The Data Are Clear: Patients Regain Weight After Stopping GLP-1 Drugs

This story is part of a series called “Ozempic: Weighing the Risks and Benefits.” It was produced in part through a grant from the NIHCM Foundation.

Looking at the data from clinical trials of new GLP-1 agonists, it’s clear that patients will need to stay on the drugs to maintain their weight loss, experts said.

At the same time, there’s a dearth of evidence as to whether strategies to mitigate weight regain — such as weaning people from the medications — might help, clinicians and researchers told MedPage Today.

“We generally do expect that when folks discontinue this medication they’ll gain at least some weight back, if not all of it,” Nate Wood, MD, MHS, of Yale School of Medicine in New Haven, Connecticut, told MedPage Today. “And the reason for that is that we really think about obesity as a chronic disease. And chronic diseases require chronic treatment.”

Weight Regain After Withdrawal

To date, a number of clinical trials have shown weight regain after discontinuing GLP-1 drugs.

In the STEP 1 trial extension, people who had been taking weekly semaglutide 2.4 mg (Wegovy) along with a lifestyle intervention regained two-thirds of the weight they had lost a year after coming off the drug.

In the first phase of the trial, which involved 1,961 adults with overweight or obesity who did not have diabetes, those on the drug lost a mean 14.9% of their body weight after 68 weeks, compared with a 2.4% loss for those on placebo. A subset of 327 participants who lost 17.3% and 2% of their weight, respectively, continued on to an extension phase.

During the extension phase, lifestyle counseling was also discontinued. Those who stopped semaglutide regained 11.6 percentage points of weight loss, compared with 1.9 percentage points for the placebo group — translating to net weight loss of 5.6% and 0.1%, respectively, at 120 weeks.

John Wilding, DM, of Aintree University Hospital in Liverpool, England, who was the corresponding author for the STEP 1 extension trial, said it’s “not really surprising that medicines don’t continue to work after people stop taking them.”

“We don’t expect this to happen for treatments for other long-term conditions, such as high cholesterol or blood pressure, and obesity is no different,” he told MedPage Today in an email.

The STEP 4 trial also studied the effects of semaglutide withdrawal among adults with overweight or obesity who didn’t have diabetes. About 800 people who had mean weight loss of 10.6% after 20 weeks on semaglutide were randomized to a maintenance dose or to placebo, along with continued lifestyle intervention.

Those who stayed on the drug for another 48 weeks continued to lose weight — an additional 7.9% on average — while those switched to placebo gained an average of 6.9% of their lost weight back, the study showed.

The SURMOUNT-4 trial focused on withdrawal from tirzepatide (Zepbound), which has a slightly different mechanism of action as it’s a combined GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist.

After 36 weeks on the drug, 670 patients had mean weight loss of 20.9%. They were then randomized to stay on the drug or switch to placebo, again with lifestyle intervention continued.

Those who continued on treatment shed additional pounds, while those switched to placebo gained back some weight, ending up at a mean weight loss of 25.3% and 9.9%, respectively, at 88 weeks.

Robert Kushner, MD, of Northwestern University Feinberg School of Medicine in Chicago, who was also an investigator on STEP 1, emphasized that in both the STEP 4 and SURMOUNT-4 trials, participants were blindly randomized to continue taking the drug or stop it.

This aspect is “very powerful,” he said. These are people who are participating in research, coming in regularly and being counseled, and feeling optimistic, he said.

Those who stayed on the medication “continued to lose weight, nicely,” he said. However, those who were blindly randomized to placebo, despite “feeling good about themselves — I’m your best research subject, I know I can do this — they all regained weight.”

These findings speak to the “underlying biology of the disease and how important medication is,” Kushner said.

Challenges of Long-Term Use

Yet there are considerations when it comes to long-term use of GLP-1 drugs, experts noted.

The potential challenges are “really the same challenges of being told you have to take a medication long-term for any disease,” Sarah Armstrong, MD, of Duke University School of Medicine in Durham, North Carolina, told MedPage Today.

Medications have to go along with you when you travel, and if you move you have to get your prescription filled in a new place, she said.

Tolerability of GLP-1 drugs may also pose a challenge, as gastrointestinal issues have commonly been reported in clinical trials. Switching between GLP-1 drugs may help some patients if they’re better able to tolerate one drug over another, Wood said.

Additionally, it is important that the medications be “very carefully titrated so that people don’t lose too much weight too quickly,” he said. If people lose more than about 2 pounds per week (or about 8 pounds per month), they are more likely to experience side effects, lose excess muscle mass, or develop gallstones.

Wood cautioned that there also can be a mental health toll associated with stopping the drugs.

“The only way that we know to convince the body that it’s not good to carry this excess weight are by these drugs that work in the brain to kind of turn off that protection mechanism and to … let the pounds fall away without the body going into crisis mode and thinking that it’s starving,” Wood explained.

To then “take away that drug and to have that noise and those extreme cravings … come back is really tragic and hard for patients to deal with,” he said.

Wood believes that for most people, the medication is indicated long-term. However, whether due to access, cost, or side effects, not everyone can stay on the drug that long, he said: “For those folks, we really wish we did have more research about what to do.”

Strategies to Maintain Weight Loss

“What we don’t have” are data on “strategies to mitigate weight regain,” Armstrong said. “We don’t know, when an ideal BMI is achieved, what the next steps really should be.”

Indeed, people will ask what should be done about weight regain after stopping GLP-1 drugs, Kushner said.

“What I can tell my clinician colleagues is we have good evidence that suddenly stopping the medication is not ideal, because in both the extension trial, and these STEP 4 and SURMOUNT-4 trials, the medication was stopped suddenly,” Kushner said. “There was no weaning of the medication. There was no dose de-escalation of the medication.”

He called on clinicians to individualize their conversations with patients. For those who have done well on GLP-1 drugs but want to stop taking them, managing these individuals “falls under the category of what I call the art of medicine,” Kushner said, “because we don’t have the data or the studies to guide us with certainty what to do.”

Clinicians can try dose tapering, intermittent therapy, different medication (such as older oral medications for weight loss that may be more cost effective), or significant lifestyle changes, he said.

“Even though we don’t have the evidence … that doesn’t mean we don’t treat patients every single day and make these decisions,” he said. “We’re just using … the best evidence and expertise that we have, and [working] with the patient.”

Kushner is hopeful for additional data that will come from a range of studies, from large randomized controlled trials to case-control studies, chart review studies, and even narrative reviews. There will be different “grades of evidence and strength of evidence that clinicians can then use and apply to their particular patient,” he said.

Meanwhile, Kushner’s message to patients who’ve successfully lost weight on GLP-1 drugs is to keep seeing their doctors: “Do not leave this practice and think that you are cured because I have very little evidence or conviction that is true.”

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