PIONEER-3: Oral Semaglutide Shows Benefit in Type 2 Diabetes

NEW ORLEANS — An oral version of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (Ozempic, Novo Nordisk) reduced HbA_1c levels more than the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin (Januvia, Merck) in patients with type 2 diabetes, new data show.

Findings from the randomized, double-blind controlled PIONEER-3 trial were presented in a poster on March 23 here at ENDO 2019: The Endocrine Society Annual Meeting and simultaneously published in JAMA by Julio Rosenstock, MD, director of the Dallas Diabetes Research Center at Medical City, Texas, and colleagues.

One of a series of 10 phase 3 trials of oral semaglutide, PIONEER-3 evaluated the drug's efficacy and safety against sitagliptin, a commonly prescribed oral glucose-lowering agent for type 2 diabetes.

A total of 1864 adults with type 2 diabetes and HbA_1c 7.0%-10.5%, despite use of metformin with or without a sulfonylurea, were randomized to one of three daily oral semaglutide doses or sitagliptin. The two higher semaglutide doses reduced HbA_1c levels significantly more than sitagliptin, but the lowest semaglutide dose did not.

However, the highest dose of semaglutide was associated with significantly more gastrointestinal side effects than the lower semaglutide doses or sitagliptin.

Results for PIONEER-1 were reported at the American Diabetes Association (ADA) 2018 Scientific Session, and findings for PIONEER-2, PIONEER-4, and PIONEER-7 were reported prior to that.

And positive topline results for PIONEER-6, the cardiovascular outcomes trial with oral semaglutide, were announced in November 2018. Full results of that trial will be announced on June 11, 2019, at the upcoming ADA annual meeting.

"Overall, the findings of the PIONEER-3 trial, along with other recent studies, indicate that the introduction of semaglutide, the first oral preparation of a GLP-1 agonist for which the subcutaneous agent has shown positive cardiovascular benefit, should be an important addition to the growing list of pharmacologic options for type 2 diabetes," writes Irl B. Hirsch, MD, professor of medicine at the University of Washington School of Medicine, Seattle, in an editorial accompanying the PIONEER-3 article published in JAMA.

However, Hirsch cautions, "if history can predict the future, many patients who could benefit from this new agent may not have access to this drug unless the cost is substantially reduced."

Potential to Be First Oral GLP-1 Agonist for Diabetes

The subcutaneously injectable form of semaglutide, which is administered once-weekly, was approved for use in type 2 diabetes in the United States in December 2017 and was the seventh injectable GLP-1 agonist on the market.

Novo Nordisk has just submitted two new drug applications (NDAs) in the United States for the oral version of semaglutide. One NDA is as an adjunct to diet and exercise to improve blood glucose control in adults with type 2 diabetes, which the company says is expected to be reviewed within 6 months. The second NDA is for cardiovascular risk reduction in adults with type 2 diabetes, which is anticipated to have a 10-month review time from the submission date, the company says.

PIONEER-3 was a randomized, double-blind, double-dummy, parallel-group, phase 3a trial conducted at 206 sites in 14 countries over 78 weeks from February 2016 to March 2018. Participants were randomized to once-daily oral semaglutide at doses of 3 mg, 7 mg, or 14 mg, or sitagliptin 100 mg, in addition to metformin with or without a sulfonylurea.

The primary outcome, percentage point change from baseline in HbA_1c at week 26, was –0.6, –1.0, and –1.3 for 3 mg, 7 mg, and 14 mg semaglutide, respectively, versus –0.8 for sitagliptin. Reductions for the two higher oral semaglutide doses were significantly greater than for sitagliptin (both P < .001), but the difference wasn't significant for the 3-mg dose (P = .09).

A key secondary endpoint was mean change from baseline in body weight at week 26, which was –1.2 kg, –2.2 kg, and –3.1 kg for the three oral semaglutide doses, respectively, and –0.6 kg for sitagliptin. Again, the differences between the drugs were significant for the higher two semaglutide doses (both P < .001) and less so for the 3-mg dose (P = .03).

Changes in HbA_1c and body weight at weeks 52 and 78 were additional secondary endpoints.

"Difficult Balance" Between Clinical Efficacy and GI Side Effects

The most frequent adverse events were gastrointestinal disorders in the semaglutide 14 mg/day group and infections in the semaglutide 3 and 7 mg/day groups as well as the sitagliptin group.

Most gastrointestinal events were mild or moderate. Nausea, the most common of these in the semaglutide 7 and 14 mg/day groups, was reported by 7.3%, 13.4%, and 15.1% of patients in the three semaglutide groups, respectively, compared with 6.9% of patients in the sitagliptin group.

Adverse events leading to premature discontinuation occurred in 5.6%, 5.8%, and 11.6% of patients in the semaglutide 3, 7, and 14 mg/day groups, respectively, and in 5.2% of patients with sitagliptin. Gastrointestinal adverse events was the main cause for discontinuation in all treatment groups.

The number and proportions of serious adverse events during treatment were similar across groups.

"The highest dosage of semaglutide tested in PIONEER 3 (14 mg/day) was associated with higher rates of gastrointestinal adverse effects and illustrates the difficult balance between clinical effectiveness and tolerability that has been a challenge in the development of GLP-1 agonists," Hirsch commented.

"There is evidence that adverse events with drugs like semaglutide wane over time while taking the treatment and can be mitigated with a slower escalation of dosage, although adverse gastrointestinal symptoms remain an important limiting factor with GLP-1 agonists," he added.

Severe or whole-blood glucose-confirmed episodes of symptomatic hypoglycemia occurred in 4.9%, 5.2%, and 7.7% of patients taking the three doses of semaglutide, respectively, and in 8.4% of those taking sitagliptin. Most cases were among patients also taking sulfonylureas.

Will Availability of Oral GLP-1 Agonists Increase Use in Type 2 Diabetes?

Hirsch noted adoption of the GLP-1 agonist class into clinical practice has been relatively slow for several reasons. The gastrointestinal side effects and overall tolerability have been barriers, as have the cost of the medications and need for subcutaneous injections.

But support for use of the class has come from the recent cardiovascular outcome trials, Hirsch said, who noted that "the results of LEADER [with liraglutide] and SUSTAIN-6 [with subcutaneous semaglutide] identify another major therapeutic advantage conferred by at least some of the GLP-1 agonists, and because cardiovascular disease remains the leading cause of mortality in patients with diabetes, this may be the ultimate treatment benefit of these agents."

However, cost is likely to continue to be a major barrier to use of all newer type 2 diabetes agents, including GLP-1 agonists, Hirsch noted.

"Other oral diabetes medications, such as metformin, sulfonylureas, and pioglitazone, are available as inexpensive generic preparations; sitagliptin will soon join this list. With greater amounts of medication expense in the United States being borne by patients, cost is increasingly a major factor in treatment decisions."

The study was funded by Novo Nordisk. Rosenstock has reported serving on scientific advisory boards and receiving honoraria or consulting fees from Eli Lilly, Novo Nordisk, Sanofi, Janssen, Boehringer Ingelheim, and Intarcia, and receiving grants/research support from Merck, Pfizer, Sanofi, Novo Nordisk, Bristol-Myers Squibb, Eli Lilly, GlaxoSmithKline, AstraZeneca, Janssen, Genentech, Boehringer Ingelheim, Intarcia, and Lexicon. Hirsch has reported receiving research support from Medtronic Diabetes and consulting for Abbott Diabetes Care, Roche, Bigfoot Biomedical, and Becton Dickinson.

ENDO 2019. Presented March 23, 2019. Poster SAT-139.

JAMA. Published online March 23, 2019. Full text, Editorial

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