Novel Oral GLP-1 Receptor Agonist Shows Promise for Type 2 Diabetes Management

A new once-daily oral medication, orforglipron, demonstrates greater reductions in HbA1c and body weight compared to oral semaglutide for adults with type 2 diabetes, according to data from the ACHIEVE-3 trial published in The Lancet. The findings suggest orforglipron could be a valuable therapeutic option for individuals seeking a non-injectable GLP-1 receptor agonist.

Study Details and Findings

The ACHIEVE-3 trial, a randomized, phase 3, open-label study, involved 1,698 adults with type 2 diabetes who were not adequately controlled with metformin. Participants had an HbA1c between 7% and 10%, a BMI of 25 kg/m² or higher, and minimal body weight changes in the preceding three months. They were assigned to receive either orforglipron (12 mg or 36 mg) or oral semaglutide (7 mg or 14 mg) for one year.

The primary endpoint was noninferiority in HbA1c change at one year. Results showed that both orforglipron groups achieved significantly greater HbA1c reductions than both oral semaglutide groups (P < .006 for all).

• HbA1c Reduction: Orforglipron 12 mg resulted in a 1.71 percentage point decline in HbA1c, while orforglipron 36 mg led to a 1.91 percentage point drop, compared to 1.23 and 1.47 percentage point reductions with semaglutide 7 mg and 14 mg, respectively.
• Glycemic Control Targets: A higher percentage of participants on orforglipron achieved HbA1c levels below 7%, 6.5%, and 5.7% compared to those on semaglutide. Specifically:
  • HbA1c < 7%: 72% (orforglipron 12 mg) and 76% (orforglipron 36 mg) vs. 54% (semaglutide 7 mg) and 64% (semaglutide 14 mg)
  • HbA1c < 6.5%: 63% (orforglipron 12 mg) and 68% (orforglipron 36 mg) vs. 38% (semaglutide 7 mg) and 48% (semaglutide 14 mg)
  • HbA1c < 5.7%: 21% (orforglipron 12 mg) and 31% (orforglipron 36 mg) vs. 7% (semaglutide 7 mg) and 12% (semaglutide 14 mg)
• Weight Loss: Orforglipron 12 mg led to a 6.1% weight loss, and orforglipron 36 mg resulted in an 8.2% decrease, compared to 3.9% and 5.3% weight loss with semaglutide 7 mg and 14 mg, respectively. The 36 mg orforglipron group experienced significantly greater weight loss than both semaglutide groups (P < .001).

Cardiometabolic Improvements

The study also revealed improvements in several cardiometabolic parameters. Decreases were observed in non-HDL cholesterol, triglycerides, LDL cholesterol, and total cholesterol with most treatment groups. The semaglutide 14 mg group showed a slight increase in total and LDL cholesterol. All groups experienced reductions in systolic blood pressure, with more pronounced decreases in the orforglipron groups.

Safety Profile

Adverse events were reported in approximately 71-75% of participants across all treatment groups. Gastrointestinal adverse events were more common with orforglipron than with semaglutide, but these events generally occurred early in the trial during dose escalation and lessened over time. Serious adverse events were reported in 4-9% of participants, with half of the serious events in the orforglipron 36 mg group occurring before reaching the maximum dose.

There were four deaths during the trial, distributed across the treatment groups. No participants discontinued treatment due to hypoglycemia. The incidence of acute pancreatitis and worsened diabetic retinopathy was similar between the two drugs.

Implications and Considerations

“Orforglipron represents a potential new therapeutic option for individuals with type 2 diabetes considering initiation of GLP-1 receptor agonist therapy who might prefer an alternative to the subcutaneous route of administration,” stated Julio Rosenstock, MD, FACE, senior scientific advisor for Velocity Clinical Research.

The researchers suggest that the choice between oral GLP-1 receptor agonists should be guided by individual patient factors, including glycemic control goals, weight loss objectives, cardiovascular risk reduction, tolerability, and convenience.

Source: Rosenstock J, et al. Lancet. 2026. doi:10.1016/S0140-6736(26)00202-3.

Disclosure: The study was funded by Eli Lilly. Dr. Rosenstock reports various financial relationships with multiple pharmaceutical companies, including Eli Lilly. Please see the study for a complete list of author disclosures.