Pharmacokinetics of the Novel Nonsteroidal Mineralocorticoid Receptor Antagonist Ocedurenone (KBP-5074) in Individuals with Moderate Hepatic Impairment.

BACKGROUND AND OBJECTIVES: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of ocedurenone in individuals with moderate hepatic impairment. METHODS: This study was an open-label, nonrandomized, multi-center study investigating the pharmacokinetics, safety, and tolerability of a single dose of 0.5 mg ocedurenone administered orally in male and female subjects with moderate hepatic impairment (Child-Pugh B, score 7-9) compared with subjects with normal hepatic function. Serial blood samples were obtained from predose through 264 h postdose for analysis of ocedurenone concentrations using a validated liquid chromatography-tandem mass spectrometry method. Free ocedurenone concentrations in plasma were determined ex vivo using equilibrium dialysis. RESULTS: Following a single oral dose of 0.5 mg ocedurenone administered to subjects with moderate hepatic impairment and subjects with normal hepatic function, ocedurenone was steadily absorbed with median time to peak drug concentration (Tmax) values of 4 and 3 h, respectively. After reaching maximum plasma concentration (Cmax), the disposition of ocedurenone appeared to be biphasic. The geometric mean t1/2 values for the moderate hepatic impairment group and normal hepatic function group were 75.6 and 65.7 h, respectively. Ocedurenone systemic exposure, as assessed by area under the plasma concentration-time curve (AUC) was 23.5-26.6% lower in subjects with moderate hepatic impairment versus subjects with normal hepatic function, whereas Cmax was 41.2% lower. Ocedurenone was determined to be > 99.7% bound to total protein in plasma. Hepatic impairment appeared not to change plasma protein binding or the unbound free fraction. Ocedurenone was safe and well-tolerated in all participants. CONCLUSIONS: Considering the long half-life of ocedurenone and previously completed clinical studies using 0.25 mg and 0.5 mg doses demonstrating efficacy and safety, the observed decreases in AUC and Cmax do not warrant a dose adjustment in patients with moderate hepatic impairment. A single 0.5 mg dose of ocedurenone was safe and well-tolerated when administered to subjects with moderate hepatic impairment and subjects with normal hepatic function. CLINICAL TRIAL IDENTIFIER ( WWW. CLINICALTRIALS: GOV ): NCT04534699.

Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo.

BACKGROUND AND OBJECTIVES: Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers. METHODS: In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics. RESULTS: The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity (AUC0-inf) by 104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0-inf by 84%. CONCLUSION: Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.

Nonclinical Pharmacokinetics, Protein Binding, and Elimination of KBP-7072, an Aminomethylcycline Antibiotic, in Animal Models.

KBP-7072 is a semisynthetic aminomethylcycline with broad-spectrum activity against Gram-positive and Gram-negative pathogens, including multidrug-resistant bacterial strains. The pharmacokinetics (PK) of KBP-7072 after oral and intravenous (i.v.) administrations of single and multiple doses were investigated in animal models, including during fed and fasted states, and the protein binding and excretion characteristics were also evaluated. In Sprague-Dawley (SD) rats, beagle dogs, and CD-1 mice, KBP-7072 demonstrated a linear PK profile after the administration of single oral and i.v. and multiple oral doses. The oral bioavailability ranged from 12% to 32%. The mean time to maximum concentration (Tmax) ranged from 0.5 to 4 h, and the mean half-life ranged from approximately 6 to 11 h. The administration of oral doses in the fed state resulted in marked reductions in the maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC) compared with dosing in fasted animals. The mean bound fractions of KBP-7072 were 77.5%, 69.8%, 64.5%, 69.3%, and 69.2% in mouse, rat, dog, monkey, and human plasma, respectively. Following a single 22.5-mg/kg oral dose of KBP-7072 in SD rats, the cumulative excretion in feces was 64% and that in urine was 2.5% of the administered dose. The PK results in animal models are consistent with single- and multiple-ascending-dose studies in healthy volunteers and confirm the suitability of KBP-7072 for once-daily oral and i.v. administration in clinical studies.

Beware of on-treatment safety analyses.

