Study shows new once-daily weight-loss pill orforglipron outperforms leading oral semaglutide in patients with type 2 diabetes on weight and A1C reduction

Eli Lilly reported Tuesday that its once-daily weight-loss pill orforglipron outperformed oral semaglutide in a 52-week phase 3 trial involving adults with type 2 diabetes inadequately controlled by metformin. According to the company, orforglipron demonstrated greater reductions in both A1C levels and body weight compared to semaglutide in the ACHIEVE-3 study.

In the ACHIEVE-3 phase 3 randomized controlled trial, Eli Lilly’s once-daily oral GLP-1 receptor agonist orforglipron demonstrated superior reductions in both A1C and body weight compared with oral semaglutide over 52 weeks in adults with type 2 diabetes inadequately controlled by metformin, according to a company news release posted Tuesday. The trial evaluated two dose pairs: orforglipron 12 mg and 36 mg versus oral semaglutide 7 mg and 14 mg.

Lilly reported that orforglipron lowered A1C by 1.9% and 2.2% at the 12 mg and 36 mg doses, respectively, compared with reductions of 1.1% and 1.4% for semaglutide 7 mg and 14 mg, based on the efficacy estimand.

In terms of weight loss, orforglipron achieved decreases of 14.6 pounds (6.7%) and 19.7 pounds (9.2%) at the two doses, compared with 7.9 pounds (3.7%) and 11.0 pounds (5.3%) with semaglutide, the company said.

Medscape’s clinical news coverage of the ACHIEVE-3 trial, which was presented at a medical meeting, corroborated these findings, reporting estimated treatment differences favoring orforglipron for both A1C and weight reduction across dose comparisons. The report cited A1C changes from baseline as -1.71% versus -1.23% for orforglipron 12 mg versus semaglutide 7 mg, and -1.91% versus -1.47% for orforglipron 36 mg versus semaglutide 14 mg. Weight loss differences were reported as -2.3%, -4.3%, and -2.8% favoring orforglipron over semaglutide across the dose pairs.

A PubMed-indexed summary of the trial described orforglipron 12 mg and 36 mg as both non-inferior and superior to semaglutide 7 mg and 14 mg for mean change in HbA1c at 52 weeks. The same source noted that orforglipron 36 mg produced larger reductions in A1C and weight than semaglutide 14 mg, reinforcing the head-to-head superiority demonstrated in the trial.

Regarding safety, Lilly noted that the adverse event profile of orforglipron was generally consistent with the GLP-1 receptor agonist class. However, Medscape reported that gastrointestinal events were the most frequent adverse effects, occurring in 59% and 58% of participants receiving orforglipron 12 mg and 36 mg, respectively, compared with 37% and 45% in the semaglutide 7 mg and 14 mg groups. The PubMed summary indicated that gastrointestinal events, discontinuations due to adverse events, and mean increases in pulse rate were higher with orforglipron than with oral semaglutide. Lilly’s release emphasized the efficacy outcomes but did not provide detailed tolerability data in the summary.

The ACHIEVE-3 trial enrolled adults with type 2 diabetes inadequately controlled by metformin and compared once-daily oral orforglipron with oral semaglutide over a 52-week period, according to Lilly’s release and the trial’s PubMed summary. The company identified the doses studied as 12 mg and 36 mg for orforglipron and 7 mg and 14 mg for oral semaglutide. The efficacy findings were reported using the efficacy estimand and percent weight change from baseline.

Eli Lilly sponsored the trial and disseminated the results through an investor news release. Medscape’s clinical news report and PubMed’s indexed publications provided additional analyses and context for the findings. A related PubMed review article highlighted that cross-trial comparisons should be interpreted cautiously and underscored the value of ACHIEVE-3’s direct head-to-head design.

In other research on orforglipron in early type 2 diabetes, Medscape reported no episodes of severe hypoglycemia and noted gastrointestinal events as the most common adverse effects. The company’s release and the indexed literature confirm that orforglipron represents a new oral GLP-1 receptor agonist option that, in this trial, outperformed the current leading oral GLP-1 therapy, semaglutide, on key measures of glycemic control and weight reduction at one year.