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SAN FRANCISCO – An experimental oral version of semaglutide agonist GLP-1 (Novo Nordisk) is safe for patients with type 2 diabetes with high cardiovascular risk (CV), with a 21% non-significant reduction in adverse cardiac events (MACE), results of the PIONEER 6 show.
John Buse, MD, of the University of North Carolina School of Medicine at Chapel Hill, and PIONEER 6's principal investigator, said: "[Oral semaglutide] is extremely effective, reasonably well tolerated and similar to liraglutide in the face-to-face study of the GLP-1 receptor agonist clbad. "
"Oral semaglutide is arguably the most effective glucose drug that promotes weight loss, with the possible exception of subcutaneous semaglutide (Ozempic), "he said at the plenary session of today's plenary session at the 2019 scientific sessions of the American Diabetes Association (ADA), during which the results of PIONEER 6 were presented. The data was also published simultaneously New England Journal of Medicine.
Vivian Fonseca, MD, Tulane University, New Orleans, Louisiana, commented independently. "The development of an oral GLP-1 receptor agonist has made me very happy." Oral semaglutide is very effective at treating type 2 diabetes from the start of treatment, including in patients with kidney failure, and has a very good safety profile, "he added. commented.
Fonseca added that, overall, "these data suggest to me that this could become the major component of diabetes management in the future, replacing much of the injectable GLP-1 receptor agonists used."
But he warned about the lack of significance in terms of reducing MACE in the study. "This raises the question of whether the oral is less effective than the injectable, especially with respect to stroke. [reduction]. More studies are needed, "he said.
The two doctors also discussed other issues related to the use of oral semaglutide, should it be approved, particularly if patients and / or physicians would prefer a pill with certain restrictions on the use of oral semaglutide. how it should be taken with an injectable once a week.
Non-inferiority compared to placebo, but no superiority
PIONEER 6 was designed to evaluate the cardiovascular safety of oral semaglutide, pending approval in the United States, compared to placebo in a population of type 2 diabetic patients with a high risk of cardiovascular events, in accordance with United States Food and Drug Administration. new drugs against diabetes.
Oral semaglutide (target dose of 14 mg, taken by 82% of patients) has been shown to be effective in reducing HbA levels1 C and weight versus placebo when used in addition to a spine of the usual treatment.
The main findings of the CV 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 have satisfied the non-inferiority test, with P <0.001, but in the superiority test, the 21% reduction observed [with semaglutide] has not reached statistical significance (P = 0.17), "he reported." This gave a risk ratio (HR) of 0.79 [95% CI, 0.57 – 1.11]"Husain said.
He pointed out that only the judgment criteria for CV death and all-cause mortality had risk ratios suggesting a potential benefit for oral semaglutide over placebo, the two secondary endpoints.
The risk of death by CV was about 50% lower in people taking oral semaglutide than in placebo (HR, 0.49, 95% CI, 0.27-0.92), the same figure for all death (HR, 0.51, 95%). Cl, 0.31-0.84).
For the end-point endpoint of nonfatal stroke, the HR was 0.74 (95% CI, 0.35 – 1.57) for patients treated with oral semi-glutide versus placebo.
PIONEER 6 had a relatively short follow-up period of just under 16 months. There was also a relatively small number of patients. Only 3,683 patients were enrolled in PIONEER 6, while the number of patients was much higher in other CV trials, such as REWIND (with dulaglutide), also reported here at ADA, and LEADER (liraglutide). ), each comprising about 9,000 patients.
In addition, the number of CV events was low in PIONEER 6.
Oral or subcutaneous semaglutide and other GLP-1 inhibitors
Fonseca made a comparison with subcutaneous semaglutide once a week, approved in 2017.
Referring to the results of the cardiovascular test for subcutaneous semaglutide in SUSTAIN 6, he said: "Subcutaneous semaglutide has achieved the criterion of non-inferiority but also of superiority. [in contrast to the oral version]. "
SUSTAIN 6 also has a slightly longer duration and maybe that makes a difference, he added, noting that, with the injectable version, there was also a significant reduction in strokes and some reduction in stroke. nonfatal myocardial infarction.
"I wonder what the difference is between administering the drug orally or subcutaneously," he observed.
