This Year in Medicine: Nonhormonal Therapies Transform Hot Flash Treatment in Menopause

In 2025, major shifts to the landscape of non-hormonal therapies available for treating vasomotor symptoms (VMS) in postmenopausal women were reported, the most recent being the FDA approval of elinzanetant (Lynkuet) in this population on October 24, 2025.

Elinzanetant, a neurokinin receptor antagonist, represents a method of treatment which, according to JoAnn V. Pinkerton, MD, division director of midlife health at UVA Health, has begun to reshape the VMS landscape.

 Thermoregulatory instability during menopause has been linked to overactivity in certain hypothalamic neurons caused by declining estrogen levels.

Understanding Neurokinin Receptor Antagonism

These neurons are known as the kisspeptin, neurokinin B, dynorphin (KNDy) system, and by interrupting this process, neurokinin receptor antagonists can reduce the frequency of hot flashes without the use of estrogen. As a dual NK1/NK3 receptor antagonist, elinzanetant may also lead to mood and sleep benefits through substance P pathways.

Ahead of the approval of elinzanetant, fezolinetant (Veozah), another neurokinin receptor antagonist, received FDA approval for treating VMS in postmenopausal women on May 12, 2023.

 By targeting the neurons that cause hot flashes as a nonhormonal option, fezolinetant can provide symptom relief without increasing breast and uterus risks.

Risks associated with hormonal therapies have previously been reported to patients through boxed warnings on the products’ labeling.

 In the Women’s Health Initiative (WHI) trials, increased risks of stroke and breast cancer were reported in patients receiving menopausal hormonal therapy (MHT).

This revelation led to class-wide boxed warnings being added to MHT starting in 2003. However, the FDA noted that WHI participants had an increased age relative to the general population receiving therapy for hot flash relief, increasing their baseline risks.

Compared to the mean age of 51 years in patients starting MHT, dementia findings in the WHI were based on women aged 65 to 79 years. The primary version of hormone therapy has also changed since this data was published, from oral conjugated equine estrogens plus medroxyprogesterone acetate to versions with transdermal estradiol, which reduces venous thrombosis risk.

Based on this information, the FDA announced actions to revise safety labelling for MHT on November 10, 2025. These changes included:

Removing warnings about cardiovascular disease, breast cancer, and dementia

Removing most references to endometrial cancer

Removing recommendations to use the lowest dose for the shortest duration

Currently, warnings about breast cancer risk remain for labeling outside of boxed warnings for systemic therapy. Further research is needed to understand the link between MHT and breast cancer.

“It's important to note that we need more data to make up for the dearth of research in this domain and until we better understand the full impact of MHT on breast cancer risk, women with a personal history of breast cancer remain ineligible for MHT,” said Nora Lansen, MD, chief medical officer at Elektra Health.

Clinical Evidence Supporting Fezolinetant

During the period of boxed warnings for hormonal options, multiple nonhormonal treatments rose in the vasomotor symptom landscape. At the 2023 ACOG Annual Clinical & Scientific Meeting, Genevieve Neal-Perry, MD, PhD, professor at the University of North Carolina at Chapel Hill, presented data regarding the safety and efficacy of fezolinetant.

The study presented included a wide diversity of patients, with 20% being non-caucasian and many identifying as Black. Obese patients were also included, despite often being excluded from hot flash-related research. Among this study population, a nearly 60% decrease in the frequency of hot flashes was reported among patients taking fezolinetant.

According to Neal-Perry, this highlights an opportunity to improve patient quality of life and financial wealth, which data has indicated are both adversely impacted by VMS. Fezolinetant was approved in 2023, making it the first approved nonhormonal therapy to manage these symptoms and support patients impacted by hot flashes.

More recently, elinzanetant was approved following positive phase 3 data from the OASIS program, which highlighted significant safety and efficacy from the medication.

 Positive outcomes included a -73.8% reduction in the frequency of moderate to severe VMS among patients taking elinzanetant between baseline and week 12, vs -47% in those taking placebo.

"It's a new option among other options for the treatment of vasomotor symptoms due to menopause—an option that has rapid onset, beneficial effects, very few side effects, and no significant adverse effects as seen with other therapies,” said James A. Simon, MD, CCD, MSCP, IF, FACOG, clinical professor of Obstetrics and Gynecology at the George Washington University.

