Oksana Hamidi, DO, is an associate professor in the division of endocrinology and metabolism at UT Southwestern Medical Center

Crinecerfont Sustains Glucocorticoid Reduction, Improves Cardiometabolic Outcomes in Classic CAH

2-year data from the phase 3 CAHtalyst Adult Study suggest treatment with crinecerfont (Crenessity) enables durable reductions in glucocorticoid (GC) dosing while supporting improvements in weight, body composition, and insulin resistance among adults with classic congenital adrenal hyperplasia (CAH).¹

Endocrine Society (ENDO) Annual Meeting 2026

, the findings extend evidence supporting the December 2024 FDA approval of crinecerfont as an adjunct to GC replacement therapy for patients aged ≥4 years with classic CAH.¹

"We were able to take these supraphysiologic doses and maintain patients on physiologic replacement as early as 24 weeks, and that improvement was maintained even up to 24 months," said study presenter and investigator Oksana Hamidi, DO, associate professor in the division of endocrinology and metabolism at UT Southwestern Medical Center, in an interview with 

. "It's not just a fluke. We saw a persistent, sustained, substantial reduction in glucocorticoid dose, and there was not a significant escape from that."

Durable Glucocorticoid Reduction Maintained Through 24 Months

The analysis included 182 adults with classic CAH enrolled in the CAHtalyst Adult Study (NCT04490915), a phase 3 randomized, double-blind, placebo-controlled trial with an ongoing open-label extension. Investigators evaluated changes in GC dose, body weight, body composition assessed by dual-energy X-ray absorptiometry, and insulin resistance through 24 months of treatment. At baseline, participants had a mean daily GC dose of 17.6 mg/m²/day hydrocortisone equivalents (HCe), corresponding to 32.3 mg/day.¹

Mean GC dose decreased by 37% from baseline to 10.9 mg/m²/day (19.9 mg/day) HCe at month 12 and remained reduced by 38% at month 24, reaching 10.6 mg/m²/day (19.4 mg/day) HCe. According to investigators, these reductions moved participants from clearly supraphysiologic GC exposure toward physiologic replacement levels.¹

Cardiometabolic Improvements Accompany GC Dose Reduction

At baseline, 71% of participants were overweight or obese, defined as a body mass index (BMI) ≥25 kg/m², and 42% had insulin resistance, defined as a homeostatic model assessment of insulin resistance (HOMA-IR) score >2.5. Mean reductions in body weight (-1.8 kg) and BMI (-0.7 kg/m²) observed at month 12 were maintained through month 24.¹

Among participants who were overweight or obese at baseline, 31% achieved >5% body weight reduction at month 12, increasing to 38% at month 24. Body composition analyses showed reductions in fat mass exceeded reductions in lean mass at both time points. By month 24, mean fat mass declined by 1.6 kg compared with a 0.8-kg reduction in lean mass.¹

Investigators also observed sustained improvements in insulin resistance. Mean HOMA-IR reductions from baseline were -0.6 at both months 12 and 24 across the overall study population. Among participants with insulin resistance at baseline, mean HOMA-IR reductions were -1.5 at month 12 and -1.7 at month 24.¹

Adults with classic CAH experience elevated rates of obesity, hypertension, dyslipidemia, and insulin resistance, although the relative contribution of chronic supraphysiologic GC exposure versus androgen excess remains an ongoing clinical question.

Hamidi noted many cardiometabolic complications observed in CAH, including increased fat mass, hypertension, osteoporosis, and insulin resistance, are commonly associated with excessive GC exposure, whereas accelerated bone growth and early puberty are more characteristic of uncontrolled androgen excess.

The findings suggest reductions in GC exposure can be achieved without sacrificing androgen control. As GC doses declined during treatment with crinecerfont, investigators observed concurrent improvements in weight, body composition, and insulin resistance.¹

"As we were able to lower glucocorticoids, while also maintaining control of androgens, we saw improvements in weight, improvements in BMI, favorable improvements in body composition with reduction in fat mass, improvement in lean mass, and improvements in insulin resistance," Hamidi said.

