PIONEER 6: Will Oral Semaglutide Live Up to Promise in Real World?

Becky McCall

June 11, 2019

SAN FRANCISCO — An investigational oral version of the GLP-1 agonist semaglutide (Novo Nordisk) is safe in patients with type 2 diabetes at high cardiovascular (CV) risk, with a nonsignificant 21% reduction in major adverse cardiac events (MACE), the results of PIONEER 6 show.

John Buse, MD, University of North Carolina School of Medicine in Chapel Hill, and principal investigator of PIONEER 6, said: "[Oral semaglutide] is wildly effective, it is reasonably well-tolerated, and similar to liraglutide in the head-to-head study of the GLP-1 receptor agonist class."

"Oral semaglutide is arguably the most effective glucose-lowering, weight loss-promoting drug full stop, except perhaps subcutaneous semaglutide (Ozempic)," he asserted in the extended session here today at the American Diabetes Association (ADA) 2019 Scientific Sessions, where the PIONEER 6 results were presented. The data were also simultaneously published in the New England Journal of Medicine.

Providing independent comment was Vivian Fonseca, MD, Tulane University, New Orleans, Louisiana. "I was very excited to see the development of an oral GLP-1 receptor agonist. Oral semaglutide is very effective in treating type 2 diabetes from early to late therapy, including patients with renal impairment, and has a very good safety profile," he commented.

Fonseca added that, overall, "These data suggest to me that this might become the major component of diabetes management in the future, replacing a lot of the injectable GLP-1 receptor agonists used."

But he cautioned about the lack of significance in terms of the reduction in MACE in the study. "It raises a question about whether the oral is not as good as the injectable, particularly regarding stroke [reduction]. More studies are needed," he said.

The two physicians also discussed other issues related to use of oral semaglutide, should it be approved, including whether or not patients and/or physicians would prefer a pill that has some restrictions on how it should be taken over a once-weekly injectable.

Noninferiority to Placebo Met, but Not Superiority

PIONEER 6 was designed to assess the CV safety of oral semaglutide, which is awaiting approval in the United States, compared with placebo in a type 2 diabetes patient population at high risk of CV events, as per the US Food and Drug Administration regulatory requirements for new diabetes drugs.

Oral semaglutide (target 14-mg dose, taken by 82% of patients) was found to effectively reduce HbA1c and weight compared with placebo when used in addition to a backbone of usual therapy.

The key CV outcomes were presented by Mansoor Husain, MD, director of the Toronto General Hospital Research Institute and professor of medicine at the University of Toronto, Ontario, Canada.

"The results met the test for noninferiority, with P < .001, but in the test for superiority, the observed 21% reduction [with semaglutide] did not reach statistical significance (P = .17)," he reported. "This gave a hazard ratio (HR) of 0.79 [95% CI, 0.57 - 1.11]," Husain stated.

He stressed that only the endpoints of CV death and all-cause mortality had hazard ratios suggestive of a potential benefit for oral semaglutide compared with placebo, both secondary endpoints.

Those taking oral semaglutide had around a 50% lower risk of dying from a CV event than those taking placebo (HR, 0.49; 95% CI, 0.27 - 0.92), a figure that was similar for any death (HR, 0.51; 95% CI, 0.31 - 0.84).

For the endpoint of nonfatal stroke, the HR was 0.74 (95% CI, 0.35 - 1.57) for those on oral semaglutide versus placebo.

PIONEER 6 had a relatively short duration of follow-up of just under 16 months. It also had a relatively small number of patients. Just 3183 patients were enrolled in PIONEER 6, whereas patient numbers have been far higher in other CV outcomes trials in this drug class such as REWIND (with dulaglutide), also reported here at ADA, and LEADER (liraglutide), which each included around 9000 patients.

Also, the number of CV events were low in PIONEER 6. 

Oral Versus Subcutaneous Semaglutide and Other GLP-1 Inhibitors

Fonseca drew comparison with once-weekly subcutaneous semaglutide, which was approved in 2017.

Referring to the cardiovascular outcome trial results for subcutaneous semaglutide in SUSTAIN 6, he said: "Subcutaneous semaglutide met the endpoint for noninferiority but also superiority [in contrast to the oral version]."

