Weight Regained Within 18 Months of Stopping GLP-1 Drugs

People who stop taking weight-loss medications for the treatment of obesity gain the weight back within an average of 1.7 years, and this rebound is accompanied by a worsening of cardiometabolic risk factors, such as glycated hemoglobin (HbA1c), systolic blood pressure, and cholesterol levels, according to a new review and meta-analysis.

For those stopping the newer, more effective drugs, such as semaglutide (Wegovy; Novo Nordisk) and tirzepatide (Zepbound; Eli Lilly), the return to baseline weight occurs by 18 months, with people gaining back an average of 0.8 kg/month.

“We know that weight regain is common after people lose weight, but we were surprised at how quickly people regained the weight after stopping medication,” lead investigator Sam West, PhD (University of Oxford, England), told TCTMD. “While people lose around 15 kilograms using semaglutide and tirzepatide, they’ve gained nearly 10 kilograms within the first year [after stopping].”

In contrast, the amount of weight lost following a behavioral weight-management program is less, as the group showed in a prior study, and the rate of regain much slower. For example, participants stopping their drug gained 0.3 kg more per month than those who stopped a behavioral program. It is nearly 4 years before the weight is fully regained when a behavioral intervention is stopped, said West.

After stopping medication, “the speed of the weight regain was the shocking factor” in the latest study, said West. “The fact that the cardiometabolic risk factors return to baseline, almost in parallel to body weight, wasn’t too surprising.”

We know that weight regain is common after people lose weight, but we were surprised at how quickly people regained the weight after stopping medication. Sam West

Erica Spatz, MD (Yale University School of Medicine, New Haven, CT), who wasn’t involved in the analysis, said that when talking to patients about starting a GLP-1 receptor agonist, most begin by thinking they’ll use the weight-loss drugs to achieve a healthy weight, which will allow them to adopt new dietary and exercise habits, and then they usually hope to come off the medications.

“Two things happen in clinic,” she said. “One is that their psychological mindset changes because they’re having a good experience with the medication and they want to continue, if possible. What I have seen is that most people want to stay on them if they’ve had success.”

The other group includes those who wish to stop, either because the drugs are no longer covered by insurance or they are experiencing side effects. “Some are not able to stay on them for a host of different reasons,” said Spatz. These data confirm the worst-case scenario, which is the potential reversal of cardiometabolic benefits that occur when the weight is regained, she said.

For Michael Miedema, MD (Minneapolis Heart Institute Foundation, MN), the up-front conversation with patients starting weight-loss medications is critical, particularly since this is not about cosmetic weight loss but improvements to cardiovascular health.

“[I tell them] the long-term game here is a bit unclear,” he told TCTMD. “There’s a chance you can come off it, but there’s a chance the weight is going to come back. We know that genetics and environment play a large role in weight management, just like [they do] for high blood pressure and for cholesterol. Some of those things aren’t completely under our control. I think that open discussion with the patient is incredibly important.”

Overall, the weight regained with medication stoppage isn’t surprising, said Miedema, noting that if people stopped their lipid-lowering therapy, cholesterol levels would rise.

In an editorial accompanying the BMJ publication, Qi Sun, MD, ScD (Brigham and Women’s Hospital, Boston, MA), called the new paper a timely one, noting that real-world data suggest a large proportion of people stop GLP-1s within 12 months of starting. The findings show that these new weight-loss drugs “should not be relied on as a magic cure for treating obesity,” he writes. Instead, they should remain as adjuncts, with healthy diet and lifestyle being the cornerstone of care.      

Nearly 10 kg Gained Back in a Year

The systematic review and meta-analysis included 37 studies with a total of 63 intervention arms and 9,341 participants. Of these, 35 were randomized controlled trials, although only 28 of these trials included a control group during the intervention and follow-up period.

The treatment arms included semaglutide (n = 8), tirzepatide (n = 7), and liraglutide (n = 12), and then a range of other weight-loss medications, such as cagrilintide, orlistat, phentermine, fenfluramine, dexfenfluramine, rimonabant, sibutramine, diethylpropion hydrochloride, lorcaserin, and topiramate. Mean treatment time with the medication was 39 weeks, and the mean follow-up period was 32 weeks.  

Overall, participants lost 8.3 kg on any weight-loss medication, with those on incretin mimetics losing 10.1 kg and those on the newer and more effective incretin mimetics losing 14.7 kg.