Crinecerfont was generally well tolerated through 24 months, with investigators reporting no new safety signals during long-term treatment.¹

Investigators noted the study was not powered to detect differences between salt-wasting and simple virilizing forms of classic CAH. Hamidi also highlighted the importance of monitoring mineralocorticoid replacement in patients with salt-wasting disease, as reductions in hydrocortisone dosing may increase the need for fludrocortisone supplementation over time.

The open-label extension lacked a placebo comparator, limiting conclusions regarding the direct contribution of GC dose reduction to observed cardiometabolic improvements. However, the findings suggest long-term treatment with crinecerfont may enable sustained reductions in glucocorticoid exposure while supporting favorable cardiometabolic outcomes in adults with classic CAH.¹

Crinecerfont is a first-in-class oral corticotropin-releasing factor type 1 (CRF1) receptor antagonist that reduces adrenocorticotropic hormone-driven adrenal androgen production in classic CAH. The agent received FDA approval in December 2024 for patients aged ≥4 years based on results from the phase 3 CAHtalyst clinical program.³˒⁴

Editor’s Note: Hamidi reports relevant disclosures wi

Neurocrine Biosciences, Xeris Pharma, Camurus, Crinetics Pharmaceuticals, and Recordati Rare Diseases.

Hamidi O, Chalmers LJ, Falhammar H, et al. Crinecerfont improves weight-related outcomes and insulin resistance in adults with classic congenital adrenal hyperplasia: 2-year results from the CAHtalyst Adult Study. Presented at: Endocrine Society Annual Meeting; June 14, 2026; Chicago, IL. Abstract ORF32-07.

Speiser PW, Arlt W, Auchus RJ, et al. Congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(11):4043-4088. doi:10.1210/jc.2018-01865

Neurocrine Biosciences. Neurocrine Biosciences announces FDA approval of CRENESSITY (crinecerfont), a first-in-class treatment for children and adults with classic congenital adrenal hyperplasia. Press release. December 13, 2024. 

https://neurocrine.gcs-web.com/news-releases/news-release-details/neurocrine-biosciences-announces-fda-approval-crenessitytm

Auchus RJ, Hamidi O, Pivonello R, et al. Crinecerfont in classic congenital adrenal hyperplasia in adults. N Engl J Med. 2024;390(20):1865-1876. doi:10.1056/NEJMoa2313917

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Two-year CAHtalyst data show crinecerfont sustained glucocorticoid reduction and improved metabolic outcomes in classic CAH.


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Elena Christofides, MD, is the chief executive officer of Endocrinology Associates, the scientific and medical advisor for Sparrow Pharmaceuticals, and a clinical associate professor at the Ohio University Heritage College of Osteopathic Medicine.

HPA-Axis Assessment Allows for Improved Corticosteroid Response Analysis

According to recent research, dual-dose cosyntropin testing effectively provides a practical framework for hypothalamic-pituitary-adrenal (HPA) axis safety assessment in a non-endocrine corticosteroid trial.

 in Chicago, Illinois, by Elena Christofides, MD, the chief executive officer of Endocrinology Associates, scientific and medical advisor for Sparrow Pharmaceuticals, and a clinical associate professor at the Ohio University Heritage College of Osteopathic Medicine, effectively provide clinicians with a way of monitoring HPA-axis safety and differentiating treatment-emergent suppression from adrenal dysfunction.

“The difficulty in this trial, like in any steroid trial in any non-endocrine condition, is the risk of adrenal suppression,” Christofides told 

 in an exclusive interview. “My job as the safety endocrinologist was to design a protocol to assess safety and avoid adrenal suppression during the course of the trial.”

The HPA axis is intrinsically associated with the body’s physical reaction to stress. Following a moment of severe stress, the axis – which includes the hypothalamus, pituitary gland, and adrenal glands – is activated to return the body to homeostasis. It releases a series of corticotropic hormones, leading to the synthesis and secretion of glucocorticoids, mineralocorticoids, and adrenal androgens.