SUSTAIN 6 also had a slightly longer duration and maybe that made a difference, he added, noting that, with the injectable version, there was also a robust reduction in stroke and some reduction in nonfatal myocardial infarction.

"It makes me wonder what the difference is in giving the drug orally or subcutaneously," he observed.

Fonseca noted that, in terms of HbA1c lowering, oral semaglutide is better than some other available oral glucose lowering agents.

"It has greater weight loss than many other oral agents available. Safety is very good overall, but rates of nausea and vomiting are higher than with SGLT2 inhibitors or DPP-4 inhibitors, but consistent with the [GLP-1 agonist] class," he said.

Oral and subcutaneous semaglutide are very similar in terms of HbA1c lowering. Nausea and vomiting are slightly lower than with subcutaneous semaglutide. Gastrointestinal adverse events leading to discontinuation were more common with oral semaglutide than placebo in PIONEER 6 (6.8% vs 1.6%).

What Will Happen in the Real World — for Patients and Physicians?

Fonseca believes existing GLP-1 agonist drug use is limited by the fact that the agents need to be injected.

"Adherence is suboptimal and in the real world there is a smaller reduction in HbA1c than in clinical trials. Injections are a burden and inconvenience to patients who want greater efficacy, few adverse events, and not [to be] injecting."

Fonseca painted an amusing picture of his typical patient who might understandably struggle with oral semaglutide compliance alongside other medications in the real world.

"As a patient, I'll have to get up, wait 30 minutes for my coffee, and before I have my coffee I take my levothyroxine and wait one more hour. And then once a week I take my alendronate and stand up without my coffee while my blood glucose is dropping with the previous day's basal insulin [before I can take semaglutide]. Don't get me wrong I think it will work but I want to see how it will pan out in practice," he said.

But Buse wasn't so sure. "I think oral [administration] makes a big difference to doctors but not much to patients. In my practice, half of patients will prefer a shot once a week than a pill for which they need to be careful how they take it," he said.

"For doctors, however, it makes a huge difference because many primary care doctors don't want to have to bring up and educate about injections," he observed.

"This is where the opportunity lies...to increase the proportion of the population that has access to GLP-1 agonists," he continued. 

If You Want a Pill, Could Semaglutide Be the Agent of Choice?

Comparing oral semaglutide with other pills for type 2 diabetes, Buse said: "Other oral agents like empagliflozin and sitagliptin are certainly better tolerated from a gastrointestinal perspective but they have other issues."

And "there is no head-to-head study [of any of these different classes of agents]. If you read the tea leaves, only subcutaneous semaglutide might be more effective as possibly seen in evidence from the phase 2 program that had very small numbers of patients."

Buse reinforced the fact that the CV outcomes trial concept was created to demonstrate safety, and with that in mind, "there is a very clear demonstration of CV safety" with oral semaglutide.

"I think the mortality data are intriguing, the point estimate of the hazard ratio is remarkable, but there is some uncertainty because it is a relatively small and short study."

The PIONEER 6 result is consistent with those of other published CV outcomes trials of GLP-1 receptor agonists, all of which confirmed CV safety, he stressed.

"Is oral semaglutide better than all the other GLP-1 receptor agonists regarding CV benefit? Absolutely not," asserted Buse.

"Is semaglutide, the molecule, better than other GLP-1 receptor agonists for CV efficacy? I can't say that, but I think they are remarkably effective glucose-lowering agents associated with the best record regarding weight loss and those have been tied to CV outcomes, so I'm optimistic."

Oral semaglutide is currently under review by the FDA, European Medicines Agency, and Health Canada, according to Buse. "If approved, oral semaglutide will be the first oral formulation of a GLP-1 receptor agonist in a tablet."

Husain has disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk. Buse has disclosed financial relationships with Neurimmune ADOCIA, AstraZeneca, Dance Biopharm Holdings, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, Zafgen, National Center for Advancing Translational Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, Sanofi, Mellitus Health, PhaseBio Pharmaceuticals, and Stability Health. Fonseca is a board member of the American Association of Clinical Endocrinologists. He has disclosed financial relationships with Novo Nordisk, Sanofi, Takeda, Bayer, Amgen, Bravo4health, and Mellitus Health.

ADA 2019 Scientific Sessions. Presented June 11, 2019.

N Engl J Med. Published online June 11, 2019. Abstract

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