Breaking Down the Science: Mechanisms of Action for New VMS Therapies
Panelists discuss how emerging therapies demonstrate promising efficacy data while highlighting the adverse metabolic and cardiovascular consequences associated with untreated vasomotor symptoms (VMS).
Episode 3
The following transcript has been edited for clarity, style, and length.
Tara K. Iyer, MD: Can you share some of the key efficacy data for these therapies?
Alexa Fiffick, DO, MBS, MSCP: Absolutely. Interestingly, both therapies have very similar study designs and outcomes. One of the most impressive findings from both is their effectiveness over a 12-week period. For example, fezolinetant, at its FDA-approved 45 mg dose, demonstrated a 75% reduction from baseline in vasomotor symptoms, including both frequency and severity. Similarly, elinzanetant also showed statistically significant reductions in symptoms by the end of the 12th week. However, one key difference is that elinzanetant often produced statistically significant improvement by week 4, whereas it may have taken a little longer for fezolinetant patients to experience similar benefits.
Iyer: Excellent. We've discussed this before, but let's share with our audience: What impact do we think offering and initiating treatment could have on long-term outcomes, particularly in vasomotor symptom (VMS) reduction?
Fiffick: I love this question because it gets to the heart of why we, as clinicians, are so passionate about caring for women during menopause and perimenopause. Untreated menopause and perimenopause are associated with adverse cardiometabolic and cognitive outcomes. Women in this stage of life are at increased risk for atherosclerotic heart disease, dementia, stroke, and other metabolic conditions.
I often reference the 2023 study by Dr Rebecca Thurston, which found that even when women weren’t aware of their hot flashes—such as during sleep—clinical monitors detected them. The study showed that the worse a patient's vasomotor symptoms, the more white matter hyperintensities appeared on MRI. For those unfamiliar, white matter hyperintensities are markers of vascular dementia. This suggests that VMS could be contributing to long-term vascular changes in the brain, which may be linked to negative cardiometabolic outcomes.
While it's still early, since these medications have only been available for a few years, we’re hopeful that treating VMS will lead to reduced cardiometabolic risks, including fewer white matter hyperintensities. What are your thoughts on that, Dr Iyer?
Iyer: I completely agree. It's a challenge because, on the one hand, we know how these symptoms impact women’s lives. Patients tell us they feel like they’re "burning from the inside out," and that it significantly disrupts their daily activities—whether at work, during a child's play, at an important meeting, or even while driving. Nighttime symptoms are particularly disruptive, leading to chronic sleep deprivation over months and even years.
But beyond the quality-of-life impact, we also have extensive literature showing that VMS are not just bothersome, they are not physiologically benign. Research has linked them to increased carotid intima-media thickness, carotid and aortic calcifications, endothelial dysfunction, reduced endothelial nitric oxide production, increased insulin resistance, elevated blood glucose levels, and increased heart rate variability. As you mentioned, they are also associated with white matter hyperintensities, and some studies even suggest an increase in urinary N-telopeptide (NTX), a bone turnover marker.
While we don’t yet have long-term data proving that treating vasomotor symptoms directly improves these outcomes, we do know that these symptoms correlate with adverse physiological changes. Given their significant negative impact on a woman's quality of life, it is critical to identify and treat them early. Hopefully, future research will confirm that treatment leads to improved long-term health outcomes, but even now, we know enough to justify prioritizing treatment for these patients.
