Oral GLP-1 drug shows substantial weight loss in large international study

A GLP-1 drug taken as a daily pill has been shown to produce substantial weight loss in people with obesity but without type 2 diabetes, an international trial has shown.

A phase 3 trial of orforglipron (from Eli Lilly and also known as Emgality), in 3,100 adults with a BMI of at least 30 or a BMI between 27 and 30 and at least one obesity-related complication found significant reductions in body weight compared with placebo over 72 weeks.

Three different doses – 6 mg, 12 mg, or 36 mg – were compared in the study in which everyone was given support around a healthy diet and physical activity.

Reporting the findings in the New England Journal of Medicine, the Canadian researchers said the oral GLP-1 drug led to a more than 10% reduction in body weight for more than half of those on the highest dose.

Overall, participants in the orforglipron group were significantly more likely than those in the placebo group to have body-weight reductions of 5% or more, 10% or more, 15% or more, and 20% or more, the researchers said.

The mean relative reduction in body weight from baseline to week 72 was 7.5% with 6 mg of orforglipron, 8.4% with 12 mg and 11.2 with 36 mg of orforglipron, compared with 2.1% in those taking placebo.

At the highest dose, 18.4% of participants had a reduction of 20% or more, they reported.

In addition, waist circumference, systolic blood pressure, triglyceride levels, and non-HDL cholesterol levels also significantly improved with orforglipron treatment.

The most common side effects were gastrointestinal problems, which were mostly mild to moderate, consistent with the GLP-1 class of medications, the researchers said.

Around 5-10% of the patients in the orforglipron groups and 2.7% of those in the placebo group stopped taking the medication.

They concluded: ‘In patients with obesity, the use of orforglipron resulted in statistically and clinically significant weight reductions and an adverse-event profile that was consistent with findings regarding other GLP-1 receptor agonists.

 ‘This could mean an expansion of obesity interventions to groups who are currently excluded due to the cost of and lack of access to injectable medications.’

The study did not compare the drug to current licensed weight loss treatments, including injectable GLP-1 medicines.

NICE has indicated it will be reviewing the evidence for orforglipron for the treatment of obesity.

It is hoped that oral version of GLP-1 drugs could be cheaper and more accessible, improve adherence and be an option for people who do not want to use injections.

Dr Stephen Lawrence, a GP and associate clinical professor at Warwick University Medical School, said the study on orforglipron had certainly attracted interest, ‘particularly as it demonstrates significant, clinically meaningful weight loss with a favourable cardiometabolic profile in a diverse population’.

He added that other oral GLP-1 drugs are in development, and if approved, could represent an important shift in obesity and diabetes management.

‘However, extending NHS access will face familiar challenges: supply limitations for GLP-1s are ongoing, and recent experience shows that NICE guidance is typically implemented in phased rollouts, prioritising those with most complex need before wider primary care adoption. 

‘Addressing affordability and capacity in current NHS services will be crucial; simply broadening medication choice will not automatically resolve structural barriers or ensure equitable service delivery.’

He said wraparound care remained a key issue as effective obesity and diabetes intervention ‘goes far beyond prescriptions’.