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SAN FRANCISCO – Oral semaglutide, an experimental agent, does not harm subcutaneous liraglutide in the reduction of HbA1 C in patients with type 2 diabetes and higher in terms of weight loss, show the results of the PIONEER 4 trial, the first study to compare the efficacy and safety of this form of semaglutide with liraglutide. The findings were reported here at the 2019 scientific sessions of the American Diabetes Association (ADA).
Both are peptide-1 receptor agonists (GLP-1) and Novo Nordisk agents. Liraglutide (Victoza) has been on the market for a few years. Oral semaglutide is pending approval by the US Food and Drug Administration, but a subcutaneous formulation of the drug (Ozempic) was approved in the United States in December 2017.
PIONEER 7 posters, comparing the efficacy and safety of once-daily oral semaglutide to a flexible dose adjustment, were also presented here in a poster, compared to sitagliptin, a PPD inhibitor. -4 (Januvia, Merck) in patients with type 2 diabetes. Oral semaglutide was better at controlling glucose and induced more weight loss than sitagliptin after 52 weeks.
The studies and accompanying comments have been published: PIONEER 4 in the Lancet and PIONEER 7 in Lancet Diabetes and Endocrinology. PIONEER is a series of 10 phase 3 trials on oral semaglutide.
Presenting data from PIONEER 4, Richard Pratley, MD, director of the Florida Hospital Diabetes Institute in Orlando, pointed out that, because many patients and providers were reluctant to initiate or intensify injection therapy, "oral semaglutide could be an effective treatment, potentially leading to earlier initiation of GLP-1 agonist therapy into the continuum of care for the treatment of diabetes. "
Significant reduction in HbA1 C and body weight with oral semaglutide compared to both subcutaneous liraglutide and placebo at week 52 suggest a long-term benefit with continued treatment with oral semaglutide, write Pratley and his co-authors .
Small differences between oral semaglutide and liraglutide
In an accompanying commentary, Jens Juul Holst, MD, University of Copenhagen, Denmark, notes that the PIONEER 4 "trial has ventured into an area in which the issue is not clear. could not have been predicted: direct comparison with one of the most commonly used GLP-1 receptor agonists subcutaneous liraglutide at 1.8 mg once daily. "
Holst, known to have discovered the GLP-1 hormone, adds that PIONEER 4 shows that the first oral agonist of GLP-1 has effects similar to those of the most widely used GLP-1 injectable agonist .
But he notes that, although significant, the overall clinical differences between oral semaglutide and subcutaneous liraglutide were small.
Given the similarity between the two agonists of GLP-1, Holst said: "We are potentially moving towards a situation in which patients and clinicians may have the choice [if oral semaglutide is approved]: take a pill or a daily injection. "
He adds that since oral semaglutide should be taken on an empty stomach 30 minutes before the meal, it may be embarrbading for some patients and other injectable GLP-1 receptor agonists are available and need only be administered only once a week.
First study comparing oral semaglutide with liraglutide
PIONEER 4 was a randomized, double-blind, double-blind, 52-week, controlled phase 3 trial of 711 patients with type 2 diabetes not controlled with metformin (with or without additional SGLT2 inhibitor therapy). Participants were randomized to receive oral semaglutide (14 mg once daily, n = 285), liraglutide once daily (1.8 mg increase, n = 284) or placebo (n = 142).
Women accounted for 48% of participants, the average age was 56 years and the average duration of diabetes was 7.6 years. Change in base rate at week 26 of HbA1 C was the primary endpoint and the change in body weight was a secondary endpoint.
Using an intention-to-treat badysis, mean change from the initial HbA value1 C at week 26 was -1.2 percentage points with oral semaglutide, -1.1% with subcutaneous liraglutide and -0.2% with placebo.
Oral semaglutide was therefore judged "not inferior" to subcutaneous liraglutide to reduce HbA1 C (estimated difference in treatment, -0.1%; P <0.0001) and higher than placebo (estimated difference in treatment, -1.1%; P <0.0001), reported Pratley.
