FDA OKs 'Game-Changer' Oral GLP-1 Agonist for Type 2 Diabetes

Miriam E. Tucker


September 20, 2019

UPDATED September 23, 2019 // The US Food and Drug Administration (FDA) has approved oral semaglutide (Rybelsus, Novo Nordisk), 7 mg and 14 mg, for the treatment of type 2 diabetes in adults to improve glycemic control along with diet and exercise.

The once-weekly injectable version of the long-acting glucagon-like peptide-1 (GLP-1) receptor agonist (Ozempic, Novo Nordisk) was approved in December 2017.

"It's going to be a game changer. There is no oral agent that can give you a 1.2% to 1.5% HbA1c reduction with a 3- to 4-kg loss...One of the barriers of the GLP-1 agonists, among other things, is [that they're] injectable," Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, told Medscape Medical News in an interview conducted on-site today at the European Association for the Study of Diabetes (EASD) 2019 Annual Meeting.

EASD President David R. Matthews, DPhil, BM, BCh, professor emeritus of diabetic medicine at University of Oxford, UK, shares the enthusiasm.

"I think it will dramatically change the management of [type 2] diabetes because until now GLP-1 agonists have only been available in injectable form. As soon as we've got an oral form, suddenly there will be many more people who would feel that it's perfectly acceptable to take."

The gastrointestinal side effects of GLP-1 agonists are slightly less with the oral form than the injectable form, and the GLP-1 receptor agonist class promotes greater weight loss than another new class of type 2 diabetes drugs, the SGLT-2 inhibitors, Matthews noted.

And Irl B. Hirsch, MD, professor of medicine at the University of Washington Medicine Diabetes Institute in Seattle, told Medscape Medical News by email: "I also am quite excited about oral semaglutide's approval. Especially in the Pacific Northwest, we very much underprescribe the GLP-1 receptor agonist class."

But Is It a Gamechanger?

However, Hirsch also said, "My feeling is this will be only a small, incremental benefit for the overall use of the class, the main reason not being gastrointestinal side effects but rather cost…It is difficult to believe this drug will be a game changer unless, of course, the price comes out lower than expected."

And Simeon I. Taylor, MD, PhD, professor of medicine at the University of Maryland School of Medicine in Baltimore, commented: "When administered as a once-weekly subcutaneous injection, semaglutide has been reported to have several extremely attractive features including best-in-class glycemic efficacy, best-in-class weight loss, and a 26% decrease in the risk for major adverse cardiovascular events."

But although once-a-day oral semaglutide "also has an attractive profile, a head-to-head clinical trial of the two formulations would be required to compare benefit-risk profiles for subcutaneous versus oral," he observed.

"It is likely that some patients will prefer the convenience of an oral drug rather than an injectable formulation...Other patients may prefer the convenience of once-weekly compared to daily administration," he continued.

Taylor added: "It will be important to review the FDA-approved prescribing information to understand whether patients will need to take special precautions in terms of the timing of taking the drug relative to eating meals. If patients need to avoid eating in proximity to an oral dose, this may have implications for their perception of convenience."

Also, Taylor said, "because of relative inefficiency of absorption of the oral formulation, the total weekly dose of oral semaglutide substantially exceeds the dose of the subcutaneous formulation."

Lastly, it will be "important to understand the pricing of the two formulations in order to assess comparative cost-effectiveness."

Oral Semaglutide Tested in PIONEER Trials

Rosenstock was a lead author on several of Novo Nordisk's phase 3 PIONEER trials, which evaluated use of oral semaglutide in a variety of treatment regimens and patient subgroups.

In PIONEER-6, for example, the drug was shown to be safe in patients with type 2 diabetes who were at high cardiovascular risk. In that trial, although there was a 21% reduction in major adverse cardiac events, it was not significant.

In PIONEER-3, oral semaglutide reduced HbA1c levels better than did the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (multiple brands).

And in PIONEER-5, in patients with both type 2 diabetes and moderate chronic kidney disease, the addition of daily oral semaglutide to metformin, sulfonylurea, and/or insulin lowered HbA1c by 1% over 26 weeks.

Room for Both Oral Semaglutide and SGLT-2 Inhibitors

Asked how oral semaglutide compares to SGLT-2 inhibitors, which are orally administered, in the management of type 2 diabetes, Rosenstock said: "The SGLT-2 inhibitors have the advantage with heart failure, no question.

"I'm not looking at this as a competitive thing. I look at both as an ideal combination with metformin. We now have metformin, oral SLGT-2 inhibitors, and an oral GLP-1 agonist. This is the ideal triple combination, not to start with, but I believe that with diabetes, you need to start with dual combination."

Indeed, Matthews said, the "environment of precision medicine is changing" in diabetes, such that there is now a shift away from the traditional paradigm of starting with lifestyle modification, moving to metformin monotherapy, and eventually adding a second drug toward a more aggressive approach of starting patients on combination therapy straightaway.

"It does look as though...people are doing better on combination than on sequential therapy," Matthews said, referring to his just-reported VERIFY study, which provided evidence for use of combination therapy with metformin and a DPP-4 inhibitor.

"I think we're moving wonderfully into a new age where we're going to have some really good specificity about the ways that we treat people with diabetes," Matthews said.

He noted, "It won't be that everyone will go onto oral semaglutide, but the reality is that a subset of people will really benefit.... It's another sea change in the environment of care of diabetes for the future."

Matthews has received research support from, serves on advisory boards for, and/or is a consultant for Janssen, Novo Nordisk, Novartis, Sanofi Aventis, Servier, Mitsubishi Tanabe, and Aché Laboratories. Rosenstock serves on scientific advisory boards and receives honoraria or consulting fees from Eli Lilly, Sanofi, Novo Nordisk, Janssen, AstraZeneca, Boehringer Ingelheim, and Intarcia and receives grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, Genentech, Janssen, Lexicon, Boehringer Ingelheim, and Intarcia.

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