Elsevier

The Lancet

Volume 394, Issue 10192, 6–12 July 2019, Pages 39-50
The Lancet

Articles
Oral semaglutide versus subcutaneous liraglutide and placebo in type 2 diabetes (PIONEER 4): a randomised, double-blind, phase 3a trial

https://doi.org/10.1016/S0140-6736(19)31271-1Get rights and content

Summary

Background

Glucagon-like peptide-1 (GLP-1) receptor agonists are effective treatments for type 2 diabetes, lowering glycated haemoglobin (HbA1c) and weight, but are currently only approved for use as subcutaneous injections. Oral semaglutide, a novel GLP-1 agonist, was compared with subcutaneous liraglutide and placebo in patients with type 2 diabetes.

Methods

In this randomised, double-blind, double-dummy, phase 3a trial, we recruited patients with type 2 diabetes from 100 sites in 12 countries. Eligible patients were aged 18 years or older, with HbA1c of 7·0–9·5% (53–80·3 mmol/mol), on a stable dose of metformin (≥1500 mg or maximum tolerated) with or without a sodium-glucose co-transporter-2 inhibitor. Participants were randomly assigned (2:2:1) with an interactive web-response system and stratified by background glucose-lowering medication and country of origin, to once-daily oral semaglutide (dose escalated to 14 mg), once-daily subcutaneous liraglutide (dose escalated to 1·8 mg), or placebo for 52 weeks. Two estimands were defined: treatment policy (regardless of study drug discontinuation or rescue medication) and trial product (assumed all participants were on study drug without rescue medication) in all participants who were randomly assigned. The treatment policy estimand was the primary estimand. The primary endpoint was change from baseline to week 26 in HbA1c (oral semaglutide superiority vs placebo and non-inferiority [margin: 0·4%] and superiority vs subcutaneous liraglutide) and the confirmatory secondary endpoint was change from baseline to week 26 in bodyweight (oral semaglutide superiority vs placebo and liraglutide). Safety was assessed in all participants who received at least one dose of study drug. This trial is registered on Clinicaltrials.gov, number NCT02863419, and the European Clinical Trials registry, number EudraCT 2015-005210-30.

Findings

Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were eligible and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 341 (48%) of 711 participants were female and the mean age was 56 years (SD 10). All participants were given at least one dose of study drug, and 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. Mean change from baseline in HbA1c at week 26 was −1·2% (SE 0·1) with oral semaglutide, −1·1% (SE 0·1) with subcutaneous liraglutide, and −0·2% (SE 0·1) with placebo. Oral semaglutide was non-inferior to subcutaneous liraglutide in decreasing HbA1c (estimated treatment difference [ETD] −0·1%, 95% CI −0·3 to 0·0; p<0·0001) and superior to placebo (ETD −1·1%, −1·2 to −0·9; p<0·0001) by use of the treatment policy estimand. By use of the trial product estimand, oral semaglutide had significantly greater decreases in HbA1c than both subcutaneous liraglutide (ETD −0·2%, 95% CI −0·3 to −0·1; p=0·0056) and placebo (ETD −1·2%, −1·4 to −1·0; p<0·0001) at week 26. Oral semaglutide resulted in superior weight loss (−4·4 kg [SE 0·2]) compared with liraglutide (−3·1 kg [SE 0·2]; ETD −1·2 kg, 95% CI −1·9 to −0·6; p=0·0003) and placebo (−0·5 kg [SE 0·3]; ETD −3·8 kg, −4·7 to −3·0; p<0·0001) at week 26 (treatment policy). By use of the trial product estimand, weight loss at week 26 was significantly greater with oral semaglutide than with subcutaneous liraglutide (−1·5 kg, 95% CI −2·2 to −0·9; p<0·0001) and placebo (ETD −4·0 kg, −4·8 to −3·2; p<0·0001). Adverse events were more frequent with oral semaglutide (n=229 [80%]) and subcutaneous liraglutide (n=211 [74%]) than with placebo (n=95 [67%]).

Interpretation

Oral semaglutide was non-inferior to subcutaneous liraglutide and superior to placebo in decreasing HbA1c, and superior in decreasing bodyweight compared with both liraglutide and placebo at week 26. Safety and tolerability of oral semaglutide were similar to subcutaneous liraglutide. Use of oral semaglutide could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care.

Funding

Novo Nordisk A/S.

Introduction

Glucagon-like peptide-1 (GLP-1) receptor agonists that are currently available for the treatment of type 2 diabetes are all administered by subcutaneous injection.1 Within the class, substantial differences in structure, dosing interval, and efficacy exist. Liraglutide is a once-daily GLP-1 receptor agonist that decreases glycated haemoglobin (HbA1c) and bodyweight in patients with type 2 diabetes across the continuum of care.2, 3 Among once-weekly GLP-1 receptor agonists, subcutaneous semaglutide has superior glycaemic control and weight loss compared with exenatide and dulaglutide.4, 5 Both liraglutide and subcutaneous semaglutide have shown a cardiovascular benefit and are recommended for patients with type 2 diabetes and cardiovascular disease.6, 7, 8

An oral formulation of semaglutide is in development. Orally delivered peptides typically have low bioavailability and so oral semaglutide is co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, which facilitates semaglutide absorption across the gastric mucosa.9 In previous trials, oral semaglutide showed significantly greater decreases in HbA1c and bodyweight compared with placebo in patients with type 2 diabetes uncontrolled by diet and exercise.10, 11 Oral semaglutide at 7 mg and 14 mg per day also resulted in significantly greater decreases in HbA1c and bodyweight over 26 weeks versus the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes uncontrolled on metformin with or without sulfonylurea.12

This phase 3a trial, PIONEER 4, is the first to compare the efficacy and safety of oral semaglutide with a subcutaneously injected GLP-1 receptor agonist, liraglutide, and placebo in patients with type 2 diabetes uncontrolled on background metformin with or without a sodium-glucose co-transporter-2 (SGLT2) inhibitor.

Section snippets

Study design

PIONEER 4 was a 52-week, randomised, double-blind, double-dummy, active-controlled, and placebo-controlled phase 3a trial undertaken at 100 trial sites in 12 countries (Croatia, Czech Republic, Germany, Hungary, Japan, Latvia, Poland, Slovakia, South Africa, Ukraine, United Arab Emirates, and the USA).

Two different questions related to efficacy were addressed through the definition of two estimands: the treatment policy estimand and the trial product estimand, which were defined on the basis of

Results

Between Aug 10, 2016, and Feb 7, 2017, 950 patients were screened, of whom 711 were enrolled and randomly assigned to oral semaglutide (n=285), subcutaneous liraglutide (n=284), or placebo (n=142). 277 (97%) participants in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group completed the 52-week trial period. All participants were given at least one dose of assigned treatment and treatment was completed without rescue medication for 223 (78%) of

Discussion

In PIONEER 4, oral semaglutide was compared with daily injections of subcutaneous liraglutide and placebo in patients with type 2 diabetes receiving metformin with or without an SGLT2 inhibitor. Using the treatment policy estimand, oral semaglutide was non-inferior to once-daily subcutaneous liraglutide given at the highest approved dose for the treatment of type 2 diabetes and superior to placebo in decreasing HbA1c at week 26. Additionally, significantly greater decreases in HbA1c were

Data sharing

Data will be shared with researchers who submit a research proposal approved by an independent review board. Access request proposals can be found at novonordisk-trials.com. Data will be made available after research completion and approval of the product and product use in the EU and the USA. Individual participant data will be shared in datasets in a de-identified and anonymised format. There will not be any limitations on how these data can be used.

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