INTRODUCTION: Assessing safety is important to evaluating new medications. In many randomized clinical trials, assessment of safety relies on so-called on-treatment analysis, where data on adverse events are collected only while the participant is taking study medication and perhaps for a few (7, 14, or 30) days after stopping. This article discusses the consequence of such failure to use intent-to-treat analyses in assessing safety. METHODS: This article discusses two approaches to analysis of safety data: intention-to-treat and on-treatment analysis with reference to principles of the design of randomized clinical trial. RESULTS: On-treatment analysis violates randomization and is often not well defined. Moreover, because the typical on-treatment analysis ignores the reason participants in clinical trials stop treatment, on-treatment analyses can lead to biased estimates of risk. Examples show biases that can result from failure to count all adverse events. An example from a study of rofecoxib shows an on-treatment analysis that led to likely underestimation of harm; an example from a study of saxagliptin shows an on-treatment analysis that led to a likely overestimate of harms. CONCLUSION: For major safety outcomes in long-term clinical trials, intention-to-treat analysis should be performed in the framework of benefit-risk evaluation. More generally, analyses of safety should be tailored to the specific question being asked with the specific study design under consideration. On-treatment analyses are subject to bias; however, the direction of that bias is not necessarily clear.

Efficacy and safety of once-weekly GLP-1 receptor agonist albiglutide (HARMONY 2): 52 week primary endpoint results from a randomised, placebo-controlled trial in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise.

AIMS/HYPOTHESIS: Additional safe and effective therapies for type 2 diabetes are needed, especially ones that do not cause weight gain and have a low risk of hypoglycaemia. The present study evaluated albiglutide as monotherapy. METHODS: In this placebo-controlled study, 309 patients (aged ≥ 18 years) with type 2 diabetes inadequately controlled by diet and exercise and who were not using a glucose-lowering agent (HbA1c 7.0-10.0% [53.00-85.79 mmol/mol], body mass index 20-45 kg/m(2), and fasting C-peptide ≥ 0.26 nmol/l) were randomised (1:1:1 on a fixed randomisation schedule using an interactive voice response system) to receive once-weekly albiglutide 30 mg (n = 102) or 50 mg (n = 102) or matching placebo (n = 105). The study treatments were blinded to both patients and study personnel. All study data were collected at individual patient clinic visits. The primary efficacy endpoint was change in HbA1c from baseline to week 52. The primary analysis was applied to the intent-to-treat population. Additional efficacy and safety endpoints were assessed. RESULTS: At week 52, both albiglutide 30 mg and 50 mg were superior to placebo in reducing HbA1c. The least-squares means treatment difference from placebo was -0.84% (95% CI -1.11%, -0.58%; p < 0.0001) with albiglutide 30 mg and -1.04% (-1.31%, -0.77%; p < 0.0001) with albiglutide 50 mg. Injection-site reactions were reported more frequently with albiglutide (30 mg: 17.8%; 50 mg: 22.2%) than with placebo (9.9%). Other commonly reported adverse events included nausea, diarrhoea, vomiting and hypoglycaemia; the incidences of these were generally similar across treatment groups. CONCLUSIONS/INTERPRETATION: Albiglutide is safe and effective as monotherapy and significantly lowered HbA1c levels over 52 weeks, did not cause weight gain, and had good gastrointestinal tolerability and a low rate of hypoglycaemia compared with placebo. Trial registration ClinicalTrials.gov NCT00849017 Funding This study was sponsored by GlaxoSmithKline.

Type 2 diabetes mellitus development programs in the new regulatory environment with cardiovascular safety requirements.

For type 2 diabetes mellitus treatment and clinical development, proper evaluation of cardiovascular risk has been required by regulatory agencies (eg, the US Food and Drug Administration) since cardiovascular safety is very important in this patient population. The US Food and Drug Administration issued general guidelines for cardiovascular safety evaluation that outlined the requirements considered adequate for cardiovascular safety evaluation. However, there are multiple options to obtain the data and fulfill these requirements. In this paper, we outline the potential pathways and challenges in various aspects of cardiovascular safety evaluation in type 2 diabetes clinical development, including study design, populations, and endpoints. Specifically, we discuss some challenges in statistical analysis which have implications for the design, implementation, and interpretation of these outcome studies.

Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: a randomized phase III study.

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 primary study end point was HbA1c 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. RESULTS: Baseline demographics were similar across treatment and renal impairment groups with overall mean age of 63.3 years, BMI of 30.4 kg/m(2), HbA1c of 8.2% (66 mmol/mol), and diabetes disease duration of 11.2 years. HbA1c change from baseline at week 26 was significantly greater for albiglutide than sitagliptin (-0.83% vs. -0.52%, P = 0.0003). Decreases in HbA1c, 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. CONCLUSIONS: Once-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.

Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro.

