Expert panelists discuss the essential role of primary care in early skin cancer detection, balancing clinical judgment with emerging AI artificial intelligence tools, and more.

Primary Care’s Role in Skin Cancer Detection

Why Do Women Suffer in Silence with Genitourinary Syndrome of Menopause?

 (GSM), yet only about 25% seek treatment for their symptoms.

This striking gap between symptom prevalence and treatment-seeking behavior represents a significant quality of life issue for millions of women navigating menopause.

at The Menopause Society 2025 Annual Meeting in Orlando, Caroline Mitchell, MD, MPH, associate professor of obstetrics, gynecology, and reproductive biology at Harvard Medical School, discussed the barriers that prevent women from getting help for GSM symptoms. Mitchell identifies a troubling cycle: many women believe their symptoms are simply an inevitable part of aging that they must endure, remaining unaware that effective treatments exist. Compounding this problem, health care practitioners often fail to ask about these symptoms during routine visits.

"I think we don't ask, and people don't tell," Mitchell explained, pointing to the dual nature of this communication breakdown. She notes that even when women intend to discuss their symptoms, GSM concerns often fall lower on the priority list during busy clinical appointments. The combination of patient embarrassment, lack of awareness about available treatments, and providers' failure to initiate these conversations creates a perfect storm of underdiagnosis and undertreatment.

Mitchell's insights underscore the need for both patient education about GSM treatment options and proactive screening by healthcare providers to ensure women receive the care they need for these common and treatable symptoms.

The following transcript was edited lightly for flow. 

 Between half and two thirds of post-menopausal women experience the symptoms, but only about a quarter seek treatment. What do we know about the reasons for that? 

I think one reason is that in surveys where people have been asked, "Have you spoken with your doctor? And if not, why not?" a significant number of people say, "Well, I thought it was just something I had to deal with. This is just part of life." They are unaware that there are treatments available, that there are interventions that could change that experience. I also think we as providers don't always ask, and many people are not comfortable bringing it up, or it's like one of a list of things, and it seems lower on the list, or people are less comfortable. And so at the end of the visit when you're, you know, walking out of the door, and so it never gets mentioned. So I think we don't ask, and people don't tell.

Shifren JL, Monz BU, Russo PA, Segreti A, Johannes CB. Sexual problems and distress in United States women: prevalence and correlates. 

. 2008;112(5):970-978. doi:10.1097/AOG.0b013e3181898cdb

Kingsberg SA, et al. Vulvar and vaginal atrophy in postmenopausal women: findings from the REVIVE (REal Women's VIews of Treatment Options for Menopausal Vaginal ChangEs) survey. 

. 2013;10(7):1790-1799. doi: 10.1111/jsm.12190

Videos

Menopause specialist Caroline Mitchell, MD, MPH, explains the dual nature of the breakdown in communication that can leave women virtually uninformed about GSM and treatment. 

Why Do Women Suffer in Silence with Genitourinary Syndrome of Menopause? 

Mazdutide, an investigational glucagon-like peptide-1 (GLP-1) and glucagon (GCG) dual receptor agonist, significantly outperformed 

 in achieving combined glycemic and weight loss targets in patients 

, according to results from the first-of-its-kind phase 3 DREAMS-3 trial announced by Innovent Biologics on October 26, 2025.

Courtesy of Peking University Health Science Center 

The trial met its primary endpoint, with 48.0% of participants in the mazdutide group achieving both HbA1c less than 7% and 10% or more reduction in body weight from baseline at 32 weeks,

 compared to 21.0% in the semaglutide group (

 <.001). DREAMS-3 represents the world's first phase 3 head-to-head comparison of a GLP-1/glucagon dual receptor agonist against semaglutide in diabetes treatment.

Investigators enrolled 349 Chinese adults with early-stage T2D (duration less than 10 years) and obesity whose glycemic and weight control remained inadequate after lifestyle intervention with or without metformin monotherapy.

 Participants had a mean age of 42.4 years, mean baseline HbA1c of 8.02%, mean body weight of 90.47 kg, and mean BMI of 32.98 kg/m².

