A new type of daily pill has proven more effective at weight loss and controlling blood sugar levels than currently available pills, according to a recent trial. The drug, known as orforglipron, could be a game-changer in the rapidly expanding market for oral weight-loss drugs.
The introduction of the injectable weight loss drug semaglutide (better known by its brand names Wegovy and Ozempic) marked a distinct shift in the weight loss drug market when it became available just a few years ago.
Semaglutide is a type of glucagon-like peptide-1 (GLP-1) drug. These drugs mimic the intestinal hormone GLP-1, which is released shortly after eating. This hormone tells the brain that you’re full, slows down digestion, and stimulates the release of insulin. GLP-1 drugs have proven highly effective in managing type 2 diabetes and promoting weight loss by replicating the effects of this hormone.
Semaglutide is widely used, but a key problem with this drug is that it must be injected into the abdomen, thigh, or back of the arm. This can be difficult for patients who have needle phobia or who do not want to self-inject due to the inconvenience.
Another logistical issue with GLP-1 injectable drugs is the need for refrigeration throughout the supply chain. This can be a challenge in low- and middle-income countries.
It is for these reasons that researchers and developers have begun investigating the effectiveness of oral versions of semaglutide.
Based on current research, oral semaglutide appears to be highly effective. However, it must be taken on an empty stomach, and users must wait 30 minutes before eating or drinking.
In addition to higher manufacturing costs, it also has lower bioavailability compared to injectable semaglutide. This means that only about 1% of the ingested drug is absorbed and becomes effective.
However, a recent phase 3 clinical trial demonstrated that a new type of oral weight loss drug may be able to overcome these problems and is more effective than currently available oral semaglutide products.
oral weight loss drugs
A recent 52-week Phase 3 trial enrolled 1,698 adults with type 2 diabetes from six countries. We set out to compare the current oral semaglutide product with orforglipron, which is also taken as a daily tablet.
The main measure the researchers were looking for was lowering HbA1c. This blood test, which reflects average blood sugar levels over a 3-month period, is a standard indicator of diabetes management. Diabetes is present if HbA1c is 6.5% or higher.
The mean baseline HbA1c was 8.3%, and after 52 weeks, they found that orforglipron was able to lower this value by an average of 1.71 to 1.91%. In comparison, oral semaglutide reduced HbA1c by only 1.47%.
Not only did orforglipron meet the trial’s goal of proving it to be as effective as oral semaglutide, it also proved superior in lowering blood sugar levels. Participants who took orforglipron lost more weight, averaging between 6.1 kg and 8.2 kg, compared with an average of 5.3 kg for participants who took semaglutide.
However, a key issue highlighted by this trial was that of tolerability.
GLP-1 drugs can cause gastrointestinal side effects such as nausea, vomiting, diarrhea, and constipation. In this latest trial, approximately 59% of participants who received orforglipron reported such symptoms, compared with 37% to 45% of participants who received semaglutide.
The reason for this difference may be that the daily peak drug concentration is more pronounced with orforglipron. As a result, approximately 10% of Orforglipron participants discontinued treatment due to side effects. Only 4% to 5% of patients taking semaglutide discontinued treatment.
Direct comparison studies of injectable GLP-1 and orforglipron have not been conducted. However, the weight loss seen in this study of type 2 diabetic patients is similar to that previously observed with GLP-1 injections.
Market impact
The results of this trial show that olforglipron, developed by Eli Lilly, is considered one of the most credible challengers to semaglutide.
Another noteworthy thing about orforglipron is that it belongs to a new category of medicines called small molecule drugs. This means that it is a synthetic compound that is small enough to be absorbed directly through the intestinal wall. There, it is able to act on the GLP-1 receptor, even though it does not have a similar structure to the GLP-1 hormone.
Oral semaglutide, on the other hand, is a peptide drug. This means that the structure of its amino acids (one of the building blocks of proteins) closely resembles that of the natural GLP-1 hormone.
Because Orforglipron is a small molecule drug, it is cheaper and easier to manufacture than peptide-based drugs such as semaglutide.
Also, like oral semaglutide, it does not require refrigeration. This provides logistical advantages over injectable GLP-1 formulations. This is a potentially important consideration for expanding access in low- and middle-income countries where cold chain infrastructure is unreliable.
However, it remains to be seen how orforglipron will perform against oral semaglutide in the broader market.
This latest trial shows it is good at controlling blood sugar levels and promoting weight loss, but the high rate of side effects and treatment discontinuation may dampen enthusiasm. In a crowded and competitive market, long-term adherence, shaped by tolerability as well as efficacy, will likely be the key differentiator.
Orforglipron is currently being tested in obese patients who do not have diabetes.
