The advent of the injectable weight-loss drug semaglutide (known better by its brand names Wegovy and Ozempic) marked a distinct shift in the weight-loss drugs market when it became available just a few years ago.

Semaglutide is a class of glucagon-like peptide-1 (GLP-1) medication. These drugs mimic the gut hormone GLP-1, which is released soon after eating. This hormone signals fullness to the brain, slowing digestion and stimulating the release of insulin. By replicating the action of this hormone, GLP-1 drugs have proven highly effective at managing type 2 diabetes and promoting weight loss.

Although semaglutide is widely used, a key issue with the drug is that it needs to be injected into the belly, thighs or back of the arm. This can make it difficult for patients with needle phobia or who don’t want to self-inject due to the inconvenience.

Another logistical issue with injectable GLP-1 drugs is that they require refrigeration throughout the supply chain. This can pose a challenge in low- and middle-income countries.

It’s for these reasons that researchers and developers have started investigating the efficacy of oral versions of semaglutide.

Based on current research, it appears that oral semaglutide is very effective. However, it must be taken on an empty stomach – and users must wait 30 minutes before eating or drinking.

Alongside being expensive to produce, it also has poor bioavailability compared with injectable semaglutide. This means only about 1% of the ingested drug is absorbed and able to exert its effects.

But a recent phase 3 clinical trial has shown that a new type of oral weight-loss pill may have overcome these issues – proving to be more effective than the current oral semaglutide products on the market.

Oral weight-loss pill

The recent 52-week phase 3 trial involved 1,698 adults with type 2 diabetes across six countries. It set out to compare current oral semaglutide products against orforglipron, which is also taken as a daily tablet.

The primary measure researchers were looking for was a reduction in HbA1c. This blood test reflecting average blood sugar levels over three months is the standard indicator of diabetes control. Diabetes is present if HbA1c is 6.5% or more.

From a baseline average HbA1c of 8.3%, it was found that after 52 weeks, orforglipron was able to reduce this value by an average of 1.71–1.91%. In comparison, oral semaglutide only reduced HbA1c by 1.47%.

Not only did orforglipron meet the trial’s goals of proving it was as effective to oral semaglutide, it proved it was superior for lowering blood sugar. The participants who took orforglipron also lost more weight – an average of 6.1kg-8.2kg, compared with 5.3kg in those taking semaglutide.

However, a key issue highlighted by the trial was one of tolerability.

GLP-1 drugs can cause gastrointestinal side-effects such as nausea, vomiting, diarrhea and constipation. In this latest trial, around 59% of participants on orforglipron reported such symptoms, compared with 37–45% on semaglutide.

The reason for this difference may be the more prominent, daily peak drug concentrations with orforglipron. The consequence was that around 10% of orforglipron participants discontinued treatment due to adverse effects. Just 4-5% of those taking semaglutide discontinued treatment.

No head-to-head trials have been done of injectable GLP-1 versus orforglipron. However, the weight loss seen in this study of people with type 2 diabetes is broadly comparable with that previously observed with injectable GLP-1.

Market implications

The trial’s results show that orforglipron, which was developed by Eli Lilly, can be considered one of semaglutide’s most credible challengers.

Another remarkable thing about orforglipron is that it belongs to a new category of drugs called small-molecule drugs. This means it’s a synthetic chemical compound small enough to be absorbed directly through the gut wall. There, it’s able to act on GLP-1 receptors, even though it isn’t of a similar structure to a GLP-1 hormone.

Oral semaglutide, on the other hand, is a peptide drug. This means the structure of its amino acids (one of the building blocks of protein) closely resembles that of the natural GLP-1 hormone.

As a small-molecule drug, orforglipron is cheaper and simpler to manufacture than peptide-based drugs such as semaglutide.

And as with oral semaglutide, it requires no refrigeration. This gives it a logistical advantage over injectable GLP-1 formulations – a potentially important consideration for expanding access in low- and middle-income countries, where cold chain infrastructure is unreliable.

It remains to be seen, however, how orforglipron will perform against oral semaglutide in the broader market.

Although this latest trial has shown it is superior for controlling blood sugar and aiding weight loss, its higher rate of side-effects and treatment discontinuation may temper enthusiasm. In a crowded and competitive market, long-term adherence – shaped as much by tolerability as by efficacy – is probably a critical differentiator.

Orforglipron is still undergoing trials in patients with obesity but without diabetes.