Combination of hormone therapy and tirzepatide linked to greater weight loss after menopause

Postmenopausal women receiving menopausal hormone therapy lost 35% more weight while taking tirzepatide, according to a study led by Mayo Clinic researchers. Concurrent use of hormone therapy and tirzepatide was also associated with improved cardiometabolic outcomes, suggesting that hormone therapy might enhance the therapeutic effects of tirzepatide in this population.

"This study provides important insights for developing more effective and personalized strategies for managing cardiometabolic risk in postmenopausal women," said Dr Regina Castaneda, postdoctoral research fellow at Mayo Clinic and first author of the study.

Hormone therapy is the most effective first-line treatment for menopausal symptoms, including hot flashes and night sweats, which affect up to 75% of postmenopausal women. While evidence on how this therapy may interact with weight-loss medications is limited, some research has shown that postmenopausal women using hormone therapy experience greater weight loss when treated with the GLP-1-based obesity medication semaglutide.

No previous studies have examined whether hormone therapy might influence outcomes with tirzepatide. Castaneda and a team of researchers set out to investigate this relationship by reviewing data from 120 participants with overweight or obesity who received tirzepatide for weight management for 12 or more months. Patients receiving tirzepatide along with hormone therapy were compared to participants with similar characteristics who were not using hormone therapy.

Between June 2022 and May 2024, 15,639 female individuals were identified and 120 were included. 40 postmenopausal women using hormone therapy were matched to 80 not using hormone therapy. Mean age was 56·4 years (SD 6·4) and 113 (94%) of 120 were White. The hormone therapy group lost more of their percentage bodyweight at last follow-up than the no hormone therapy group (–19.2% [SD 9.9, SE 1.6] vs –14.0% [SD 8.0, SE 0.9]; mean difference –5.2%, 95% CI 1.90–8.54, p=0.0023), with a higher proportion of women in the hormone therapy group reaching a total percentage bodyweight change of ≥20%, ≥25%, and ≥30%. Both groups had improvements in glycaemia, blood pressure, and concentration of liver enzymes, with additional reductions in diastolic pressure, and concentrations of triglycerides and aspartate aminotransferase in women using hormone therapy.

"In this observational study, women who used menopausal hormone therapy lost about 35% more weight than women taking tirzepatide alone. Because this was not a randomised trial, we cannot say hormone therapy caused additional weight loss," added Dr Maria Daniela Hurtado Andrade, endocrinologist at Mayo Clinic and senior author of the study. "It is possible that women using hormone therapy were already engaged in healthier behaviours, or that menopause symptom relief improved sleep and quality of life, making it easier to stay engaged with dietary and physical activity changes."

Castaneda explained that while more studies that control for these factors are needed, the findings are clinically meaningful.

"The magnitude of this difference warrants future studies that could help clarify how GLP-1-based obesity medications and menopausal hormone therapy may interact. Interestingly, preclinical data suggest a potential synergy, with oestrogen appearing to enhance the appetite-suppressing effects of GLP-1.”

"Next, we plan to test these observations in a randomized clinical trial and determine if benefits extend beyond weight loss — specifically, whether hormone therapy also enhances the effects of these medications on cardiometabolic measures," adds Dr. Hurtado Andrade. "If confirmed, this work could speed the development and adoption of new, evidence-based strategies to reduce this risk for millions of postmenopausal women navigating this life stage."

This research was funded by the Mayo Clinic Center for Women's Health Research.

The findings were reported in the paper, ‘The role of menopause hormone therapy in modulating tirzepatide-associated weight loss in postmenopausal women with overweight or obesity: a retrospective cohort study’, published in The Lancet Obstetrics, Gynaecology, & Women’s Health Home. To access this paper, please click here (log-in maybe required)