By Dr Mohgah Elsheikh: A major breakthrough in diabetes and weight management was unveiled this week at the 2025 American Diabetes Association (ADA) Scientific Sessions. The spotlight was on Orforglipron, a new oral GLP-1 receptor agonist, which has shown impressive results in a Phase 3 trial, ACHIEVE-1, published simultaneously in the New England Journal of Medicine (NEJM). This much-anticipated study confirms that Orforglipron, a first-in-class oral, nonpeptide GLP-1 receptor agonist, significantly improves blood sugar control and supports weight loss in people with early type 2 diabetes.

 

What is Orforglipron?

Orforglipron is a small molecule GLP-1 receptor agonist taken once daily by mouth. Unlike current GLP-1 options such as Semaglutide (Wegovy/Ozempic) or Tirzepatide (Mounjaro), which are injectable peptide-based drugs, Orforglipron is:

• Taken orally – no needles required
• Does not need refrigeration – easier to store and transport
• Can be taken with or without food – more flexible dosing
• Easier and cheaper to produce than peptide-based drugs

 

The ACHIEVE-1 Trial: Key Findings

This international Phase 3 study included 559 adults with early type 2 diabetes, who were managing their condition with diet and exercise alone. Participants had a starting HbA1c (a measure of average blood sugar levels) between 7.0% and 9.5%, and a BMI of at least 23 kg/m².

They were randomly assigned to receive daily doses of Orforglipron (either 3 mg, 12 mg, or 36 mg) or a placebo for 40 weeks.

 

Blood Sugar Control: Significant Reductions in HbA1c

The primary goal of the study was to see how much Orforglipron could lower HbA1c. All three doses of Orforglipron significantly outperformed placebo, with mean HbA1c levels falling to between 6.5% and 6.7% at the end of the study. Participants on the lowest 3 mg dose dropped their HbA1c by an average of 1.24% and those on the higher doses achieved even greater reductions of up to 1.48%. In contrast, the placebo group only saw a 0.4% drop in HbA1c. 

 

Weight Loss: Meaningful Results

A key secondary outcome was weight loss. People taking Orforglipron experienced dose-dependent weight loss over the 40-week period of between 4.5% of their starting weight on the lowest dose and an average of 7.6% weight loss on the highest dose. In comparison, those on placebo lost just 1.7% of their body weight. These results are comparable to the weight loss on injectable Semaglutide 1mg weekly.

 

Side effects and safety

As with other GLP-1 medications such as Wegovy and Mounjaro, the most common side effects were gastrointestinal, including nausea and diarrhoea. These symptoms were mostly mild to moderate and occurred during the dose escalation phase.

Importantly, there were no episodes of severe hypoglycaemia (low blood sugar) and the number of participants who stopped taking the drug due to side effects was relatively low.

 

Why does this matter? 

Orforglipron is the first nonpeptide oral GLP-1 receptor agonist to demonstrate such promising results in a large-scale Phase 3 trial. If approved, Orforglipron could radically improve the way we treat type 2 diabetes, and potentially obesity, around the world by:

·      Improving medication access for those who struggle with injectable treatments

·      Reducing manufacturing and storage costs

·      Reaching more patients in low-resource settings

 

Looking ahead

Orforglipron is still in development, and further studies, including those focusing on weight management in people without diabetes, as well as studies looking at its effects on heart and liver health, are ongoing. Still, these early results are promising and signal a shift toward a more inclusive, scalable, and patient-friendly future in diabetes and obesity care.

In a field that is rapidly evolving, Orforglipron stands out as a hopeful new option that could help close the access gap and improve outcomes for millions of people around the world.