American Diabetes Association Scientific Sessions
American Diabetes Association Scientific Sessions
June 09, 2019
5 min read

PIONEER: Oral semaglutide proves superior to empagliflozin, noninferior to liraglutide for lowering HbA1c

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SAN FRANCISCO — Favorable results from two PIONEER trials of an oral version of the GLP-1 receptor agonist semaglutide were presented at the American Diabetes Association Scientific Sessions.

Richard E. Pratley

In PIONEER 2, oral semaglutide (Novo Nordisk) was associated with superior HbA1c reductions vs. the oral SGLT2 inhibitor empagliflozin (Jardiance, Boehringer Ingelheim) as well as significant weight loss at 52 weeks.

In PIONEER 4, the agent was shown to be noninferior to the injectable GLP-1 receptor agonist liraglutide (Victoza, Novo Nordisk) and superior to placebo in terms of HbA1c reductions, and also superior to both liraglutide and placebo in terms of weight loss at 26 weeks.

“Oral semaglutide ... is the first GLP-1 receptor agonist that has entered into phase 3 development. It’s a tablet formation and has the potential to become a new treatment for type 2 diabetes,” Richard E. Pratley, MD, the Samuel E. Crockett chair in diabetes research and medical director of AdventHealth Diabetes Institute, said during his presentation. “But what we’d really like to do is see how it stacks up against other medications in head-to-head studies, like SGLT2 inhibitors and, importantly, GLP-1 receptor agonists.”

As Endocrine Today previously reported, oral semaglutide showed superior HbA1c reductions vs. the oral DPP-IV inhibitor sitagliptin (Januvia, Merck) in the PIONEER 3 trial.

Each of the studies presented compared efficacy and safety of 14 mg daily oral semaglutide with another agent for adults with type 2 diabetes uncontrolled with metformin. Based on discussions with regulatory agencies, each study employed two estimands: the treatment policy estimand, which assessed outcomes in all participants regardless of discontinuation or use of other diabetes medications, and the trial product estimand, which assessed outcomes only in participants who continued in the trial and did not use rescue medications.

Semaglutide vs. SGLT2 inhibitor

Eduard Montanya

In the 52-week, open-label trial PIONEER 2, researchers randomly assigned participants to 14 mg daily semaglutide (n = 411; 50% men; mean age, 57 years; mean diabetes duration, 7.2 years; mean HbA1c, 8.1%; mean body weight, 91.9 kg) or 25 mg empagliflozin daily (n = 410; 51% men; mean age, 58 years; mean diabetes duration, 7.7 years; mean HbA1c, 8.1%; mean body weight, 91.3 kg), according to presenter Eduard Montanya, MD, PhD, professor in the department of clinical sciences at the University of Barcelona.

Among the semaglutide group, 97.1% completed the trial, as did 94.4% of the empagliflozin group, and rates of those who completed the trial on the study medications were similar for the two groups: 78.5% for the semaglutide group and 82.3% for the empagliflozin group.


At week 26, HbA1c was reduced more from baseline with semaglutide (treatment policy mean reduction, –1.3%; trial product mean reduction, –0.9%; P .0001) than with empagliflozin (treatment policy mean reduction, –1.4%; trial product mean reduction, –0.9%) for superiority of semaglutide over empagliflozin. Similar results were seen at week 52.

The proportion of participants who achieved an HbA1c of less than 7% was greater with semaglutide (treatment policy, 66.8%; trial product, 70.3%) than with empagliflozin (treatment policy, 40%; trial product, 40.7%) at 26 weeks and similarly at 52 weeks (P .0001 for all).

At week 52, but not at week 26, semaglutide was shown to be similar to empagliflozin in terms of body weight reduction, according to Montanya. At week 52, based on the trial product estimand, the semaglutide group had lost a mean –4.7 kg vs. –3.8 kg with empagliflozin (P .05).