Alongside this outcome, a mean change in symptom severity of -1.2 was reported in elinzanetant patients, vs -0.8 in placebo patients. Additionally, sleep disturbances were measured using the Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form, with mean score reductions of -9.4 and -5.7, respectively, reported by week 12.

While 70% of patients taking elinzanetant reported treatment-emergent adverse events, only 4.2% were serious, and none of these severe events were considered treatment-related. For those taking placebo, rates were 61.1% and 1.9%, respectively.

According to Pinkerton, these positive effects begin to appear within days, with sustained efficacy recorded 52 weeks through clinical trials. While longer-term safety data is ongoing, Pinkerton stated these early findings are encouraging.

“For many years, hormone therapy was really the only highly effective therapy that we had, but now we have an understanding of how the pathogenesis of vasomotor symptoms are coming from the central role of these neurokinin receptors,” said Pinkerton.

This highlights an alternative method to hormonal therapy, which was the only reliable option for hot flashes among postmenopausal women for many years. Currently, the OASIS-4 trial is evaluating the potential of elinzanetant for breast cancer survivors in endocrine therapy, providing vital treatment to this population.

Fezolinetant and elinzanetant present with different risk and side effect profiles, and Neal-Perry has highlighted how this allows patients to choose the one preferred based on their individual health profile.

 For example, elinzanetant has been linked to increased drowsiness, but this outcome has not been reported from fezolinetant, making the former more beneficial in women with sleep problems.

Alongside health benefits, access may differ between the 2 methods, with fezolinetant’s earlier approval leading it to be included on more insurance formularies vs elinzanetant. Potential increases in liver enzymes have been reported in both medications, though protocols may differ.

Real-world evidence has also emerged to highlight additional benefits of fezolinetant. This includes early data indicating increased efficacy from fezolinetant against hot flashes when compared with selective serotonin reuptake inhibitors. Additionally, a favorable safety profile has been reported alongside minimal liver concerns in practice.

To further personalize symptom relief, Neal-Perry noted real-world studies are being conducted. Additional effects are being investigated, such as whether neurokinin receptor antagonists can modify long-term risks of cardiovascular disease, inflammation, and cognitive decline associated with severe, untreated hot flashes.

“The reason this is so important is that it’s been many years since we’ve had anything new and novel on the market to treat hot flashes, and quite frankly, it has only been with these 2 drugs that we have a treatment that’s specific,” said Neal-Perry.

Looking ahead, research is ongoing for other nonhormonal vasomotor symptom therapies, such as cendifensine, which was discussed in an interview with 

and Rebecca Dunsmoor-Su, MD, chief medical officer for Gennev.

 The efficacy of cendifensine across multiple doses was evaluated in a phase 2 clinical trial.

Clinically meaningful improvements were reported for all tested doses, with an 82% reduction in moderate to severe hot flashes reported by week 4 in women taking the lower dose. By week 12, this reduction increased to 92%.

There were also significant reductions in symptom severity. By weeks 4 and 12, severity reductions of 42% and 59%, respectively, were reported in patients receiving lower doses. Greater effects were observed in patients taking higher doses, indicating the efficacy of cendifensine toward reducing both the frequency and severity of hot flashes.

Dunsmoor-Su highlighted these findings as significant because of cendifensine’s novel mechanism of action. Compared to fezolinetant and elinzanetant, which target the KNDy system, cendifensine acts through the monoamine system, which allows for improvements in serotonin, norepinephrine, and dopamine signaling alongside KNDy modulation.

Thanks to this broader mechanism, cendifensine can be used to manage symptoms that often coincide with hot flashes, such as mood changes and food cravings. Larger phase 3 trials will allow optimal dosing to be confirmed, alongside confirming effectiveness and further assessing safety.

“After those larger trials are done, then that drug can go up to the FDA to look for approval for this indication, and possibly other indications if they get [a] good signal on those,” said Dunsmoor-Su.

