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Weekly GLP-1 Receptor Agonist Albiglutide Versus Diabetes Care Volume 37, October 2014 2723 Lawrence A. Leiter,1 Molly C. Carr,2 Efficacy and Safety of the Once- Murray Stewart,2 Angela Jones-Leone,2 CLIN CARE/EDUCATION/NUTRITION/PSYCHOSOCIAL Rhona Scott,3 Fred Yang,2 and Weekly GLP-1 Receptor Agonist Yehuda Handelsman4 Albiglutide Versus Sitagliptin in Patients With Type 2 Diabetes and Renal Impairment: A Randomized Phase III Study Diabetes Care 2014;37:2723–2730 | DOI: 10.2337/dc13-2855 OBJECTIVE To evaluate weekly subcutaneous albiglutide versus daily sitagliptin in renally impaired patients with type 2 diabetes and inadequately controlled glycemia on a regimen of diet and exercise and/or oral antihyperglycemic medications. RESEARCH DESIGN AND METHODS In this phase III, randomized, double-blind, multicenter, 52-week study, the pri- mary study end point was HbA1c change from baseline at week 26 in patients with renal impairment, as assessed with estimated glomerular filtration rate and cat- egorized as mild, moderate, or severe (‡60 to £89, ‡30 to £59, and ‡15 to £29 mL/min/1.73 m2, respectively). Secondary end points included fasting plasma glucose (FPG), weight, achievement of treatment targets, hyperglycemic rescue, and safety. 1Division of Endocrinology and Metabolism, Li Ka RESULTS Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, St. Michael’s Hos- Baseline demographics were similar across treatment and renal impairment pital, University of Toronto, Toronto, Ontario, groups with overall mean age of 63.3 years, BMI of 30.4 kg/m2,HbA of 8.2% Canada 1c 2 (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA change from GlaxoSmithKline, King of Prussia, PA 1c 3GlaxoSmithKline, Uxbridge, Middlesex, U.K. baseline at week 26 was significantly greater for albiglutide than sitagliptin 4Metabolic Institute of America, Tarzana, CA 2 2 P ( 0.83% vs. 0.52%, = 0.0003). Decreases in HbA1c, FPG, and weight were seen Corresponding author: Lawrence A. Leiter, through week 52. Time to hyperglycemic rescue through week 52 was significantly [email protected]. longer for albiglutide than sitagliptin (P = 0.0017). Results of safety assessments Received 5 December 2013 and accepted 23 June were similar between groups, and most adverse events (AEs) were mild or mod- 2014. erate. The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as Clinical trial reg. no. NCT01098539, clinicaltrials follows: overall, 31.7%, 25.2%; diarrhea, 10.0%, 6.5%; nausea, 4.8%, 3.3%; and .gov. vomiting, 1.6%, 1.2%, respectively. This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/ CONCLUSIONS suppl/doi:10.2337/dc13-2855/-/DC1. Once-weekly albiglutide therapy in renally impaired patients with type 2 diabetes © 2014 by the American Diabetes Association. Readers may use this article as long as the work provided statistically superior glycemic improvement with almost similar tolera- is properly cited, the use is educational and not bility compared with daily sitagliptin therapy. for profit, and the work is not altered. 2724 Albiglutide in Type 2 Diabetes Renal Impairment Diabetes Care Volume 37, October 2014 The steady rise in the prevalence of type in patients with type 2 diabetes and re- related to pancreatitis, and other events 2 diabetes worldwide has become a ma- nal impairment whose glycemia was in- identified by the pharmacovigilance jor health care issue due to associated adequately controlled on their current group as related to pancreatitis, as well increases in patient morbidity and mor- regimen of either diet and exercise or as amylase and/or lipase measurements tality secondary to cardiovascular, renal, specific antihyperglycemic therapy. (three or more times the upper limit of and neurological disease complications normal) regardless of suspected etiology, and the rising monetary and resource RESEARCH DESIGN AND METHODS to determine whether adjudication for costsneededtomanagethesecompli- Study Design pancreatitis was warranted. cations. Renal insufficiency is a com- This phase III, randomized, double- After randomization, patients who mon comorbidity in patients with type blind, active-controlled, two parallel- experienced persistent hyperglycemia 2 diabetes, and the prevalence of group, multicenter, 52-week study (Har- qualified, on the basis of prespecified chronic kidney disease (CKD) in pa- mony 8) (GlaxoSmithKline study number HbA1c and/or fasting plasma glucose tients with type 2 diabetes has been GLP114130) compared the efficacy and (FPG) values, to undergo masked dose increasing (1), with the reported over- safety of once-weekly subcutaneous in- titration followed by hyperglycemia res- all incidence of renal impairment in pa- jections of albiglutide with that of daily cue as needed (Supplementary Table 2). tients with