Little Difference With Oral Semaglutide vs Liraglutide in Diabetes

Becky McCall

June 11, 2019

SAN FRANCISCO — Oral semaglutide, an investigational agent, is noninferior to subcutaneous liraglutide in reducing HbA1c in patients with type 2 diabetes and superior in terms of weight loss, show results of the PIONEER 4 trial, the first study to compare the efficacy and safety of this form of semaglutide with liraglutide. The results were reported here at the American Diabetes Association (ADA) 2019 Scientific Sessions.

Both are glucagon-like peptide-1 (GLP-1) receptor agonists and both are Novo Nordisk agents. Liraglutide (Victoza) has been on the market for some years. Oral semaglutide is awaiting approval by the US Food and Drug Administration, but a subcutaneous formulation of the drug (Ozempic) was approved in the United States in December 2017.

Also presented here in a poster were findings from PIONEER 7, which compared the efficacy and safety of oral semaglutide once daily with flexible dose adjustment versus the DPP-4 inhibitor sitagliptin (Januvia, Merck) in patients with type 2 diabetes. Oral semaglutide was better at controlling glucose and induced more weight loss compared with sitagliptin after 52 weeks.

Both studies and accompanying commentaries have been published: PIONEER 4 in the Lancet and PIONEER 7 in Lancet Diabetes & Endocrinology. PIONEER is a series of 10 phase 3 trials of oral semaglutide.

Presenting the PIONEER 4 data, Richard Pratley, MD, director of the Florida Hospital Diabetes Institute, Orlando, pointed out that because many patients and providers are reluctant to initiate or intensify therapy by injection, "oral semaglutide might be an effective treatment option, potentially leading to earlier initiation of GLP-1 agonist therapy in the diabetes treatment continuum of care."

Significant reductions in HbA1c and bodyweight with oral semaglutide compared with both subcutaneous liraglutide and placebo at week 52 suggest a long-term benefit with continued oral semaglutide therapy, writes Pratley and coauthors.

Small Differences Between Oral Semaglutide and Liraglutide

In an accompanying comment, Jens Juul Holst, MD, University of Copenhagen, Denmark, notes the PIONEER 4 trial "ventured into an area in which the outcome could not have been predicted: direct comparison with one of the most used GLP-1 receptor agonists, once-daily subcutaneous liraglutide at 1.8 mg."

Holst, who is known for discovering the GLP-1 hormone, adds that PIONEER 4 shows the first oral GLP-1 agonist has effects that are similar to those of the most widely used injectable GLP-1 agonist.

But he notes that although significant, the overall clinical differences between oral semaglutide and subcutaneous liraglutide were small.

Given the similarity between the two GLP-1 agonists, Holst says: "We are potentially moving towards a situation in the future in which patients and clinicians could have a choice [if oral semaglutide is approved]: to take a pill or a daily injection."

He adds that, because oral semaglutide must be taken on an empty stomach 30 minutes prior to food, it might be inconvenient for some patients, and that other injectable GLP-1 receptor agonists are available that only need to be given once weekly.

First Study to Compare Oral Semaglutide With Liraglutide

PIONEER 4 was a randomized controlled, double-dummy, double-blind, 52-week phase 3 trial of 711 patients with type 2 diabetes uncontrolled with metformin (with or without additional SGLT2 inhibitor treatment). Participants were randomized to oral semaglutide (dose escalated to 14 mg once daily; n = 285), once-daily liraglutide (dose escalated to 1.8 mg; n = 284), or placebo (n = 142).

Women comprised 48% of participants, mean age was 56 years, and mean diabetes duration was 7.6 years. Change from baseline to week 26 in HbA1c was the primary endpoint, and change in body weight was a secondary endpoint.

Using an intent-to-treat analysis, mean change from baseline in HbA1c to week 26 was –1.2 percentage points with oral semaglutide, –1.1% with subcutaneous liraglutide, and −0.2% with placebo.

Oral semaglutide was therefore deemed "noninferior" to subcutaneous liraglutide in reducing HbA1c (estimated treatment difference, −0.1%; P < .0001), and superior to placebo (estimated treatment difference, −1.1%; P < .0001), reported Pratley.

