Weight loss drugs based on GLP-1 agonists, such as Ozempic, are already getting a lot of attention for diabetes and weight loss. A large study adds an unexpected element: associated with progestin hormones, they also seem to reduce the risk of
uterine cancer.
Endometrial cancer, which affects the lining of the uterus, is the most common gynecological cancer in rich countries, particularly among women who are overweight, diabetic or with insulin resistance. Progestins are already used to slow down endometrial hyperplasia or heavy bleeding, but they do not act directly on these metabolic factors. The research team therefore wondered whether more direct treatment of these metabolic factors could help prevent the disease.
Uterine cancer: GLP-1 + progestins associated with a 66% risk reduction
Researchers analyzed the global TriNetX database, rich in anonymized medical records. They identified 444,820 women aged at least 18, followed between 2005 and 2022, presenting endometrial hyperplasia or benign uterine pathology and all receiving a progestin. Although endometrial hyperplasia is not cancer, it can be considered a precancerous condition. Researchers classify injuries into three levels of severity. If left untreated, these lesions can sometimes develop into cancer. Endometrial hyperplasia can present with painful menstrual periods, bleeding between cycles (menorrhagia), and bleeding after menopause (metrorrhagia). In some cases, no symptoms are present. Treatment is based on progestins or surgery, depending on the severity of the lesions and the patients’ desire to become pregnant.
Among them, 18,414 also received a GLP-1 receptor agonist (GLP-1RA), compared to 426,406 taking progestin alone. After statistical matching (i.e. to have two statistically comparable groups), 15,747 patients were compared in each group. The primary endpoint was the incidence of endometrial cancer.
During follow-up, 0.5% of women on the GLP-1/progestin combination developed cancer, compared to 1.8% on progestin alone, i.e. risk reduction of approximately 66%. This protective signal remained present regardless of age, body mass index, initial risk level or route of progestin administration. “In this cohort study of women with benign uterine pathology or endometrial hyperplasia, the addition of GLP-1RA to progestin therapy was associated with a lower risk of endometrial cancer.”the researchers concluded in JAMA Network Open.
Fewer cancers and fewer hysterectomies
The authors also compared other regimens, including metformin (the most prescribed anti-diabetic). The GLP-1 agonist plus progestin combination was linked to a lower cancer risk than the metformin plus progestin combination. A triple therapy combining GLP-1, metformin and progestin showed a further reduced risk compared to metformin plus progestin and progestin alone. In absolute terms, cancer rates nevertheless remained low in all groups.
The team was interested in the use of hysterectomy, often proposed to prevent progression to cancer. In women taking GLP-1 and progestin, the risk of hysterectomy was 53% lower at two years and 41% lower at five years than taking progestin alone. In the subgroup at high risk for atypical EIN hyperplasia, the trend was in the same direction, potentially suggesting less removal of the uterus in these patients.
A promising avenue, but still experimental
Biologically, GLP-1 agonists reduce weight, improve blood sugar and insulin resistance, thereby limiting endometrial exposure to uncounteracted estrogens. Preclinical work also shows that when combined with progestins, they increase the expression of the progesterone receptor, reduce the viability of tumor cells and could raise resistance to progesterone via different metabolic pathways. “These results suggest that GLP-1RAs may improve endometrial outcomes not only through metabolic regulation but also by potentially modulating hormonal signaling pathways.” wrote the authors.
The limitations of this study remain significant: it is a retrospective study, based on file coding, with the possibility of unmeasured confounding factors and therefore a correlation link but not necessarily a causal link. For the moment, these drugs are not prescribed to prevent uterine cancer, and the authors call for prospective clinical trials before any changes in practices.