Krewson C. FDA approves elinzanetant (Lynkuet) for vasomotor menopausal symptoms. Contemporary OB/GYN. October 24, 2025. Accessed October 29, 2025. 

https://www.contemporaryobgyn.net/view/fda-approves-elinzanetant-lynkuet-for-vasomotor-menopausal-symptoms

Pinkerton JV, Liss J. Special Report: How neurokinin receptor antagonists are reshaping the VMS treatment landscape. Contemporary OB/GYN. October 27, 2025. Accessed October 30, 2025. 

https://www.contemporaryobgyn.net/view/special-report-how-neurokinin-receptor-antagonists-are-reshaping-the-vms-treatment-landscape

Ebert M. 'It's about time,' fezolinetant approval and latest research showcased at annual meeting. May 19, 2023. Accessed October 30, 2025. 

https://www.contemporaryobgyn.net/view/-it-s-about-time-fezolinetant-approval-and-latest-research-showcased-at-annual-meeting

Ebert M. FDA initiates removal of boxed warnings, requests updated labeling for menopausal hormone therapy. November 10, 2025. Accessed December 8, 2025. 

https://www.contemporaryobgyn.net/view/fda-initiates-removal-of-boxed-warnings-from-hormone-therapy-for-menopause

Neal-Perry G. Genevieve Neal-Perry, MD, PhD, discusses new nonhormonal treatments for hot flashes. Contemporary OB/GYN. December 8, 2025. Accessed December 8, 2025. 

https://www.contemporaryobgyn.net/view/genevieve-neal-perry-md-phd-discusses-new-nonhormonal-treatments-for-hot-flashes

Dunsmoor-Su R. Rebecca Dunsmoor-Su, MD, highlights reduced hot flashes from cendifensine. Contemporary OB/GYN. December 4, 2025. Accessed December 8, 2025. 

https://www.contemporaryobgyn.net/view/rebecca-dunsmoor-su-md-highlights-reduced-hot-flashes-from-cendifensine

Articles

In 2025, significant advancements in non-hormonal therapies for vasomotor symptoms (VMS) in postmenopausal women were noted, with the FDA approving elinzanetant, a neurokinin receptor antagonist. This approval follows fezolinetant's earlier approval, both offering alternatives to hormonal therapies, which have been associated with increased risks of stroke and breast cancer. Elinzanetant demonstrated a notable reduction in VMS frequency and improved sleep quality. Future therapies like cendifensine, targeting the monoamine system, show promise in further enhancing treatment options for VMS and associated symptoms.

Menopause care transforms with FDA-approved nonhormonal treatments, offering effective relief from hot flashes and improving quality of life for women.

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This Year In Medicine

Nonhormonal Therapies Transform Hot Flash Treatment in Menopause

Tim Smith joined the MJH Life Sciences team in 2022 and is currently an associate editor for HCPLive. He is also the executive producer of two podcasts: Skin of Color Savvy and The Medical Sisterhood. Previously, he was the producer of the Lungcast podcast. He graduated from UC Berkeley and worked in multimedia journalism as a staff writer prior to joining MJH. You can contact him at tsmith@mjhlifesciences.com.

 is associated with a notable elevation in patients’ risk of malignancy, new findings suggest, particularly with cutaneous cancers.

Sheng-Hsiang Ma, MD, of Taipei Veterans General Hospital, led a team of other investigators in authoring this study evaluating links between risk of various forms of cancer and prurigo nodularis. The skin disease has previously been associated with different systemic conditions such as 

, chronic kidney disease, chronic hepatitis C infection, and psychiatric disorders.

Additionally, Ma and colleagues highlighted prior data suggesting neural sensitization and prurigo nodularis’s increased nerve growth factor expression serving as potential influences on tumor growth among different types of patients.

“This study aims to elucidate the association between [prurigo nodularis] and the risk of malignancy, with the goal of informing clinical practice and guiding future research direction,” Ma and coauthors wrote.

Ma et al's study involved a retrospective cohort design, with the team drawing on data from the TriNetX database. TriNetX is a global federated research network designed to gather de-identified electronic health records from participating healthcare systems, including both community hospital and academic center data. Within this platform, there is longitudinal, continuously updated clinical data from more than 130 million patients, the majority of whom are US-based.

The TriNetX analytics interface is designed to allow access to detailed information on patients' different diagnoses, demographic data, medication exposures, laboratory findings, and any previous procedures. Data extraction and analysis occurred in February 2025, with Ma and colleagues using a subset of TriNetX that includes 68 healthcare organizations known as the US Collaborative Network.