Participants were randomly assigned to receive either mazdutide 6 mg or semaglutide 1 mg for 32 weeks in an open-label, multicenter trial. The mazdutide arm then continued into an extension period with different doses for another 24 weeks based on whether participants achieved their weight loss targets.

At week 32, mazdutide demonstrated superior efficacy across multiple metabolic parameters. The mean HbA1c reduction from baseline reached -2.03% in the mazdutide group versus -1.84% in the semaglutide group (p<0.05). Mean percentage weight reduction measured 10.29% with mazdutide compared to 6.00% with semaglutide (

"As the world's first approved GCG/GLP-1 dual receptor agonist, mazdutide has demonstrated superior efficacy in glucose lowering and weight loss over semaglutide in the latest phase 3 clinical trial," Professor Linong Ji, principal investigator of DREAMS-3 at Peking University People's Hospital, said in a statement.

 "Mazdutide also provides multiple metabolic benefits and has a favorable safety profile, making it a new-generation GLP-1-based therapy suitable for Chinese patients."

The overall safety profile of mazdutide was consistent with previous clinical studies, according to Innovent. Researchers identified no new safety signals. The most common adverse events were gastrointestinal symptoms, with  investigators reporting these as mostly mild to moderate in severity.

Lead investigator Ji emphasized the clinical importance of dual metabolic targets in this patient population. "Among the vast population with T2D in China, the proportion of those with comorbid obesity has been increasing," he noted. "Previous studies have indicated that, compared with non-obese patients with diabetes, patients with T2D and comorbid obesity experience more challenging glycemic control, along with a significant increase in cardiovascular mortality risk and overall cardiovascular disease risk."

Mazdutide functions as a mammalian oxyntomodulin analogue. Beyond the effects of GLP-1 receptor agonists on promoting insulin secretion, lowering blood glucose, and reducing body weight, mazdutide may also increase energy expenditure and improve hepatic fat metabolism through glucagon receptor activation. Clinical studies have shown the agent reduces waist circumference, blood lipids, blood pressure, serum uric acid, liver enzymes, and liver fat content while improving insulin sensitivity.

Innovent plans several additional clinical studies of mazdutide, including trials in adolescents with obesity, metabolic dysfunction-associated steatohepatitis, heart failure with preserved ejection fraction, and a higher-dose head-to-head study versus tirzepatide in moderate to severe obesity.

Specifically, the company has completed or is conducting 7 phase 3 clinical trials: 

GLORY-1, GLORY-2, and GLORY-3 for obesity and overweight

GLORY-OSA for obstructive sleep apnea with obesity

 DREAMS-1, DREAMS-2, and DREAMS-3 for T2D 

GLORY-1, DREAMS-1, DREAMS-2, and DREAMS-3 have already met their primary endpoints, the company said. 

Innovent’s Mazdutide shows superiority in glycemic control with weight loss over semaglutide in head-to-head phase 3 clinical trial DREAMS-3. News release. Innovent Bio. October 28, 2025 Accessed October 29, 2025.  https://en.innoventbio.com/InvestorsAndMedia/PressReleaseDetail?key=558 

A study comparing IBI362 vs semaglutide in Chinese adults with early type 2 diabetes and obesity. ClinicalTrials.gov identifier: NCT06184568. Updated January 15, 2025. Accessed October 28, 2025. https://clinicaltrials.gov/study/NCT06184568?intr=IBI362%20&rank=6

Articles

The phase 3 DREAMS-3 trial is the fist phase 3 head-to-head comparison of a GLP-1/glucagon dual receptor agonist against semaglutide in diabetes treatment.

Mazdutide Demonstrates Superior Glycemic Control and Weight Loss vs Semaglutide in Head-to-Head Trial 

 agent valiltramiprosate (ALZ-801) significantly slowed 

ε4 allele, the strongest genetic risk factor for 

 The findings, from the phase 3 APOLLOE4 clinical trial, were recently published in the journal 

, according to valiltramiprosate developer Alzheon.

In the 78-week trial, participants with mild cognitive impairment (MCI) due to AD who received valiltramiprosate showed 52% slower cognitive decline and nearly complete preservation of functional ability compared with participants who were treated with placebo. Imaging results supported these findings, with hippocampal atrophy slowed by 26% in the MCI group and 18% in the overall population.

