Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes

Abstract

Objective:

Liraglutide is a once-daily human glucagon-like peptide-1 (GLP-1) analogue developed for the treatment of type 2 diabetes mellitus (T2DM). In Phase 2 and Phase 3 trials, largely conducted in populations of European descent, liraglutide has been shown to lower HbA_1C, weight and systolic blood pressure with a low risk of hypoglycaemia. This Phase 3, 24-week, multi-centre, double-blind, double dummy, randomised parallel-group trial compared the efficacy and safety of liraglutide and glibenclamide monotherapy in Japanese subjects with T2DM, inadequately controlled with diet therapy or oral antidiabetic drug (OAD) monotherapy.

Research design and methods:

A total of 411 Japanese subjects were randomised 2:1 to liraglutide (n = 272) or glibenclamide (n = 139). Liraglutide was administered at a maximum planned dose of 0.9 mg once daily. Glibenclamide was administered once or twice daily at a planned maximum dose of 2.5 mg/day, before or after meals.

Clinical trial registration:

NCT00393718.

Results:

After 24 weeks, glycaemic control with liraglutide was non-inferior/superior to glibenclamide, with HbA_1C at 24 weeks of 6.99% (SE ± 0.07) with liraglutide and 7.50% (±0.09) with glibenclamide (difference, −0.5%; 95% CI −0.70 to 0.30; p < 0.0001). Mean fasting plasma glucose (FPG) levels at 24 weeks were significantly lower with liraglutide (7.6 mmol/l [SE ± 0.1]) vs glibenclamide (8.3 mmol/l [±0.1]; difference, −0.72 mmol/l; 95% CI −1.0 to −0.4; p < 0.0001). Weight was reduced by −0.92 kg from a baseline of 65.2 kg in liraglutide-treated patients, compared with weight gain of +0.99 kg from a baseline of 64.8 kg with glibenclamide (difference, −1.91 kg; 95% CI −2.34 to −1.48; p < 0.0001). A significantly lower rate of minor hypoglycaemic episodes was achieved with liraglutide compared with glibenclamide (p < 0.0001), and no major hypoglycaemic episodes were reported in either treatment group. The most common gastrointestinal AEs were diarrhoea (liraglutide, 6.3%; glibenclamide, 3.8%) and constipation (liraglutide, 5.6%; glibenclamide, 3.8%). Nausea was infrequent (liraglutide, 4.5%; glibenclamide, 1.5%).

Conclusions:

Liraglutide monotherapy, administered once daily for 24 weeks in Japanese subjects with T2DM, was well tolerated. Compared with glibenclamide monotherapy, liraglutide achieved superior glycaemic control and weight outcome, and a significantly lower incidence of hypoglycaemia. Future studies, comprising a greater proportion of true therapy-naïve Japanese patients, will be beneficial in order to establish the true add-on efficacy of liraglutide monotherapy in patients with T2DM.

Key words::

• GLP-1
• Hypoglycaemia
• Liraglutide
• Type 2 diabetes
• Weight regulation

Transparency

Declaration of funding

This study was conducted as part of the development program for liraglutide, and was supported by Novo Nordisk Pharma Ltd, Japan.

Declaration of financial/other relationships

M.F.R. and T.N. have disclosed that they are employees of Novo Nordisk, and Y.S. and K.K. have disclosed that they are advisors to Novo Nordisk.

Peer reviewers may receive honoraria from CMRO for their review work. Peer Reviewer 1 has disclosed he/she is a stockholder of Merck & Co. Inc.; Peer Reviewer 2 has disclosed that he/she has no relevant financial relationships.

Acknowledgements

The authors wish to thank Elena Mills, Stephanie Finucane, and Lisa Sullivan of Watermeadow Medical plc for their assistance in the preparation of this manuscript. Funding for editorial assistance for this manuscript was provided by Novo Nordisk A/S.