- Postmenopausal women taking tirzepatide and hormone therapy lost more body weight than those on tirzepatide alone.
- Hormone therapy users also had additional improvements in diastolic blood pressure, triglycerides, and liver enzymes.
- The observations will be tested in a randomized clinical trial to determine whether benefits may extend beyond weight loss.
Postmenopausal women on the GLP-1 medication tirzepatide (Zepbound) for obesity lost more weight if they were also using menopause hormone therapy, a retrospective cohort study indicated.
Among 120 women with overweight or obesity on tirzepatide, hormone therapy users lost 19.2% of their body weight, while those not using hormone therapy treatment lost 14% (P=0.0023), reported Maria Daniela Hurtado Andrade, MD, PhD, of the Mayo Clinic in Jacksonville, Florida, and colleagues.
"Women in the hormone therapy group lost 35% more body weight than those in the no hormone therapy group and showed notable improvements in key cardiometabolic parameters, supporting a potential enhancing effect of hormone therapy on tirzepatide's therapeutic effect," the researchers wrote in Lancet Obstetrics, Gynaecology, & Women's Health.
Both groups had improvements in fasting glucose, HbA1c, HDL cholesterol, alanine aminotransferase, and systolic blood pressure, but hormone therapy users also had significant reductions in diastolic pressure, triglycerides, and aspartate aminotransferase. Total cholesterol and LDL cholesterol were stable in hormone therapy users and slightly increased in nonusers.
"Although these improvements probably stem from the greater weight loss in this group, hormone therapy might also exert independent beneficial effects due to the well-established physiological actions of estrogen on glucose and lipid metabolism, liver function, vascular health, and its favorable effect on mitigating visceral fat deposition," the researchers noted.
"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," said Hurtado Andrade in a statement. "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."
Menopause is a critical window that can dramatically increase cardiovascular disease risk in women with obesity, Hurtado Andrade and team explained. The findings emphasize the importance of personalized obesity management strategies that account for menopausal status, they noted.
Accompanying commentary authors Roberto Vettor, MD, of the University of Padova in Italy, and Mikiko Watanabe, MD, PhD, of the University of Rome, noted that weight-loss responses to GLP-1 agents are known to be more pronounced in women, but their blunted responses in older postmenopausal women suggest an important role for sex steroids, especially estrogen.
"These findings add complexity to sex differences in treatment with GLP-1 receptor agonists and GLP-1-GIP receptor agonists and warrant stratification in randomized controlled trials, not only by sex, but also by menopausal stage," they suggested.
Vettor and Watanabe added that it is unclear whether the findings reflect GLP-1-GIP signaling -- currently only found in tirzepatide as far as approved agents go -- or whether they're reflective of GLP-1 signaling, which would also translate to other agents like semaglutide (Wegovy).
Hurtado Andrade and team examined data on postmenopausal women in the Mayo Clinic Health System from June 2022 to May 2024. All were treated with tirzepatide for weight management for at least 12 months. Two-thirds of women were taking at least a 10-mg tirzepatide dose each week.
At baseline, the average age in the cohort was 56.4 years; 94% of participants were white, and 77% had obesity. Many had comorbid dyslipidemia (75%), hypertension (63%), or type 2 diabetes (53%).
Systemic hormone therapy users were propensity score-matched 1:2 to nonusers based on age, body mass index, age at menopause, type of menopause, prior obesity medication use, and diabetes status. Most hormone therapy users (68%) were on transdermal estradiol and 33% were on an oral option.
Hormone therapy users were more likely to achieve weight losses of at least 20% (45% vs 24%, P=0.022), 25% (28% vs 8%, P=0.005), and 30% (18% vs 4%, P=0.015) by month 15.
A total of 40% of women reported any side effects. Gastrointestinal side effects were the most common, occurring in 30% of hormone therapy users and in 43% of those without hormone therapy treatment. Other adverse events didn't differ between the groups and included headache (4%), hypoglycemia (3%), fatigue (1%), and urticaria (1%).
Limitations included possible selection bias since the data reflected only women taking tirzepatide for at least 1 year. Also, the cohort was comprised largely o
Disclosures
The study was supported by the National Institutes of Health and Mayo Clinic Center for Women's Health Research.
Hurtado Andrade reported relationships with Novo Nordisk, the National Institutes of Health, the Mayo Clinic Center for Women's Health Research, and Phenomix Sciences. Co-authors reported relationships with Gila Therapeutics, Phenomix Sciences, the Mayo Clinic, the National Institutes of Health, Vivus Pharmaceuticals, Novo Nordisk, Apollo Endosurgery, Satiogen Pharmaceuticals, Spatz Medical, Rhythm Pharmaceuticals, Regeneron, Boehringer Ingelheim, Era Women's Health Platform, PriMed, AiCME, MedAll, Medscape, Weight Watchers, and Bayer Pharmaceuticals.
Vettor and Watanabe reported relationships with Eli Lilly and Novo Nordisk.
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