GLP-1R agonist withdrawal effect on weight loss and cardiovascular risks remains unmet need: GlobalData

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

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

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 per cent weight regain at week 88, and the cardiometabolic risk factors that had improved during Zepbound treatment were reversed.

Costanza Alciati, Pharma Analyst, 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 per cent 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.”