Oral semaglutide resulted in superior weight loss (–4.4 kg) compared with liraglutide (–3.1 kg) (estimated treatment difference, −1.2 kg; P = .0003) and placebo (estimated treatment difference, −3.8 kg; P < .0001).

In his commentary, Holst remarks that participants "were selected according to predefined criteria and represent the typical patient with obesity, without major complications, and with moderate severity and duration of [type 2 diabetes]...which means that outcomes of this therapy in other patient groups are uncertain."

And he points out that, because oral semaglutide is absorbed in the stomach in a pH-sensitive manner, it is unknown whether the drug will be as effective in patients with gastric pathologies (eg, duodenal ulcer or atrophic gastritis).

The safety and tolerability of oral semaglutide were consistent with subcutaneous liraglutide and the GLP-1 receptor agonist class as a whole.

PIONEER 7: Oral Semaglutide vs Sitagliptin

Meanwhile, in PIONEER 7, patients with type 2 diabetes taking oral once-daily semaglutide with flexible dose adjustment (3, 7, or 14 mg; based on efficacy and tolerability) had superior glycemic control and weight loss compared with the DPP-4 inhibitor sitagliptin 100 mg after 52 weeks of treatment (both added to existing glucose-lowering therapy).

Not all patients needed the highest dose of oral semaglutide to achieve the target HbA1c of < 7% (< 53 mmol/mol).

"The proportion of participants who achieved this target with oral semaglutide was over twice that in the sitagliptin group, despite the flexible dose-adjustment approach and despite twice as many participants receiving additional glucose-lowering drugs in the sitagliptin group compared with the oral semaglutide group," say the authors led by Thomas Pieber, MD, University of Graz, Austria.

The safety profile of oral semaglutide was consistent with that expected of subcutaneous GLP-1 agonists, according to the poster at the conference. Nausea was the most common adverse event associated with oral semaglutide (occurring in 21% of patients).

However, in an accompanying commentary, Michael A. Nauck, MD, and Juris J. Meier, MD, both from St Josef-Hospital, Bochum, Germany, point out that "most of the side effects and drug discontinuations occurred in the first 8 weeks, when all participants randomly assigned to oral semaglutide took 3 mg/day per protocol."

"This early discontinuation could mean that one should consider an even lower starting dose [of oral semaglutide] than 3 mg/day, which would hopefully provoke less adverse events leading to drug discontinuation."

They conclude by suggesting that "additional studies exploring flexible dosing regimens with both lower and higher doses of oral semaglutide than were used in PIONEER 7 would be beneficial."

Pratley reports lecture and consulting fees from AstraZeneca; consulting fees from Boehringer Ingelheim, Eisai, GlaxoSmithKline, and Mundipharma; grants, lecture and consulting fees from Glytec, Janssen, Novo Nordisk, Pfizer, and Takeda; grants from Lexicon Pharmaceuticals; and grants, and consulting fees from Ligand Pharmaceuticals, Lilly, Merck, and Sanofi Aventis. Nauck has been a member of advisory boards or has consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, GlaxoSmithKline, Hoffman La Roche, Menarini/Berlin Chemie, MSD, Novo Nordisk, and Versatis; has received grant support from Eli Lilly, Menarini/Berlin-Chemie, MSD, and Novartis; and has served on speakers' bureaus for AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini/Berlin Chemie, MSD, Novo Nordisk, and Sun Pharma. Meier has received consulting and speaker honoraria from AstraZeneca, Eli Lilly, MSD, Novo Nordisk, and Sanofi; and has received research support from Eli Lilly, Boehringer Ingelheim, MSD, Novo Nordisk, Novartis, and Sanofi.

ADA 2019 Scientific Sessions. Presented June 8 (PIONEER 4, Abstract OR-55) and June 10, 2019 (PIONEER 7, Abstract 983-P).

Lancet. Published online June 8, 2019. PIONEER 4, Editorial

Lancet Diabetes Endocrinol. Published online June 10, 2019. PIONEER 7, Editorial

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