Oral semaglutide resulted in a greater weight loss (-4.4 kg) compared with liraglutide (-3.1 kg) (estimated treatment difference, -1.2 kg; P = 0.0003) and placebo (estimated difference in treatment, -3.8 kg; P <.0001).
In his commentary, Holst remarks that participants "were selected according to pre-defined criteria and represent the typical patient suffering from obesity, without major complications, with a moderate severity and duration of [type 2 diabetes]… which means that the results of this therapy in other groups of patients are uncertain ".
And he points out that, because oral semaglutide is absorbed in the stomach in a pH-sensitive way, it is not known whether the drug will be as effective in patients with gastric diseases (eg for example, duodenal ulcer or atrophic gastritis).
The safety and tolerability of oral semaglutide was consistent with that of subcutaneous liraglutide and the clbad of GLP-1 receptor agonists.
PIONEER 7: Oral semaglutide vs sitagliptin
Meanwhile, at PIONEER 7, patients with type 2 diabetes taking oral semaglutide once a day with flexible dose adjustment (3, 7 or 14 mg, based on efficacy). and tolerance) had greater glycemic control and weight loss than the DPP-4 sitagliptin 100 mg inhibitor after 52 weeks of treatment (both added to existing hypoglycemic treatment).
Not all patients required the highest dose of oral semaglutide to reach target HbA.1 C <7% (<53 mmol / mol).
"The proportion of participants who achieved this goal with oral semaglutide was more than twice that of the sitagliptin-treated group despite flexible dose adjustment and double the number of participants receiving hypoglycemic drugs in the sitagliptin-treated group compared to the treatment group, "say authors led by Thomas Pieber, MD, University of Graz, Austria.
The safety profile of oral semaglutide was consistent with that expected of subcutaneous agonists of GLP-1, according to the poster at the conference. Nausea was the most common adverse event badociated with oral semaglutide (occurred in 21% of patients).
However, in a comment, doctors Michael A. Nauck and Juris J. Meier, of the St Josef Hospital-Hospital in Bochum, Germany, point out that "most of the side effects and dropouts of weeks, when all participants randomly badigned to oral semaglutide took 3 mg / day per protocol. "
"This early interruption could mean that we should consider an even lower initial dose [of oral semaglutide] 3 mg / day, which hopefully would cause fewer adverse events leading to discontinuation of the drug. "
They conclude by suggesting that "other studies exploring flexible dosing regimens with doses of oral semaglutide both lower and higher than those used in PIONEER 7 would be beneficial".
Pratley Announces Conference and Advisory Fees from AstraZeneca; consulting fees of Boehringer Ingelheim, Eisai, GlaxoSmithKline and Mundipharma; grant, conference and advisory fees from Glytec, Janssen, Novo Nordisk, Pfizer and Takeda; grants from Lexicon Pharmaceuticals; and grants and consulting fees from Ligand Pharmaceuticals, Lilly, Merck and Sanofi Aventis. Nauck has been a member of advisory boards or consulted for AstraZeneca, Boehringer Ingelheim, Eli Lilly, Fractyl, GlaxoSmithKline, Hoffman La Roche, Menarini / Berlin Chemie, MSD, Novo Nordisk and Versatis; received a grant from Eli Lilly, Menarini / Berlin-Chemie, MSD and Novartis; and has been a speaker for AstraZeneca, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Menarini / Berlin Chemie, MSD, Novo Nordisk and Sun Pharma. Meier has received fees from consultants and speakers from AstraZeneca, Eli Lilly, MSD, Novo Nordisk and Sanofi; and has received research support from Eli Lilly, Boehringer Ingelheim, MSD, Novo Nordisk, Novartis and Sanofi.
ADA 2019 Scientific Sessions Presented on June 8 (PIONEER 4, summary OR-55) and June 10, 2019 (PIONEER 7, summary 983-P).
Lancet. Posted online 8 June 2019. PIONEER 4, Editorial
Lancet Diabetes Endocrinol. Posted online June 10, 2019. PIONEER 7, Editorial
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