However, in trials involving corticosteroids outside of an endocrine specialty, baseline HPA-axis status is rarely considered relevant. This limits clinicians’ ability to determine the full effects of corticosteroids on the patients, as adrenal dysfunction and standard, treatment-emergent suppression may present similarly. To this end, Christofides and colleagues undertook the present study, titled CESSA.

CESSA was a randomized, double-blind, placebo-controlled study in adults with ulcerative colitis of the rectum. A total of 200 patients were randomly assigned to either next-generation hydrocortisone acetate (ngHCA) 90 mg once daily or twice daily, or to placebo. Patients were not permitted to use alternative corticosteroids.

The team initially used standard-dose 250 µg cosyntropin to filter out primary adrenal insufficiency. Follow-up safety visits utilized 1 µg cosyntropin at days 29, 39, and, if indicated, 53. Additionally, investigators conducted pharmacokinetic sampling for plasma corticosteroid levels on days 1, 15, and 28.

Of the 200 participants initially included and randomized, 25 were referred for targeted safety follow-up. Overall, 104 patients showed alterations to the HPA axis during the study; of these, 3 placebo recipients had persistent secondary adrenal suppression requiring endocrinology referral, which showed non-study corticosteroid exposure. All patients who were administered active study drug recovered HPA-axis function by the end of the safety period at day 53.

While the trial’s results ultimately included potential confounding for both safety and efficacy assessments, Christofides and colleagues determined that this study provided an effective framework to help address a significantly overlooked risk in patients assigned to receive corticosteroid treatment.

“We’re in need of more precise drug therapy metrics so that we can track that during a PK study,” Christofides said. “My preference would be if we could have some sort of continuous metabolic monitor where we’re measuring cortisol constantly, and we know what the patient’s endogenous cortisol rhythm is going into a trial – it would not be hard to then extrapolate whether their cortisol rhythm is expected based on the drug pharmacokinetics or not.”

Editors’ Note: Christofides reports disclosures with Ascendis, Eli Lilly, Novo Nordisk, Recordati, Corcept, Crinetics, and others.

Christofides E, Ensign M. Dual-dose Cosyntropin Stimulation Testing to Assess HPA-axis Safety and Identify Non-Study Corticosteroid Exposure in a Phase 3 Ulcerative Colitis Trial. Abstract presented at the Endocrine Society (ENDO) Annual Meeting 2026, Chicago, IL. June 13-15, 2026.

Joseph DN, Whirledge S. Stress and the HPA Axis: Balancing Homeostasis and Fertility. Int J Mol Sci. 2017;18(10):2224. Published 2017 Oct 24. 

Elena Christofides, MD, discusses her recent analysis of patients with ulcerative colitis receiving corticosteroids.

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Brian E. Lacy, PhD, MD, a board-certified gastroenterologist at the Mayo Clinic in Jacksonville.

Abdominal Pain and Bloating: When to Consider HAE, MCAS, and EGIDs

Abdominal pain and bloating rank among the most common complaints in clinical medicine and the hardest to pin down.

and immunologists, the challenge is knowing when to step in and what to look for when traditional GI workups come back unremarkable. Conditions including hereditary angioedema (HAE), mast cell activation syndrome (MCAS), and eosinophilic GI disorders can all present with episodic abdominal symptoms, yet they remain low on the radar of most primary care providers and even gastroenterologists seeing these patients first.

The topic was among those addressed at the 

 spoke with presenter Brian E. Lacy, PhD, MD, a board-certified gastroenterologist at the Mayo Clinic in Jacksonville, about how he approaches this differential from the gastroenterology side and where collaboration with allergy and immunology becomes essential.

When a patient presents with intermittent bloating and no clear etiology, Lacy organizes the differential around 5 major causes: dietary indiscretion such as lactose or fructose excess, constipation, intestinal methanogen overgrowth or SIBO, visceral hypersensitivity as seen in IBS and functional dyspepsia, and abdominophrenic dyssynergia, a motility disorder in which patients become severely bloated after eating and often describe looking pregnant.

