Not Just for Celebs: Oral Semaglutide Helps Overweight/Obese Shed Pounds in OASIS 1

Hollywood’s new BFF, semaglutide, led to a more clinically meaningful drop in body weight in adults with overweight or obesity, but without type 2 diabetes (T2D), according to a placebo-controlled trial.

They reported in The Lancet that, among 667 assigned to oral semaglutide 50 mg or placebo, the estimated mean body-weight change from baseline to week 68 was –15.1% versus –2.4% with placebo, for an estimated treatment difference of –12.7 percentage points (95% CI, –14.2 to –11.3; P<0.0001).

And more participants reached body-weight reductions of at least 5% with the oral agent versus placebo. Of course, adverse events (AEs) were more common with semaglutide, mostly gastrointestinal (GI), but they were mild to moderate, the authors stated.

They boasted that semaglutide is "the first oral GLP-1 receptor agonist to be investigated for the treatment of obesity in adults with overweight or obesity," and that the "results indicate that oral semaglutide 50 mg could provide an effective, future option for people with overweight or obesity who would benefit from a GLP-1 receptor agonist."

It’s certainly marquee-worthy news for a drug that’s been the talk of the town, or at least Tinseltown: "It should have been no mystery, then, that when the people of Hollywood started dropping dozens of pounds in a matter of weeks, it wasn’t that everyone had suddenly started practicing moderation and logging 10,000 steps. It seemed like overnight everyone knew someone who was injecting semaglutide," according to a 2022 Vanity Fair article.

Injectable semaglutide was FDA approved in 2021 for chronic weight management in adults with obesity or overweight with at least one weight-related condition (high blood pressure, T2D, or high cholesterol), and stated that the agent must be used along with reduced-calorie diet and increased physical activity.

That didn’t matter to celebs and or even to non-celebs, who jumped on the semaglutide-for-slimming-down bandwagon. A drug shortage then ensued, with the drug’s manufacturer blaming high demand, per a 2023 ASHP report.

And this was despite words of warning from healthcare providers that the agent needed to be used in the right clinical context. "It is important to remember that obesity is heterogeneous, chronic and complex. "There is no cure for obesity. It requires lifelong treatment that’s not one size fits all," said Vijaya Surampudi, MD, of the University of California Los Angeles (UCLA) Weight Management Program in a 2023 UCLA Health article.

OASIS 1 was done at 50 outpatient centers in nine countries in east Asia, Europe, and North America from September to November 2021. Patient age in the total study population was 50 and about three-fourths were women; around three-fourths were White. Baseline total body weight was 105.4 kg (around 230 lbs) and mean BMI was 37.5 kg/m². The authors reported that 39% had pre-diabetes, 46% had dyslipidemia, 40% had OSA, 1% had coronary artery disease, 1% had cerebrovascular disease, and 29% had at least one comorbidity.

"Participants received oral semaglutide 50 mg or placebo once per day for 68 weeks as an adjunct to lifestyle intervention, followed by 7 weeks of off-treatment follow-up," Knop’s group explained, adding that semaglutide was administered with escalated dosing. "If a participant could not tolerate the 50 mg maintenance dose, a lower dose could be used at the investigator’s discretion, with at least one attempt to re-escalate to 50 mg recommended."

However, 76% of patients were on the 50-mg dose by the end of week 20. Finally, OASIS 1 enrollees were "encouraged to record their food intake and physical activity every day via an app or similar tool," they said.

Knop and co-authors reported that 92% of the patients on the study drug experienced AEs versus 86% on placebo, with GI events—nausea, constipation, diarrhea, and vomiting—reported in 80% and 46%, respectively. Gallbladder disorders were seen in 4% versus 1%, respectively.

There were no cases of pancreatitis, which has been previously tied to GLP-1 receptor agonists. Another related symptom with this class of drug is an increase in heart rate, which occurred with semaglutide (4.1 bpm) versus a decrease with placebo (0.4 bpm).

Trial limitations included the predominantly White patient population and the strict eligibility criteria. Also, some patients stuck with 25-mg semaglutide, and findings from another OASIS study will determine if that’s a workable dose, the authors said.

They stressed that GI AEs were "typically transient and…resolved without permanent trial product discontinuation," and that GI events peaked during the semaglutide dose-escalation phase.

OASIS 1 was presented at the 2023 American Diabetes Association (ADA) meeting, and is one of a quartet of trials testing semaglutide as a weight-loss drug.

Another study, PIONEER PLUS, also was presented at ADA. It evaluated three doses of oral semaglutide for reducing HbA1c and body-weight in adults with inadequately controlled T2D.