“Despite the progress in approved therapies for [Alzheimer] disease, there remains a major unmet need for treatments that combine safety, efficacy, and access,” Susan Abushakra, MD, Alzheon chief medical officer and principal investigator of the trial, said in a statement.

 “Prespecified analyses demonstrated clinically meaningful benefits at the MCI stage, along with large and consistent slowing of brain atrophy—key indicators of neuroprotection.”

ε4) allele, the strongest genetic risk factor for AD, is found in approximately 15% of people with the disease, and confers an 8- to 12-fold higher lifetime risk for AD and accelerates progression.

 Individuals who are homozygous for the gene accumulate high levels of soluble beta-amyloid (Aβ) oligomers, recognized as the most neurotoxic amyloid species, long before plaque formation.

Current antiamyloid antibodies (AAA) target plaques but carry amyloid-related imaging abnormality (ARIA) rates of approximately 33% to 41% in 

ε4 homozygotes; treatment frequently requires extensive MRI safety monitoring and infusion centers.

 Valiltramiprosate, by contrast, is an oral, brain-penetrant small molecule that blocks Aβ monomers from aggregating into oligomers, acting upstream in the amyloid cascade.

“Our goal was to neutralize the earliest toxic Aβ assemblies before irreversible neuronal injury occurs,” Abushakra said. “The APOLLOE4 trial provides the most comprehensive dataset to date on 

ε4 homozygotes, underscoring our precision-medicine approach to addressing the needs of patients most at risk for Alzheimer’s disease.”

The double-blind, placebo-controlled trial enrolled 325 

ε4 carriers aged 50–80 years in North America and Europe, all with early symptomatic AD (mild cognitive impairment [MCI] or mild dementia). Participants received valiltramiprosate 265 mg twice daily or placebo for 78 weeks. The authors noted that the early AD population in APPOLLOE4 was similar to the cohorts in the pivotal trials of the anti-amyloid antibodies.

Although Abushakra and colleagues reported that the primary endpoint—change in ADAS-Cog13 score in the overall population, did not reach statistical significance, prespecified subgroup analysis of participants with MCI revealed marked benefits

decline in daily function on the Disability Assessment for Dementia (

The magnitude of cognitive effect, the authors said, exceeded the commonly accepted 30% threshold for clinical meaningfulness, suggesting stabilization of function for roughly 18 months.

MRI and diffusion tensor imaging further demonstrated broad neuroprotective effects, including 35% less cortical thinning and 22% less whole-brain atrophy, with tissue integrity preserved across gray and white matter regions.

“The slowing of brain atrophy across multiple regions, combined with meaningful cognitive and functional effects in MCI patients, provides compelling evidence of neuroprotection,” APOLLOE4 investigator Marwan Sabbagh, MD, said in the statement.

Valiltramiprosate demonstrated a favorable safety profile throughout 78 weeks of treatment. The most common adverse effects (AEs) were mild or transient, nausea, decreased appetite, weight loss. Fewer than 5% of participants discontinued treatment as a result of any AEs.

Most importantly, the study team observed no increase in vasogenic brain edema or microhemorrhage. Incidence of ARIA-E was identical between treatment and placebo groups (3.4%), and new microhemorrhages occurred less often with valiltramiprosate.

“The favorable safety profile differentiates valiltramiprosate from other anti-amyloid approaches, especially in 

ε4 homozygotes, who are most susceptible to serious side effects such as ARIA,” Aidan Power, MB, BCh, MRCPsych, Alzheon chief development officer, said.

He added that the results “reinforce valiltramiprosate’s potential to become the first oral agent capable of slowing [Alzheimer] pathology in these genetically distinct patients.”

APOLLOE4 is the largest clinical trial ever conducted in symptomatic 

ε4 patients, according to Alzheon. Its consistent cognitive, functional, and imaging findings—together with the absence of vascular safety issues—support early therapeutic intervention targeting soluble amyloid species, the company said.

Among the study's limitations the authors acknowledged its limited ethnic diversity (89% White) and a smaller-than-planned MCI subgroup (125 participants), but the converging clinical and imaging data suggest a robust treatment signal.