He noted that abdominal pain requires a separate framework. He said that he breaks it down into new-onset versus chronic abdominal pain to help clinicians narrow down the impacted pathway.

HAE is typically the last condition a clinician thinks to check for. Because the condition affects roughly 1 in 50,000 people, it sits well below more common diagnoses on most clinicians' working lists. Rather, clinicians will often look for more prevalent conditions, such as an ulcer, a hernia, or new-onset inflammatory bowel disease.

After standard workup fails to produce a diagnosis, Lacy said that a clinician should start thinking about allergic etiologies. Clinically, HAE abdominal attacks tend to present as discrete episodes separated by symptom-free intervals, with significant bloating and distension and, crucially, dilated intestinal loops on imaging.

"Usually, the diagnostic test, some imaging study, sets a light bulb off in a lot of clinicians' heads that something else is going on,” he said.

MCAS presents a related but distinct diagnostic challenge. Lacy cautioned that despite growing patient awareness of the condition, true MCAS is uncommon. He uses episodic symptom patterns and multi-organ involvement as the primary clinical filters.

"When somebody reports daily abdominal pain or daily bloating, that is not likely to be MCAS," he said. "They should have episodes separated in time by where they don’t have symptoms, [and] they should have at least two different organ systems involved.”

He noted that skin and GI tract symptoms are a classic pairing. If a patient has these episodes, Lacy recommends checking the serum tryptase to ensure it is above baseline.

For eosinophilic GI disorders, the diagnostic gap lies largely in procedural practice. Because the mucosa can appear grossly normal on endoscopy, the condition is frequently dismissed after a "normal" scope. Lacy stressed that gastroenterologists need to take multiple biopsies across GI segments and alert the pathologist in advance to stain specifically for eosinophils—and for mast cells when MCAS is also on the table.

"There has to be a heightened sense of awareness and…good communication with the person doing the procedure [and] the pathologist,” he said.

Editor’s note: Relevant disclosures for Lacy include Ardelyx, Salix Pharmaceuticals, and IRONWOOD PHARMACEUTICALS.

Upper Abdominal Pain. Cleveland Clinic. Accessed June 15, 2026. 

https://my.clevelandclinic.org/health/symptoms/24736-upper-abdominal-pain

Lacy B. Evaluation and Management of Intermittent Abdominal Pain and Bloating. Poster presented at the Eastern Allergy Conference (EAC) in Palm Beach, Florida, on May 29. 

Gastroenterologist Brian Lacy, MD, PhD, discusses how to differentiate HAE, MCAS, and eosinophilic GI disorders in patients with unexplained abdominal pain and bloating.

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Alex Hillenbrand is an assistant editor for 

. She earned her BA in English from Lafayette College in 2023 and went on to write for pop culture, entertainment, and sports media outlets before joining MJH Life Sciences in 2025. In her free time, Alex enjoys cooking, going on walks, and meeting new people. Contact her at mjhlifesciences.com.

In a real-world study of 36,647 adults receiving injectable semaglutide (Wegovy), investigators identified baseline factors associated with weight loss trajectories, including sex, cardiometabolic comorbidities, and prior challenges with weight consistency.

Endocrine Society (ENDO) 2026 Annual Meeting

 in Chicago, Illinois, by senior author Hans Johnson, MBChB, MRes, MSc, of the University of Bristol, and co-authors from Voy and Boston Children’s Hospital. The study aimed to characterize real-world patterns of weight loss ancand identify factors that may inform individualized prediction tools.

“Whilst weight loss outcomes with injectable semaglutide are well characterised in randomised trials, emergent evidence suggests that the magnitude of weight loss with GLP-1 receptor agonists may be associated with baseline comorbidities,” wrote Johnson and colleagues. “Understanding factors associated with weight loss outcome variation could inform the development of individualised prediction tools.”

