Most people are familiar with the concept of a weight setpoint. The setpoint is the body’s somewhat “natural” weight – seems like we always drift back to a particular number. When we diet, if we get too severe in our restriction, the body moves into a kind of starvation state, our energy utilization (fat burn) drops and we hang onto the weight. And we slowly drift back to where we were (unless you’ve yo-yo’d so much that you actually end up drifting even higher). It’s really hard to reset our set points.
The new GLP-1 weight loss medications – Wegovy, Ozempic, Mounjaro have proven themselves to be very helpful for many, if not most people. Most overweight people (that’s nearly ½ of America) have some measure of insulin resistance, and thus these medications make sense, and work. Of course, like all medications, there can be side effects, and some can be really severe. Even so, they are a tremendous step forward for many, many people who have struggled with their weight.
As many of us would have expected, it appears that the GLP-1 meds may not be able to eliminate the set point problem. It is likely that most people will be able to RESET their set points to a lower number, then seemingly virtually everyone will plateau. This is no surprise – a metabolic process will work according to the overall environment. Likely the situations that influenced the weight gain in the first place will continue to have some sway of the future.
It doesn’t mean that people should avoid the medication. If there’s a good reason to start it, it’s worth the try. Only understand that the weight loss rainbow may not end in a kettle of gold. Though for many, it’s a lot more than spare change!
FROM MEDPAGE TODAY/ BY SOPHIE PUTKA
The GLP-1 Agonist Plateau No One's Talking About
— Weight stabilization is no surprise to specialists, but for patients it's more complicated
The declines in body weight that patients experience with injectables like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro) are no exception to the concept that nothing lasts forever.
Eventually, everybody reaches a "plateau," even on newer GLP-1 receptor agonists. It's a phase at which the body reaches a new "settling point," specialists said, and weight, along with other metabolic markers like blood pressure and HBA1c stabilize, or fluctuate only slightly. For some, this may mean a gradual increase in appetite or "food noise"; others may be able to maintain their current state.
Studies have shown that, on average, this plateau happens at a little over a year with semaglutide. Even so, physicians say some patients are surprised to learn that there's a limit to what these medications can do.
"Everyone will plateau, of course. No one on my watch has disappeared. No one has vanished," Jody Dushay, MD, an endocrinologist at Beth Israel Deaconess Medical Center in Boston, told MedPage Today. "It's alarming to me that people find that surprising, but everyone will reach a plateau and there's no way to know when you start the medication what that will be, what percent weight loss that will be, and how quickly they will reach it."
Gitanjali Srivastava, MD, an obesity medicine specialist at Vanderbilt University Medical Center in Nashville, Tennessee, noted that "we see that often and it's a question that gets asked frequently. There's going to be a new homeostatic balance that's achieved, and we see that with any other disease phenomenon."
For example, Srivastava told MedPage Today that a patient will not become hypotensive after a certain amount of time on a blood pressure medication, or have blood glucose levels decrease indefinitely with diabetes medications. "Evolutionarily, we need to be able to do that, so we can protect against the extremes," she added. "Because the alternative is that you continue to wither away, and that can be dangerous."
It's still unclear what may predispose patients to longer or shorter responses to GLP-1 agonists, but Dushay said that, typically, early responses tend to predict later ones. If a patient experiences steep weight loss on lower doses of semaglutide, for example, they can stay on a lower dose for longer, with more time to uptitrate if necessary. Patients on semaglutide for type 2 diabetes also tend to experience less weight loss overall, she said.
Karl Nadolsky, DO, an endocrinologist and obesity medicine specialist at Holland Hospital in Michigan, told MedPage Today in an email that "a history of childhood obesity with any suspicion [of] specific genetic or syndromic etiology" might also hint at a predisposition to hyporesponse.
Specialists have said that before prescribing this class of medication, they thoroughly discuss what to expect, from side effects to plateauing and the possibility of non-response. Dushay noted that it's important that providers set these expectations with patients, and for patients to seek out doctors who have the time and clinical experience to do so.
In clinical trials that looked at semaglutide 2.4 mg per week, participants' weight loss tapered off around week 60, with about 10% to 15% of body weight lost. Semaglutide's effect on blood pressure and HBA1c appeared to plateau even earlier. Spanning 2 years, patients hit a weight plateau once again around 60 weeks, and were able to maintain that weight for the remainder of the study. In the Surmont Trial which looked at various doses of tirzepatide for 72 weeks, participants on the 5-mg dose had reached a plateau within 60-72 weeks, but this was not the case on the higher doses. A 2-year trial is expected to offer more insight.
However, clinicians are more interested in what such averages hide. It's nearly impossible to know how well a patient will respond to semaglutide or tirzepatide, and individuals may have wildly different medical histories, medications, and comorbidities that all affect how well, and for how long, a given drug may work.
Fatima Cody Stanford, MD, MPH, MPA, MBA, an obesity medicine specialist at Massachusetts General Hospital in Boston, pointed out that a patient's expectation may not match their ultimate response to a GLP-1 agonist. "Everybody comes in and they're like, 'I want to do what this person did' -- they have their family, their friend, their sister, their brother, cousin, aunt, and I'm like, 'well, we don't know,'" she said. "The only people that I expect to respond almost identically are identical twins."
Stanford said she would like to see studies on GLP-1 agonists in the future that stratify patient response by various characteristics like genetics. Right now, she noted, weight-loss drugs require a lot of trial and error. Predicting the likelihood of success for individual patients would save time -- and money. "When a new cancer drug comes out, not everyone's like, 'ooh, there's a new cancer drug, let's just start everyone on that.' Right? Nobody does that," she said. "I want to know who the drug is right for."
"If I know that, on average, this person is going to be a really poor responder to a GLP-1 agonist, I won't [prescribe it]," she added. "It is a really arduous pathway for a lot of reasons -- access, coverage, prior authorization. It's burdensome. It's burdensome on the patient, it's burdensome on the system, it's burdensome on me."
Experts said it's common for patients to want more. For example, they may bring their blood glucose within a normal range, go off of blood pressure medications, and maintain overall positive health outcomes with a GLP-1 agonist, but hit a "plateau" and still want to lose weight.
Ultimately, this is where psychological and societal ambitions collide with clinical ones.
Patients are "having to negotiate with what society tells them, so they're still 200 pounds and society says 'for your height and weight you should be 125,' even though their health looks amazing," Stanford said. "Not always, but often, they still want to be whatever this number is."
Dushay said it's rare for patients to achieve the weight loss goal they arrive at an initial consult with. Often, Dushay's noticed, this goal is the weight they were on their wedding day. "I think that some of it is literally [that] they want to weigh that," she said. "But I think there is a big component of 'I want to rewind time.'"
"I've almost never had someone hit a plateau when they were like, 'okay, I'm good.'"
In the meantime, clinicians have strategies to move past a plateau if a patient hasn't yet met important clinical goals. Generally, some said they might increase the dose if possible, if the patient can tolerate it well. Failing that, they can supplement with a second drug that targets a different neuronal or hormonal pathway, like phentermine (Lomaira). Dushay said that in practice she's noticed that "drug holidays" or stopping and restarting a GLP-1 agonist, have typically not affected plateaus.