In their analysis, the team's study population was made up of adults diagnosed with prurigo nodularis (n = 10,941). These individuals were matched in a 1:1 ratio to subjects who did not have prurigo nodularis (n = 10,941). Ma and coauthors' matching criteria included comorbid conditions, demographic characteristics, and medication utilization. Their study's main endpoint was the hazard ratio for the development of malignancy taking place in the period between 3 months - 5 years following the study's index date. Hazard ratios and corresponding 95% confidence intervals were estimated via Cox proportional hazards regression models.

Overall patients with prurigo nodularis, compared with matched controls, were shown by Ma et al to be at a significantly higher risk of malignancy development, with a hazard ratio of 2.10 (95% CI, 1.81–2.43).

 The investigators found elevated risks were especially pronounced for specific types of cancer, including basal cell carcinoma (HR 2.49; 95% CI, 1.68–3.69), cutaneous squamous cell carcinoma (HR 4.24; 95% CI, 2.69–6.69), hematopoietic malignancies (HR 1.97; 95% CI, 1.26–3.06), cancers impacting the respiratory system (HR 1.86; 95% CI, 1.23–2.82), gastrointestinal cancers (HR 1.87; 95% CI, 1.24–2.81), and female genital cancers (HR 2.77; 95% CI, 1.29–5.95).

Ma and colleauges' findings of malignancy risk suggest prurigo nodularis is linked with a markedly raised malignancy risk. In specific, the team highlighted the strongest associations being with cutaneous cancers. While the analysis's retrospective and observational design was acknowledged by Ma and coauthors to limit causal inference, the robust sampling, large sample size, and use of real-world data strengthen the validity of their data.

Ma et al's observations highlight the value of raising clinical awareness and surveillance. Additionally, the investigative team's data support the necessity for future prospective studies to validate these links, as well as to clarify potential biological mechanisms and determine whether routine cancer screening may be helpful for individuals with skin condition.

“Large-scale, prospective studies are warranted to confirm these associations, elucidate underlying mechanisms, and assess the potential benefits of risk-adapted malignancy surveillance in this high-risk population,” the team wrote.

YY Lin, YC Wang, TL Chen, et al. Association Between Prurigo Nodularis and Malignancy: A Real-World Multicenter Retrospective Cohort Study. The Journal of Dermatology (2025): 1–7, 

Ferraguti G, Terracina S, Fiore M, et al. Nerve Growth Factor and the Role of Inflammation in Tumor Development. Curr Issues Mol Biol. 2024 Jan 23;46(2):965-989. 

Prurigo nodularis is linked to an increased risk of malignancy, particularly cutaneous cancers, according to recent research. The study, led by Dr. Sheng-Hsiang Ma, utilized a retrospective cohort design with data from the TriNetX database, involving over 10,000 patients with prurigo nodularis. Findings revealed a significantly higher risk of various cancers, including basal cell carcinoma and cutaneous squamous cell carcinoma. Despite limitations in causal inference, the study underscores the need for heightened clinical awareness and further prospective studies to explore these associations and potential cancer screening benefits.

Prurigo nodularis was shown to be linked with a significantly increased risk of malignancy, especially with cutaneous cancers.

Dermatology

The HCPLive dermatology page is a resource for medical news and expert insights on skin disease. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments for dermatologic conditions, and more.

Prurigo Nodularis Linked to Increased Risk of Malignancy, Especially Skin Cancers

Andrew Bomback, MD, MPH, is an assistant professor of medicine at Columbia University Medical Center.

Positive phase 3 VALIANT results showed pegcetacoplan reduced proteinuria by 68% and stabilized kidney function in adult and adolescent patients with 

 and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN).

The findings also reported evidence of C3 deposit clearance, including in patients with post-transplant recurrent C3G, highlighting pegcetacoplan’s potential to directly target pathogenic complement activity.

Pegcetacoplan is a PEGylated cyclic peptide designed to bind C3 and C3b, inhibiting C3 activation and downstream complement cascade signaling, including the alternative pathway amplification loop. This C3-targeted therapy is intended to regulate excessive complement activation. 

, the US Food and Drug Administration (FDA) approved pegcetacoplan for use in patients with C3G and IC-MPGN based on 26-week results from the VALIANT trial. 