Investigators conducted a retrospective open cohort analysis of adults initiating injectable semaglutide through a UK-based digital weight loss service. Cox proportional hazards models and mixed-effects models were used to evaluate factors associated with weight loss outcomes. Data extraction occurred in November 2025.

The final analysis cohort included 36,647 adults with a mean age of 45.76 years. Of these, 7,077 (19.31%) had 6-month follow-up data and 2,329 (6.36%) had 12-month follow-up data available.

Women were more likely than men to achieve ≥20% total body weight loss at 12 months (Hazard Ratio [HR], 1.93; 

Several baseline comorbidities were associated with a lower likelihood of achieving ≥20% total body weight loss at 12 months, including diabetes (HR, 0.71; 

 <.001), hypertension (HR, 0.76; P <.001), and sleep apnea (HR, 0.62;

 <.001). No significant associations were observed for metabolic dysfunction-associated fatty liver disease or asthma.

In multivariate mixed-effects models evaluating 12-month weight loss trajectories, prior challenges with weight consistency, erectile dysfunction, polycystic ovary syndrome, and sleep apnea were significantly associated with lower percentage weight loss during semaglutide treatment.

Investigators noted that baseline clinical and behavioral factors may help “pattern” weight loss responses in real-world semaglutide use. They added that factors influencing treatment persistence may also contribute to observed variability in outcomes, representing a potential source of bias. Future research should consider integrating these variables into clinical prediction tools to support counseling, goal setting, and treatment decision-making.

“Future research should consider integrating these factors into clinical prediction tools to provide individualised estimates of the benefits of semaglutide. These could be beneficial for counselling, expectation/goal setting and treatment decisions,” investigators concluded.

Johnson H, Clift AK, Reisel D, Huang D, Reis B. Baseline predictors of real-world weight loss outcomes with injectable semaglutide: cohort analysis of over 36,000 individuals. Poster presented at: ENDO 2026 Annual Meeting; June 14, 2026; Chicago, IL.

Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. 

 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183

Articles

A retrospective open-cohort analysis of 36,647 adults initiating injectable semaglutide via a UK digital weight-loss service evaluated baseline predictors of real-world weight-loss trajectories. Follow-up was limited (19.3% at 6 months; 6.4% at 12 months). Female sex was associated with higher likelihood of achieving ≥20% total body weight loss at 12 months, whereas diabetes, hypercholesterolemia, hypertension, and sleep apnea were associated with reduced likelihood. Mixed-effects modeling also linked prior weight-consistency challenges and select comorbidities to attenuated 12-month percentage weight loss.

Baseline characteristics, including sex and comorbidities, were associated with semaglutide weight loss outcomes in >36,000 adults.


Sex, Comorbidities Linked to Semaglutide Weight Loss Trajectories

A pooled analysis of the phase 3 SKYLIGHT 1, 2, and 4 trials found low rates of central nervous system (CNS) adverse events with fezolinetant (Veozah), a selective neurokinin 3 (NK3) receptor antagonist approved for moderate to severe menopausal vasomotor symptoms (VMS).

Presented at the Endocrine Society (ENDO) Annual Meeting 2026 by Marla Shapiro, C.M., CCFP, MHSc, FRCPC, FCFP, MSCP, Professor in the Department of Family and Community Medicine at the University of Toronto, the analysis included > 3100 women followed for up to 52 weeks.

Rates of CNS adverse events were low and generally similar between fezolinetant and placebo, with no signal for depression, memory impairment, somnolence, abuse liability, or suicidal ideation or behavior. The findings help address questions about CNS safety that have accompanied fezolinetant since its introduction as the first non-hormonal, non-gabapentinoid treatment for VMS, given its central action within the hypothalamus.

The HCPLive content team spoke with Shapiro about the findings, their clinical relevance, and what they mean for women who cannot or choose not to use menopausal hormone therapy.

: Can you provide a brief overview of your study and its findings?

