Oral GLP-1 Therapy Orforglipron Demonstrates Significant Weight Loss in Landmark Trial

Key Takeaways: 

• The ATTAIN-1 phase III trial found that the oral GLP-1 drug orforglipron led to clinically meaningful weight loss and metabolic improvements in people living with obesity or overweight.
• Average weight loss reached 12.4% with the highest dose, alongside significant improvements in waist circumference, blood pressure, and lipid profiles.
• Orforglipron may provide a more accessible alternative for individuals reluctant to use injections or living in areas with limited cold-storage infrastructure.
  
  
  

A new oral alternative to injectable GLP-1 therapies

An investigational oral GLP-1 drug, orforglipron, has been shown to promote substantial weight loss and improve cardiovascular and metabolic health markers in a large, international phase III clinical trial. The ATTAIN-1 study, published on 17 September in The New England Journal of Medicine, was led by researchers from Weill Cornell Medicine, McMaster University, York University, and collaborating institutions.

The study enrolled 3,127 participants with obesity or overweight who had obesity-related complications such as hypertension. None of the participants had diabetes. Participants were randomised to receive a placebo or one of three daily oral doses of orforglipron – 6 mg, 12 mg, or 36 mg – alongside guidance on maintaining a healthy diet and regular physical activity.

Meaningful weight loss across all doses

Over 72 weeks, individuals treated with orforglipron experienced dose-dependent weight loss:

• 7.8% reduction in body weight with the 6 mg dose
  
• 9.3% reduction with the 12 mg dose
  
• 12.4% reduction with the 36 mg dose
  

By comparison, participants in the placebo group lost an average of just 2.1% of their initial body weight.

Adverse events were consistent with those observed for other GLP-1 receptor agonists, mainly mild to moderate gastrointestinal effects including nausea, vomiting, and diarrhoea.

Clinical and public health implications

“The findings suggest that orforglipron could offer an important new option for people with obesity, especially those reluctant to use injections or who live in places where cold storage for injectable medications is limited,” said Dr Louis Aronne, Director of the Comprehensive Weight Control Center and Sanford I. Weill Professor of Metabolic Research at Weill Cornell Medicine, who served as a lead investigator for the ATTAIN-1 trial.

“ATTAIN-1 represents another milestone in developing effective treatments for obesity. In addition, the distribution and storage of a small molecule is less expensive, and scalability is simpler. Given the worldwide demand, these are important factors in making treatment available to those in need,” Dr Aronne added.

Dr Aronne is also an internist specialising in diabetes and obesity at NewYork-Presbyterian/Weill Cornell Medical Center.

Improvements beyond weight loss

Although the weight reduction achieved with orforglipron was slightly lower than that typically seen with injectable GLP-1 therapies such as semaglutide or tirzepatide, the study reported robust cardiometabolic benefits. Participants on orforglipron demonstrated greater reductions in:

• Waist circumference
  
• Systolic blood pressure
  
• Non-HDL cholesterol and triglyceride levels
  
• Glycated haemoglobin (HbA1c)
  

These improvements underline the drug’s potential to reduce the risk of major obesity-related complications, including cardiovascular disease and type 2 diabetes.

Why oral GLP-1 drugs could be game-changing

Injectable GLP-1 drugs, which are peptide-based therapies, have already transformed obesity and type 2 diabetes management worldwide. When taken long-term, they can help people lose more than 15% of their body weight and substantially lower the risk of heart attack, stroke, kidney disease, and sleep apnoea.

However, injectable GLP-1 medications require cold storage and are vulnerable to breakdown by stomach enzymes if taken orally. Orforglipron is different – it is a “small-molecule” drug designed to be taken as a pill, potentially lowering costs and simplifying global distribution.

Study scope and sponsorship

The ATTAIN-1 trial was sponsored by Eli Lilly and Company, which manufactures orforglipron as well as the injectable GLP-1 drug tirzepatide (marketed as Mounjaro for type 2 diabetes and Zepbound for chronic weight management). The trial was conducted across 137 sites in nine countries, including the United States, Canada, Japan, Brazil, Spain, and Saudi Arabia.

Disclosure: Dr Louis Aronne serves as a paid consultant and advisory board member for Eli Lilly and Company.