Adverse events, mostly related to nausea, diarrhea and vomiting, were similar in both groups. Nausea diminished over time and was reported by 20% of the semaglutide group and 2% of the empagliflozin group; 11% of the semaglutide group discontinued due to adverse events vs. 4% for of the empagliflozin group. Hypoglycemic event rates were low in both groups, according to Montanya.

Favorable results from two PIONEER trials of an oral version of the GLP-1 receptor agonist semaglutide were presented at the American Diabetes Association Scientific Sessions.
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“At week 26, oral semaglutide was superior to empagliflozin for reducing HbA1c. Superiority for body weight reduction was not confirmed, but at week 52 oral semaglutide significantly reduced HbA1c and also reduced body weight when analyzed based on the trial product estimand vs. empagliflozin,” Montanya said. “In the safety analysis, semaglutide was well-tolerated, and the safety was found similar to what has been seen for other GLP-1 receptor agonists.”

Semaglutide vs. GLP-1 injection

In the 52-week, randomized, double-blind trial PIONEER 4, researchers assigned 285 adults to semaglutide, 284 adults to 1.8 mg liraglutide per day and 142 adults to placebo. Groups were substantially similar with 48% women, 73% white, mean age of 56 years, mean HbA1c of 8%, mean diabetes duration of 7.6 years, 26% prescribed an SGLT2 inhibitor, and mean BMI of 33 kg/m2.

At 26 weeks, similar reductions in HbA1c were observed in the semaglutide group vs. the liraglutide group for noninferiority of semaglutide to liraglutide. Semaglutide was superior in reducing HbA1c to placebo. At 52 weeks, reductions in HbA1c were significantly greater for the semaglutide group (both estimands mean reduction, –1.2%) vs. the liraglutide group (both estimands mean reduction, –1.2%; P ˂ .01) and the placebo group (both estimands mean reduction, –0.2%; P ˂ .0001) .


The proportion of participants who achieved an HbA1c of less than 7% or less than 6.5% were similar for the semaglutide and liraglutide groups at 26 weeks; at 52 weeks, the semaglutide participants were significantly more likely than the liraglutide participants to achieve an HbA1c of less than 6.5% based on both estimands, according to data simultaneously published in The Lancet.

At 26 weeks, weight loss of at least 5% was observed among more of the semaglutide group (treatment policy, 43.5%; trial product, 46.2%) vs. the liraglutide (treatment policy, 27.7%; trial product, 28.3%; P .01) and placebo groups (treatment policy, 7.5%; trial product, 7.1%; P .0001). Weight-loss results were maintained at 52 weeks, according to Pratley, for superiority of semaglutide to liraglutide.

Adverse events — mostly gastrointestinal and nausea, in particular —were more common with semaglutide (80% of participants) than with liraglutide (74%) or placebo (67%) but were consistent with the GLP-1 receptor agonist class in general, according to Pratley.

“My view is that as many patients and, indeed, providers are reluctant to intensify or initiate therapy with an injectable, oral semaglutide may be a very effective treatment option to allow earlier use of GLP-1 receptor agonists,” Pratley said. – by Jill Rollet

Editor's note: The article was updated on June 12, 2019 to indicate that in PIONEER 4 the HbA1c reduction with liraglutide was –1.2%. The editors regret the error.


Montanya E, et al. 54-OR.

Pratley RE, et al. 55-OR. Both presented at: American Diabetes Association 79th Scientific Sessions; June 7-11, 2019; San Francisco.

Pratley R, et al. Lancet. 2019;doi:10.1016/S0140-6736(19)31271-1.

Disclosures: Montanya reports he serves on advisory panels for AstraZeneca, Novo Nordisk and Servier; is a consultant to Merck and Novartis Pharmaceuticals; receives research support from Menarini Group; and is on the speakers bureau for Novo Nordisk. Pratley reports he is a consultant to Sanofi US and has other relevant financial relationships with AstraZeneca, Eli Lilly, GlaxoSmithKline, Janssen, Lexicon Pharmaceuticals, Ligand Pharmaceuticals, Merck, Mundipharma, Novo Nordisk, Pfizer, Sanofi and Takeda Development Center Americas.