A nonhormonal treatment for menopausal hot flashes may offer additional benefits for body composition, according to new research presented at the 2025 American College of Obstetricians and Gynecologists (ACOG) Annual Clinical & Scientific Meeting in Minneapolis.
Fezolinetant, a selective neurokinin-3 receptor (NK3R) antagonist approved for treating moderate to severe vasomotor symptoms (VMS) associated with menopause, demonstrated small but consistent reductions in waist circumference and body roundness index (BRI) over 52 weeks of treatment while maintaining stable weight and BMI.
The findings come from a comprehensive pooled analysis of three phase 3 clinical trials in the SKYLIGHT development program, presented by lead researcher Dr. Nanette Santoro of the University of Colorado Anschutz Medical Campus.
Study Design and Participant Characteristics
The analysis included data from 1,830 postmenopausal women who received fezolinetant for up to 52 weeks across the SKYLIGHT 1, SKYLIGHT 2, and SKYLIGHT 4 trials. Participants in SKYLIGHT 1 and 2 were initially randomized to placebo or fezolinetant (30 mg or 45 mg) for 12 weeks before continuing into an active-treatment extension. SKYLIGHT 4 was designed as a 52-week placebo-controlled safety study.
At baseline, participants had a mean age of 55.3 years, with 65.2% self-identifying as White, 30.3% as Black or African American, 1.8% as Asian, and 2.8% as "Other." The study population had a mean weight of 82.6 kg, mean BMI of 30.4 kg/m², and mean waist circumference of 96.3 cm. Notably, more than half (53.3%) of participants had a BMI ≥30 kg/m².
Key Findings on Body Composition
After 52 weeks of treatment, researchers observed several notable changes in body composition metrics:
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Waist Circumference: Decreased by 0.88 cm (SE 0.24) with fezolinetant 45 mg and by 0.82 cm (SE 0.25) with fezolinetant 30 mg, compared with only 0.15 cm (SE 0.34) in the placebo group.
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Body Roundness Index: BRI, which estimates visceral fat and ranges from 1 to 16 (higher scores indicating wider, rounder bodies), decreased by 0.11 (SE 0.03) with fezolinetant 45 mg and by 0.10 (SE 0.03) with fezolinetant 30 mg, versus a negligible reduction of 0.01 (SE 0.04) with placebo.
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Weight: Remained relatively stable across all groups, with modest mean increases of 0.15 kg (SE 0.18) with fezolinetant 45 mg, 0.23 kg (SE 0.18) with fezolinetant 30 mg, and 0.47 kg (SE 0.22) with placebo.
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BMI: Showed minimal changes of +0.06 kg/m² (SE 0.07) with fezolinetant 45 mg, +0.10 kg/m² (SE 0.07) with fezolinetant 30 mg, and +0.18 kg/m² (SE 0.08) with placebo.
Clinical Significance for Menopausal Women
These findings address important clinical concerns about body composition changes during menopause. Up to 80% of women experience vasomotor symptoms during this transition, which often coincide with unfavorable changes in body composition.
"Both weight gain and increases in and redistribution of total body fat and abdominal fat during the menopausal transition elevate risks for cardiovascular and metabolic conditions," Dr. Santoro explained in an interview. These conditions include insulin resistance, type 2 diabetes, hypertension, and hyperlipidemia.
The observed reductions in waist circumference and BRI, while modest, suggest potential benefits for central adiposity—a key risk factor for cardiometabolic disease in postmenopausal women.
Potential Mechanisms
While the exact mechanism behind these body composition changes remains unclear, Dr. Santoro suggested some possibilities. "We know that fezolinetant improves sleep. It's possible that better sleep could translate into lower cortisol levels and less abdominal fat," she noted.
"Poor sleep is associated with higher risk for metabolic syndrome, including central obesity, elevated blood pressure, dyslipidemia, and insulin resistance. So it's plausible that some of the observed body shape changes could reflect metabolic benefits driven indirectly by improved sleep."
Safety Profile
The safety profile of fezolinetant remained consistent with previous reports. Weight increase was reported as a treatment-emergent adverse event (TEAE) in 0.7% of participants taking fezolinetant 45 mg, 2.0% of those on fezolinetant 30 mg, and 1.1% of participants receiving placebo.
Researchers reported that BMI had no discernible effect on overall safety outcomes, including TEAEs, serious adverse events, and liver biochemistry.
Broader Context and Implications
Fezolinetant is currently approved at a dose of 45 mg once daily for treating moderate to severe VMS in multiple regions worldwide, including North America, Europe, Asia, and Australia. Previous analyses of the SKYLIGHT trials confirmed that fezolinetant significantly improved vasomotor symptom frequency and severity at 4 and 12 weeks compared with placebo.
This new analysis suggests fezolinetant may offer a dual benefit for menopausal women—effectively treating hot flashes and night sweats while potentially helping to maintain favorable body composition during a life stage when metabolic changes often occur.
Dr. Santoro emphasized that while this was a post hoc analysis without formal statistical testing, the findings point to an area worth studying further. "If fezolinetant leads to a reduction in central fat, that would be an important health marker," she concluded.
The results provide clinicians with additional information to consider when discussing treatment options with patients experiencing menopausal symptoms, particularly those concerned about weight gain and body composition changes during this transition.
