Eli Lilly recently published the results of a Phase III trial investigating the maintenance of Zepbound’s weight loss effects in overweight and obesity patients. Zepbound is Eli Lilly’s new glucagon-like peptide-1/gastric inhibitory polypeptide (GLP-1/GIP) dual agonist, approved by the FDA in November 2023, showing great promise compared to the other GLP-1R agonists on the market. However, the issue of rebound upon drug withdrawal remains an unmet need in the GLP-1R agonist space, says GlobalData, a leading data and analytics company.

According to the results of the SURMOUNT-4 trial investigating the maintenance of Zepbound’s weight loss effects in overweight and obesity patients, patients who switched from Zepbound to placebo at week 36 of the study experienced 14% weight regain at week 88, and the cardiometabolic risk factors that had improved during Zepbound treatment were reversed.

Costanza Alciati, Pharma Analyst at GlobalData, comments: “Weight regain and reversal of cardiometabolic improvements are a huge limitation for all marketed GLP-1R agonists, not only for Zepbound.”

Results from the STEP 1 trial extension study investigating changes in bodyweight and cardiometabolic risk factors upon semaglutide treatment withdrawal show that upon treatment withdrawal at week 68, patients regained 11.6% of bodyweight by week 120. Cardiometabolic risk improvements also reverted back to baseline in patients who stopped the treatment by week 120.

Alciati continues: “This rebound effect upon GLP-1R agonist withdrawal makes patients “dependent” on the drugs unless they are ready to lose some of the results. GLP-1R agonists are considered a chronic, long-term therapy to be taken indefinitely once treatment has started, and although for pharma companies it is great news economically, for patients it is a huge burden. From a side effects point of view, GLP-1R agonists can cause gastrointestinal disturbances, such as nausea and vomiting, which can become an issue in the long-term as they can disrupt daily life.”

Furthermore, from an economic perspective, the chronic long-term use of GLP-1R agonists is very expensive for patients and healthcare systems, especially in the US where the annual cost of therapy for a person taking Zepbound is over $13,000. The rebound effect upon GLP-1R agonists withdrawal needs to be investigated further and new drug developments should aim to mitigate this big limitation and find ways in which GLP-1R agonists could be used as short-term therapies without causing weight regain and cardiometabolic risk reversal.

Alciati concludes: “Although Zepbound seems to be more effective for weight loss compared to the other GLP-1R agonists on the market, the problem of rebound upon withdrawal remains an unmet need in the GLP-1R agonist space, and it needs to be further investigated and mitigated.”