The new crop of drugs on the market for type 2 diabetes and obesity, including popular drugs like Ozempic and Wegovy, are more effective for weight loss than any previous drug, but doctors and researchers say there’s still room for improvement.
Next-generation options now under development may be easier and more convenient to take, boost weight loss, and offer additional health benefits.
“This is very good news,” said Dr. Louis Aronne, director of the Center for Comprehensive Weight Management at Weill Cornell Medicine. “We need drugs that work in different ways.”
Some of the most advanced experimental drugs are medications that can be taken in pill form rather than injections. Ozempic and Mounjaro, currently approved for type 2 diabetes, and Wegovy, cleared for weight loss, are 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 at 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 to 2.4% for people taking a placebo.
Novo Nordisk said the results, which were not published in a peer-reviewed journal, were similar to the weight loss seen with injectable Wegovy. Side effects were also similar, the company said; gastrointestinal problems such as nausea and diarrhea are more common with this class of drugs, known as GLP-1 analogues. Novo Nordisk said the “vast majority were mild to moderate and subsided over time”.
The company said it plans to apply for regulatory approval in the US and Europe this year, and availability will depend on how it prioritizes its drugs. and manufacturing capacity; Wegovy is currently being rationed for some patients as demand outstrips supply.
However, despite coming in pill form, oral semaglutide – sold under the brand name Rybelsus for type 2 diabetes – can still be tricky to take, doctors say.
“Patients taking Rybelsus should be educated about the strict requirements before and after oral administration,” said Dr. Priya Jaisinghani, an endocrinologist and specialist in obesity medicine at NYU Langone Health. They cannot eat, drink anything but 4 ounces of water, or take other medications within 30 minutes of taking the medication, or its effects could be diminished, she said.
Other oral GLP-1 drugs are in development and can be taken with food, including two from Pfizer. The company published data in the journal JAMA Network Open this week on the use of a twice-daily pill called danuglipron in people with type 2 diabetes. higher over 16 weeks, which the researchers said was comparable to other drugs in the class. Side effects were also similar.
Pfizer has a second experimental drug in development, lotiglipron, designed to be taken by mouth once a day. The company plans to choose one of the drugs to move into late-stage clinical trials for both diabetes and obesity, expected to begin next year.
Nearly two dozen other experimental drugs are now in development, designed to be taken as pills for obesity and related conditions, according to research by financial firm TD Cowen.
“A pill, of course, would be more appealing to most people,” said Dr. Willa Hsueh, director of the Diabetes and Metabolism Research Center at Ohio State University’s Wexner Medical Center. In addition to avoiding injections, pill versions may be better if people need to stop taking the drug because of side effects because they don’t last as long, she noted. A pill can also be useful for weight maintenance, once people have achieved a certain level of weight loss with injectable drugs, she said.
But Hsueh also pointed out that “some patients prefer an injection once a week over a pill, especially if they already take a handful of pills daily.”
There is also no shortage of injectable drugs being developed, with many attempting to overcome the weight loss seen with the options currently available.
Eli Lilly’s tirzepatide, approved for type 2 diabetes like Mounjaro, led to 21% weight loss at the highest dose during a 72-week obesity clinical trial, 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 early 2024. It builds on the 15% weight loss seen in Wegovy by adding a target beyond GLP-1, called GIP.
“Where semaglutide has a GLP-1 effect and tirzepatide has two effects, GIP and GLP-1 – so it has greater weight loss – [in] in the next generation of drugs, some will have three effects,” said Aronne of Weill Cornell.
One such drug, also in development at Lilly, targets a target called glucagon in addition to GIP and GLP-1. Aronne, who has served as a principal investigator in obesity clinical trials and consults for companies developing weight-loss drugs, calls it “triple G.”
“It seems to go beyond the 25% weight loss,” Aronne said.
Lilly said it hopes to begin late-stage testing of the drug, called retatrutide, this year.
If successful, it could 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 will have more treatments that are even more effective,” said Aronne.
Other drugs still in early development are aimed at improving fat loss from the liver, which could help with conditions such as non-alcoholic steatohepatitis, which Aronne said was becoming a leading cause of liver failure and the need for transplants. Another experimental drug targets a receptor in muscle to prevent loss of lean body mass 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 fast, and some experts see current therapies as just the beginning of a renaissance in weight management drug discovery and related applications.
“We’re in the first round,” said Raymond Stevens, chief executive of biotechnology company Structure Therapeutics, which is working on oral GLP-1s. “We’re still learning a lot about exactly how to titrate the drugs, how much weight loss certain individuals should have. So it’s the early days.”
Oral drugs can provide an option for titration, or increasing the dose over time, that doesn’t cause as many gastrointestinal side effects as people may have with injected versions, Stevens said.
Hsueh of Ohio State University noted that 5% to 10% of patients cannot tolerate the nausea, vomiting and other side effects that currently available medications can cause.
But the first thing she said needs improvement about meds is insurance coverage. She says that many insurers consider cosmetics for weight loss and refuse to cover the drugs, which cost more than $1,000 a month.
A clinical trial due this summer could change that if successful, 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 do not have type 2 diabetes – where semaglutide has already been shown to have a protective effect.
“I think it’s really critical” to test the degree to which these drugs have protective health effects, Aronne said, “and very exciting that we’re at this point.”