Shapiro: What this looked at was the central nervous system safety effect of this NK3 antagonist, fezolinetant. Looking at all the data that we have out there, we looked at several things in terms of treatment-emergent adverse events, which were things like headache, dizziness, fatigue, and somnolence. I'm often asked about things like brain fog, which is a very popular term, but not a term that we actually can tease out — that may come in under things like effect on memory, which is another CNS safety adverse event that we looked at.

When we looked at these treatment-emergent adverse events, be they headache, dizziness, fatigue, or somnolence, what we found was that compared to our placebo group, or our 45 mg treatment — that's our on-label dose, which came to North America and everywhere all over the world — there was really no significant differences in the drug-related treatment-emergent adverse events in each of those categories. For example, if you look at things like headache in our placebo group, of about the 7.5 to 8% that we saw, about less than 3% were thought to be related to the drug as adjudicated by our adjudicators. If you look at fezolinetant, you see the exact same thing — the same treatment-emergent adverse events of headaches were about 8.2%, but only 2.3% were thought to be related to the drug. The same is true for dizziness, fatigue, and somnolence.

One thing that's really important is that the incidence of these effects — whether they're fatigue or dizziness or headache or somnolence or mood changes — they really did not lead to treatment withdrawal. We also did the Columbia Suicide Severity Rating Scale, and there was really no treatment effect of fezolinetant on suicidal ideation or behavior. So really, when we look at the safety-reported events in any of the treatment arms, including the 30 mg that didn't come to market, what we saw was a remarkable similarity between all of them. There really was nothing that we saw in any of the exposure-adjusted incidence rates in these particular areas that were identified as so-called central nervous system safety concerns.

: Fezolinetant represents a different therapeutic approach for vasomotor symptoms, targeting neurokinin 3 receptors rather than estrogen pathways. What motivated the need to specifically examine central nervous system safety, and what were the key concerns clinicians had when this mechanism was introduced?

Shapiro: Whenever this is our first on-label, non-hormonal option, understanding what hot flashes and vasomotor symptoms are — we now understand the relationship between stimulation and antagonism of both estrogen and neurokinin B at the level of the KNDy neuron. We now understand that when estrogen is withdrawn in menopause, you get overstimulation of the KNDy neuron because of the neurokinin impact in terms of the receptor. So the notion of developing a drug with a targeted mechanism of action is very exciting for women who cannot, will not, or do not want to use menopausal hormone therapy, which typically has been used as the on-label gold standard.

This represents novel science and on-label new therapeutics. And I think that when a new therapeutic comes, everybody wants to know the same thing: does it work? Is it safe? Does it work? Yes — we saw marked reductions as early as one week in both the frequency of hot flashes and, of the residual hot flashes, the severity. So now you want to know, what about safety? And people say, well, this is a brain mechanism, this is working in the brain. So are there CNS safety signals we should be aware of, because we're talking about the hypothalamus and the medial preoptic nucleus, which is where these receptors are. So it was important to be able to do the data work to look at the typical CNS safety signals that one would expect — things like fatigue, dizziness, headache, and somnolence. We wanted to make sure there was no signaling or alarm telling us that there are CNS events here that are impacting these women, particularly when it comes to, for example, next-day somnolence, or next-day fatigue, or dizziness, or headache. And it's very reassuring that, particularly in the placebo and the fezolinetant 45 mg, which is the dose that came to market, we really do not see any treatment-emergent adverse events related to the medication versus placebo.

: This pooled analysis of SKYLIGHT 1, 2, and 4 included more than 3,000 women and found similar rates of CNS adverse events across groups. Which findings do you consider most clinically meaningful?

Shapiro: I think what's clinically meaningful is all of it. If we look at things like effect on memory — women often talk about brain fog, and that's one of the things they worry about. You want to make sure that the medication you're using is not exacerbating what one typically associates with menopause, and even late perimenopause. The fact that there was no change in depression, no change in dizziness or headache, or next-day fatigue or somnolence — these are critical for us to be able to say to women that the things you're concerned about, in terms of quality of life, are not going to be exacerbated by the medication you're using.

