Lilly says orforglipron tops Wegovy pill in diabetes trial

Eli Lilly's oral GLP-1 agonist orforglipron was more effective than Novo Nordisk's recently launched Wegovy pill in a head-to-head diabetes trial, but likely won't answer the question of which is better.

The results of the ACHIEVE-3 trial – published in The Lancet – showed that orforglipron scored higher on various weight loss and glucose control measures than oral Wegovy (semaglutide) across a range of doses for both drugs.

However, the daily doses of oral Wegovy (7 mg and 14 mg) selected for the trial are relatively modest, and lower than the maximum 25 mg allowable under the drug's label as an obesity treatment.

Higher doses of oral semaglutide have been shown to achieve greater glucose control in prior studies and are expected to be included in filings to expand its label to include type 2 diabetes.

Meanwhile, there are differences in side effects between the two drugs that could also have an impact on their take-up – assuming, of course, that orforglipron is approved for marketing. Lilly said it has now filed the drug in more than 40 countries, reiterating its anticipation of a decision in the US in the second quarter.

ACHIEVE-3 was carried out in 1,698 people living with type 2 diabetes inadequately controlled with metformin, who received orforglipron at either 12 mg or 36 mg per day or one of the two oral Wegovy doses.

The primary endpoint was the change in glucose control (measured using the HbA1c biomarker) at 52 weeks, and the highest dose of orforglipron achieved a 2.2% reduction, compared to a 1.4% with the top dose of Wegovy.

Patients taking orforglipron 36 mg also lost 9.2% of weight at that timepoint, compared to 5.3% with semaglutide 14 mg, which Lilly said represented "73.6% greater relative weight loss."

Meanwhile, nausea and vomiting – the most common side effects with incretin-based therapies for diabetes and weight loss – were reported by patients to be more common with orforglipron than with semaglutide, with a similar finding for diarrhoea and constipation.

The proportion of patients who stopped treatment because of side effects was doubled with Lilly's drug, at 9% to 10% compared to 4% to 5% - depending on dose – for semaglutide.

Lilly said the results showed "potential advantages" for orforglipron compared to semaglutide in T2D, whilst also pointing out that its drug does not have some of the dosing restrictions of Novo Nordisk's drug, such as the need to take it after overnight fasting and avoid ingesting any fluids or other medications for 30 minutes thereafter.

A Lancet editorial accompanying the study, written by diabetes specialists Michael Nauck and Michael Horowitz, concludes that "the outcomes of the current study should not be interpreted to indicate that orforglipron is, generally speaking, more efficacious than oral semaglutide."

They suggest that patients who need a substantial improvement in glucose control or body weight might prefer orforglipron, while those with a higher priority for tolerability might favour semaglutide.

That view was echoed by Prof Naveed Sattar of the University of Glasgow in the UK, who also noted that oral semaglutide has the advantage of proven cardiovascular benefit, whereas similar evidence for orforglipron is not yet available.

"Overall, the field is moving toward treatments that meaningfully improve weight, blood sugar, and cardiovascular risk at the same time. These more holistic approaches, which also benefit patient well-being, are likely to offer the greatest benefits for people living with type 2 diabetes," he said.

"Incretin-based therapies associated with considerable intentional weight loss may well become first-line treatments for type 2 diabetes within the next decade, potentially helping many people achieve remission for several years."

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