Alzheon has launched an ongoing long-term extension study (APOLLOE4-LTE) to evaluate valiltramiprosate over 3.5 years, as well as a separate phase 2 biomarker trial assessing its effects on phosphorylated tau and other Alzheimer biomarkers.

The results reinforce valiltramiprosate’s potential to become the first oral agent capable of slowing Alzheimer pathology in 

ε4 carriers, a population at high genetic risk and with limited safe treatment options.

Abushakra S, Power A, Watson D, et al. Clinical efficacy, safety and imaging effects of oral valiltramiprosate in APOEε4/ε4 homozygotes with early Alzheimer’s disease: results of the Phase III, randomized, double‑blind, placebo‑controlled, 78‑week APOLLOE4 trial.

. Published online September 28, 2025. doi:10.1007/s40265-025-02250-5 

Alzheon announces peer-reviewed scientific publication of results from pivotal APOLLOE4 Phase 3 trial of oral valiltramiprosate/ALZ-801 in APOE4/4 homozygous individuals with early Alzheimer’s disease. News release. October 14, 2025. Accessed October 28, 2025. https://alzheon.com/alzheon-announces-peer-reviewed-scientific-publication-of-results-from-pivotal-apolloe4-phase-3-trial-of-oral-valiltramiprosate-alz-801-in-apoe4-4-homozygous-individuals-with-early-alzheimers/ 

Saunders AM, Strittmatter WJ, Schmechel D, et al. Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s disease. 

 1993;43:1467–72. doi:10.1212/wnl.43.8.1467.  

Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. 

. 1993;261:921–3. doi:10.1126/science.8346443 

Van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21. doi:10.1056/NEJMoa2212948.  

32. Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. 

 2023;330:512–27. doi:10.1001/jama.2023.13239

Valiltramiprosate is a novel disease modifying therapy designed to inhibit formation of soluble neurotoxic amyloid oligomers, acting upstream in the amyloid cascade. 

Investigational Oral Agent ALZ-801 Slows Brain Atrophy and Cognitive Decline in APOE4 Homozygotes with Early AD 

Chapter 3: neffy (epinephrine nasal spray)

Chapter 5: How to prescribe neffy

Chapter 4: Shared Decision Making in Anaphylaxis Care

When to Use Epinephrine in Anaphylaxis

Chapter 2: How to Improve Epinephrine Preparedness

Chapter 1: When to Use Epinephrine in Anaphylaxis

artificial intelligence (AI)-driven intervention 

based on the Diabetes Prevention Program (DPP) achieved outcomes comparable to traditional human-led programs in helping adults with 

 reduce their risk of progressing to diabetes, according to results from the first phase 3 randomized controlled trial to directly compare the 2 approaches.

, found that 31.7% of participants referred to the AI-powered program and 31.9% referred to human coaching met CDC benchmarks for 

 at 12 months, a difference that met the prespecified criterion for noninferiority. Notably, the AI program demonstrated higher rates of both initiation (93.4% vs 82.7%) and completion (63.9% vs 50.3%) compared with traditional programs, according to the results.

"Even beyond diabetes prevention research, there have been very few randomized controlled trials that directly compare AI-based, patient-directed interventions to traditional human standards of care," Nestoras Mathioudakis, MD, MHS, principal investigator and comedical director of the Johns Hopkins Medicine Diabetes Prevention & Education Program, said in a Johns Hopkins statement.

For the parallel-group, pragmatic noninferiority trial, conducted from October 2021 to December 2024, Mathioudakis and colleagues enrolled 368 middle-aged adults (median age 58 years) with prediabetes and overweight or obesity from 2 US clinical sites in Maryland and Pennsylvania. The cohort was 71% women; 61% self-identified as White, 27% as Black, and 6% as Hispanic.

Participants were randomly assigned to receive referral to either a fully automated AI-powered DPP mobile app powered by reinforcement learning algorithms or 1 of 4 CDC-recognized human coach-led programs. A critical component of the study, according to the authors, the research team did not promote engagement after referral, following up only at 6 and 12 months to assess real-world effectiveness.