OBJECTIVE: GLP-1 receptor agonists may provide an alternative to prandial insulin for advancing basal insulin therapy. Harmony 6 was a randomized, open-label, active-controlled trial testing once-weekly albiglutide vs. thrice-daily prandial insulin lispro as an add-on to titrated once-daily insulin glargine. RESEARCH DESIGN AND METHODS: Patients taking basal insulin (with or without oral agents) with HbA1c 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 HbA1c change from baseline at week 26. RESULTS: At week 26, HbA1c decreased from baseline by -0.82 ± SE 0.06% (9.0 mmol/mol) with albiglutide and -0.66 ± 0.06% (7.2 mmol/mol) with lispro; treatment difference, -0.16% (95% CI -0.32 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 (-0.73 ± 0.19 kg vs. +0.81 ± 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%). CONCLUSIONS: Weekly albiglutide is a simpler therapeutic option than thrice-daily lispro for advancing basal insulin glargine therapy, resulting in comparable HbA1c reduction with weight loss and lower hypoglycemia risk.

HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin.

OBJECTIVE: To compare the efficacy and safety of weekly albiglutide with daily sitagliptin, daily glimepiride, and placebo. RESEARCH DESIGN AND METHODS: Patients 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 HbA1c from baseline at week 104. Secondary end points included fasting plasma glucose (FPG), weight, and time to hyperglycemic rescue. RESULTS: Baseline characteristics were similar among the albiglutide (n = 302), glimepiride (n = 307), sitagliptin (n = 302), and placebo (n = 101) groups. Baseline HbA1c 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 HbA1c compared with placebo (-0.9% [-9.8 mmol/mol]; P < 0.0001), sitagliptin (-0.4% [-4.4 mmol/mol]; P = 0.0001), and glimepiride (-0.3% [-3.3 mmol/mol]; P = 0.0033). Outcomes for FPG and HbA1c were similar. Weight change from baseline for each were as follows: albiglutide -1.21 kg (95% CI -1.68 to -0.74), placebo -1.00 kg (95% CI -1.81 to -0.20), sitagliptin -0.86 kg (95% CI -1.32 to -0.39), glimepiride 1.17 kg (95% CI 0.70-1.63). 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. CONCLUSIONS: Added to metformin, albiglutide was well tolerated; produced superior reductions in HbA1c and FPG at week 104 compared with placebo, sitagliptin, and glimepiride; and resulted in weight loss compared with glimepiride.

Effect of renal impairment on the pharmacokinetics, efficacy, and safety of albiglutide.

BACKGROUND: Chronic kidney disease is frequently present in patients with type 2 diabetes mellitus (T2DM). New therapeutic options in this patient subpopulation are needed. OBJECTIVES: Assess the effect of renal impairment on the pharmacokinetics (PK), efficacy, and safety of albiglutide in single- and multiple-dose studies. METHODS: Pharmacokinetics, safety, and efficacy of once weekly albiglutide in patients with T2DM was assessed from a single-dose (30 mg), nonrandomized, open-label study (N = 41) including subjects with normal and varying degrees of renal impairment, including hemodialysis, and a pooled analysis of 4 phase 3, randomized, double-blind (1 open-label), active or placebo-controlled multiple-dose studies. The pooled analysis of the latter 4 studies (N = 1113) was part of the population PK analysis, which included subjects with normal and varying degrees of renal impairment (mild, moderate, severe) treated with albiglutide (30 to 50 mg) to primary end points of 26 to 52 weeks. RESULTS: Single-dose PK showed area-under-the-curve ratios (and 90% CIs) of 1.32 (0.96-1.80), 1.39 (1.03-1.89), and 0.99 (0.63-1.57) for the moderate, severe, and hemodialysis groups, respectively, relative to the normal group. Results indicate that modest increases in plasma concentration of albiglutide were observed with the severity of renal impairment. There was a trend for more glycemic lowering as the estimated glomerular filtration rate decreased. The severe group had a higher frequency of gastrointestinal (eg, diarrhea, constipation, nausea, and vomiting) and hypoglycemic (with background sulfonylurea use) events compared with patients with mild or moderate renal impairment. CONCLUSION: The PK, efficacy, and safety data indicate that albiglutide has a favorable benefit/risk ratio in patients with T2DM and varying degrees of renal impairment, and the need for a dose adjustment is not suggested. Experience in patients with more severe renal impairment is very limited, so the recommendation is to use albiglutide carefully in this population. CLINICAL TRIAL REGISTRATION: (ClinicalTrials.gov):NCT00938158, NCT00849017, NCT00838916, NCT00839527, NCT0198539.