After stopping treatment, the average weight regained across all treatments was 4.8 kg in the first year and 6.0 kg with all incretin mimetics. After stopping semaglutide or tirzepatide, the average weight regained in the first year was 9.9 kg. All participants were projected to return to their baseline weight 1.7 years after stopping any weight-loss medication, by 1.6 years with the incretin mimetics, and by 1.5 years after stopping semaglutide or tirzepatide.

In studies reporting HbA1c, weight-loss drugs reduced levels by 0.9 mmol/mol during active treatment, followed by a 0.05-mmol/mol monthly increase after the medications were stopped. Similar trends were seen with fasting plasma glucose levels. Active treatment cut systolic blood pressure by 5.8 mm Hg, but the level increased by 0.5 mm Hg per month after stopping the weight-loss medications. Diastolic blood pressure, reduced by 3.7 mm Hg with treatment, increased by a monthly rate of 0.2 mm Hg once treatment stopped. Cholesterol concentrations and triglycerides levels also rebounded.

Fasting plasma glucose, systolic blood pressure, and triglyceride levels returned to baseline levels within a year of stopping medication while HbA1c and diastolic blood pressure took a little longer (1.4 years).

Weight Regained Even With Behavioral Support

There was no evidence in this analysis that the intensity of behavioral support given alongside medication affected the amount of weight regained after treatment. There also was no sign that continued as opposed to no support affected the speed at which patients regained weight.

“We think that when people follow a behavioral weight-management program, they’re given coping skills to deal with their hunger or ways of managing when feeling hungry during a diet,” said West. “Medications work to make you feel less hungry and that’s how they help you lose weight. It’s possible the medications potentially undermined those conscious efforts to manage hunger or even physical activity. When the treatment with medication stops, those coping skills are the only recourse available, but if you’ve not practiced them for a period of time while losing weight, it might be that they’re not there to help you maintain the weight loss.”

West stressed, however, that such reasoning is speculation at this stage and requires further research.

For Miedema, it isn’t too surprising that weight regain was slower when a behavioral intervention was halted, because participants likely carried some of those lifestyle changes forward even after the program ended.

“They’re not forced to stop the healthy behavior, so their weight regain would be then less significant over time,” he said. “If they were forced to stop those healthy behaviors, the weight gain would probably be similar to stopping the GLP-1.”

To TCTMD, Spatz said that behavioral programs had no impact on the amount or speed of weight regained after stopping the medication is one of the more disappointing findings. However, the new paper is a systematic review and there are no details on the type of behavioral programs adopted by participants, she noted. Also, there is heterogeneity of effect, meaning there are some people who will maintain weight loss by adopting lifestyle changes.

One aspect of research that is needed is whether longer-term treatment with GLP-1 receptor agonists could rewire the body’s metabolic status such that people would be reprogrammed to maintain a different body weight, said Spatz. In such a scenario, she wondered whether the weight-loss medication could alter the biology so people wouldn’t require lifelong treatment. While the present analysis found that the length of treatment did not impact weight regain, the follow-up was likely insufficient to address the question.

“Let’s say you are on a GLP-1 for 5 years,” she speculated. “Is that sufficient to say that, hormonally, these incretin hormones have changed and that our brains are no longer getting those messages that we’re hungry? I think that’s an open question.”

West emphasized that the new medications are an extremely effective and valuable tool for the treatment of obesity. While obesity is a chronic, relapsing condition, there remains some uncertainty around whether patients need to continue to take the drugs for life.

“Some kind of treatment needs to continue,” he said. “Whether what is offered is more medication, or they’re transferred to some kind of behavioral support, we still don’t know what’s best to do there, but clearly lifelong treatment of some kind is needed in order to help with long-term weight-loss maintenance.”

At his center, which has a large number of patients taking GLP-1s, experiences vary, said Miedema. Some patients lose lots of weight and keep it off when they stop the medication, because they’ve developed a new, healthy lifestyle. Some patients regain a little bit of weight so they’ll restart on a low-dose GLP-1, while others come off the medications and regain the weight pretty rapidly.

“In the field of diabetes, we’ve had people on these medications for years and years and years,” he said. “A lot of this withdrawal of medication comes down to cost issues and insurance coverage.”