Fonseca noted that in terms of HbA1 C Oral semaglutide is better than some other oral hypoglycemic agents available.
"The weight loss is greater than many other oral agents available. Safety is generally good, but nausea and vomiting are higher than SGLT2 or DPP-4 inhibitors, but they are consistent with [GLP-1 agonist] clbad, "he said.
Oral and subcutaneous semaglutide are very similar in terms of HbA1 C lowering. Nausea and vomiting are slightly lower than those of subcutaneous semaglutide. Gastrointestinal adverse events leading to discontinuation of treatment 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 doctors?
Fonseca believes that the current use of GLP-1 agonist drugs is limited by the fact that the agents must be injected.
"The adhesion is suboptimal and in the real world, there is a lower reduction in HbA1 C than in clinical trials. Injections are a burden and inconvenience for patients who want greater efficiency, fewer side effects, and [to be] l & # 39; injection. "
Fonseca has painted a fun picture of his typical patient who might have oral compliance issues with semaglutide alongside other drugs in the real world.
"As a patient, I have to get up, wait 30 minutes for my coffee, and before taking my coffee I take my levothyroxine and wait an hour more, then once a week I take my alendronate and get up. without my coffee while my blood sugar drops with the basal insulin of the day before [before I can take semaglutide]. Do not get me wrong, I think it will work, but I want to see how it goes in practice, "he said.
But Buzzard was not so sure. "I think oral [administration] makes a big difference for doctors but not a lot for patients. In my office, half of patients will prefer a once-a-week injection to a pill for which they must pay attention to how they take it, "he said.
"For doctors, however, it makes a huge difference because many primary care physicians do not want to have to educate and educate about injections," he observed.
"It is there that lies the opportunity (…) to increase the proportion of the population with access to GLP-1 agonists," he continued.
If you want a pill, could semaglutide be the agent of choice?
Comparing oral semaglutide with other drugs for type 2 diabetes, Buse said: "Other oral agents such as empagliflozin and sitagliptin are certainly better tolerated than other drugs. a gastrointestinal point of view, but they have other problems. "
And "there is no head-to-head study [of any of these different clbades of agents]. If you read tea leaves, only subcutaneous semaglutide could be more effective, as can be seen from the results of the Phase 2 program, which had a very small number of patients. "
Buse also pointed out that the concept of testing CV results was created to demonstrate safety and, in this spirit, "there is a very clear demonstration of the safety of CVs" with oral semaglutide.
"I think the mortality data is intriguing, the point estimate of the risk ratio is remarkable, but there is some uncertainty because it is a relatively small and short study."
The result of PIONEER 6 is consistent with that of other published trials on the cardiovascular effects of GLP-1 receptor agonists, all of which have confirmed the safety of the CV, he said.
"Is oral semaglutide better than all other GLP-1 receptor agonists in terms of the benefits of CV? Absolutely not," said Buse.
"Is the semaglutide, the molecule, better than other GLP-1 receptor agonists for the efficacy of CVs? I can not say, but I think they are remarkably effective hypoglycemic agents badociated to the best result in terms of weight loss and that have been linked CV results, so I'm optimistic ".
Oral semaglutide is currently being reviewed by the FDA, the European Medicines Agency and Health Canada, according to Buse. "If it is approved, oral semaglutide will be the first oral formulation of a GLP-1 receptor agonist in a tablet."
Husain revealed his financial relations with AstraZeneca, Boehringer Ingelheim, Janssen, Merck and Novo Nordisk. Buse revealed financial relationships with Neurimmune ADOCIA, AstraZeneca, Biopharm Holdings Dance, Eli Lilly, MannKind, NovaTarg, Novo Nordisk, Senseonics, vTv Therapeutics, Zafgen, National Center for the Promotion of Translation Sciences, the National Institute Diabetes and Digestion and Childhood Disease, Mellitus Health, PhaseBio Pharmaceuticals and Stability Health. Fonseca is a board member of the American Association of Clinical Endocrinologists. He revealed financial relationships with Novo Nordisk, Sanofi, Takeda, Bayer, Amgen, Bravo4health and Mellitus Health.
ADA 2019 Scientific Sessions Presented on June 11, 2019.
N Engl J Med. Posted online June 11, 2019. Summary
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