The US Food and Drug Administration 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. Other physicians share the enthusiasm. "I also am quite excited about oral semaglutide's approval. Especially in the Pacific Northwest, we very much underprescribe the GLP-1 RA [receptor agonist] class. My feeling is this will be only a small, incremental benefit for the overall use of the class, the main reason not being GI [gastrointestinal] side effects but rather cost," Irl B. Hirsch, MD, professor of medicine, University of Washington Medicine Diabetes Institute in Seattle, told Medscape Medical News. Hirsch is not yet sold on calling it a game changer, though. "The report last week by the Institute for Clinical and Economic Review concluded that oral semaglutide would underperform Jardiance [empagliflozin, a sodium-glucose cotransporter–2 (SGLT-2) inhibitor from Lilly] in terms of cost-effectiveness. In such a cost-sensitive environment, which I suspect will become more so over time, it is difficult to believe this drug will be a game changer unless, of course, the price comes out lower than expected," he said. Also asked to comment, EASD President David R. Matthews, DPhil, BM, BCh, professor emeritus of diabetic medicine at the University of Oxford, United Kingdom, told Medscape Medical News, "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 with the injectable form, and the GLP-1 receptor agonist class promotes greater weight loss than does another new class of type 2 diabetes drugs, the SGLT-2 inhibitors, Matthews noted. 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, there was a nonsignificant 21% reduction in major adverse cardiac events. 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-2s 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, refering to his just-reported VERIFY study, which provided evidence for use of combination therapy with 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." Source
