Oral semaglutide 25 mg appears to be just as effective in promoting weight loss and other beneficial outcomes as are the investigational 50-mg oral dose and the injectable 2.4-mg dose (Wegovy), in new research.
Data from Novo Nordisk’s OASIS 4 trial suggest that “oral semaglutide 25 mg may represent an efficacious option for the treatment of overweight and obesity, particularly in patients who prefer oral administration,” W. Timothy Garvey, MD, professor in the Department of Nutrition Sciences at the University of Alabama at Birmingham (UAB), said on November 6 at the Obesity Society’s Obesity Week 2024 meeting.
In an interview with Medscape Medical News, Garvey, who is also senior scientist at the UAB Nutrition Obesity Research Center, added, “There's a principle in medicine that you always use the lowest dose that has highest efficacy, and for oral semaglutide for obesity, that appears to be the 25-milligram dose. We need oral medicines to offer as an option for patients that could lead to a longer persistence in adherence to obesity medications, which is a big problem. Less than half the people maintain their adherence after a year.”
Asked to comment, session moderator and obesity researcher Joseph A. Skelton, MD, professor of pediatrics at Wake Forest University School of Medicine, Winston-Salem, North Carolina, said that OASIS 4 was “extremely well done, especially given that we’re all concerned about the high prevalence of people stopping these medications at a year…I love the idea of trying to find these lower doses and increasing options for people.”
(The oral semaglutide approved for treating type 2 diabetes [Rybelsus] is sold in 7-mg and 14-mg doses.)
Lower May Be Better
OASIS 4 was a double-blind, randomized, placebo-controlled 64-week multicenter trial involving a total of 307 participants with overweight/obesity randomized 2:1 to oral semaglutide 25 mg or placebo. Of those, 167 in the semaglutide 25 mg and 76 in the placebo groups completed the trial.
For the co-primary endpoint change in body weight at week 64 (including 52-week maintenance and 7-week follow-up periods), there was a drop of 13.6% with oral semaglutide vs just 2.2% with placebo (P < .0001), based on in-trial observation regardless of adherence. For the analysis including just the on-treatment period, those reductions were 16.6% and 2.7%, respectively (P < .0001).
For the other co-primary endpoint, 79.2% semaglutide vs 31.1% placebo lost at least 5% of their body weight, 63.0% vs 14.4% lost ≥ 10%, 50.0% vs 5.6% lost ≥ 15%, and 29.7% vs 3.3% lost ≥ 20%. All were statistically significant differences, at P < .0001.
On the Impact of Weight on Quality of Life-Lite Clinical Trials Version, change from baseline scores were 16.2 with oral semaglutide vs 8.4 for placebo (P = .0006) and the proportion of participants achieving clinically meaningful increases in those scores (≥ 14.6 points) were 55.3% vs 34.8% (P = .0022).
Waist circumference was also significantly reduced from baseline with oral semaglutide, by 12.2 cm vs 2.8 cm (P < .0001). Both systolic and diastolic blood pressure dropped more with semaglutide than placebo, but not significantly. However, the inflammatory marker C-reactive protein dropped from baseline by 46.4% vs just 4.2% with placebo, a significant difference (P < .0001).
A1c dropped by 0.29 percentage points vs just 0.06 with placebo (P = .0012) and fasting plasma glucose by 6.6 mg/dL, while rising by 0.4 mg/dL in the placebo group (P = .0012). Lipid levels also improved more with oral semaglutide.
Overall adverse events occurred in 93.1% on oral semaglutide and 85.3% with placebo, and gastrointestinal adverse events in 74% and 42.2%, respectively. Other types of adverse events didn’t differ between the groups. The proportions experiencing severe adverse events were less in the semaglutide group (3.9% vs 8.8%), although adverse events leading to permanent treatment discontinuation were slightly higher with oral semaglutide (6.9% vs 5.9%). There were no deaths.
The estimated treatment difference from placebo in body weight change of −11.4% in OASIS 4 (P < .0001) was similar to the −12.7% (P < .0001) seen with the 50-mg oral semaglutide dose studied in OASIS 1 and the −12.4% (P < .0001) difference with subcutaneous semaglutide 2.4 mg in the STEP 1 trial. “All had pretty comparable efficacy,” Garvey noted.
The side-effect profiles, including frequency of gastrointestinal side effects, were also similar across the three trials. However, Garvey added, “the mean duration of nausea in those patients that experienced nausea was shorter in patients on a 25-milligram dose, 13 days, whereas the mean duration of nausea was greater, 19 days, in those in OASIS 1 taking 50 milligrams a day.”
Garvey has consulted for Boehringer Ingelheim, Carmot Therapeutics/Roche, Eli Lilly and Company, Fractyl Laboratories, Inogen, Lilly, Merck, Novo Nordisk, and Zealand Pharma; has ownership interest (stock, stock options in a publicly owned company) for Bristol Myers Squibb, Isis, Lilly, and Novartis; serves as site principal investigator for Carmot Therapeutics/Roche, Eli Lilly and Company, Epitomee Medical, Lilly, Neurovalens, Novo Nordisk, and Zealand Pharmaceuticals; and as a data monitoring committee member for Boehringer Ingelheim and Eli Lilly and Company. Skelton is editor in chief of the journal Childhood Obesity.
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