New oral GLP-1 drugs could offer more options for weight loss

Oral weight loss medications are now a reality.

Recent studies, published on September 16 and 17 in the New England Journal of Medicine, highlight two new oral medications that can significantly aid weight loss in individuals with obesity.

These drugs belong to the GLP-1 class, which has gained significant traction in recent years, including well-known brands such as Ozempic, Wegovy, Mounjaro, and Zepbound. While the majority of GLP-1 medications are currently administered via injections using a pen-like device and require refrigeration, the new oral options offer a more convenient alternative.

According to Sean Wharton, an obesity medicine clinician and researcher at the Wharton Medical Clinic in Ontario, the oral versions streamline the entire process — from production to administration. “They’re straightforward to manufacture, distribute, and consume,” he states.

More treatment options are beneficial for patients, says Daniel Drucker, an endocrinologist from the University of Toronto, who has contributed to the foundational research of GLP-1 drugs but was not part of the recent studies. “There’s definitely a substantial market for these medications,” he adds.

The FDA greenlit the first GLP-1 drug for type 2 diabetes in 2005 and followed suit with a weight-loss specific drug in 2014. Since then, many new versions have emerged. These medications mimic certain gut hormones, effectively suppressing appetite and slowing down digestion, which helps manage blood sugar levels and cravings. Emerging research also indicates a range of additional health benefits they may provide.

Studies indicate that GLP-1 medications like semaglutide can decrease the likelihood of heart attacks and strokes, alleviate symptoms of kidney and liver disease, and even treat sleep apnea, among other advantages. Drucker describes the evidence base supporting these drugs as “unprecedented.” There are also hints that semaglutide and similar drugs could mitigate addiction and potentially reduce cancer risks.

In 2019, the FDA approved Rybelsus, an oral version of semaglutide by Novo Nordisk, designed specifically for type 2 diabetes management rather than weight loss. One of the newly conducted trials examined a high-dose version of the drug (25 mg compared to Rybelsus’s maximum of 14 mg). The study tracked over 300 participants for up to 64 weeks, revealing an average weight reduction of nearly 14% among those taking the medication.

The second trial explored orforglipron, another oral GLP-1 from Eli Lilly. Unlike the larger synthetic molecule semaglutide, orforglipron is a smaller molecule, both of which function by imitating GLP-1. The orforglipron study involved over 3,000 participants over a duration of up to 72 weeks, with the highest dose yielding an average weight loss of around 11%.

“I was really thrilled,” Wharton expresses. Although the weight loss observed with these oral formulations may not match that of the latest injectable GLP-1 drugs, the convenience of having affordable and accessible oral options is substantial. Both pills require daily consumption, while many injections are administered weekly.

The pill form of orforglipron eliminates the need for injectors and refrigeration, making it simpler to produce, according to Drucker. “One would hope that savings in production costs could eventually benefit consumers.” Currently, injectable GLP-1 medications can cost approximately $500 monthly for those paying out of pocket. A representative from Lilly mentioned that it is too soon to determine the pricing for the new pills or how they may be covered by insurance.

In both trials, the side effects recorded were similar to those seen with existing GLP-1 drugs, including nausea, vomiting, diarrhea, and constipation, which generally diminish over time, according to Wharton. Notably, they did not encounter the liver toxicity issues that affected earlier small-molecule GLP-1 medications.

This past April, Pfizer announced the cessation of its danuglipron development, marking the second drug the company has dropped due to concerns over liver side effects. Wharton notes that the molecular structures of the discontinued products differ from that of orforglipron, potentially explaining the absence of such complications with the latter.

Drucker reassures that orforglipron appears to be quite safe, but emphasizes the necessity for more extensive long-term studies involving larger populations. It might take between five to ten years for the medical community to thoroughly understand the associated risks and benefits of this drug, he cautions.

Wharton is optimistic that both of these oral medications will be available to the public by 2026, subject to their FDA approval timeline. He believes providing these pills as treatment options is crucial for improving accessibility, as many individuals, particularly from marginalized backgrounds, currently face barriers to obtaining GLP-1 medications for financial or other reasons.

These new pills might enhance access to necessary treatments for those in need, Wharton asserts. “This could be a step toward addressing that disparity gap a little more effectively.”