Personalized push notifications for weight management, physical activity, and nutrition

Active data collection: weight measurements, meal logging

Passive data collection: geolocation, accelerometry

Fully automated, asynchronous delivery via mobile app

Group video conferences (remote delivery due to COVID-19 pandemic)

16 weekly core sessions followed by biweekly to monthly maintenance sessions

The primary composite outcome required maintaining HbA1c below 6.5% throughout the study plus achieving at least one of the following:

 of weekly moderate-to-vigorous physical activity

Clear Noninferiority for the AI-Based Program

The risk difference of −0.2% (one-sided 95% CI, −8.2%) fell well within the noninferiority margin of −15%, demonstrating the AI program was not worse than human coaching. Individual components of the composite endpoint showed similar directional consistency: 16.9% of AI participants versus 20.0% of human-coached participants achieved 5% weight loss, while 12.6% versus 12.4% achieved the combined weight loss and physical activity target.

"The greatest barrier to DPP completion is often initiation, hindered by logistical challenges like scheduling," study cofirst author Benjamin Lalanim now a medical student at Harvard Medical School, said in the statement.

 "So, in addition to clinical outcomes, we were interested in learning whether participants were more likely to start the asynchronous digital program after referral."

When Mathioudakis, Lalanim, et al reviewed engagement data, they observed distinct patterns between groups. Among AI participants who achieved the primary outcome, 74% were program completers compared with 56% in the human-led group.

 “This suggests intervention exposure may play a more central role in the AI-led DPP, which depends on continuous self-directed engagement,” the team wrote. The structured coach-led formats, on the other hand, may allow participants to benefit with less concentrated time investment.

"Unlike human-coached programs, AI-DPPs can be fully automated and always available, extending their reach and making them resistant to factors that may limit access to human DPPs, like staffing shortages," Lalani said. "So, while the black-box nature of AI is a commonly cited barrier to clinical adoption, our study shows that the AI-DPP can provide reliable personalized interventions."

The study's 85.1% retention rate and alignment with expected community-based DPP outcomes (20% achieving 5% weight loss, within the typical 13.5%-35.5% range) support the validity of the findings and the adequacy of program delivery in both arms.

The findings carry particular significance given that only 3% of US adults with prediabetes currently participate in DPPs, despite an estimated 97.6 million Americans having the condition.

 With approximately 1,549 CDC-recognized DPP programs nationwide, which translates to 1 program per 63,000 adults with prediabetes, scalability remains a critical barrier. Further, the authors cite research showing that only 35% of those referred to a DPP ultimately participate. 

Among the study’s limitations, Mathioudakis and fellow investigators acknowledge the unmasked design, use of surrogate rather than diabetes incidence outcomes, and recruitment of motivated volunteers with high baseline physical activity levels and educational attainment from only two sites, limiting generalizability.

As AI continues to evolve, these findings suggest that fully automated behavioral interventions may offer a viable complement, though not necessarily a replacement, for traditional human-coached diabetes prevention programs, the authors said.

Looking ahead, the study team is interested in exploring how the AI app outcomes they observed translate to broader, underserved, real-world patient populations who may not have the time or resources to engage in traditional lifestyle intervention programs. They emphasize that primary care providers, in particular, may consider AI-led DPPs for patients in need of a lifestyle change program, especially those with considerable logistical constraints.

Mathioudakis N, Lalani, B, Abusamaan MS, et al. An AI-powered lifestyle intervention vs human coaching in the Diabetes Prevention Program: a randomized clinical trial. 

 Published online October 27, 2025. doi:10.1001/jama.2025.19563 

AI-powered Diabetes Prevention Program shows similar benefits to those led by people. News release. Johns Hopkins Medicine. October 27, 2025. Accessed October 27, 2025. https://www.hopkinsmedicine.org/news/newsroom/news-releases/2025/10/ai-powered-diabetes-prevention-program-shows-similar-benefits-to-those-led-by-people 

About prediabetes and type 2 diabetes. CDC National Diabetes Prevention Program. Updated May 15, 2024. Accessed October 27, 2025. https://www.cdc.gov/diabetes-prevention/about-prediabetes-type-2/index.html 

Ackermann RT, O’Brien MJ. Evidence and challenges for translation and population impact of the Diabetes Prevention Program. 