Vanita R. Aroda, MD, of Brigham and Women’s Hospital/Harvard Medical School in Boston, and co-authors, including Knop, reported in The Lancet that 25-mg and 50-mg semaglutide proved superior to 14-mg for the trial’s primary endpoint of a change in [HbA1c] from baseline to week 52.

PIONEER PLUS was conducted from January to September 2021 in 177 sites in 14 countries with 1,606 patients (58.3% male; mean age 58.2) who received one of the three semaglutide doses. Mean baseline HbA1c was 9.0% and mean body weight was 96.4 kg. The majority of patients in the study-drug arms were White. The majority were on metformin.

Aroda’s group reported the following mean changes in HbA1c at week 52 for the different doses of semaglutide; AE rates; and mean changes in body weight from baseline, respectively:

• 14-mg: –1.5 percentage points; 76%; –4.7%.
• 25-mg: –1.8 percentage points, –0.27 estimated treatment difference (ETD, 95% CI, -0.42 to -0.12; P=0.0006); 79%; –7.3%, –2.29 ETD (95% CI, –3.09 to –1.48).
• 50-mg: –2.0 percentage points, –0.53 ETD (95% CI, –0.68 to –0.38; P<0.0001). 80%; –8.5%, –14.81 ETD (95% CI, –20.72 to –8.89).

Once again, mild-to-moderate GI disorders occurred more frequently with oral semaglutide 25 mg and 50 mg than with 14 mg. As with OASIS 1, AEs "seemed to occur most frequently during dose escalation and appeared to peak at week 16, which could potentially prevent individuals from reaching the higher doses at which greater glycemic efficacy was seen," Aroda’s group said.

While there were 10 deaths during the trial, none were deemed as treatment related. The most deaths occurred in the 25-mg group, and included cases of lung cancer, brain cancer, myocardial infarction, and circulatory collapse.

Aroda and co-authors noted that the "safety profile of oral semaglutide 25 mg and 50 mg reported in our study was consistent with the known profile of the GLP-1 receptor agonist class and with the profile reported across previous PIONEER trials," such as PIONEER 3 and PIONEER 4.

Study limitations included the fact that the protocol did not allow for a dose below 14 mg, which "may not reflect real-world practice," and the fact that "it was not possible to assess whether the efficacy and tolerability of oral semaglutide were directly affected specifically by the new formulation. It is therefore possible that the additional benefit of the 25 mg and 50 mg doses was not only dose related, but also reflected the higher bioavailability of this formulation," Aroda’s group stated.

But in an accompanying comment, Christina H Sherrill, PharmD, of High Point University in High Point, North Carolina, and Andrew Y. Hwang, PharmD, of MCPHS University in Boston, pointed out that a "strength of this trial lies is that it resembles usual clinical practice by allowing continuation of previous antidiabetic medications…and flexibility in the dosing titration schedule based on" GI AEs.

Still, they warned that the results may not be generalized to populations under-represented within the trial, and individuals on concurrent antidiabetic medications that were excluded from the trial, such as thiazolidinediones or insulin."

Sherill and Hwang also said that a 2-mg dose of semaglutide proved effective in the SUSTAIN FORTE trial so "[a]dditional investigations are necessary to establish whether the superior glycemic reduction seen at these higher doses translates into cardiovascular risk reduction, which would further elucidate the place in therapy of high-dose oral semaglutide."

OASIS 1 and PIONEER PLUS were funded by Novo Nordisk. Some co-authors are company employees.

Knop reported relationships with, and/or support from, 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, Zucara, Chr Hansen, Structure Therapeutics, Antag Therapeutics, and Medicinsk Vægttabsbehandling ApS, as well as holding a patent for GIP peptide analogues. Co-authors reported relationships with, and/or support from, multiple entities including Novo Nordisk.

Aroda reported relationships with, and/or, support from Applied Therapeutics, Fractyl, Novo Nordisk, and Pfizer. Co-authors reported relationships with, and/or support from, multiple entities including Novo Nordisk.

Sherrill reported support from the National Association of Chain Drug Stores Foundation, American Association of Colleges of Pharmacy, Pharmacy Times Continuing Education/Abbott. Hwang reported no relationships relevant to the contents of this paper to disclose.

Knop FK, et al "Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, doubleblind, placebo-controlled, phase 3 trial" Lancet 2023; DOI: 10.1016/S0140-6736(23)01185-6.

Aroda VR, et al "Efficacy and safety of once-daily oral semaglutide 25 mg and 50 mg compared with 14 mg in adults with type 2 diabetes (PIONEER PLUS): a multicentre, randomised, phase 3b trial" Lancet 2023; DOI: 10.1016/S0140-6736(23)01127-3.

Sherrill CH, Hwang AY "The pursuit of optimal semaglutide dosing in type 2 diabetes continues" Lancet 2023; DOI: 10.1016/S0140-6736(23)01233-3.