Real-world data presented by Amgen at ObesityWeek 2025 delivers a clear, cautionary message about the long-term management of obesity: stopping glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with significant weight regain, reinforcing the concept of obesity as a chronic condition requiring sustained intervention.

Simultaneously, other research highlights the critical importance of managing cardiovascular risk factors, particularly LDL cholesterol, in high-risk patients with obesity and diabetes. The data adds to a growing body of evidence on the challenges of treating obesity and type 2 diabetes with GLP-1 RAs, especially weight regain after stopping treatment.

In an interview with the Drug and Device World, Dr. Michael Weintraub, MD, Clinical Assistant Professor of Medicine, Division of Endocrinology, NYU Langone Health, discusses the new data and its importance.

The Inevitability of Weight Recurrence

The study, “Weight change after GLP-1 discontinuation in US patients living with overweight/obesity or diabetes,” analyzed data from over 1.2 million US patients. It found that persistence on GLP-1 therapy is challenging, dropping to just 38% at 12 months. For those who stopped treatment and had follow-up weight data, the trend was clear: weight recurrence began quickly and continued over time.

The analysis showed that at 3 months post-discontinuation, patients had regained an average of 4.5% of their weight. This figure climbed to 5.9% at 6 months and reached 7.5% at one year. Dr. Weintraub, the study’s author, contextualizes these findings within the established understanding of these medications.

“We know that abrupt stoppage of the medication will lead to weight recurrence,” said Dr Weintraub. “We already observed this in the clinical trials with Novo Nordisk’s semaglutide (STEP 4 – NCT03548987) and Eli Lilly’s tirzepatide (SURMOUNT 4 – NCT04660643). This real-world data analysis confirms what we observed in these clinical trials that stopping the medication leads to weight regain. For this reason, in my clinic, I never abruptly stop the medication.”

Predictors of Greater Regain

The study uncovered specific patient factors that predicted a more pronounced weight rebound. Contrary to what one might expect, those who experienced the greatest success on the medication were the most vulnerable to regain after stopping.

“Those who experienced the greatest weight loss while taking a GLP-1 RA had the greatest weight recurrence (regain) after discontinuation of the medication,” explained Dr. Weintraub. “Those with initial weight loss of 5-10% regained 5.1% of their weight after discontinuation. Those with greater than 20% weight loss had average weight regain of 9.2%.”

In absolute terms, this translated to a regain of 7.8 kg for the group that had initially lost ≥20% of their body weight. The presence of type 2 diabetes was another key differentiator. Patients without diabetes experienced greater weight recurrence (6.7% or 6.3 kg) compared to those with diabetes (5.6% or 5.2 kg).

A Mandate for Chronic, Adaptive Management

The data powerfully challenge the notion of GLP-1 RAs as short-term solutions. The high discontinuation rates and subsequent rapid weight regain point to the need for a paradigm shift in how these treatments are framed and managed.

“Obesity is a chronic disease and will require chronic treatment,” stated Dr. Weintraub. “That chronic treatment could change over time, however. It could be one medication now, it could be a lower dose of that medication in the future along with increased lifestyle modifications. It could be a different medication or even bariatric surgery in the future. The important thing to recognize is without some combination of long-term intervention, the patient will experience weight recurrence.”

This perspective suggests a more nuanced approach than indefinite treatment at a maximum dose. Dr. Weintraub elaborated on a potential strategy for dose management in certain scenarios: “In certain situations when a patient’s weight has reached a goal and their obesity-related comorbidities are well-controlled, we can gradually decrease the dose and observe whether we can continue to maintain the weight loss with lower doses of medication.”

Confronting Cardiovascular Risk in a High-Risk Population

While managing weight is crucial, it is one component of a broader health picture for patients with obesity, many of whom also have diabetes and cardiovascular disease. A separate Amgen-sponsored study, “Assessment of Risk Reduction of Recurrent Cardiovascular Events in Patients With ASCVD and Diabetes,” focused on this high-risk population.

The research used NHANES data and the TIMI risk score to model the impact of controlling key risk factors—LDL-C, HbA1c, and BMI—in patients with both atherosclerotic cardiovascular disease (ASCVD) and diabetes who had suboptimal control of these metrics.

The findings were striking. For this population, achieving guideline-recommended LDL cholesterol goals delivered the most significant individual benefit in reducing the predicted 3-year risk of recurrent cardiovascular events, such as heart attack or stroke.

“The study demonstrated that for people with ASCVD and diabetes, reaching guideline-recommended LDL cholesterol goals delivers significant clinical benefit in reducing recurrent cardiovascular events,” said Brian Bradbury, Vice President and Head of Center for Observational Research, Amgen, in an interview.

The modeling showed that individually managing LDL-C to 55 mg/dL provided a 24% predicted relative risk reduction, compared to an 8% reduction from managing HbA1c to 7%. “Combined management of risk factors provides the highest predicted cardiovascular risk reduction (37%) but among individual risk factors, the study found that managing LDL-C to 55 mg/dL had the greatest predicted CV risk reduction (24%),” Bradbury added.

The Critical Care Gap in LDL-C Management

Despite its proven benefit, LDL-C remains a neglected frontier in the management of these complex patients. The study underscores a significant care gap that needs to be addressed through updated clinical pathways.

“Among patients with multiple risk factors and comorbidities like ASCVD and diabetes, LDL-C is often undertested and undertreated,” noted Bradbury. “Regular LDL-C testing and intensive LDL-C lowering to achieve guideline-recommended goals are critical to reduce the risk of recurrent CV events in this population. Optimal management of risk factors together will result in the greatest risk reduction.”

He concluded with a clear recommendation for systemic change: “Clinical pathways should emphasize a comprehensive approach to risk management, integrating these targets into routine patient care for all patients with CV risk, but especially those with ASCVD and diabetes.”

Addressing Residual Risk and the Path Forward

Even with ambitious composite control of LDL-C to 55 mg/dL, HbA1c to 7%, and BMI to 25, a substantial residual CV risk remains. This points to the need for a holistic, patient-centered approach that looks beyond these three factors.

“Many different conditions contribute to cardiovascular disease, including elevated LDL-C, lipoprotein(a), high triglycerides, obesity, diabetes, and hypertension,” explained Bradbury. “While some individuals may be affected by a single risk factor, many experience multiple coexisting conditions. A comprehensive, patient-centered approach that addresses the full spectrum of coexisting conditions, both individually and collectively, with tailored interventions, is essential to reducing the burden of CVD.”

Synthesis for Patient Care

Together, these two studies presented by Amgen paint a complementary picture for managing complex chronic diseases. The GLP-1 data argue for the sustainability of effective obesity treatments, framing them as long-term partners in health rather than quick fixes. The cardiovascular risk analysis provides a clear roadmap for where to focus efforts to protect the most vulnerable patients from life-threatening events, with intensive LDL-C management offering the most powerful individual tool.

The overarching theme is that chronic diseases require chronic, proactive, and multifaceted management strategies. For obesity, this means supporting persistence on effective therapies or developing strategic de-escalation plans. For cardiovascular risk in patients with diabetes and ASCVD, it means closing the gap in LDL-C testing and treatment to unlock significant reductions in future events. In both cases, a proactive, long-term view is essential for optimizing patient outcomes.