The randomized, double-blind, placebo-controlled, multicenter phase 3 VALIANT trial evaluated the efficacy and safety of pegcetacoplan over 26 weeks. The primary endpoint was proteinuria reduction, measured by the urine protein-to-creatinine ratio (uPCR). Secondary endpoints included C3c staining, assessed via immunofluorescence microscopy on kidney biopsy samples, and kidney function, measured by estimated glomerular filtration rate (eGFR).

Study investigators evaluated 124 patients ≥ 12 years of age with native and post-transplant kidneys, marking it as the first and largest trial conducted in this patient population.

In patients treated with pegcetacoplan (n = 63), investigators reported a 68.3% uPCR reduction (95% Confidence Interval [CI], –76.3 to –57.7; 

<.0001) compared to placebo (n = 61). They also observed significant reductions in C3c staining (

<.0001), including 71% of patients achieving zero C3 staining intensity, and clinically significant eGFR stabilization, with a difference of +6.3 mL/min/1.73 m2 compared to placebo (nominal 

, many patients achieved remission (≤0.5 g/g) or normalization (≤0.2 g/g) in uPCR, underscoring sustained proteinuria reductions and stable eGFR in the pegcetacoplan-treated patient population.

For additional insight into pegcetacoplan’s potential in C3G and primary IC-MPGN and the VALIANT data, the editorial team of 

 spoke with study investigator Andrew Bomback, MD, MPH, the director of clinical research in the nephrology division at Columbia University, in the following Q&A:

What is the therapeutic rationale for targeting C3 with pegcetacoplan in C3G and IC MPGN, and how does this approach differ from other complement-directed strategies?

These diseases are driven by hyperactivity and loss-of-control of the alternative complement pathway, and C3 is a major protein involved in activating this pathway; targeting C3 with pegcetacoplan is intended to restore control of the alternative pathway and thus halt any ongoing kidney injury from complement.

Can you walk us through the key elements of the VALIANT trial design?

This trial enrolled C3G and primary IC-MPGN patients, both those with disease in their native kidneys and those with recurrent disease in transplanted kidneys. Enrollment was primarily C3G patients with native kidney disease. Participants were randomized to pegcetacoplan versus placebo for 6 months, with a biopsy done at 6 months as part of the trial's endpoints, and then there was an open label extension of an additional 6 months.

What are some of the key findings, and what do they mean for the current treatment landscape for C3G and primary IC-MPGN?

With C3G and primary IC-MPGN trials, the key outcomes to focus on are proteinuria reductions, GFR changes, and histologic markers of complement activation. This trial met all of its endpoints, with a highly significant reduction in proteinuria (about 65%), improved GFR trajectory compared to placebo, and almost 75% of patients on active drug clearing all the C3 from their biopsies at 6 months. This means the drug is an effective treatment at halting disease progression in patients with these diseases and is doing so by targeting the pathogenesis of injury.

Could you elaborate on the clinical significance of achieving complete clearance of C3 deposits in 71% of treated patients?

We don't have reliable non-invasive biomarkers that can tell us a drug has restored control of the complement pathway, so we currently need a biopsy showing this degree of C3 clearance to show that complement activity has been checked and control restored.

Were there any unexpected adverse events or tolerability issues that warrant attention or might affect patient selection?

No, other than some skin reactions to the subcutaneous injections and some cases of pneumococcal pneumonia, which highlights the importance of vaccinations against encapsulated organisms for any patients taking the drug.

How do you envision pegcetacoplan fitting into the broader landscape of complement inhibitors now emerging for glomerular diseases?

Right now, its use is solely in the realm of C3G and primary IC-MPGN, and I think it will be (along with iptacopan, the other drug recently approved) used for a large majority of C3G and primary IC-MPGN patients, since these are usually progressive diseases.

Where do you see the field headed in terms of complement-focused drug development for glomerular diseases over the next few years?

We already have a complement inhibitor for atypical hemolytic uremic syndrome (aHUS), 1 for IgA nephropathy (IgAN), and 2 for C3G, so I think this is a growing field that will continue to show efficacy in other glomerular injuries.

What are the larger implications for C3G patients?

This is a major achievement for C3G patients who have put a lot of effort into getting trials done appropriately, and I am happy for this community that they now have drugs to change what was previously considered to be a grim natural history. I think we'll see major changes in outcomes for these disease groups.

