Orforglipron: new GLP-1 pill beats Rybelsus for weight loss

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A new tablet-based medication has beaten oral semaglutide (Rybelsus) for weight loss. Let's unpack the results to see what they really mean.

You've probably heard of Wegovy and Mounjaro, the two most popular weight loss medications available in the UK. But did you know other, similar drugs are in development?

One of these new drugs, orforglipron, has recently undergone a phase 3 clinical trial – the final trial phase before a drug goes to market.

And here's where things get interesting. Recently published trial results show that orforglipron is more effective for weight loss than oral semaglutide (available in the UK as Rybelsus).¹

Semaglutide is the active ingredient in Wegovy. Does that mean that orforglipron could be a viable, tablet-based alternative to Wegovy injections?

Well, it's not quite as simple as that. But these new results are interesting nonetheless – especially for those who use oral GLP-1 medications for both weight loss and type 2 diabetes.

Let's take a closer look at the results and what they really mean.

Going head to head: orforglipron vs oral semaglutide

The study, dubbed 'ACHIEVE-3', is part of a series of phase 3 clinical trials looking at orforglipron for weight loss and type 2 diabetes. It's the first 'to directly compare the efficacy and safety of two oral GLP-1 receptor agonists in a randomised controlled trial', reports Medscape.²

The part about 'directly comparing' the two drugs is important. Because the researchers studied orforglipron and oral semaglutide under identical conditions, they can make firm conclusions about which is safer or more effective.

Nearly 1,700 people took part in the study. After 52 weeks of treatment, the researchers found that:

Those taking the highest dose of orforglipron lost 9.2% of their body weight on average. Those taking the highest dose of semaglutide lost an average of 6.2%.³

High-dose orforglipron users saw blood sugar reduced by 1.91% on average, compared to 1.47% for semaglutide.³

These results show that orforglipron is more effective for weight loss and blood sugar management than the currently available doses of oral semaglutide.

Unpacking the results

The ACHIEVE-3 study is good news for Eli Lilly, the company behind orforglipron. It adds weight to the growing evidencethat orforglipron will prove to be an effective, tablet-based treatment option for obesity and type 2 diabetes.

However, there are a few caveats to keep in mind.

The study only looked at people with type 2 diabetes

Picture of a person in consultation with a doctor.

ACHIEVE-3 exclusively studied the drugs' effects on adults with type 2 diabetes.¹ That means we can't be sure how these effects will translate to people without diabetes.

Injectable semaglutide (Wegovy) isn't part of the picture

The trial didn't compare orforglipron with semaglutide injections (Wegovy), so we can't make a like-for-like comparison. However, we know from previous trial results that injectable Wegovy yields an average weight loss of 14.9%⁴. That suggests Wegovy and other injectable weight loss medications remain the most effective options for those looking to lose weight.

The doses match Rybelsus, but Rybelsus isn't an option for weight loss

The study compared 12mg and 36mg doses of orforglipron with 7mg and 14mg doses of oral semaglutide. Those oral semaglutide doses match Rybelsus – the only tablet-based drug containing semaglutide that's currently available in the UK.

However, Rybelsus isn't licensed for weight loss in the UK. It's only meant to be prescribed to help people with type 2 diabetes manage their blood sugar, with weight loss as a secondary benefit.

Higher-dose oral semaglutide is now available, but the study didn't look at it

Novo Nordisk has recently launched an oral semaglutide tablet in the US.⁵ Like the semaglutide injection, it's sold under the name 'Wegovy' and is designed as a weight loss treatment.

This new Wegovy tablet is available in doses as high as 25mg, because higher doses have proven more effective for weight loss.⁶ However, the ACHIEVE-3 study didn't compare orforglipron with these higher doses.

Orforglipron seems to have stronger side effects than Rybelsus

In the ACHIEVE-3 study, more orforglipron users (around 58%) reported side effects than semaglutide users (37% to 45%). In addition, around twice as many orforglipron users discontinued treatment because of side effects.

In its favour, orforglipron has a simpler dosing schedule than Rybelsus. It only needs to be taken once per day and can be taken at any time. Rybelsus, on the other hand, must be taken daily on an empty stomach, with doses planned around mealtimes.

Ultimately, then, orforglipron might suit those who want the most effective option for weight loss and blood sugar and are willing to accept stronger side effects. Rybelsus, meanwhile, may suit those who want to trade milder side effects for tighter dosing rules and less powerful effects.

Semapen is a UK-based provider of expert-led weight loss programmes, including options that harness the latest injectable weight loss medications. For more news, follow our blog.

Sources

1. Rosenstock, J. et al. (2026) "Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial" The Lancet https://doi.org/10.1016/S0140-6736(26)00202-3

2. Yasgur, B.S. (2026) New Oral GLP-1 Beats Oral Semaglutide for A1c, Weight Loss. Medscape. Retrieved from https://www.medscape.com/viewarticle/new-oral-glp-1-beats-oral-semaglutide-a1c-weight-loss-2026a10006jd

3. Livingston, R. (2026) ACHIEVE-3: Orforglipron Achieves Superiority to Oral Semaglutide in Poorly Controlled T2D. HCPLive. Retrieved from https://www.hcplive.com/view/achieve-3-orforglipron-achieves-superiority-to-oral-semaglutide-in-poorly-controlled-t2d

4. Wilding, J.P.H. et al. (2021) "Once-Weekly Semaglutide in Adults with Overweight or Obesity" The New England Journal of Medicine, 384(11) https://doi.org/10.1056/NEJMoa2032183

5. Gronholt-Pedersen, J. & Satija, B. (2026) Novo launches Wegovy weight-loss pill for sale in US. Reuters. Retrieved from https://www.reuters.com/sustainability/boards-policy-regulation/novo-nordisk-sell-wegovy-pill-us-self-pay-patients-starting-149-per-month-2026-01-05/

6. Wharton, S. et al. (2025) "Oral Semaglutide at a Dose of 25 mg in Adults with Overweight or Obesity" The New England Journal of Medicine, 393(11) https://doi.org/10.1056/NEJMoa2500969

This article was reviewed and approved by Lujain Alhassan, Bariatric Nutritionist, on 22 March 2026.

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