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In the real world, the use of semaglutide (Wegovy) and tirzepatide (Zepbound) produce far less weight loss than in the randomized clinical trials, largely because people discontinue using them early or use lower maintenance doses, new research found.

Data from electronic health records of patients seen during 2021-2023 at the Cleveland Clinic’s Ohio and Florida centers also yielded some surprises: A large majority, over 80% of patients, were using low maintenance doses of the medications (ie, the treatment dose used for the longest period of time). And even after early discontinuation (within 3 months), there wasn’t the rapid weight regain seen in some of the trials. Improvements in A1c were also seen among those with prediabetes even after discontinuation.

The findings, published on June 10, 2025 in Obesity, are the latest from a team that has previously reported on the high prevalence of discontinuation of weight-loss medications. Now, they’re delving further into the phenomenon, lead author Hamlet Gasoyan, PhD, a researcher with Center for Value-Based Care Research, Cleveland Clinic, Cleveland, told Medscape Medical News.

“Even though we did know that…discontinuation with these medications is common, and we already knew from randomized trials that after discontinuation patients tend to regain weight, we don’t really know the whole picture of use patterns in the real world in terms of timing of discontinuation, and most importantly, what patients can expect in terms of changes in their weight and also, if they have prediabetes, changes in their glycemic control based on discontinuation status,” Gasoyan said.

The finding of the prevalent use of low maintenance doses and the association between that and the clinical outcomes was a surprise. “We did not expect to see such a stark difference between what is happening in clinical trials vs in the real world,” he noted.

Asked to comment, Timothy Garvey, MD, the Charles E. Butterworth, Jr professor and university professor at The University of Alabama at Birmingham (UAB) and director of the UAB Diabetes Research Center at Birmingham, Alabama, called the study “really, really great,” and said that it fills in some of the knowledge gaps regarding real-world use of these drugs.

“[Many] people never even fill the prescription, and then by a year, more than half are off it…This paper really documents this very well and shows it to be multifactorial. It also shows that we’re not in a position to have pharmacotherapy to treat this disease on a chronic basis,” said Garvey, who was lead investigator for several pivotal randomized clinical weight-loss trials for both semaglutideand tirzepatide.

Garvey also noted that the findings regarding sub-maximal dose use are novel and valuable. “Obesity medicine experts kind of know this, but it [hasn’t been] knowledge because it [had] never been published in a peer reviewed journal, so this makes it knowledge.”

Low Maintenance Doses, Lower Weight Loss 

The study included electronic health record data from 7881 adults with overweight or obesity but not diabetes who initiated injectable semaglutide (n = 6109) or tirzepatide (n = 1772) during 2021-2023.

During the first year, 21.6% on semaglutide and 16.4% on tirzepatide discontinued the drug early (within 3 months of initiating), while 31.4% and 34.1%, respectively, discontinued later (within 3-12 months). The rest — 47.0% (n = 2874) with semaglutide and 49.4% (n = 876) with tirzepatide — stayed on the drug beyond a year.

By contrast, 1-year discontinuation rates in the main phase 3 randomized clinical trials were 17.1% with once-weekly semaglutide 2.4 mg (STEP 1), and 14.2%-16.4% for tirzepatide (SURMOUNT-1), the authors noted.

Most of the patients, 80.8%, were on low maintenance doses, defined as below 1.7 mg semaglutide and below 10.0 mg for tirzepatide.

Of 6477 individuals with 1-year data available, the mean overall percentage weight reduction was 8.7%. By medication, weight reduction at 1 year was 7.7% with semaglutide and 12.4% with tirzepatide.

In comparison, the average weight loss in the phase 3 clinical trials was 14.9% for once-weekly semaglutide 2.4 mg, 15.0% for tirzepatide 5 mg, and 20.9% for tirzepatide 15 mg.