Editor’s Note: Bomback reports relevant disclosures with Amgen, Genentech, Novartis, and others.

The New England Journal of Medicine Publishes Positive Phase 3 VALIANT Results of EMPAVELI® (pegcetacoplan) for C3G and Primary IC-MPGN | Apellis Pharmaceuticals, Inc. Apellis Pharmaceuticals, Inc. Published 2025. Accessed December 15, 2025. 

https://investors.apellis.com/news-releases/news-release-details/new-england-journal-medicine-publishes-positive-phase-3-valiant

Nester CM. VALIANT: Pegcetacoplan Shows Sustained Efficacy in C3G and IC-MPGN. 

. Published November 17, 2025. Accessed December 15, 2025. 

https://www.hcplive.com/view/valiant-pegcetacoplan-shows-sustained-efficacy-in-c3g-and-ic-mpgn-with-carla-nester-md

October 2024 - Volume 35 - Issue 10S : Journal of the American Society of Nephrology. Lww.com. Published 2024. 

https://journals.lww.com/jasn/fulltext/2024/10001/valiant__a_randomized

Pegcetacoplan has demonstrated significant efficacy in reducing proteinuria and stabilizing kidney function in patients with C3 glomerulopathy (C3G) and primary immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN), as evidenced by the phase 3 VALIANT trial. The trial highlighted pegcetacoplan's ability to clear C3 deposits and target pathogenic complement activity. Approved by the FDA in 2025, this C3-targeted therapy offers a promising treatment option for these progressive diseases, with a notable reduction in proteinuria and improved glomerular filtration rate (GFR) compared to placebo.

Bomback, MD, MPH answers HCPLive’s questions regarding phase 3 VALIANT results and pegcetacoplan’s therapeutic ability in C3G and IC-MPGN. 

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 Insights page is a resource for professional video interviews with leading clinical experts and investigators across all specialties of medicine.

Nephrology

The HCPLive nephrology page is a resource for medical news and expert insights on kidney disease. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments in nephrology, and more.

C3 Glomerulopathy

The HCPLive C3 glomerulopathy page is a resource for medical news and expert insights on C3G. This page features expert-led coverage, articles, videos and research on the therapies and development of treatments in C3G, and more.

Phase 3 VALIANT Results for Pegcetacoplan In C3G, IC-MPGN, With Andrew Bomback, MD

Abigail Brooks is an assistant managing editor for 

She joined MJH Life Sciences in August 2023 shortly after graduating from Monmouth University where she earned her BA in Communication with a concentration in Public Relations/Journalism and later an MA in Interactive Digital Media. She enjoys traveling, running, and reading books. She can be reached at abrooks@mjhlifesciences.com.

New research is shedding light on the hepatic benefits of glucagon-like peptide-1 receptor agonist (GLP-1 RA) use among patients with 

, particularly for hepatocellular carcinoma (HCC) risk reduction.

The systematic review and meta-analysis drew data from a pooled population of 2.3 million patients and demonstrated a clinically meaningful 42% reduction in HCC risk among patients with T2DM using GLP-1 RAs. Of note, the magnitude of benefit varied by comparator drug and baseline liver disease status.

“HCC represents a growing global health burden, with T2DM recognized as an independent risk factor conferring a 2–3 fold increased risk,” David Sacerdoti, MD, an associate professor in the department of medicine at the University of Verona and colleagues wrote.

 “The rising prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), affecting 30% of adults worldwide and 70% of those with T2DM, has created an urgent need for effective HCC prevention strategies.”

GLP-1 RAs have had a profound impact across multiple disciplines in medicine, among the earliest and most transformative being T2DM. Emerging evidence suggests that these agents may also confer hepatoprotective effects, as demonstrated by semaglutide (Wegovy) injection 2.4 mg’s 2025 US Food and Drug Administration approval for the treatment of adults with 

metabolic dysfunction-associated steatohepatitis (MASH)

. Existing research on the benefit of GLP-1 RAs in the context of HCC prevention have yielded mixed results and are constrained by notable methodological limitations.

