Weight-loss drugs like Mounjaro, containing the tirzepatide molecule, have revolutionized the treatment of obesity in recent years, allowing certain patients to lose up to a quarter of their body weight. This spectacular efficiency quickly aroused worldwide enthusiasm. But a recent study carried out as part of the Surmount-4 trial, the results of which were published in the journal JAMA Internal Medicine, warns of the effects of stopping treatment.
Carried out by researchers, notably from the University of Glasgow and the pharmaceutical company Eli Lilly, this research highlights a massive weight gain, accompanied by a degradation of metabolic health markers. At a time when these treatments are increasingly prescribed, this study questions their place in a sustainable health strategy, and relaunches the debate on drug dependence in the fight against obesity.
Tirzepatide, therapeutic effectiveness framed by a treatment strategy
Tirzepatide constitutes the active ingredient of the drug Mounjaro developed by the Eli Lilly laboratory. It belongs to a class of treatments called GIP/GLP-1 receptor agonists. It works by stimulating two intestinal hormones involved in the regulation of appetite and blood sugar. This leads to a significant reduction in the feeling of hunger and better management of energy metabolism. Its effectiveness has been documented in several clinical trials, including OVERMOUNT-1 And
SURMOUNT-2before the test SURMOUNT-4 does not look at the sustainability of the effects.
Patients included in SURMOUNT-4 were all obese (BMI ≥ 30) or overweight with weight-related comorbidity. For 36 weeks, they received tirzepatide combined with dietary advice and supervised physical activity. This combination allowed them to lose on average 20% of their initial weight. And above all with notable improvements in metabolic health markers. However, this first phase represented only a prelude to the key question posed by the trial: what happens once treatment is stopped?
The second phase of the study consisted of dividing the participants into two groups. One continued tirzepatide for an additional 52 weeks. The other received a placebo, without either the patients or the researchers knowing which group each belonged to. This double-blind methodology made it possible to objectively evaluate the difference between maintaining and stopping treatment. It was necessary to understand whether the benefits of the drug could be sustained over time, or depend exclusively on the continuity of therapy.
Rapid weight regain and immediate impact on cardiovascular health
Test results SURMOUNT-4 then reveal a worrying phenomenon. After stopping tirzepatide, 82% of patients regained at least 25% of the weight they had lost. In some, recovery even reached or exceeded 75% of the initial loss within 52 weeks. This weight gain is correlated with a rapid deterioration of several key indicators of cardiovascular and metabolic health.
Researchers observed a deterioration in LDL cholesterol (“bad” cholesterol), an increase in blood pressure and an increase in blood sugar. However, all of these parameters improved during the active treatment phase. The data shows a direct relationship between the amount of weight regained and the extent of metabolic breakdown. Those who gained the most weight saw their indicators return to levels comparable to those at baseline.
This observation comes as no surprise to Professor Naveed Sattar of the University of Glasgow, explains
The Guardian. He has worked on previous trials involving similar drugs. He explains that excess weight constitutes “a well-known driver” of metabolic imbalances. When weight loss is reversed, the risk factors logically reappear.
These results call for particular vigilance in the use of these medications. The promise of significant metabolic improvement exists. However, it seems to depend entirely on the continuation of treatment. As soon as the pharmacological stimulus ceases, the beneficial effects regress.
Stopping treatment questions the obesity management strategy
The reversibility of the effects of tirzepatide raises an essential question in obesity medicine. Should we consider these treatments as long-term, or even lifelong, therapies? Unlike an infection treated with antibiotics or a one-off intervention, obesity is long-term. It is now classified as a chronic disease by the World Health Organization. However, a chronic illness requires ongoing care.
Jonathan Benger, chief medical officer of NICE (National Institute for Health and Care Excellence) in the United Kingdom, insists on the need for structured support. He reminds, to
the Independentthat the post-treatment transition constitutes “a critical period”. Furthermore, stopping without follow-up can reverse all the progress made. NICE recommends continuity of care including personal monitoring tools, support groups, and community interventions.
Professor Jane Ogden, a health psychologist at the University of Surrey, adds a behavioral dimension. Weight-loss medications do not necessarily change patients' eating habits. Some people stop cooking, planning their meals or paying attention to their nutritional intake, relying solely on the effect of the treatment. This pharmacological dependence, when it is not compensated by a lasting change in lifestyle, becomes a vulnerability.
The implications are clear. Researchers do not question the effectiveness of tirzepatide. But its interruption without a maintenance strategy leads to a rapid return to initial conditions. This calls for fully integrating these treatments into a multidisciplinary medical approach.
Demonstrated effectiveness, but use to be regulated over the long term
The results of SURMOUNT-4 are part of a context where obesity treatments based on GLP-1 and GIP agonists are experiencing worldwide growth. Tirzepatide, in particular, has generated great enthusiasm for its ability to produce weight loss greater than that observed with previous treatments such as semaglutide (Ozempic). However, this test brings an essential nuance: its effectiveness depends on continuity.
The issue no longer lies solely in the performance of the drug, but in the capacity of the health system to offer a sustainable prescribing framework, based on rigorous medical criteria and long-term monitoring. The question of cost is also central. Prolonged treatment represents a significant financial burden on public health systems. Hence the need to evaluate its long-term benefit in terms of reduction of complications (diabetes, stroke, heart attack) and mortality.
Caution is also required in specific populations. Other studies cited by the authors report potential risks if treatment is stopped before pregnancy, including an increased risk of gestational diabetes and obstetric complications. Professor Sattar, however, tempers these results, calling not to conclude too hastily in the absence of specific controlled trials.
Finally, the study SURMOUNT-4 confirms the importance of a consistent public health message. No medication can, on its own, resolve a problem as multifactorial as obesity. Tirzepatide remains a powerful tool. However, it must be integrated into a long-term strategy, adapted to individual realities, with clear, realistic and sustainable medical objectives.
Source: Horn DB, Linetzky B, Davies MJ, et al. “Cardiometabolic Parameter Change by Weight Regain on Fatigue Withdrawal in Adults With Obesity: A Post Hoc Analysis of the SURMOUNT-4 Trial”. JAMA Intern Med. Published online November 24, 2025.
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