We know this medication will separate out very quickly in terms of responders. As early as week one, we saw a 61% reduction in the frequency of hot flashes, and then of the residual hot flashes that remain, we saw marked decreases in severity. So being able to answer the questions about safety is very important for women. They want to know: does it work? Is it safe? Those are the two big questions that everybody has.

: How do these safety findings affect your approach when considering fezolinetant for women who cannot or prefer not to use menopausal hormone therapy?

Shapiro: The elegant science behind the NK3 antagonist is just so exciting, because it allows us to understand the mechanism of action of what a hot flash and a night sweat actually is. We never knew that before. By having this very elegant science — recognizing that when estrogen is removed, the agonist activity on the KNDy neurons means that having antagonists at the NK3 receptors blocks this overstimulation, and therefore makes a difference in hot flashes and night sweats — is just so exciting.

For many women who are either a hormone caution or a hormone contraindication, but also women who see themselves as not wanting menopausal hormones as their therapeutic option, this opens the doorway to an effective medication. And having safety data allows us to say safe and effective — which is the goal of any new therapeutic.

: Are there particular patient populations — such as women with a history of mood disorders, sleep disturbances, or sensitivity to CNS-active medications — where these data are especially relevant?

Shapiro: One would imagine that when you identify that population, you want to make sure you're not going to give them a medication that's going to exacerbate something that may be pre-existing. These are not contraindications to using the medication, and the fact that these were not exclusion criteria for women who entered into the study is meaningful. Given the large number of women in the study and the randomization, you often have women with these concerns already represented. It's very difficult to tease them out because they're non-entrance criteria.

So one would imagine that if we do not see a difference in any of these red-flag events in either the placebo group or the pooled analysis of SKYLIGHT 1, 2, and 4 — which is a very large, representative sample of women in that age group — I think that we can be very reassured.

In clinical practice, many menopausal symptoms overlap with mood changes, sleep disruption, and cognitive concerns. How should clinicians distinguish underlying menopausal symptoms from potential treatment-related effects when evaluating these patients?

Shapiro: The first question before that question is, how do we evaluate women to know whether something is related to a menopause symptom or is it comorbid and pre-existing — and often that's very difficult to do. For many women who come in with multiple symptoms, many of which may or may not be exacerbated by menopause, what we talk about is: what is our goal of treatment? Our goal of treatment is usually, in women who are having 30, 40, 50 hot flashes, to reduce the frequency and the severity so that they can be in the workplace, not be disrupted in their activities of daily living.

So I think that's what we focus on, and to be able to say to them that we don't have any evidence that this medication will exacerbate any of these underlying symptoms. We'll have to see — as your hot flashes and night sweats get better, does your mood get better? We know from the PROMISE data that there is improvement in sleep. Does the improvement in sleep improve some of these other symptoms, or are they really comorbid conditions that merit treatment in and of themselves, separate from their hot flashes and sweats?


Editor’s Note: Shapiro reports relevant disclosures with Astellas Pharmaceuticals and others. 

Shapiro M. Central Nervous System Safety of Fezolinetant From Pooled Analysis of 52-Week, Phase 3 Studies (SKYLIGHT 1, 2, and 4). Presented at: ENDO 2026; June, 2026; Chicago, IL.

Safety of Fezolinetant for Treatment of Moderate to Severe Vasomotor Symptoms Due to Menopause: Pooled Analysis of Three Randomized Phase 3 Studies.

 Adv Ther. 2025;42:1147-1164. doi:10.1007/s12325-024-03073-8.

Pooled phase 3 data from SKYLIGHT 1, 2, and 4 (>3100 women; up to 52 weeks) showed low, placebo-like rates of CNS adverse events with fezolinetant 45 mg. Headache, dizziness, fatigue, and somnolence were uncommon and rarely adjudicated as drug-related, with minimal impact on discontinuation. No signals emerged for depression, memory impairment/“brain fog,” abuse liability, or suicidal ideation/behavior on C-SSRS. These findings mitigate concerns related to hypothalamic NK3 antagonism while supporting a rapid-onset, nonhormonal option for vasomotor symptoms.

