Orforglipron: A new player in the weight loss arena?The novel oral, non-peptide glucagon-like peptide-1 receptor agonist (GLP-1 RA) orforglipron gains the upper hand over the current leading oral GLP-1 RA, semaglutide, in individuals with type 2 diabetes (T2D) inadequately controlled on metformin in the phase III ACHIEVE-3 study.
“Orforglipron met the primary objective of noninferiority and the multiplicity-controlled key secondary objective of superiority to semaglutide in mean change from baseline in HbA1c at week 52,” said the researchers.
A total of 1,698 participants (mean age 53.9 years, 51.4 percent men) were randomized 1:1:1:1 to receive orforglipron 12 or 36 mg or semaglutide 7 or 14 mg QD for 52 weeks. The mean HbA1c was 8.3 percent, mean BMI 35.1 kg/m2, and mean body weight 97 kg. [Lancet 2026;407:1147-1160]
At week 52, the mean changes in HbA1c were greater with orforglipron (–1.71 percent and –1.91 percent for 12 and 36 mg, respectively) than with semaglutide (–1.23 percent and –1.47 percent for 7 and 14 mg). The estimated treatment differences (ETDs) ranged from –0.24 to –0.68 percent.
By end of treatment, the final mean HbA1c was lower with orforglipron than with semaglutide (6.1–6.4 percent vs 6.8–7.2 percent).
Compared with the semaglutide groups, the orforglipron groups had more participants achieving the HbA1c target values of <7 percent (72–76 percent vs 54–64 percent), ≤6.5 percent (63–68 percent vs 38–48 percent), and <5.7 percent (near-normoglycaemia; 21–31 percent vs 7–12 percent).
Of note, almost all participants who developed near-normoglycaemia did not have level 2 or 3 hypoglycaemia. “These [suggest] that stricter glycaemic targets (beyond 6.5 percent) could now be feasibly and safely achieved with oral therapy,” the researchers noted.
Week 52 also saw greater mean percentage reductions in body weight in the orforglipron (12 mg: –6.1 percent; 36 mg: –8.2 percent) than the semaglutide group (7 mg: –3.9 percent; 14 mg: –5.3 percent). ETDs were –2.3 percent (orforglipron 12 mg vs semaglutide 7 mg), –4.3 percent (orforglipron 36 mg vs semaglutide 7 mg), and –2.8 percent (orforglipron 36 mg vs semaglutide 14 mg; p<0.0001 for all).
More than half of orforglipron recipients lost ≥5 percent of their body weight (59–69 percent); with semaglutide, the proportions were lower (37–49 percent). The percentages of participants with ≥10 percent body weight reduction were also greater with orforglipron than with semaglutide (28–44 percent vs 13–21 percent), as were those with ≥15 percent reduction (12–23 percent vs 5–6 percent).
Weight loss of 5–15 percent has been recommended as the primary management target for many individuals with T2D. A 5–10 percent reduction may confer metabolic improvements, while >10 percent reduction may have disease-modifying effects, including potential diabetes remission and cardiovascular (CV) risk reduction. [Diabetes Care 2022;45:1252-1259; N Engl J Med 2002;346:393-403]
The most frequent adverse events (AEs) were gastrointestinal (GI) events, occurring more frequently with orforglipron than semaglutide (58–59 percent vs 37–45 percent). As a result, discontinuation rates due to GI AEs were higher with the former than the latter (9–10 percent vs 4–5 percent).
According to the researchers, most cases of nausea, vomiting, and diarrhoea in the orforglipron groups were mild to moderate in severity, occurred early (during the dose-escalation period), and waned over time.
Fewer orforglipron vs semaglutide recipients completed study treatment with rescue therapy for severe persistent hyperglycaemia (2–3 percent vs 6–12 percent).
Of the four deaths reported, three were adjudicated to a CV cause (one in the orforglipron 12-mg group and two in the semaglutide 7-mg group) and one to a non-CV cause (a malignancy in the orforglipron 36-mg group).
“The overall safety profiles of both orforglipron and semaglutide were consistent with the GLP-1 RA class,” the researchers said.
Most approved GLP-1 RAs are peptide-based and require subcutaneous administration to enable absorption, reduce first-pass metabolism, and avoid proteolytic degradation in the GI tract. However, some patients tend to shy away from injectables, and oral semaglutide is the only oral option. [Clin Ther 2020;42:1812-1817.e2; Adv Ther 2021;38:721-738]
Moreover, oral semaglutide has food and fluid intake limitations to improve bioavailability. Orforglipron is designed for daily oral administration without food or water restrictions, the researchers noted.
“An oral non-peptide GLP-1 RA with the physiological benefits of peptide-based GLP-1 RAs, without the need for injections, would allow further tailoring of therapy to meet individual preferences of patients and prescribers,” the researchers said.
The current results underscore orforglipron as an important advancement in the oral treatment landscape for T2D and may address key barriers associated with current incretin-based therapies, they added.
“[Orforglipron offers] a new highly efficacious and safe option for individuals seeking effective glycaemic and weight control without the use of injections or administration restrictions,” the investigators concluded.