Weight-loss treatment is on the verge of a dramatic shift – again

By Meg Tirrell, CNN

(CNN) — At the end of a seemingly ubiquitous commercial for telehealth company Ro, a characteristically flabbergasted Charles Barkley speaks for us all when he remarks, “Wait, you’re telling me they have a GLP-1 pill for weight loss now?”

They do – and it turns out to be as wildly popular as its injectable predecessors. Just about 10 weeks after it was approved by the US Food and Drug Administration, the Wegovy pill is now estimated to be part of the daily regimen of about 400,000 Americans. And the field of weight-loss treatment is on the verge of even more head-spinning change.

A second pill is under review at the FDA, expected to hit the market as soon as next month, and many more are in clinical trials. Some companies are testing drugs that only need to be taken once a month. And an even more powerful next generation of medicines is quickly approaching, churning out trial results – including some new ones Thursday – that leave current options in the dust in terms of efficacy.

“We are entering this kind of phase two of using the GLP-1 system,” said Dr. Jody Dushay, an endocrinologist at Beth Israel Deaconess Medical Center and assistant professor at Harvard Medical School.

The next wave could be driven by cost and convenience as much as by new approaches to treatment. The weight-loss pills – the one already on the market and the one waiting to be approved – have brought prices to new lows for US patients in a deal that both drugs’ makers struck with the Trump administration, even as insurance coverage can remain spotty for many.

And the more powerful drugs on the horizon could bring options for people who don’t get enough benefit from currently available therapies – but also, doctors warned, the risk of inappropriate use.

‘Triple G’

One such drug is retatrutide, a weekly injectable medicine in development at Eli Lilly, which also makes Mounjaro for diabetes and Zepbound for weight loss.

Those drugs are based on the active ingredient tirzepatide, which mimics two hormones: GLP-1 and GIP. Retatrutide ups the ante by adding a third, called glucagon, earning it the moniker “Triple G.”

It’s breaking records for weight loss induced with medicines; in clinical trial results reported in December, retatrutide led to average loss of up to 29% of participants’ body weight after 68 weeks, or about 71 pounds, in a study of people with knee osteoarthritis. The drug was also associated with reduced knee pain.

In new results released Thursday on type 2 diabetes, with which patients tend to lose less weight with medications, Lilly said the drug lowered A1C blood sugar levels by an average of 1.7% to 2% at 40 weeks and produced average weight loss of up to 17%, or about 37 pounds. That exceeds results for Mounjaro, which showed an average A1C reduction of 1.7% and weight loss of about 9% at the highest dose in a separate trial.

“It’s looking like perhaps we are approaching another level” with drugs like retatrutide, said Dr. Judith Korner, an endocrinologist and director of the Metabolic and Weight Control Center at Columbia University Vagelos College of Physicians and Surgeons.

Novo Nordisk, which competes with Lilly with its drugs Ozempic and Wegovy, is in the Triple G game as well, reporting average weight loss of almost 20% after 24 weeks in a mid-stage study of another experimental drug in China last month.

The company is also pursuing other approaches, including a drug called CagriSema that combines semaglutide – the active ingredient in Ozempic and Wegovy – with cagrilintide, which targets another hormone called amylin. But in clinical trials, it hasn’t kept up with Lilly’s tirzepatide, much less retatrutide, although Novo Nordisk is testing higher doses.

Still, while the new combinations “would be great for people who need to lose more weight,” Korner said, “not everyone needs the so-called big gun.”

Drugs like retatrutide may be most appropriate for someone who has a body mass index above 45 – above 30 is considered obese – and for whom existing drugs haven’t worked sufficiently, Dushay said.

She estimates that about 10% of her patients either don’t get enough benefit from current medicines or can’t tolerate the side effects, which typically are gastrointestinal in nature, including nausea and vomiting.

Retatrutide has shown similar side effects, as well as a prickling sensation known as dysesthesia. And some participants have dropped out of retatrutide trials because they felt that they lost too much weight.

“There are these cases where retatrutide will be able to really make a difference,” Dushay said. But she worries that its souped-up results could be dangerous if it’s used inappropriately.

“What’s going to happen if people take it for just a little bit of weight loss?” she asked. Already, “you’re starting to see some Hollywood images of body types that are so shocking. So there is a little bit of concern about that.”

It’s a concern that has been pervasive enough for existing drugs that Lilly released a commercial ahead of the 2024 Oscars urging against “vanity” use.

That was at a time when the drugs’ supply was a problem. “It matters who gets them,” the ad’s tagline said.

Now, supply is ramped up, including for pill versions of GLP-1s that are also changing the treatment landscape.

Two new weight-loss pills

The Wegovy pill was approved in December, and the speed with which people started using it broke records, according to one Wall Street firm, which said it became the fastest drug launch in history. Some analyses of early uptake show that it’s enticing at least some users who haven’t tried GLP-1 therapies before, suggesting that some may have preferred a noninjectable option. Many of the new prescriptions have been written by general practitioners, rather than weight-loss specialists.

But the Wegovy pill isn’t expected to be alone on the market for long. Eli Lilly – continuing a nearly century-long duel with Novo Nordisk that began with insulin and is escalating with GLP-1s – anticipates FDA approval of its own pill, called orforglipron, before the end of June.

A key differentiator is that it can be taken at any time of day, with or without food and drink, whereas the Wegovy pill has more restrictions. Since the latter is a version of semaglutide, which is typically given by injection, it’s been specially formulated to be taken orally. Thus it’s finickier than a typical pill: It must be taken first thing in the morning, with just a small amount of water, and no food, drinks or other medicines for at least 30 minutes.

For that reason, Korner said, orforglipron will be her go-to choice for people who decide they want to take a GLP-1 pill.

“If you don’t take the Wegovy pill just right, very little of the drug is actually absorbed,” Korner said. “So it’s better to be able to remove that from the equation and not have to worry, ‘is my patient taking the pill correctly?’”

Changes in affordability

Cost is an important consideration as well, and there too, the weight-loss drug space has seen rapid transformation. The pills are priced at $149 a month for the lowest doses if patients pay out of pocket, through a deal struck with the Trump administration in November through its TrumpRx drug pricing initiative.

The companies also offer direct-pay prices for the injectable drugs, but they still cost hundreds of dollars a month out of pocket. Still, those prices can be the best for people whose insurance won’t cover the medicines, which can still be a major problem, Dushay said.

This year, Blue Cross Blue Shield of Massachusetts announced that it would stop covering GLP-1s for obesity, saying the drugs’ costs were driving insurance premiums too high. It suggested that patients consider buying the drugs directly from manufacturers.

Medicare is a brighter spot, expanding coverage for some patients as part of the November deal, but still doesn’t cover weight-loss drugs for all who might want them.

Trouble with insurance coverage is a key reason Dushay said she’s seen patients switch to the Wegovy pill. And although orforglipron is expected to get the same starting price, if there’s a differential, Korner said, that could be a deciding factor for her.

“If they’re paying out of pocket and one is less expensive than the other and I think that they both are probably as good,” she said, “then I would switch.”

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