reviewed by Pedro Marques-Vidal

Obesity is not only rising; it is accelerating. Global prevalence of obesity has tripled since the 1970s, with over one in eight people worldwide now living with obesity (1). The World Obesity Atlas 2023 report projected that by 2035, one-fourth of the world population will be affected by overweight and obesity.

Obesity is far from a mere cosmetic concern; it is a chronic condition with serious health consequences such as type 2 diabetes mellitus, cardiovascular diseases (CVD), and multiple cancers. In 2019, obesity was responsible for more than 5 million deaths (2), and approximately two-thirds of obesity-related excess mortality is attributable to CVD (3).

While lifestyle modification remains the cornerstone of obesity management, for many individuals, lifestyle change alone is often not enough to achieve or to sustain clinically meaningful weight loss. The interest has therefore shifted towards the use of anti-obesity medications, which has been shown to be effective not only on weight reduction, but also on cardiometabolic benefits, such as improvements in blood pressure, sugar control and better lipid profiles.

Reflecting emerging evidence on these medications, the 2024 European Society of Cardiology (ESC) Clinical Consensus Statement stated obesity as a major cardiovascular risk factor and recommended multidisciplinary management. This includes pharmacological therapies, particularly for individuals with BMI ≥ 30 kg/m² or ≥ 27 kg/m² with one or more comorbidities (4). Similarly, the WHO has also recently issued its first global guideline supporting the use of Glucagon-Like Peptide-1 (GLP-1) therapies in treating obesity (5). As a result, prescriptions for agents, such as semaglutide and tirzepatide have skyrocketed, and these drugs are now widely used in clinical care across Europe and beyond, supported by a strong commercial expansion into the anti-obesity market.

Yet, a critical question remains: What happens next, when treatment is withdrawn? Do the benefits remain or quickly fade away?

A recent study by Deborah B. Horn et al, published in JAMA Internal Medicine, highlights this critical insight into what happens when tirzepatide treatment is withdrawn (6). The study investigated whether cardiometabolic improvements achieved during tirzepatide treatment were maintained or reversed with the possible weight regain after withdrawal of the treatment.

This post hoc analysis of the SURMOUNT-4 trial included tirzepatide-treated obese participants who initially achieved a clinically meaningful (at least 10%) weight reduction after 36 weeks initial treatment, who were then randomized to placebo till 52 weeks.

Tirzepatide treatment for the first 36 weeks was associated with improvements in weight, waist circumference, blood pressure, lipid profile, and haemoglobin A1c. Nevertheless, one year after the withdrawal, weight regain was common despite continued non-pharmacological interventions: half of the participants regained more than 50% of the weight loss, and at least one-fourth of the participants regained more than 75% of the weight loss.
Importantly, the study also found that the greater the weight loss the bigger the reversal of improvements of cardiometabolic initially achieved with the tirzepatide therapy. Compared to the participants who regained less than 50% of the weight loss, those who regained more than 75% experienced larger deterioration.

• Waist circumference: +0.8 cm vs +14.7 cm
• Systolic blood pressure: +6.8 mmHg vs +10.4 mmHg
• Diastolic blood pressure: +2.8 mmHg vs +4.3 mmHg
• Triglycerides: +5.5% vs +18.9%
• Non-HDL cholesterol: -0.4% vs +10.8%
• HbA1c: +0.14% vs +0.35%
• Fasting insulin: -0.4% vs +26.3%  

Strengths of the study include randomized withdrawal design, continued lifestyle intervention in the placebo group, objective measurement of cardiometabolic parameters and long-term follow up over a year. Limitations include post-hoc nature, lack of detailed data on dietary assessment and physical activity; the categorical weight classification design might miss the weight regain cutoff associated with the treatment withdrawal.
Overall, the study by Deborah B. Horn et al reinforced the definition proposed by the world obesity federation: obesity is a chronic, relapsing, progressive disease, a condition requiring long-term management strategies. Lifestyle modifications should be central in obesity management and should be strengthened, not relaxed, during pharmacotherapy. Short-term pharmacotherapies are less likely to preserve cardiovascular risk reductions. Instead, long-term weight management strategies, combining lifestyle management with appropriate sustained pharmacotherapy, should be prioritized. Further research is required to better understand the long-term benefits and risks of withdrawal from pharmacological therapies and strategies to sustain weight and cardiometabolic benefits beyond pharmacotherapies.

Note: The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.