According to a recent trial, a new type of daily pill has proven to be more effective than its currently available counterparts for weight loss and blood sugar control. The drug, known as orforglipron, could be a game changer for the rapidly expanding oral weight loss drug market.
By Martin White for Conversation
The arrival of the injectable weight loss drug semaglutide (better known by its brand names Vigovi and Ozympic) marked a significant change in the weight loss drug market when it was available only a few years ago.
Semaglutide is a class of glucagon-like peptide-1 (GLP-1) drugs. This drug mimics the gut hormone GLP-1, which is released soon after a meal. This hormone signals fullness to the brain, slows digestion and stimulates the release of insulin. By mimicking the action of this hormone, GLP-1 drugs have proven to be very effective in managing type 2 diabetes and promoting weight loss.
Although semaglutide is widely used, a major issue with the drug is that it needs to be injected into the abdomen, thighs, or back of the hand. This can make it difficult for patients with needle phobia or who do not want to inject themselves because of the discomfort.
Another logistical issue with injectable GLP-1 drugs is that they require refrigeration in the supply chain. This can pose a challenge in low- and middle-income countries.
It is for these reasons that researchers and developers have begun to investigate the effectiveness of oral versions of semaglutide.
Based on current research, oral semaglutide appears to be the most effective. However, it should be taken on an empty stomach – and users should wait 30 minutes before eating or drinking.
In addition to being expensive to manufacture, it also has poorer bioavailability than injectable semaglutide. This means that only 1% of the drug consumed is absorbed and is able to exert its effects.
But recent Phase 3 clinical trials have shown that a new type of oral weight loss pill may eliminate these issues — proving to be more effective than the current oral semaglutide products on the market.
Oral weight loss pills
A recent 52-week phase 3 trial involved 1,698 adults with type 2 diabetes in six countries. It is intended to compare current oral semaglutide products with orforgliprone, which is also taken as a daily tablet.
The primary measure the researchers looked at was the reduction in HbA1c. This blood test reflects the average blood sugar level over three months and is a standard indicator of diabetes control. Diabetes is present if HbA1c is 6.5% or more.
From the 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 to prove that it was as effective as oral semaglutide, it proved that it was better at lowering blood sugar. Participants taking orforglipron also lost more weight – an average of 6.1kg-8.2kg, compared to 5.3kg in those taking semaglutide.
However, a key issue highlighted by the trial was one of tolerance.
GLP-1 drugs can cause gastrointestinal side effects such as nausea, vomiting, diarrhea, and constipation. In this latest trial, about 59% of orforgliperone participants reported such symptoms, compared to 37-45% in semaglutide.
The reason for this difference may be that the daily concentration of the drug with orforgliperone is more pronounced. The result was that about 10% of orforglipron participants discontinued treatment due to adverse effects. Only 4-5% of those taking semaglutide discontinued treatment.
No trials of injectable GLP-1 versus orforglipron have been performed. However, the weight loss seen in this study of people with type 2 diabetes was largely comparable to that previously seen with injectable GLP-1.
Market effects
Trial results show that orforglipron, developed by Eli Lilly, can be considered one of the most reliable challenges to semaglutide.
Another interesting thing about orforglipron is that it belongs to a new category of drugs called small molecule drugs. This means that it is a synthetic chemical compound that is small enough to be absorbed directly through the intestinal wall. There, it is able to act on GLP-1 receptors, even if it is not structurally identical to the GLP-1 hormone.
Oral semaglutide, on the other hand, is a peptide drug. This means that the structure of these amino acids (one of the building blocks of protein) closely resembles the natural GLP-1 hormone.
As a small molecule drug, orforgliperone is cheaper and simpler 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.
However, it remains to be seen how orforglipron will perform against oral semaglutide in the wider market.
Although recent trials have shown it to be effective at controlling blood sugar and helping with weight loss, its high rate of side effects and discontinuation of treatment may dampen interest. In a crowded and competitive market, long-term follow-up – in terms of efficacy as well as endurance – is probably a key differentiator.
Orforglipron is still under trial in obese patients but without diabetes.
Martin White is Professor of Metabolic Medicine at the University of Surrey.
This article was republished from him conversation Under a Creative Commons license.
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