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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 could be easier and more convenient to take, boost weight loss, and offer additional health benefits.
That\’s really good news, said Dr. Louis Aronne, director of the Comprehensive Center for Weight Management at Weill Cornell Medicine. We need drugs that work in different ways.
Some of the more advanced experimental drugs are drugs 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 licensed 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% of people who took a placebo.
Novo Nordisk said the results, which weren\’t 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 decreased over time.
The company said it expects to apply for regulatory approval in the US and Europe this year, and availability will depend on how it prioritizes its medicines. and on production capacity; Wegovy is currently rationing some patients as demand outstrips supply.
However, despite being available in tablet form, oral semaglutide sold under the brand name Rybelsus for type 2 diabetes can still be tricky to take, doctors say.
Patients taking Rybelsus must be educated about the stringent requirements before and after oral administration, said Dr. Priya Jaisinghani, an endocrinologist and obesity medicine specialist at NYU Langone Health. They cannot eat, drink more than 4 ounces of water or take any other medicines within 30 minutes of taking the drug, or its effects could be reduced, she said.
Other oral GLP-1 drugs that can be taken with food are in development, 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. The interim study found that the medicine lowered blood sugar and led to loss of weight at higher doses over 16 weeks that the researchers said were comparable to other drugs in the class. The side effects were also similar.
Pfizer has a second investigational medicine in development, lotiglipron, designed to be taken by mouth once a day. The company plans to pick one of the drugs to advance in late-stage clinical trials in both diabetes and obesity, which are scheduled 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 Wexner Medical Center. In addition to avoiding injections, pill versions might be better if people need to stop taking the drug because of side effects, because they wouldn\’t last long, she noted. A pill could 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 to a pill, especially if they already take a handful a day.
There is also no shortage of injectable drugs under development, with many attempting to overcome the weight loss seen with currently available options.
Eli Lilly\’s tyrzepatide, approved for type 2 diabetes like Mounjaro, led to 21 percent weight loss at the highest dose in a 72-week obesity clinical trial, according to findings published last year in 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\’s based on the 15 percent 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 it has higher weight loss [in] the next generation of drugs, some will have three effects, said Aaron Weill Cornells.
One such drug, also under development at Lilly, targets a target called glucagon in addition to GIP and GLP-1. Aronne, who has worked as a principal investigator in obesity clinical trials and a consultant to companies developing weight-loss drugs, calls it triple G.
It looks like more than 25 percent weight loss will go, Aaron said.
Lilly said it plans to begin late-stage trials of the drug, called retatrutide, this year.
If 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 further weight loss.
We will have more treatments that are even more effective, Aronne said.
Other drugs still in development aim to improve fat loss in the liver, which could help with conditions like nonalcoholic steatohepatitis, which Aaron says is 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 hit the market. Some are at risk of failing in clinical trials. But the field is moving rapidly, and some experts see current therapies as just the beginning of a renaissance in weight management drug discovery and applications.
We\’re in the first inning, said Raymond Stevens, chief executive officer of biotech company Structure Therapeutics, which is working on oral GLP-1s. We\’re still learning so much about how exactly to titrate the meds, how much weight loss some people should have. So it\’s early days.
Oral drugs may provide an option for dose titration or escalation over time, which doesn\’t cause as many gastrointestinal side effects as people might have with injectable 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 he said needs to be improved about medicines is their insurance coverage. He says many insurers consider the weight loss cosmetic and refuse to cover the drugs, which are priced in excess of $1,000 a month.
A clinical trial expected to have results this summer could change that if it\’s 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 don\’t have type 2 diabetes where semaglutide has already shown a protective effect.
I think it\’s really critical to test the degree to which these drugs have protective effects on health, Aronne said, and that\’s been very exciting at this point.
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