Fezolinetant's CNS safety Profile Reassures Across More Than 3,000 Women in Pooled Phase 3 Analysis at ENDO 2026

Fezolinetant Shows No CNS Safety Signal in Pooled Analysis of 3100 Women, With Marla Shapiro, CM

Elena Christofides, MD, discusses the interim results of CAPTAIN-T2D, a trial that plans to evaluate clofutriben’s efficacy in these patients.

Type 2 Diabetes

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CAPTAIN-T2D: Interim Results Display High Cortisol Prevalence in Difficult-to-Control T2D

David Fleischer, MD, professor of pediatrics at Children’s Hospital Colorado.

Phase 3 VITESSE subgroup data show response rates of 46% to 48% in children with peanut allergy and concomitant asthma, atopic dermatitis, or food allergies, says David Fleischer, MD.

Food Allergy

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VIASKIN Peanut Patch Efficacy Holds in Kids With Atopic Comorbidities

Experts introduce the 2026 AACE type 2 diabetes algorithm’s new classification pathway and frame misclassification—especially of adult-onset type 1 diabetes—as a central problem the update is designed to address.

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Rethinking “Type 2”: Inside the 2026 AACE Diabetes Classification Algorithm

Michelle Min, MD, MSCi, is an associate professor and serves as the director of Rheumatologic Dermatology at the UC Irvine School of Medicine.

In her SDPA interview, Min discusses dermatology and rheumatology collaboration, exploring treatment options for connective tissue disease.

Diagnostic Pearls and New Therapies in Connective Tissue Disease, With Michelle Min, MD

Elif Oral, MD, is a professor in the Division of Metabolism, Endocrinology, and Diabetes at the University of Michigan.

Elif Oral, MD, discusses the clinical implications of the recent data emphasizing metreleptin’s anti-drug antibodies and their llack of impact on efficacy.

Dyslipidemia

Implications of the Phase 4 Trial of Metreleptin in Patients With General Lipodystrophy

ENDO 2026 data suggest tirzepatide may improve renal transplant eligibility in patients with T2D, CKD, and severe obesity. 

Tirzepatide (Zepbound) Improves Kidney Transplant Eligibility in T2D and CKD With Severe Obesity

Elif Oral, MD, discusses her recent presentation at ENDO 2026 covering a phase 4 trial of the immunogenicity of metreleptin in this rare disease.

Metreleptin-Neutralizing Antibodies Do Not Impact Treatment Outcomes in Generalized Lipodystrophy

At ENDO 2026, findings suggest SBP reductions in adults with diabetes are driven by weight loss, not GLP-1 therapy type.


Type 1 Diabetes

Weight Loss, Not GLP-1 Therapy, Predicts Systolic Blood Pressure Change in Diabetes 

This SDPA interview highlights the connection between dermatology and rheumatology, noting diagnoses that can be challenging for rheumatologists.

Key Diagnostic and Therapeutic Pearls for Connective Tissue Disease, With Michelle Min, MD

Ryan Livingston joined the MJH Life Sciences team in March of 2025, shortly after graduating from TCNJ with a bachelor’s degree in English. He enjoys creative writing, reading, and scuba diving. He can be reached at rlivingston@mjhlifesciences.com.

New data presented at ENDO 2026 have indicated substantially lower basal insulin and bolus insulin dose requirements in this population following discharge.

Heart Failure

The HCPLive heart failure page is a resource for medical news and expert insights on HF. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments for heart disease, reduced and preserved ejection fraction, and more.

Latest News

Crinecerfont Sustains Glucocorticoid Reduction, Improves Cardiometabolic Outcomes in Classic CAH

HPA-Axis Assessment Allows for Improved Corticosteroid Response Analysis

Abdominal Pain and Bloating: When to Consider HAE, MCAS, and EGIDs

Sex, Comorbidities Linked to Semaglutide Weight Loss Trajectories

Fezolinetant Shows No CNS Safety Signal in Pooled Analysis of 3100 Women, With Marla Shapiro, CM