In Lancet yesterday, Julio Rosenstock and colleagues published the results of a head-to-head comparison of orforglipron versus oral semaglutide in adults with type 2 diabetes and a BMI greater than 25. Headlines would have you believe this was a clear win for orforglipron over semaglutide. But it’s not quite that simple.

The Study Details

The average BMI in this trial was 35. The primary objective was to determine if orforglipron was at least as good as oral semaglutide for reducing HbA1c. It was a 52-week study.

In short, Rosenstock et al found that orforglipron not only matched, but also surpassed, the reductions in HbA1c produced by the  formulation and doses of oral semaglutide used in this study. People taking orforglipron also lost more weight than those taking oral semaglutide.

However, discontinuations of therapy for adverse events were more common with orforglipron than with oral semaglutide. At the top dose of orforglipron, 10% of patients could not tolerate it. For oral semaglutide, the number was 5%.

Who Wins?

Lilly, obviously, is quite enthusiastic about these results for their drug (orfo). The company issued a press release with Rosenstock saying:

“Orforglipron 12 mg and 36 mg doses outperformed oral semaglutide 7 mg and 14 mg diabetes-related doses on every key endpoint we measured, including A1C and weight loss, with improvements appearing as early as four weeks and sustained throughout the study.”

But this is not an easy win for Lilly on two counts. One is the inferior tolerability. The other is the question of whether they were comparing to an obsolete version of oral semaglutide.

Version 1.0 of Oral Semaglutide

You see, there are two versions of oral semaglutide in play now. One is the formulation known as Rybelsus, launched more than six years ago. We’ll call that version 1.0. It has done OK in the marketplace, but not great. The bioavailability of it is very poor, 0.4 – 1.0%. Tolerability has been an issue.

Then in January, Novo Nordisk launched an updated formulation of oral semaglutide as Wegovy tablets for obesity treatment. We’ll call this version 2.0. The bioavailability is still not great, but at 1 – 2%, it’s twice as good as version 1.0. So the dosing is lower than it was with the original formulation.

For obesity, the dose went down from 50 mg with the original formulation to 25 mg with the new formulation. For diabetes, FDA just approved the new formulation with a top dose of 9 mg. The top dose for Rybelsus is 14 mg. The new prescribing information tells us clearly – these two formulations are not interchangeable.

Does It Matter?

So will the new formulation make a difference? We simply do not know. Clinicians are saying that Wegovy tablets are yielding better results than they would have expected from their experience with Rybelsus. That could be the hype of the Wegovy pill launch talking. Or it could be a real difference in patient experiences.

We will need data and more time in market to know with any confidence.

Click here for the study in Lancet and here for a commentary alongside it. For further perspective on this study, click here, here, and here.

Tablet Versus Tablet, illustration created for ConscienHealth with ChatGPT image generation