To explore the association between GLP-1RA use and HCC risk in patients with T2DM, investigators searched PubMed, Embase, Web of Science, Cochrane Library, and conference abstracts from inception through June 2025. Inclusion criteria were cohort studies comparing GLP-1RA users to non-users, patients with T2DM, HCC incidence as outcome, and hazard ratios (HR) with 95% confidence intervals (CI) reported or calculable.

The search yielded 606 potentially relevant articles across 4 databases, of which 9 encompassing 2,283,835 total patients ultimately met the inclusion criteria. These studies were published between 2022 and 2025 and utilized large administrative databases or electronic health records from the United States (n = 4), Sweden (n = 1), Korea (n = 1), and Taiwan (n = 3). All included studies were retrospective observational, and 7 out of 9 employed propensity score methods to address confounding.

Upon analysis, GLP-1RA use was associated with a 42% reduced HCC risk (pooled HR, 0.60; 95% CI, 0.41 to 0.88), with substantial heterogeneity (

 <.001). Investigators noted the protective association was consistent across most studies, though effect magnitudes varied considerably by comparator:

Versus insulin (HR, 0.29; 95% CI, 0.13 to 0.67)

Versus oral agents (HR, 0.81; 95% CI, 0.63 to 1.05)

Versus no treatment (HR, 0.77; 95% CI, 0.52 to 1.14)

Meta-regression identified the use of insulin as a comparator as the strongest predictor of effect size (β = −0.74; SE, 0.27; 

 = .025), explaining 55% of between-study variance. Additionally, baseline cirrhosis showed a trend toward reduced efficacy (HR, 0.41; SE, 0.23; 

Network meta-analysis ranked GLP-1RAs highest for HCC prevention (SUCRA, 0.89; mean rank, 1.7), followed by SGLT-2 inhibitors (SUCRA, 0.78; rank, 2.3), DPP-4 inhibitors (SUCRA, 0.70; rank, 3.0), mixed agents (SUCRA, 0.45; rank, 4.0), sulfonylureas (SUCRA, 0.11; rank, 5.7), and insulin (SUCRA, 0.08; rank, 5.9). Further head-to-head comparisons showed GLP-1RAs were superior to insulin (HR, 0.29; 95% CI, 0.13 to 0.67), sulfonylureas (HR, 0.54; 95% CI, 0.31 to 0.94), and additionally indicated a nonsignificant trend toward superiority over SGLT-2 inhibitors (HR, 0.87; 95% CI, 0.52 to 1.45).

“These findings, combined with GLP-1RAs' established cardiovascular benefits, support the preferential use of GLP-1RAs in T2DM patients at risk for HCC,” investigators concluded.

 “Application of these findings could potentially reduce the rising global burden of metabolic-associated liver disease and HCC.”

Dalbeni A, Vicardi M, Natola LA, et al. Glucagon-Like Peptide-1 Receptor Agonists and Hepatocellular Carcinoma Prevention: A Meta-Analysis and Clinical Decision Framework. 

Brooks A. FDA Approves Semaglutide (Wegovy) Injection 2.4 mg for Noncirrhotic MASH. HCPLive. August 15, 2025. Accessed December 15, 2025. 

https://www.hcplive.com/view/fda-approves-semaglutide-wegovy-injection-2-4-mg-for-noncirrhotic-mash

Recent research highlights the potential of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in reducing hepatocellular carcinoma (HCC) risk among type 2 diabetes (T2DM) patients. A meta-analysis of 2.3 million patients showed a 42% reduction in HCC risk with GLP-1 RA use. The protective effect varied by comparator drug and liver disease status. GLP-1 RAs ranked highest for HCC prevention compared to other diabetes treatments. These findings suggest GLP-1 RAs could play a significant role in managing the global burden of metabolic-associated liver disease and HCC.

Findings link GLP-1 RA use to reduced HCC risk in patients with type 2 diabetes, with benefits partly attributable to avoiding insulin's potential hepatotoxicity.

Hepatology

MASH / MASLD

The HCPLive MASH & MASLD page is a comprehensive resource for clinical news and insights on metabolic dysfunction-associated steatotic liver disease and steatohepatitis. This page consists of interviews, articles, podcasts, and videos on the research, treatment and development of therapies for fatty liver disease, steatohepatitis, and more.

