The promise of new weight-loss drugs

In June 2021, FDA approved semaglutide as a treatment for chronic weight management in obese or overweight adults. The drug, which is made by Novo Nordisk, mimics a hormone called glucagon-like peptide-1 (GLP-1) to target areas of the brain that regulate appetite and food intake. Previously, it was used to treat type 2 diabetes.

Semaglutide is available in two forms: Ozempic, a treatment for type 2 diabetes, and Wegovy, a higher dose of the drug approved for weight loss. In a clinical trial of Wegovy, patients lost an average of 15% of their body weight over 68 weeks, leading many experts to call it a "game-changer" for obesity treatments.

Since then, semaglutide and other similar drugs have skyrocketed in popularity, though potential side effects of taking these drugs, as well as their long-term impact, are still largely unknown.

Why these drugs may not be effective for everyone

According to Putka, there are two reasons why semaglutide may not work for some patients: they either don't respond to the drug or the side effects of the drug become too severe for them to continue taking it.

Non-responders

According to recent guidelines from the Endocrine Society, a weight-loss medication is considered "effective" if patients lose more than 5% of their body weight within three months. This criterion is also commonly used by both physicians and insurers.

In a clinical trial for semaglutide, around 86.4% of participants who took the drug lost more than 5% of the body weight over 68 weeks while the remaining patients (13.6%) did not. Endocrinologists and obesity specialists have also said that a similar percentage of their own patients either do not lose weight while on semaglutide or see very little change in weight.

These experts say that the early response to semaglutide is a good indication of how it'll work long-term, but it's less clear why some people may not respond to the drug. Currently, there is no way to predict "where someone will fall along the bell curve of a weight-loss response to GLP-1 agonists," Putka writes.

Gitanjali Srivastava, an internist and director of the obesity medicine program at Vanderbilt University Medical Center, 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."

Karl Nadolsky, an endocrinologist and obesity medicine specialist at Holland Hospital, agreed with Srivastava, saying that comorbidities, such as early-onset severe obesity in childhood, endocrine disorders, developmental delays, and early trauma, could all make a patient less responsive to weight-loss drugs.

Even when there are no potential complicating factors, experts said some patients just don't see the changes they expect from a drug. In general, more research on genetic factors, endocrine disorders, and medications that could interact with GLP-1 drugs is needed to better understand how to effectively treat different patients.

Experts have also said that even when patients don't lose weight while on the drugs, they may see other health benefits. For example, patient can experience improvement in cardiovascular and glycemic markers of type 2 diabetes regardless of whether significant weight is 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, an endocrinologist at Beth Israel Deaconess Medical Center. "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."

Severe side effects

"[G]astroinestinal side effects are more the rule than exception with GLP-1 agonists," Putka writes, and some of these side effects, which can include nausea, vomiting, and diarrhea, can be severe.

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

In clinical trials testing semaglutide for type 2 diabetes, 11.5% of patients taking the 0.5 mg dose and 14.5% of patients taking the 1.0 mg dose prematurely discontinued treatment due to severe side effects. In comparison, only 5.7% and 7.6% of the placebo groups discontinued treatment early.

Similarly, Nadolsky estimated that around 10% of his patients experience side effects severe enough to make them want to stop taking semaglutide. However, he also noted that there are ways to address factors that may be exacerbating the side effects, such as diet.

"[I]f 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.

In the end, if none of those changes work, physicians may have to switch their patients to a different medication. For example, Srivastava said that one of her patients who had no weight loss with a GLP-1 drug switched to a low dose of oral phentermine, "and she's done so well." (Putka, MedPage Today, 6/28)

Weight management drugs like Ozempic and Wegovy are getting a lot of attention, and we've been getting a lot of questions about what this new generation of drugs could mean for healthcare business. The Radio Advisory podcast dedicated an entire episode to the topic — here's what they focused on.