For over three years, it has become clear that drugs from the Ozempic family are here to stay, as they have marked a necessary turning point in the face of obesity. The treatment landscape has undergone a radical transformation with the arrival of GLP-1 receptor agonists, the clinical name for also known as GLP-1 analogues: drugs that have shown weight reductions between 15% and 20%.
However, challenges persist such as the chronic use of treatment and weight regain after its interruption; issues that are also a subject of intense debate. Recently, a systematic review published in eClinicalMedicine has shed light on these issues.
The research analysed a total of 48 studies, focusing its main analysis on six randomized controlled clinical trials that combined the experience of 3,236 participants. The goal was to describe what happens when the treatment is stopped. The researchers determined that weight recovery follows a predictable and decelerated pattern.
Antonio Vidal-Puig, one of the signatories of the study and a researcher at the University of Cambridge, emphasizes that the so-called rebound effect or "regain" should not be seen as a binary event of "on or off", but as a structured clinical intervention that requires phenotyping and monitoring.
The data is revealing: one year after drug withdrawal, patients regain on average 60% of the lost weight during the treatment. The model extrapolates that this gain tends to stabilize or enter a stabilization phase around 75.3% of the lost weight. This suggests that even though most of the benefits are lost, there remains a residual benefit of 25% in the long term. This figure could equate to a reduction of 4-5% compared to the patient's initial weight, which still holds metabolic relevance.
Vidal-Puig highlights the urgency of evaluating body composition (lean mass). He warns that the health risk does not only lie in the regained weight, but in the quality of what is regained. If a substantial part of the lost weight was lean mass, there is a risk that the regained weight is mainly visceral or hepatic fat, which can worsen insulin resistance even if the total weight is lower than at the beginning. Therefore, he suggests that withdrawal trials include strength tests and measurements of ectopic fat.
Additionally, Vidal-Puig differentiates between patients who discontinue treatment due to side effects or costs and those who could benefit from a gradual decrease. For him, ideal candidates for a gradual decrease are those with early appetite control, stable weight phases, and improvements in metabolic markers, as long as they maintain resistance exercise and adequate protein intake. In contrast, those with a high burden of visceral fat or long-standing diabetes likely need long-term maintenance.
This is not the first study to address the issue of the so-called "rebound effect" of these drugs. Just earlier this year, a meta-analysis was published in the British Medical Journal (BMJ), which went beyond weight recovery. This work emphasized the disease, the remission of pathologies that condition the patient's health: controlled blood pressure, low cholesterol levels, and an improved diabetes situation. Diego Bellido highlighted the idea advocated by the Spanish Society for the Study of Obesity (Seedo): "Obesity is a chronic condition that requires treatment as such."
From a perspective outside of these studies, Andreea Ciudin, coordinator of the Morbid Obesity Unit at Vall d'Hebron Hospital, offers a strong view in this line: "Obesity is a chronic condition that requires lifelong treatment, just like diabetes or hypertension."
Ciudin rejects the term "rebound effect" as she considers it a lack of biological knowledge. She argues that if a drug that corrects the biological alterations of obesity is withdrawn, "it is normal for the disease to reappear." She uses a powerful analogy: "if you quit smoking in time, the lung recovers; but if there is already chronic bronchitis or cirrhosis, healthy habits (diet and exercise) alone are insufficient, and permanent pharmacological treatment or even transplantation is required."
Regarding muscle mass, Ciudin agrees that focusing solely on total weight and BMI is insufficient. However, she points out that in some studies, "although muscle is lost, patients gain functionality, indicating an improvement in muscle quality." For her, the prescription of daily resistance exercise along with the drug is not optional, and its absence could even be considered malpractice.
The endocrinologist from Vall d'Hebron also strongly criticizes access limitations based on cost. Here, she explains that in no other serious illness is the correct treatment so conditioned by the patient's purchasing power. Therefore, she advocates for a national health plan that recognizes obesity as a disease and finances medications, warning that "delaying treatment will only increase long-term costs due to the emergence of comorbidities."
Both the study and the experts agree that current guidelines, such as the NICE recommendation in the UK to limit the use of semaglutide to two years, are insufficient and could undermine long-term effectiveness. The evidence shows that forced discontinuation is counterproductive and that the future of obesity care should be based on individualized cessation strategies, continuous multidisciplinary support, and a real recognition of the chronic and biological nature of this disease.