PIONEER 4 shows a GLP-1 tablet can match an injection

A phase 3a trial published in The Lancet on July 6, 2019 reported that a daily GLP-1 pill lowered blood sugar as much as a daily GLP-1 injection, and cut more weight, in people with type 2 diabetes ^[1]. The trial, called PIONEER 4, compared oral semaglutide escalated to 14 mg against subcutaneous liraglutide escalated to 1.8 mg and against placebo ^[1].

What the trial did

Researchers recruited patients at 100 sites in 12 countries ^[1]. To qualify, people had to be 18 or older, have an HbA1c between 7.0% and 9.5% (53–80.3 mmol/mol), and be on a stable dose of metformin of at least 1500 mg or the maximum they could tolerate, with or without an SGLT2 inhibitor ^[1]. Of 950 people screened, 711 were eligible and were randomly assigned 2:2:1 to oral semaglutide (285), subcutaneous liraglutide (284), or placebo (142) for 52 weeks ^[1]. The study was double-blind and "double-dummy," meaning participants took both a tablet and an injection so no one knew which active drug they were getting ^[1].

Participants were on average 56 years old, and 341 of 711 (48%) were female ^[1]. Completion rates were high: 277 (97%) in the oral semaglutide group, 274 (96%) in the liraglutide group, and 134 (94%) in the placebo group finished the 52-week period ^[1].

The numbers at 26 weeks

The primary endpoint was the change in HbA1c from baseline to week 26 ^[1]. Average HbA1c fell 1.2% with oral semaglutide, 1.1% with injected liraglutide, and 0.2% with placebo ^[1]. Oral semaglutide met the bar for non-inferiority to liraglutide, with an estimated treatment difference of −0.1% (95% CI −0.3 to 0.0; p<0.0001) against a pre-set margin of 0.4%, and it beat placebo by 1.1% (95% CI −1.2 to −0.9; p<0.0001) ^[1].

The trial used two different ways of analyzing results, called estimands. The primary "treatment policy" estimand counted everyone regardless of whether they stopped the study drug or added rescue medication ^[1]. Under the second "trial product" estimand, which assumes people stayed on the drug without rescue medication, oral semaglutide lowered HbA1c significantly more than liraglutide (−0.2%, 95% CI −0.3 to −0.1; p=0.0056) ^[1].

On weight, the confirmatory secondary endpoint, oral semaglutide produced a 4.4 kg (about 9.7 lb) loss at week 26 versus 3.1 kg (about 6.8 lb) with liraglutide and 0.5 kg with placebo ^[1]. The difference versus liraglutide was 1.2 kg (95% CI −1.9 to −0.6; p=0.0003), and versus placebo 3.8 kg ^[1]. Using the trial product estimand, the advantage over liraglutide widened to 1.5 kg ^[1].

Side effects were common in all groups. Adverse events occurred in 229 people (80%) on oral semaglutide, 211 (74%) on liraglutide, and 95 (67%) on placebo ^[1]. The authors concluded that the safety and tolerability of the pill were similar to the injection ^[1]. The trial was funded by Novo Nordisk and is registered as NCT02863419 ^[1].

Why it matters for patients

Until this point, GLP-1 receptor agonists were approved only as injections ^[1]. PIONEER 4 was the first large head-to-head test showing that a tablet version could hold its own against a widely used daily injection on the measure doctors watch most, HbA1c, while also removing more weight ^[1]. For people who avoid or delay GLP-1 therapy because of needles, that changes the menu of options. The authors wrote that an oral option "could potentially lead to earlier initiation of GLP-1 receptor agonist therapy in the diabetes treatment continuum of care" ^[1].

Some important caveats come straight from the design. The comparison was against liraglutide 1.8 mg, not against injected semaglutide, so this trial does not say how the pill stacks up against the stronger weekly shots ^[1]. The headline results are at week 26, even though the trial ran 52 weeks ^[1]. And roughly four out of five people on the tablet reported an adverse event of some kind ^[1]. The source does not report cost, insurance coverage, or US regulatory status.

What happens next

The Lancet published a linked commentary by J.J. Holst on the same date asking "Which to choose, an oral or an injectable glucagon-like peptide-1 receptor agonist?" ^[1]. A correction notice, "Department of Error," was also published in the July 6, 2019 issue; the source listing does not describe what was corrected ^[1].