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

Abstract

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 ≤ 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.

Key words::

• Albiglutide
• GLP-1
• Incretin
• Japanese
• Type 2 diabetes mellitus

Transparency

Declaration of funding

Funding for this study was provided by GlaxoSmithKline (NCT00530309).

Declaration of financial/other relationships

Y.S. has disclosed that he has participated in advisory panels for GlaxoSmithKline, NovoNordisk and other pharmaceutical companies. H.N., T.K., M.A.B., F.Y. and M.S. have disclosed that they are employees and stockholders of GlaxoSmithKline. H.M. has disclosed that he is an employee of GlaxoSmithKline.

Some peer reviewers receive honoraria from CMRO for their review work. The peer reviewers of this paper have disclosed that they have no relevant financial relationships.

Acknowledgment

The authors acknowledge the following employees of GlaxoSmithKline for their contributions: Kenneth Pomerantz, PhD, for editorial suggestions and management of manuscript development; and Hui Zhi, PhD for assistance with the statistical analyses. Editorial support also was provided by Daniel Clarke, PhD (assistance with the production of draft outline, production of manuscript first draft, assembling tables and figures, collating author comments), Joelle Escoffery, PhD (assistance with the production of draft outline, production of manuscript first draft, assembling tables and figures, collating author comments, fact checking, referencing), Michelle Evans, PhD (assembling tables and figures, collating author comments), Jessica Roth-Cross, PhD (fact checking and referencing), Beverly Stanley (copyediting), Sean Tarricone (graphic services) and Tracey Wood, PhD (assistance with the production of draft outline and manuscript first draft, assembling tables and figures), at Meditech Media, Hamilton, NJ, USA and London, UK, which was funded by GlaxoSmithKline.

The albiglutide study group is comprised of the authors of this manuscript and Takashi Eto, MD, PhD (PS Clinic, Fukuoka, Japan); Masami Fujita, MD, PhD (Shinanozaka Clinic, Tokyo, Japan) and Yukikuni Sakata, MD, PhD, (Honjo Clinic, Tokyo, Japan).

All authors contributed to the interpretation of the data and the development and approval of the manuscript. All authors were fully involved in the manuscript development and assume responsibility for the direction and content.

Portions of data from this study were presented at the American Diabetes Association 69th Scientific Sessions, New Orleans, LA, USA, June 5–9, 2009.