OBJECTIVETo evaluate the efficacy, safety, and tolerability of incremental doses of albiglutide, a long-acting glucagon-like peptide-1 receptor agonist, administered with three dosing schedules in patients with type 2 diabetes inadequately controlled with diet and exercise or metformin monotherapy.RESEARCH DESIGN AND METHODSIn this randomized multicenter double-blind parallel-group study, 356 type 2 diabetic subjects with similar mean baseline characteristics (age 54 years, diabetes duration 4.9 years, BMI 32.1 kg/m2, A1C 8.0%) received subcutaneous placebo or albiglutide (weekly [4, 15, or 30 mg], biweekly [15, 30, or 50 mg], or monthly [50 or 100 mg]) or exenatide twice daily as an open-label active reference (per labeling in metformin subjects only) over 16 weeks followed by an 11-week washout period. The main outcome measure was change from baseline A1C of albiglutide groups versus placebo at week 16.RESULTSDose-dependent reductions in A1C were observed within all albiglutide schedules. Mean A1C was similarly reduced from baseline by albiglutide 30 mg weekly, 50 mg biweekly (every 2 weeks), and 100 mg monthly (−0.87, −0.79, and −0.87%, respectively) versus placebo (−0.17%, P < 0.004) and exenatide (−0.54%). Weight loss (−1.1 to −1.7 kg) was observed with these three albiglutide doses with no significant between-group effects. The incidence of gastrointestinal adverse events in subjects receiving albiglutide 30 mg weekly was less than that observed for the highest biweekly and monthly doses of albiglutide or exenatide.CONCLUSIONSWeekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.

OBJECTIVETo compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo. RESEARCH DESIGN AND METHODSPatients with type 2 diabetes receiving metformin were randomized to albiglutide (30 mg), sitagliptin (100 mg), glimepiride (2 mg), or placebo. Blinded dose titration for albiglutide (to 50 mg) and glimepiride (to 4 mg) was based on predefined hyperglycemia criteria. The primary end point was change in HbA 1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue. RESULTSBaseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA 1c was 8.1% (65.0 mmol/mol); mean age was 54.5 years. The mean doses for albiglutide and glimepiride at week 104 were 40.5 and 3.1 mg, respectively. At week 104, albiglutide significantly reduced HbA The difference between albiglutide and glimepiride was statistically significant (P < 0.0001). Hyperglycemic rescue rate at week 104 was 25.8% for albiglutide compared with 59.2% (P < 0.0001), 36.4% (P = 0.0118), and 32.7% (P = 0.1504) for placebo, sitagliptin, and glimepiride, respectively. Rates of serious adverse events in the albiglutide group were similar to comparison groups. Diarrhea (albiglutide 12.9%, other groups 8.6-10.9%) and nausea (albiglutide 10.3%, other groups 6.2-10.9%) were generally the most frequently reported gastrointestinal events. CONCLUSIONSAdded to metformin, albiglutide was well tolerated; produced superior reductions in HbA 1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.

OBJECTIVEGLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, activecontrolled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. RESEARCH DESIGN AND METHODSPatients taking basal insulin (with or without oral agents) with HbA 1c 7-10.5% (53-91 mmol/mol) entered a glargine standardization period, followed by randomization to albiglutide, 30 mg weekly (n = 282), subsequently uptitrated to 50 mg, if necessary, or thrice-daily prandial lispro (n = 281) while continuing metformin and/or pioglitazone. Glargine was titrated to fasting plasma glucose of <5.6 mmol/L, and lispro was adjusted based on glucose monitoring. The primary end point was the difference in the HbA 1c change from baseline at week 26. RESULTSAt week 26, HbA 1c decreased from baseline by 20.82 6 SE 0.06% (9.0 mmol/mol) with albiglutide and 20.66 6 0.06% (7.2 mmol/mol) with lispro; treatment difference, 20.16% (95% CI 20.32 to 0.00; 1.8 mmol/mol; P < 0.0001), meeting the noninferiority end point (margin, 0.4%). Weight decreased with albiglutide but increased with lispro (20.73 6 0.19 kg vs. +0.81 6 0.19 kg). The mean glargine dose increased from 47 to 53 IU (albiglutide) and from 44 to 51 IU (lispro). Adverse events for albiglutide versus lispro included severe hypoglycemia (0 vs. 2 events), documented symptomatic hypoglycemia (15.8% vs. 29.9%), nausea (11.2% vs. 1.4%), vomiting (6.7% vs. 1.4%), and injection site reactions (9.5% vs. 5.3%). CONCLUSIONSWeekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA 1c reduction with weight loss and lower hypoglycemia risk.

OBJECTIVETo 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 METHODSIn this phase III, randomized, double-blind, multicenter, 52-week study, the primary study end point was HbA 1c change from baseline at week 26 in patients with renal impairment, as assessed with estimated glomerular filtration rate and categorized as mild, moderate, or severe ( ‡60 to £89, ‡30 to £59, and ‡15 to £29 mL/min/1.73 m 2 , respectively). Secondary end points included fasting plasma glucose (FPG), weight, achievement of treatment targets, hyperglycemic rescue, and safety. RESULTSBaseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years, BMI of 30.4 kg/m 2 , HbA 1c of 8.2% (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA 1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin (20.83% vs. 20.52%, P = 0.0003). Decreases in HbA 1c , FPG, and weight were seen through week 52. Time to hyperglycemic rescue through week 52 was significantly longer for albiglutide than sitagliptin (P = 0.0017). Results of safety assessments were similar between groups, and most adverse events (AEs) were mild or moderate. The incidences of gastrointestinal AEs for albiglutide and sitagliptin were as follows: overall, 31.7%, 25.2%; diarrhea, 10.0%, 6.5%; nausea, 4.8%, 3.3%; and vomiting, 1.6%, 1.2%, respectively. CONCLUSIONSOnce-weekly albiglutide therapy in renally impaired patients with type 2 diabetes provided statistically superior glycemic improvement with almost similar tolerability compared with daily sitagliptin therapy.

Breaking down the entire structure of a material implies severing all the bonds between its atoms either by applying work or by heat transfer. Because bond-breaking is indifferent to either means, there is a kind of equivalence between heat energy and strain energy. Based on this equivalence, we assume the existence of a constant maximum storage of energy that includes both the strain energy and the corresponding equivalent heat energy. A temperaturedependent fracture strength model is then developed for ultrahigh temperature ceramics (UHTCs). Model predictions for UHTCs, HfB 2 , TiC and ZrB 2 , are presented and compared with the experimental results. These predictions are found to be largely consistent with experimental results.