type 2 diabetes ranging oral sitagliptin in renally impaired pa- Given the blinded nature of the study, from15to35%(basedonestimated tients with type 2 diabetes. Renal impair- uptitration also occurred in the sitaglip- glomerular filtration rate [eGFR] ,60 ment was defined as mild (eGFR $60 to tin group, but the actual dose received mL/min/1.73 m2)(2–4). #89 mL/min/1.73 m2), moderate (eGFR did not change. Patients continued to Current treatment options for glyce- $30 to #59 mL/min/1.73 m2), or severe receive study medication in a blinded mic control are significantly limited for (eGFR $15 to #29 mL/min/1.73 m2) fashion after rescue. patients with type 2 diabetes and CKD based on the MDRD formula (22). Albiglu- The primary end point of the study was (5,8–11), which often leads to the in- tide (30 mg) was given subcutaneously to evaluate the efficacy of albiglutide troduction of sulfonylurea and insulin once weekly (with treatment-masked compared with that of sitagliptin on the therapy to maintain glycemic control. uptitration, if needed, to 50 mg weekly), change in HbA1c from baseline at week Further, therapeutic options for glyce- and sitagliptin was dosed based on the 26. Secondary end points over time in- mic control can be associated with sig- eGFR value at randomization per the cluded HbA1c, FPG, body weight, propor- nificant risks of hypoglycemia, weight sitagliptin package insert. All patients tion of patients who met prespecified gain, and fluid retention, which may continued to receive their prescribed HbA1c treatment targets, time to hy- add to the complexity of maintaining oral antihyperglycemic medication reg- perglycemic rescue, and population blood glucose, body weight, and blood imen (metformin, thiazolidinedione, pharmacokinetics of albiglutide. Pharma- pressure in this population (12–15). sulfonylurea, or any combination of cokinetics are not reported here, as a Albiglutide, a novel, long-acting glu- these oral antihyperglycemic medica- population model that combined data cagon-like peptide 1 receptor (GLP-1R) tions) for the duration of the study from this and three other phase III studies agonist, was designed to retain the ther- with the exception of patients with was reported separately (23). Safety end apeutic actions of GLP-1 while having a GFR ,60 mL/min/1.73 m2,whowere points over time included evaluations greatly extended duration of action. Al- washed off their background metfor- of AEs and SAEs, safety events of special biglutide was synthesized through ge- min. Instructions for downtitration of interest, clinical laboratory parameters, netic modification that resulted in the sulfonylureas were also provided to vital sign measurements, electrocardio- attachment of two modified recombi- avoid hypoglycemia. gram readings, and physical examinations. nant human GLP-1 fragments linked in There were four specific study peri- Immunogenicity was also evaluated. tandem to the amino terminus of the ods: prescreening and screening (~2 There were no changes to the statistical coding sequence for human albumin, weeks), run-in (4 weeks), treatment pe- plan, which was finalized before the da- and it retains GLP-1 glucose-dependent riod (52 weeks, including 26 weeks of tabase was frozen and treatment codes insulinotropic activities both in vitro and initial treatment and evaluation for pri- were unblinded. in vivo (16). With a half-life of approxi- mary efficacy and safety followed by an This study was conducted in accor- mately 5 days, the pharmacokinetic additional 26 weeks of treatment for dance with International Conference profile of albiglutide allows for once- secondary efficacy and safety assess- on Harmonisation Good Clinical Practi- weekly subcutaneous injections (16–20). ments), and posttreatment follow-up ces and the Declaration of Helsinki, and To date, reported clinical studies, in- (8 weeks). Patient assessments during all patients provided written informed cluding a phase I study in patients with the treatment period varied between consent before they participated in this varying degrees of renal impairment weekly and quarterly. Independent, study. (GLP108370), have shown albiglutide to blinded adjudication and review of all be an effective, safe, and tolerable ther- suspected cardiovascular events took Patients apy when administered to patients with place over the entire treatment period. Male and nonpregnant, nonlactating fe- type 2 diabetes (16–21). An independent, blinded pancreatitis male patients $18 years of age with his- This study was conducted to compare adjudication committee reviewed all re- torical diagnoses of type 2 diabetes were the efficacy, safety, and tolerability of ported adverse events (AEs) of pancreati- enrolled. Patients were required to have albiglutide given
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