mol]; P < 0.001); mean HbA1c values were 6.9% (52 mmol/mol), 7.2% (55 mmol/mol), and 7.4% (57 mmol/mol), respectively. Weight and SBP reductions were greater with exenatide QW plus dapagliflozin (-3.31 kg and -4.5 mmHg) versus exenatide QW (-1.51 kg and -0.7 mmHg; both P < 0.001) but similar to those with dapagliflozin (-2.28 kg and -2.7 mmHg; P = 0.057 and P = 0.100, respectively). The exenatide QW plus dapagliflozin regimen was well tolerated with no unexpected safety findings; more patients treated with exenatide QW experienced gastrointestinal and injection site-related adverse events. No major hypoglycemia occurred.ConclusionsAmong patients with type 2 diabetes uncontrolled with metformin, exenatide QW plus dapagliflozin provided sustained improvements in glycemia, weight, and SBP over 52 weeks, with no unexpected safety findings.

Project description:BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disease with substantial morbidity, mortality, and economic impacts. Glucagon-like peptide-1 (GLP-1) receptor agonists, such as once-daily (QD) liraglutide and once-weekly (QW) exenatide, are FDA-approved treatment for T2DM. Head-to-head trials and meta-analyses comparing these agents have reported clinically meaningful improvements but small differences in glycemic control between both agents. In this study, we calculate and compare the cost-effectiveness implications of these alternative effectiveness outcomes.MethodsWe developed a decision model to evaluate the short-term cost-effectiveness of exenatide QW 2 mg versus liraglutide QD 1.8 mg in T2DM patients, with effectiveness measured as reduction in glycated hemoglobin (HbA1c). In the base case, the model tracks change in HbA1c and direct medical expenditure over a 6-month time horizon. We calculated and compared the cost per 1% reduction in HbA1c of models populated with clinical data from a head-to-head randomized, controlled trial (DURATION-6) and a network meta-analysis. Expenditure inputs were derived from wholesale acquisition costs and published sources.ResultsIn the base case, 6-month expenditure for the liraglutide and exenatide strategies were $3,509 and $2,618, respectively. Using clinical data from DURATION-6 and the network meta-analysis, the liraglutide strategy had an incremental cost per 1% reduction in HbA1c of $4,773 and $27,179, respectively. The most influential model parameters were drug costs, magnitude of HbA1c reduction in patients on treatment for >1 month, and liraglutide gastrointestinal adverse event rate. In probabilistic sensitivity analyses (PSA) using DURATION-6 data, the exenatide strategy was optimal at willingness-to-pay levels below $4,800 per 1% reduction in HbA1c. In a PSA using meta-analysis data, the exenatide strategy was dominant.ConclusionsOur modeled results demonstrate that the effectiveness and cost-effectiveness of liraglutide QD 1.8 mg relative to exenatide QW 2 mg depend largely on the chosen source of the clinical data.

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A Review of the Long-Term Efficacy, Tolerability, and Safety of Exenatide Once Weekly for Type 2 Diabetes.

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A Review of the Long-Term Efficacy, Tolerability, and Safety of Exenatide Once Weekly for Type 2 Diabetes.

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