GLP-1 RA drugs show cancer risk reduction but weight regain after cessation

GLP-1 receptor agonist drugs demonstrate significant reductions in endometrial cancer risk when combined with progestin therapy, while a meta-analysis reveals that patients regain most lost weight after stopping these medications. The findings highlight both a potential oncologic benefit and a clinical challenge associated with the widely used medications.

A retrospective cohort study published in JAMA Network Open found that GLP-1 receptor agonists combined with progestins are significantly more effective at reducing endometrial cancer risk compared to progestins alone in female patients with endometrial hyperplasia or other nonmalignant uterine conditions. The study included 444,820 female patients aged 18 years or older who were diagnosed with endometrial hyperplasia or benign uterine pathology and received progestin, with a mean age of 35.5 years. Among them, 18,414 patients received GLP-1RA combined with progestins, with a mean age of 43.1 years. Patients receiving GLP-1RA and progestins had a significantly lower risk of endometrial cancer than those receiving progestin alone (hazard ratio, 0.34; 95% CI, 0.27-0.44) or progestin and metformin (hazard ratio, 0.30; 95% CI, 0.15-0.59). Triple therapy with GLP-1RA, metformin, and progestin was more effective at reducing endometrial cancer risk than metformin and progestin (hazard ratio, 0.37; 95% CI, 0.25-0.53).

Meanwhile, a systematic review and meta-analysis published online March 4 in eClinicalMedicine characterized the trajectory of weight regain after GLP-1 RA cessation in adults with overweight or obesity. The review included 48 relevant studies, comprising randomized controlled trials, nonrandomized interventional studies, and observational studies. The researchers found that after cessation of GLP-1 RAs, weight consistently rebounded. A nonlinear meta-regression included six randomized controlled trials with 3,236 participants. The analysis indicated that 60% of the weight lost during treatment was regained one year postcessation. Weight trajectories were extrapolated beyond 52 weeks; weight regain was estimated to plateau at 75.3 percent of the weight lost on treatment. The rate constant was 0.0302 per week, corresponding to a 23.0-week half-life. A moderate risk for bias was seen in most studies.

The researchers noted that even though people regain most of the weight they have lost, they still maintain some of the weight loss. However, it remains unknown if the same proportion of lean mass is recovered. If the regained weight is disproportionately fat, individuals may ultimately be worse off than before in their fat-to-lean mass ratio, which may have adverse consequences for their health.