Experimental drugs aim to surpass weight-loss stars like Ozempic and Wegovy

By Meg Tirrell, CNN

(CNN) — The new crop of drugs on the market for type 2 diabetes and obesity, including popular medications like Ozempic and Wegovy, is more effective for weight loss than any previous medications, but doctors and researchers say there’s still room for improvement.

Next-generation options now in development may be easier and more convenient to take, turbo-charge weight loss and offer additional health benefits.

“This is all really good news,” said Dr. Louis Aronne, director of the Comprehensive Weight Control Center at Weill Cornell Medicine. “We need drugs that work in different ways.”

Some of the most advanced experimental drugs are medicines that can be taken in pill form, rather than as injections. Ozempic and Mounjaro, which are currently approved for type 2 diabetes, and Wegovy, which is cleared for weight loss, are all given as self-injections once a week.

Novo Nordisk, which makes Ozempic and Wegovy, has a daily tablet version of the same drug, called semaglutide, approved for diabetes and is testing it in a higher dose for weight loss. In late-stage study results released this week, the drug was found to help people lose 15% of their body weight over 68 weeks, compared with 2.4% for people who took a placebo.

Novo Nordisk said the results, which haven’t been published in a peer-reviewed journal, were similar to the weight loss seen with injectable Wegovy. The side effects were also similar, the company said; gastrointestinal issues like nausea and diarrhea are most common with this class of drugs, known as GLP-1 analogues. Novo Nordisk said the “vast majority were mild to moderate and diminished over time.”

The company said it plans to file for regulatory approval in the US and Europe this year, and availability would depend on how it prioritizes its medicines and on manufacturing capacity; Wegovy is currently being rationed for some patients as demand outpaces supply.

However, despite coming in tablet form, oral semaglutide – sold under the brand name Rybelsus for type 2 diabetes – can still be complicated to take, doctors say.

“Patients taking Rybelsus have to be instructed about strict requirements before and after oral administration,” said Dr. Priya Jaisinghani, an endocrinologist and obesity medicine specialist at NYU Langone Health. They can’t eat, drink anything other than 4 ounces of water or take other medicines within 30 minutes of taking the drug, or its effects could be diminished, she said.

Other oral GLP-1 drugs are in development that can be taken with food, including two from Pfizer. The company published data in the journal JAMA Network Open this week on use of a twice-daily pill called danuglipron in people with type 2 diabetes. The midstage trial found that the medicine lowered blood sugar and led to weight loss at higher doses over 16 weeks that researchers said was comparable to other drugs in the class. Side effects were also similar.

Pfizer has a second experimental medicine in development, lotiglipron, that’s designed to be taken orally once a day. The company plans to choose one of the medicines to advance into late-stage clinical trials in both diabetes and obesity, expected to start next year.

Nearly two dozen other experimental drugs are now in development that are designed to be taken as pills for obesity and related conditions, according to research from financial firm TD Cowen.

“A pill, of course, would be more attractive to most people,” said Dr. Willa Hsueh, director of the Diabetes and Metabolism Research Center at the Ohio State University’s Wexner Medical Center. In addition to avoiding injections, pill versions could be better if people need to stop taking the drug because of side effects, because they wouldn’t last as long, she noted. A pill could also be helpful for weight maintenance once people have reached a certain level of weight loss on injectable drugs, she said.

But Hsueh also pointed out that “some patients prefer a once-a-week injection rather than a pill, especially if they already take a handful of pills daily.”

There’s no shortage of injectable drugs being developed as well, with many attempting to surpass the weight loss seen with currently available options.

Eli Lilly’s tirzepatide, approved for type 2 diabetes as Mounjaro, led to weight loss of 21% at the highest dose over a 72-week clinical trial on obesity, according to results published last year in the New England Journal of Medicine.

The drug is expected to receive FDA approval for weight loss in people without diabetes this year or in early 2024. It builds on the 15% weight loss seen for Wegovy by adding a target in addition to GLP-1, called GIP.

“Where semaglutide has a GLP-1 effect and tirzepatide has two effects, GIP and GLP-1 – so that has greater weight loss – [in] the next generation of drugs, some will have three effects,” Weill Cornell’s Aronne said.

One of these medications, also in development at Lilly, aims at a target called glucagon in addition to GIP and GLP-1. Aronne, who has served as primary investigator on obesity clinical trials and consults for companies developing weight loss drugs, calls it “triple G.”

“That seems like it’ll go beyond 25% weight loss,” Aronne said.

Lilly said it expects to start late-stage trials of the medicine, called retatrutide, this year.

If it’s successful, it may compete with a combination drug from Novo Nordisk known as CagriSema, a combination of semaglutide and a compound called cagrilintide that works by stimulating a hormone called amylin to produce additional weight loss.

“We’re going to have more treatments that are even more effective,” Aronne said.

Other medicines still earlier in development aim to improve fat loss in the liver, which could help with conditions like nonalcoholic steatohepatitis, which Aronne said is becoming a major cause of liver failure and a need for transplants. Another experimental drug targets a receptor in muscle to prevent lean body mass loss as part of overall weight loss.

It could be years before many of these drugs reach the market. Some are likely to fail in clinical trials. But the field is moving quickly, and some experts see the current therapies as only the beginning of a renaissance in drug discovery for weight management and related applications.

“We’re in the first inning,” said Raymond Stevens, chief executive of biotech company Structure Therapeutics, which is working on oral GLP-1s. “We’re still learning so much about exactly how to titrate the medicines, how much weight loss should certain individuals have. So it’s the early days.”

Oral drugs may provide an option for titrating, or increasing the dose over time, that doesn’t cause as many gastrointestinal side effects as people may have with injectable versions, Stevens said.

Hsueh, of the Ohio State University, noted that 5% to 10% of patients can’t tolerate the nausea, vomiting and other side effects that the currently available drugs can cause.

But the first thing that she said needs to be improved about the medicines is their insurance coverage. She says many insurers consider weight loss cosmetic and refuse to cover the drugs, which are priced at more than $1,000 per month. 

A clinical trial expected to have results this summer may change that if it succeeds, Aronne said. Novo Nordisk is testing whether Wegovy helps reduce the risk of heart disease and stroke in people who are overweight or obese but who don’t have type 2 diabetes – where semaglutide has shown a protective effect already.

“I think it’s really critical” to test the degree to which these medicines have protective health effects, Aronne said, “and very exciting that we’re at this point.”

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