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Will the Semaglutide Oral live to promise in the real world?



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

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

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

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

Fonseca added that in general, "These data suggest that this may become the major component of diabetes control in the future, replacing many of the injectable agonists of the used GLP-1 receptor."

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

The two physicians also discussed other issues related to the use of oral semaglutide if it is approved, including whether patients and / or physicians would prefer a pill that has some restrictions on how it should be taken in an injectable once a week.

Non-inferiority to placebo, but not superiority

PIONEER 6 was developed to evaluate the cardiovascular safety of oral semaglutide, which is pending approval in the United States, compared to placebo in a population of patients with type 2 diabetes at high risk of CV events, according to regulatory requirements of the Food and Drug Administration from the USA. new medicines for diabetes.

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

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

"The results completed the non-inferiority test, with P <.001, but in the test of superiority, the observed reduction of 21% [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]"Said Husain.

He pointed out that only outcomes of CV death and all-cause mortality had risk ratios suggestive of a potential benefit for oral semaglutide compared to placebo, both of which were secondary outcomes.

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

For non-fatal stroke outcome, HR was 0.74 (95% CI, 0.35 – 1.57) for those on oral semaglutide versus placebo.

PIONEER 6 had a relatively short follow-up period of just under 16 months. It also had a relatively small number of patients. Only 3183 patients were enrolled in PIONEER 6, while the number of patients was much higher in other studies of cardiovascular outcomes in this class of drugs such as REWIND (with dulaglutide), also reported here in the ADA, and LEADER (liraglutide), which included about 9000. patients.

In addition, the number of CV events was low in PIONEER 6.

Semaglutide Oral Versus Subcutaneous and Other Inhibitors of GLP-1

Fonseca compared the subcutaneous semagglut once a week, which was approved in 2017.

Referring to the results of the cardiovascular outcome study for subcutaneous semagglut in SUSTAIN 6, he said: "Subcutaneous semagglut reached the endpoint for non-inferiority but also superiority [in contrast to the oral version]"

SUSTAIN 6 also lasted a little longer 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 noted.

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

"Safety is very good overall, but the rates of nausea and vomiting are greater than with SGLT2 inhibitors or with DPP-4 inhibitors, but consistent with [GLP-1 agonist] class, "he said.

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

What will happen in the real world – for patients and doctors?

Fonseca believes that current use of GLP-1 agonist drugs is limited by the fact that 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 wish to be more effective, fewer adverse events and [to be] injecting ".

Fonseca painted an amusing image of his typical patient who understandably can fight against oral adhesion to semaglutide along with other medicines in the real world.

"As a patient, I'm going to have to get up, wait 30 minutes for my coffee, and before I have my coffee, I take my levothyroxine and wait another hour. And once a week, I take my alendronate and get up without coffee while my glucose in the blood is falling with basal insulin the day before [before I can take semaglutide]. Do not get me wrong, I think it will work, but I want to see how this will work in practice, "he said.

But Buse was not so sure. "I think that oral [administration] makes a big difference for doctors, but not much for patients. In my practice, half of patients 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, this makes a huge difference because many primary care doctors do not want to have to educate about injections," he noted.

"That's where the opportunity … is 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 type 2 diabetes pills, Buse said, "Other oral agents like empagliflozin and sitagliptin are certainly better tolerated from the gastrointestinal point of view, but they have other problems."

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

Buse reinforced the fact that the concept of CV outcome study was designed 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 risk rate is remarkable, but there is some uncertainty because it is a relatively small and short study."

The result of PIONEER 6 is consistent with the results of other published CV trials of GLP-1 receptor agonists, all of which have confirmed the safety of CV, he emphasized.

"Oral semaglutide is better than all other GLP-1 receptor agonists over the CV benefit – not absolutely," said Buse.

"Is semaglutide, the molecule, any better than other GLP-1 receptor agonists for CV efficacy?" I can not say that, but I think they are remarkably effective glucose-lowering agents associated with the best registry in relation to the loss of weight and CV results, 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 semaggluton will be the first oral formulation of a GLP-1 receptor agonist in one tablet."

Husain disclosed financial relationships with AstraZeneca, Boehringer Ingelheim, Janssen, Merck and 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. Submitted on June 11, 2019.

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

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