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Type 2 Diabetes

GLP-1 RA Use Linked to 42% Hepatocellular Carcinoma Risk Reduction in T2DM

Chelsie Derman is an associate editor for 

who covers psychiatry, sleep medicine, geriatrics, migraine, and allergy. She joined MJH Life Sciences in September 2023 after graduating from The College of New Jersey with a bachelor’s degree in journalism and professional writing. In her free time, she enjoys creative writing and reading.

 granted roxadustat an Orphan Drug Designation for the treatment of 

, announced by FibroGen, Inc., on December 15, 2025.

“The Orphan Drug Designation granted to roxadustat for MDS underscores the significant treatment gap in this indication and highlights patients’ need for additional convenient treatments that can provide [a] durable response,” said FibroGen Chief Executive Officer Thane Wettig, MBA.

 “Roxadustat showed an improvement in transfusion-independence in a subset of patients with high transfusion burden in a post-hoc analysis from the Phase 3 MATTHERHORN trial, which, along with its favorable tolerability profile and oral route of administration, has the ability to set it apart from current second-line treatments.”

An estimated 58,000 people in the United States are living with lower-risk MDS, describing a group of disorders characterized by dysfunctional progenitor blood cells and stem cells. The vast majority, about 85%, develop anemia, a condition associated with elevated cardiovascular risk and increased reliance on blood transfusions.

For patients who become transfusion dependent, rates of cardiac events, infections, and iron overload rise. Meanwhile, transfusion-dependent patients experience significant fatigue, cognitive dysfunction, and reduced quality of life.

Currently, less than half of patients (35% - 40%) on current first-line treatments, including luspatercept, imetelstat, or lenalidomide, reach transfusion independence. Even if transfusions help, relief is often temporary and may not be worth the trouble to dose-calibrate. At the moment, patients have limited options for second- or third-line treatments.

A post hoc analysis of the phase 3 MATTERHORN trial showed that roxadustat was associated with greater transfusion independence than placebo among patients with a high baseline transfusion burden. Among patients receiving ≥ 4 units of red blood cells over 8 weeks at baseline, 36% (8/22) treated with roxadustat achieved transfusion independence for at least 56 days, compared with 7% (1/15) of those receiving placebo within 28 weeks (nominal 

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor that stimulates erythropoiesis by increasing endogenous erythropoietin production, enhancing iron absorption and mobilization, and suppressing hepcidin. The agent is currently approved for the treatment of anemia in patients with chronic kidney disease on dialysis in Europe, Japan, and several other countries.

“Our team is finalizing the phase 3 protocol in this patient population for submission to the FDA in the fourth quarter of 2025,” Wettig added.

FibroGen. Roxadustat Granted Orphan Drug Designation for the Treatment of Myelodysplastic Syndromes by the U.S. Food and Drug Administration. GlobeNewswire. Published December 15, 2025. Accessed December 15, 2025. 

https://www.globenewswire.com/news-release/2025/12/15/3205285/33525/en/Roxadustat-Granted-Orphan-Drug-Designation-for-the-Treatment-of-Myelodysplastic-Syndromes-by-the-U-S-Food-and-Drug-Administration.html

FibroGen Announces Positive Type C Meeting with the FDA for Roxadustat in Patients with Anemia Associated with Lower-Risk Myelodysplastic Syndromes | FibroGen, Inc. FibroGen, Inc. Published 2025. Accessed December 15, 2025. https://investor.fibrogen.com/news-releases/news-release-details/fibrogen-announces-positive-type-c-meeting-fda-roxadustat

Roxadustat has received Orphan Drug Designation from the FDA for treating myelodysplastic syndromes (MDS), highlighting the need for more effective treatments. MDS affects approximately 58,000 individuals in the U.S., with 85% developing anemia, leading to increased cardiovascular risks and transfusion dependency. Current first-line treatments achieve limited transfusion independence. Roxadustat, an oral HIF-PH inhibitor, demonstrated improved transfusion independence in a Phase 3 trial, showing promise as a second-line treatment. The drug is already approved for anemia in chronic kidney disease patients in several countries.

FibroGen’s oral HIF-PH inhibitor showed improved transfusion independence in high–high-transfusion-burden MDS patients in a post hoc phase 3 MATTERHORN analysis.

FDA News

Hematology

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FDA Grants Orphan Drug Designation to Roxadustat for Myelodysplastic Syndromes

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.

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