Potential modification of the UKPDS risk engine and evaluation of macrovascular event rates in controlled clinical trials.

BACKGROUND: The aim of this study was to evaluate a modified UKPDS risk engine in order to establish a risk prediction benchmark for the general diabetes population. METHODS: Data sources were summary demographic and risk factor data from the major type 2 diabetes mellitus outcomes studies, including ACCORD, ADVANCE, VADT, RECORD, PROactive, ADOPT, and BARI 2D. Patients in these studies spanned a wide spectrum of disease, from drug-naïve to insulin-dependent. Cardiovascular events/major adverse coronary events (CVE/MACE) were primary or safety end points. Overall observed rates for cardiovascular events/MACE were summarized, and the observed annualized event rates were calculated using linear approximation. Simulation studies were then conducted using original (cardiovascular history excluded) and modified (cardiovascular history included) United Kingdom Prospective Diabetes Study (UKPDS) models; the predicted event rates were then compared with the observed event rates for all studies. The consistency of the predicted rates derived from each model was then evaluated using descriptive statistics and linear regression. RESULTS: The original UKPDS model tended to overestimate event rates across studies. The ratio of predicted events versus observed MACE ranged from 0.9 to 2.0, with mean of 1.5 ± 0.4 and a coefficient of variation of 26% (R(2) = 0.80). However, cardiovascular risk predictions were more precise using a modified UKPDS model; the ratio of predicted versus observed MACE events ranged from 1.8 to 2.4, with a mean of 2.1 ± 0.25 and a coefficient of variation of 13% (R(2) = 0.94). CONCLUSION: A modified UKPDS model which includes adjustments for prior cardiovascular history has the potential for use as a tool for benchmarking and may be useful for predicting cardiovascular rates in clinical studies. This modification could be further evaluated, recalibrated, and validated using patient-level information derived from prospective clinical studies to yield greater predictability.

Safety, tolerability, pharmacokinetics and pharmacodynamics of albiglutide, a long-acting GLP-1-receptor agonist, in Japanese subjects with type 2 diabetes mellitus.

OBJECTIVE: To investigate safety, pharmacokinetics and pharmacodynamics of albiglutide in Japanese subjects with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: This randomized, single-blind, placebo-controlled study examined four doses/dose schedules of subcutaneously (sc) administered albiglutide: 15 mg weekly, 30 mg weekly, 50 mg biweekly, and 100 mg monthly (cohorts A-D, respectively) in 40 subjects (mean age 54.5 years, mean range of glycosylated hemoglobin [HbA(1c)] 7.1-8.3%), over a 4-week treatment period. MAIN OUTCOME MEASURES: Safety parameters, including adverse events, clinical laboratory tests, vital signs, and 12-lead electrocardiogram; plasma concentrations of albiglutide; and pharmacodynamic parameters, including change from baseline and weighted mean AUC(0-4) in plasma glucose, glucagon, insulin, and C-peptide levels. CLINICAL TRIAL REGISTRATION: NCT00530309. RESULTS: At day 29, mean changes from baseline (vs. placebo) in fasting plasma glucose (FPG) were: cohort A, -1.92 mmol/L; B, -1.98 mmol/L; C, -1.74 mmol/L; D, -0.73 mmol/L; changes in weighted mean glucose AUC(0-4) were: cohort A, -2.86 mmol/L; B, -3.58 mmol/L; C, -2.51 mmol/L; D, -1.44 mmol/L (for FPG and AUC(0-4), all p < or = 0.002 except 100 mg sc monthly, p = NS); changes from baseline HbA(1c) were: cohort A, -0.58%; B, -0.57%; C, -0.63%; and D, -0.51% (all p < 0.03). Albiglutide sc had a median half-life of 5.3 days, plasma apparent systemic clearance of 68.7 mL/h, and apparent volume of distribution of 12.6 L. Incidence of adverse events was low and comparable to sc placebo in all albiglutide treatment arms except 100 mg sc monthly, where gastrointestinal (GI) adverse events were most common. Limitations of this study include the small sample size, short treatment duration, and enrollment of predominantly male subjects. CONCLUSIONS: Weekly and biweekly albiglutide improved glycemic control and were well-tolerated in Japanese subjects with type 2 diabetes mellitus.

Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing.

OBJECTIVE: To 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 METHODS: In 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/m(2), 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. RESULTS: Dose-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. CONCLUSIONS: Weekly albiglutide administration significantly improved glycemic control and elicited weight loss in type 2 diabetic patients, with a favorable safety and tolerability profile.