麻豆传媒

When former U.K. Prime Minister Boris Johnson's that semaglutide (Ozempic/Wegovy) didn't work for him, it served as a reminder that not all patients garner its reported weight-loss benefits.

In general – and aside from cost issues -- there are two main reasons semaglutide doesn't work as a weight-loss agent: patients just don't respond to it, or they get side effects so severe they have to stop. Johnson fell into that latter category.

麻豆传媒 reached out to experts to better understand both categories of patients, what proportion experience these effects, and why these outcomes occur. (Note that semaglutide is approved to treat type 2 diabetes under the brand name Ozempic, while it is approved for weight-loss under the brand name Wegovy.)

Non-Responders

There's not one agreed-upon definition of a semaglutide "non-responder," but the Endocrine Society's say that a weight-loss medication is "effective" if their patients lose more than 5% of their body weight within 3 months, a criterion widely used by physicians and insurers.

In a , around 86.4% of participants taking semaglutide lost more than 5% of their body weight over 68 weeks, or a year and a half. The rest, or, 13.6%, did not -- and it's unclear what that percentage would be within 3 months.

Endocrinologists and obesity specialists told 麻豆传媒 that if they had to guess, a similar percentage of their patients also do not lose weight with semaglutide injections, or see very little change. They said an early response to the injections is a good indicator of long-term effects.

Less clear is the "why" of non-response, experts said. There are no known biological markers that can predict where someone will fall along the bell curve of a weight-loss response to GLP-1 agonists.

Gitanjali Srivastava, MD, an adult and pediatric obesity medicine specialist and director of the obesity medicine program at Vanderbilt University Medical Center in Nashville, Tennessee, said there may be "a blunting of response particularly in patients with type 2 diabetes that have been prescribed a GLP-1 agonist."

"Typically, the people that are non-responders tend to be sicker," she said. "They tend to have more complicated metabolic derangements. They have a lot of complications [like] psychosocial issues that may be going on in their life."

She cited the examples of transplant or dialysis patients, those with liver failure, or people with serious psychosocial disorders.

Existing clinical trials may not capture these nuances, Srivastava said, because typically, "an obesity drug clinical trial is enrolling patients that are relatively healthier and kind of have a clean metabolic profile picture." In the real world, non-response could be higher, she said.

Karl Nadolsky, DO, an endocrinologist and obesity medicine specialist at Holland Hospital in Michigan, echoed Srivastava's observations on comorbidities. He said that early onset severe obesity in childhood, endocrine disorders, and developmental delays may all make a patient less responsive to GLP-1 agonists, as can early trauma, like sexual abuse.

But other times, there are no complicating factors – a patient just doesn't see the changes they expect, experts said.

More research on genetic factors, endocrine disorders, and medications that could interact with this class of drugs are needed, experts said, to get a better picture of how to best treat every patient.

They also noted that even if a patient doesn't lose weight on the drugs, they may see other benefits, such as cardiovascular and glycemic markers of type 2 diabetes.

Cardiovascular and glycemic markers of type 2 diabetes might improve with semaglutide or other GLP-1 agonists, with or without a certain percentage of body weight lost.

"You could lose like 3% [body weight] but that could all be in your waist and therefore, your liver function tests improved. You get improvement of, say, visceral body fat, maybe you get improvement in blood sugar or blood pressure," said Jody Dushay, MD, an endocrinologist at Beth Israel Deaconess Medical Center in Boston. "To just say, 'Okay, what is the scale telling me, if I should continue this or not?' as the only read out, I think, would be a mistake."

Side Effects

What about patients who have to stop the medication because they can't tolerate it? Dushay said gastrointestinal side effects are more the rule than exception with GLP-1 agonists.

"People don't understand that the side effects can be very, very severe," she said. "There is a non-small percentage of people who absolutely, really feel horrible on these medications and can't continue to take them."

Patients who don't feel any symptoms like nausea, vomiting, or diarrhea, she said, are the minority. Indeed, in the past week, Dushay said she had a wave of patients at various stages of treatment with GLP-1 agonists reach out to her about their symptoms.

In testing 0.5 mg and 1.0 mg of semaglutide for 104 weeks, 11.5% and 14.5% of participants, respectively, discontinued treatment prematurely because of nausea, vomiting or diarrhea, versus 5.7% and 7.6% in the placebo group.

Dushay said stopping the medication over severe side effects is more common than non-response. One had such severe diarrhea that she couldn't leave her house over the weekend, for instance. Another had debilitating daily vomiting, she said.

Srivastava, on the other hand, said that only rarely has she seen side effects bad enough to halt the treatment, "but we do see it, sometimes several patients per week," she said.

Nadolsky guessed that maybe 10% of his patients get side effects serious enough that they want to discontinue. "But if we really focus on some of the dietary factors that they may be struggling with that exacerbate nausea and vomiting, or even diarrhea or constipation, we can often modify those things, maybe reduce the dose and try to titrate back up, and resolve those," he said. "So it's relatively rare."

Physicians said it's not usually possible to predict who will experience the most serious side effects, and that every patient is different.

In Nadolsky's experience, however, diet is "the thing that's in common, absolutely. ... High fat, processed, refined restaurant food." He's turned to the for managing symptoms.

Patients' tolerance for various levels of discomfort can vary -- and physicians say that for the most part, the body eventually adjusts, but the length of time varies by patient.

Dushay said that in the case of weekly injections, side effects diminish the further away from the day of injection the patient is. Titrating up a dose can bring on more side effects, and Dushay said many people have to titrate more slowly than the minimum recommended by Novo Nordisk for Ozempic.

Srivastava said in a typical scenario, she would stop the medication, and have a patient build appetite back with crackers or small meals, prescribe an anti-nausea medication, and have them start a week after they feel normal again on a lower dose, with doses spaced further apart.

Dushay said she had one patient determined to keep trying to reintroduce a GLP-1 agonist, even after stopping twice because of side effects. She switched from daily liraglutide (Saxenda) to weekly semaglutide (Wegovy), Dushay said, and "literally the third time was a charm, and she was doing fine on it."

Physicians say insurance coverage can throw another hurdle in the way of managing poor reactions. Often, Nadolsky said, insurance coverage will not allow him to keep patients on a low dose indefinitely, even if a patient can't tolerate a higher dose.

"They'll let you do like, another month of the 1.7 [mg Wegovy], or maybe start over one time, but, boy, they're kind of weird about that," he said. "It's inappropriate, in my opinion."

Dushay agreed that many insurers won't keep paying for Wegovy if a patient doesn't lose 5% of body fat in 3 months -- even though there is no cut-off point when semaglutide is used to treat type 2 diabetes.

"There's this pervasive global bias against using medication therapy for obesity," Nadolsky said. "We've always approved all these medications for type two diabetes, which is ... an adiposity-based complication. But as far as getting it approved for weight, there's this historic myth or stigma of it being a cosmetic thing."

Ultimately, physicians say they may switch to a different treatment. Srivastava, for example, said that one of her patients with no weight loss on a GLP-1 agonist switched to a low dose of oral phentermine, "and she's done so well."

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