In the current trial, among those with early, late, or no discontinuation, the percentage weight losses were 3.6%, 6.8%, and 11.9%, respectively (P < .001). The trends were similar by medication: 2.9%, 5.8%, and 10.9%, respectively, for semaglutide and 7.0%, 10.4%, and, 15.3%, respectively, for tirzepatide.

Individuals who continued taking the medications at high maintenance doses (1.7 mg, 2.0 mg, or 2.4 mg of semaglutide or 10.0 mg, 12.5 mg, or 15.0 mg of tirzepatide) lost a mean of 14.7% at 1 year, including 13.7% with semaglutide and 18.0% with tirzepatide.

In multivariate analysis, the odds of achieving ≥ 10% weight loss at 1 year were significantly higher among those who continued taking the medication (adjusted odds ratio [aOR], 4.68 [vs early discontinuation] and 1.74 [vs late discontinuation]), who took tirzepatide vs semaglutide (aOR, 2.46), who used high vs low medication doses (aOR, 2.39), and who were women vs men (aOR, 1.86).

Prevention of Diabetes Progression, Even After Quitting

Among the 895 patients who had prediabetes at baseline and A1c measurements at 1 year, the mean absolute A1c reduction at 1 year was 0.3 percentage points overall, 0.1 for those who discontinued early, 0.2 for those with late discontinuation, and 0.4 for those who didn’t discontinue (P < .001). Overall A1c reduction at 1 year was 0.3 points with semaglutide and 0.4 with tirzepatide.

A total of 53.9% of the baseline prediabetes group converted to normoglycemia at 1 year, including 33.1% with early discontinuation, 41.0% with late discontinuation, and 67.9% of those who stayed on the medications. Progression to type 2 diabetes occurred in 6.5%, 4.4%, and 1.7% of those groups, respectively.

“That’s a very encouraging finding, which confirms the efficacy of this medications for the prevention of type 2 diabetes but also highlights the importance of persistence with treatment if the goal is prevention of type 2 diabetes,” Gasoyan said.

What Are People Doing After They Drop the Drug?

Although the patients who discontinued the drugs lost significantly less weight than those who continued taking them, “weight trajectories remained surprisingly stable after discontinuation throughout the study follow-up period. This contrasts what has been observed after medication discontinuation at the end of randomized trials,” Gasoyan and colleagues wrote.

To understand this finding, the investigators also looked at other measures the patients might have taken after discontinuation, such as other medications or adopting new lifestyle habits or undergoing bariatric surgery. They’ll report those findings soon, Gasoyan said.

At the same time, he noted, “it’s easier to maintain smaller weight loss compared to maintaining a larger weight loss.”

The team is also planning to report findings for why patients discontinued the medications. “We are gathering information on independent predictors that hopefully in the future could help us develop a prediction tool to give relatively reasonable estimates on what a patient can expect at the time of treatment initiation,” Gasoyan told Medscape Medical News.

Garvey is looking forward to newer, better obesity drugs. “The unmet clinical need is a medicine that’s well tolerated, that gives us 15 or 20% weight loss, is affordable and is accessible...We don’t have that, and this is the consequence…Everyone’s fixated on [GLP-1 receptor agonists], but I don’t think we’re going to get past these [gastrointestinal] side effects…There are a lot of other drugs in early phases.”

Gasoyan had no disclosures. Garvey served on advisory boards, conducted clinical trials, and/or served on data monitoring committees for Boehringer Ingelheim; Eli Lilly and Company; Novo Nordisk; Pfizer; Fractyl Health, Inc.; Alnylam Pharmaceuticals, Inc.; Inogen; Zealand Pharma; Allurion; Carmot Therapeutics/Roche; Terns Pharmaceuticals; Neurocrine Biosciences; Keros Therapeutics; Gan & Lee Pharmaceuticals; Regeneron; Epitomee; Neurovalens; Viking Therapeutics, Inc.; and the Milken Family Foundation.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in the Washington Post, NPR’s Shots blog, and Diatribe. She is on X (formerly Twitter) @MiriamETucker and BlueSky @miriametucker.bsky.social.