Orforglipron, an oral GLP-1 medication, demonstrated superior weight loss and blood glucose control compared with oral semaglutide in patients with type 2 diabetes (T2D).
In ACHIEVE-3 (NCT06045221), the first head-to-head phase 3 trial of oral glucagon-like peptide-1 receptor agonists (GLP-1 RAs), orforglipron (Eli Lilly and Company) outperformed oral semaglutide (Wegovy in a pill; Novo Nordisk) in adults with type 2 diabetes (T2D) inadequately controlled with metformin hydrochloride (Glucophage; Bristol Myers Squibb), according to results published in The Lancet.1,2
Orforglipron dosed at 12 mg and 36 mg was superior to oral semaglutide at 7 mg and 14 mg across all primary and key secondary end points, including providing significant improvements in weight loss and blood glucose control. The novel oral medication also demonstrated clinically meaningful improvements from baseline across key cardiovascular risk factors, such as total cholesterol, triglycerides, and systolic blood pressure. Improvements appeared as early as 4 weeks, according to Julio Rosenstock, MD, clinical professor of medicine at The University of Texas Southwestern Medical Center and lead investigator of ACHIEVE-3.1,2
"ACHIEVE-3 gives us the first head-to-head comparison between 2 oral GLP-1 receptor agonist therapies in adults with type 2 diabetes, and the differences were clinically meaningful," Rosenstock said in a news release from Eli Lilly and Company. “Orforglipron 12-mg and 36-mg doses outperformed oral semaglutide 7-mg and 14-mg diabetes-related doses on every key end point we measured, including [hemoglobin] A1C [HbA1C] and weight loss, with improvements sustained throughout the study."1
ACHIEVE-3 enrolled 1698 participants across 131 medical centers in Argentina, China, Japan, Mexico, and the US. Participants were randomly assigned to receive orforglipron 12 mg or 36 mg, or oral semaglutide 7 mg or 14 mg once daily. All participants had T2D with baseline HbA1C between 7.0% and 10.5% and were taking metformin at doses of at least 1500 mg/d.1,2
Trial Name: A Study of Orforglipron (LY3502970) Compared With Semaglutide in Participants With Type 2 Diabetes Inadequately Controlled With Metformin (ACHIEVE-3)
ClinicalTrials.gov ID: NCT06045221
Sponsor: Eli Lilly and Company
Completion Date: August 22, 20256
At 52 weeks, orforglipron 36 mg reduced HbA1C by 2.2% from a baseline of 8.3%, compared with a 1.4% reduction with oral semaglutide 14 mg. Orforglipron 12 mg achieved a 1.9% decline. A greater proportion of participants receiving orforglipron achieved HbA1C below 7% at week 52.1,2
Weight loss outcomes strongly favored orforglipron. Participants receiving orforglipron 36 mg lost 9.2% of body weight (approximately 19.7 lb), compared with 5.3% (approximately 11.0 lb) with oral semaglutide 14 mg. The orforglipron 12 mg dose produced 6.7% weight loss (approximately 13.7 lb), whereas oral semaglutide 7 mg led to 3.7% weight loss (approximately 8.0 lb).1,2
The overall safety profile of orforglipron was consistent with the GLP-1 RA class. The most common adverse events for both orforglipron and oral semaglutide included nausea, diarrhea, vomiting, dyspepsia, and decreased appetite.1
Treatment discontinuation rates due to adverse events were higher with orforglipron than oral semaglutide. Discontinuation rates were 8.7% for orforglipron 12 mg and 9.7% for orforglipron 36 mg, compared with 4.5% for oral semaglutide 7 mg and 4.9% for oral semaglutide 14 mg. Incidence of gastrointestinal events was higher with orforglipron, particularly during dose escalation, according to the study investigators.1,2
A mean increase in pulse rate was observed with orforglipron, consistent with effects seen in other GLP-1 RA trials.2
Pharmacists will play critical roles in counseling patients on orforglipron if approved. In the lead-up to approval, pharmacists should monitor its regulatory pathway, including its featuring in the FDA Commissioner’s National Priority Voucher pilot program. Once approved, key considerations include patient education on dose titration schedules, managing gastrointestinal adverse effects during escalation, and counseling on the flexible dosing schedule that distinguishes orforglipron from oral semaglutide.3,4
Unlike oral semaglutide, which requires careful timing around meals and other medications, orforglipron's food-independent administration may simplify patient counseling. However, pharmacists should be prepared to address higher rates of gastrointestinal adverse events and treatment discontinuations compared with oral semaglutide.5
For patients unable or unwilling to use injectable GLP-1 RAs, oral formulations provide important alternatives. The American Diabetes Association recommends GLP-1 RAs with proven cardiovascular benefit as preferred add-on therapy after metformin and lifestyle intervention in patients with T2D and established atherosclerotic cardiovascular disease. GLP-1 RAs are also recommended when there is a compelling need to minimize hypoglycemia or promote weight loss.5
The ACHIEVE-3 results demonstrate that orforglipron offers superior glycemic control and weight reduction compared with currently available oral semaglutide. If approved, orforglipron could expand treatment options for patients seeking oral alternatives to injectable GLP-1 therapies.