2020;20(3):9. doi:10.1007/s11892-020-1293-4

After 1 year of coaching by the AI app or a DPP-associated coach, reductions in weight and HbA1c and increases in physical activity were equal, an outcome with great promise for scalability. 

AI-Powered Diabetes Prevention Program Intervention Matches Human Coaching in Landmark Trial

A phase 3 clinical trial of estetrol (E4), a naturally occurring estrogen under investigation for the treatment of moderate to severe 

 found no effect on blood pressure after 1 year of treatment, even among women with 

The findings, from the E4COMFORT II trial, were presented by Andrew Kaunitz, MD, of the University of Florida College of Medicine–Jacksonville, and colleagues at the 2025 annual meeting of The Menopause Society, October 21-25. 

E4COMFORT II was a multicenter, 2-part phase 3 study conducted in the United States and Canada that evaluated the efficacy and safety of estetrol 15 mg and 20 mg in postmenopausal 

 All participants had normal baseline blood pressure (equal to or less than 130/80 mm Hg), according to the study abstract.

In the double-blind, placebo-controlled portion of the study, 579 participants were randomly assigned to receive estetrol 15 mg (n=192), estetrol 20 mg (n=193), or placebo (n=194) once daily for 1 year. The open-label safety phase enrolled 430 participants, all of whom received estetrol 20 mg once daily for an additional year.

The investigators analyzed changes in blood pressure from baseline to one year, using analyses of covariance to compare estetrol and placebo groups.

Blood pressure fluctuated only slightly during treatment, with minimal increases observed across all groups, including placebo-treated participants. After 1 year, no statistically significant differences in changes from baseline were found between estetrol-treated participants and those receiving placebo (

 >.05). The absence of blood pressure effects held true regardless of whether women had normal or elevated baseline HbA1c levels.

Cardiometabolic Risk Factors Common at Baseline. 

Although only women with normal baseline blood pressure were enrolled, many participants presented with cardiometabolic risk factors:

HbA1c ≥5.7% (pre-diabetes range): 43.4%

These risk factors were evenly distributed among the treatment groups. Baseline mean blood pressure values were similar, and the presence of higher HbA1c levels did not appear to influence blood pressure outcomes.

A Contrast to Estetrol’s Effects in Younger Women

Estetrol 15 mg is already approved as the estrogenic component in a combined oral contraceptive (COC) with drospirenone 3 mg. That formulation has previously been shown to lower blood pressure in premenopausal women up to age 45 with high-normal baseline levels, by an average of −7.6 mm Hg systolic and −4.0 mm Hg diastolic.

However, the current phase 3 findings in postmenopausal women demonstrate no such blood pressure effect, even at similar or higher estetrol doses and despite the inclusion of women with cardiometabolic risk factors.

The results suggest that estetrol, when used alone for menopausal symptom management, may not alter blood pressure regulation in postmenopausal women, a population in whom cardiovascular safety remains an important consideration in hormone therapy decisions, the authors concluded.

 Phase 3, multicenter, double-blind, placebo-controlled (efficacy) and open-label (safety) trial

: Postmenopausal women aged 40–65 years with normal baseline blood pressure

 Estetrol 15 mg, estetrol 20 mg, or placebo daily for one year

Findings: No significant change in systolic or diastolic blood pressure vs placebo (p>0.05)

 One-year estetrol treatment had no effect on blood pressure, including in women with prediabetes or lipid abnormalities.

Kaunitz A, Kapoor E, Taziaux M, Rezette I, Archer D, Doux. A phase 3 trial of estetrol in postmenopausal women with moderate to severe vasomotor symptoms shows no effect on blood pressure, including in women with cardiovascular risk factors. Poster presented at: The Menopause Society’s 2025 Annual Meeting; October 21-25, 2025; Orlando, FL. Accessed October 24, 2025. 

Lee A, SYed YY. Estetrol/drospirenone: a review in oral contraception. 

2022;82(10):1117–1125. doi: 10.1007/s40265-022-01738-8

The phase 3 E4COMFORT II trial found no impact on BP after 1 year of treatment in postmenopausal women with elevated HbA1c, lipids, and TGs. 