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Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study

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Summary

Background

As new members of a drug class are developed, head-to-head trials are an important strategy to guide personalised treatment decisions. We assessed two glucagon-like peptide-1 receptor agonists, once-weekly albiglutide and once-daily liraglutide, in patients with type 2 diabetes inadequately controlled on oral antidiabetic drugs.

Methods

We undertook this 32-week, open-label, phase 3 non-inferiority study at 162 sites in eight countries: USA (121 sites), Australia (9 sites), Peru (7 sites), Philippines (7 sites), South Korea (5 sites), UK (5 sites), Israel (4 sites), and Spain (4 sites). 841 adult participants (aged ≥18 years) with inadequately controlled type 2 diabetes and a BMI between 20 and 45 kg/m2 were enrolled and randomised in a 1:1 ratio to receive albiglutide 30 mg once weekly titrated to 50 mg at week 6, or liraglutide 0·6 mg once daily titrated to 1·2 mg at week 1 and 1·8 mg at week 2. The randomisation schedule was generated by an independent randomisation team by the permuted block method with a fixed block size of 16. Participants and investigators were unmasked to treatment. The primary endpoint was change from baseline in HbA1c for albiglutide versus liraglutide, with a 95% CI non-inferiority upper margin of 0·3%. The primary analysis was by modified intention to treat. The study is registered with ClinicalTrials.gov, number NCT01128894.

Findings

422 patients were randomly allocated to the albigultide group and 419 to the liraglutide group; 404 patients in the abliglutide group and 408 in the liraglutide group received the study drugs. The primary endpoint analysis was done on the modified intention-to-treat population, which included 402 participants in the albiglutide group and 403 in the liraglutide group. Model-adjusted change in HbA1c from baseline to week 32 was −0·78% (95% CI −0·87 to −0·69) in the albigludite group and −0·99% (–1·08 to −0·90) in the liraglutide group; treatment difference was 0·21% (0·08–0·34; non-inferiority p value=0·0846). Injection-site reactions occurred in more patients given albiglutide than in those given liraglutide (12·9% vs 5·4%; treatment difference 7·5% [95% CI 3·6–11·4]; p=0·0002), whereas the opposite was the case for gastrointestinal events, which occurred in 49·0% of patients in the liraglutide group versus 35·9% in the albiglutide group (treatment difference −13·1% [95% CI −19·9 to −6·4]; p=0·00013).

Interpretation

Patients who received once-daily liraglutide had greater reductions in HbA1c than did those who received once-weekly albiglutide. Participants in the albiglutide group had more injection-site reactions and fewer gastrointestinal events than did those in the liraglutide group.

Funding

GlaxoSmithKline.

Introduction

Clinical studies have consistently shown that injectable glucagon-like peptide-1 (GLP-1) receptor agonists improve diabetes control by promoting glucose-dependent insulin secretion, reducing postprandial glucagon secretion, and inducing satiety and weight loss.1, 2 Liraglutide is a once-daily GLP-1 receptor agonist that is acylated to prolong its half-life.3 Albiglutide is a GLP-1 receptor agonist composed of a dipeptidyl peptidase 4- resistant GLP-1 dimer fused to recombinant human albumin, with a half-life of roughly 5 days.4, 5, 6, 7 In a previous phase 2 trial, albiglutide reduced HbA1c at doses of 30 mg weekly (–0·87% [SD 0·65]), 50 mg every 2 weeks (–0·79% [0·98]), and 100 mg monthly (–0·87% [0·87]) compared with placebo.5 The lowest frequency of gastrointestinal adverse events was reported with the 30 mg weekly dose.5

In this head-to-head phase 3 trial, we compare the efficacy and safety of once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes uncontrolled on their existing oral antidiabetic treatment to provide objective evidence about the benefits and limitations of these two members of the GLP-1 receptor agonist drug class.

Section snippets

Study design and participants

Harmony 7 was a randomised, open-label, parallel-group, multicentre, phase 3 study, with the aim of assessing the efficacy and safety of once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes uncontrolled on oral antidiabetic drugs. The study comprised four periods: screening, 4 weeks of run-in and stabilisation, 32 weeks of treatment, and 8 weeks of post-treatment follow-up. Data were collected from participants between May 5, 2010 (first participant, first

Results

841 patients with type 2 diabetes were enrolled in this study, and 812 were randomly allocated to the two study drugs (404 albiglutide and 408 liraglutide; figure 1). Table 1 summarises the baseline characteristics of the trial participants, most of whom were already on two or more oral antidiabetic drugs. Mean adherence in the albiglutide group was greater than 98%, based on returned investigational product single-dose pens; we could not accurately calculate adherence for patients assigned to

Discussion

Head-to-head trials are an important strategy to assess the range of clinical benefits and limitations of different compounds (panel).10, 11, 12, 13 Our findings show clinically relevant glycaemic lowering with both albiglutide and liraglutide. The predefined statistical outcome for non-inferiority of albiglutide of a 95% CI upper margin of 0·3% was not met. Additionally, both GLP-1 receptor agonists in this study led to weight loss; however, weight loss was less with albiglutide than with

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