Thursday, June 4, 2026

GLP-1 medicine improves liver health independent of weight loss

Lunenfeld-Tanenbaum Research Institute

Researchers at Toronto's Sinai Health have found that semaglutide – the active ingredient in popular weight loss drugs that mimic the gut hormone GLP-1 – acts directly on a subset of liver cells to improve organ function and does so independently of weight loss. The finding challenges long-held assumptions about how GLP-1 medicines work in the liver and could reshape how physicians treat metabolic liver disease.

For years, the liver benefits of semaglutide have puzzled scientists. The drug was known to lover blood sugar and promote weight loss, but patients’ livers were improving in ways that those effects alone could not explain.

“We’ve seen in clinical trials that patients who lose very little weight see the same reductions in liver inflammation, scarring and enzyme levels as those who lose a great deal of weight. Now we know why,” said Dr. Daniel Drucker, a senior investigator at the Lunenfeld-Tanenbaum Research Institute, who led the study.

Dr. Drucker’s has been at the forefront of GLP-1 research since the 1980s when his pioneering discoveries helped lay the groundwork for the development of GLP-1 medicines.

After transforming treatment of type 2 diabetes and obesity, semaglutide and other GLP-1 medicines have been approved for other conditions including MASH, for metabolic dysfunction-associated steatohepatitis. MASH is a severe form of fatty liver disease in which fat buildup, inflammation and tissue scarring can lead to cirrhosis and liver failure. It affects about 25 per cent of Canadian adults and because it is closely linked with obesity and type 2 diabetes, treatment typically includes lifestyle interventions to reduce weight.

Now Dr. Drucker and his team have revealed that semaglutide acts directly on the liver to reduce inflammation and scarring and improve organ function in a way that is independent of weight loss, as described in a paper published in Cell Metabolism.

Their finding overturns a prevailing assumption in the field that liver cells do not carry the receptor that semaglutide binds to, meaning the drug had no direct route to the organ.

Postdoctoral fellow Dr. Maria Gonzalez-Rellan spearheaded the work that combined sophisticated mouse models of MASH with deep molecular analyses of liver cells. Her work identified two cell types carrying semaglutide receptors: liver sinusoidal endothelial cells (LSECs) and immune T cells.

Although LSECs account for only about three per cent of liver cell volume, they proved to be the key driver of semaglutide’s liver benefits. LSECs line the tiniest blood vessels in the liver and are studded with pores that allow them to act as a molecular sieve, filtering substances passing between the liver and the bloodstream. Dr. Gonzalez-Rellan showed that semaglutide reversed MASH in mice that lacked the brain receptors controlling appetite demonstrating that weight loss is not required for liver benefits. In a further test, mice lacking LSEC receptors showed no liver improvement on semaglutide even after losing 20 per cent of their body weight.

Detailed molecular analyses of liver cell types showed that semaglutide shifts gene activity in LSCEs, prompting them to release anti-inflammatory molecules that act on the broader liver environment, pushing it toward a state more closely resembling a healthy, disease-free liver.

“It turns out that the receptor responsible for these benefits is in a very specialized population of liver cells. And this receptor orchestrates the production of molecules that talk to many different types of liver cells to calm down the inflammatory environment that is the problem in metabolic disease,” said Dr. Drucker, who is also a University Professor of medicine at the University of Toronto.

The findings carry practical implications. GLP-1 medicines have become widely prescribed, yet their mechanism of action in the body, beyond appetite suppression and blood sugar control, have remained incompletely understood. Knowing that semaglutide improves liver health independently of weight loss could influence prescribing decisions. Physicians may choose lower doses that avoid the side effects associated with the higher doses needed for significant weight loss, potentially also lowering costs for patients, said Dr. Drucker.

He added, “We're not saying weight loss isn't important because many things improve when patients lose weight. But we now know that weight shouldn't be the only measure of success, because GLP1 medicines will improve liver health whether or not the patient loses weight.”

Journal

Cell Metabolism

DOI

10.1016/j.cmet.2026.03.011

Weight-loss drugs could tackle Alzheimer’s – study

A new study has found comprehensive evidence that ‘weight-loss’ GLP-1 receptor agonists such as semaglutide are effective in tackling the biological drivers of Alzheimer’s disease.

The study, published in the journal Molecular and Cellular Neuroscience, examined 30 preclinical studies investigating the effects of four GLP-1 receptor agonists – liraglutide; semaglutide; exenatide; and dulaglutide – on Alzheimer’s disease pathology.

The researchers, from Anglia Ruskin University (ARU), found consistent evidence from animal and cell studies that these drugs, commonly prescribed for people living with type 2 diabetes, reduce the buildup of amyloid‑beta and tau, the two hallmark proteins linked to the development and progression of Alzheimer’s.

The review found 22 studies showed reductions in amyloid‑beta, a protein that forms sticky plaques in the brain. 19 studies found reductions in hyperphosphorylated tau, the form of tau protein that creates harmful tangles within neurons. Liraglutide, the most extensively studied drug, consistently reduced both amyloid‑beta and tau pathology.

Dulaglutide and semaglutide also demonstrated positive effects on these proteins, though fewer studies were available. Exenatide studies yielded mixed results, with some showing reductions in amyloid or tau and others showing no effect.

Evidence in humans is still emerging. Of the two clinical trials that featured in the study, a 26‑week trial of liraglutide found no reduction in amyloid levels or cognitive improvement, but did show preservation of brain glucose metabolism, an indicator of neuronal function. An 18‑month trial of exenatide showed no significant changes in amyloid or tau in cerebrospinal fluid – the clear liquid that surrounds and protects the brain – but did reduce amyloid‑beta in extracellular vesicles, a potential early biomarker.

Alzheimer’s disease is the most common form of dementia in the UK, affecting around 900,000 people. The number is expected to rise significantly over the next decade. Despite decades of research, effective treatments remain limited.

Lead author Dr Simon Cork, Physiology lead at Anglia Ruskin University’s School of Medicine, said: “This new review provides one of the most comprehensive analyses so far of how GLP‑1 drugs interact with the underlying mechanisms of Alzheimer’s.

“Our study highlights several biological pathways by which GLP‑1 drugs may influence Alzheimer’s, including reducing inflammation, improving insulin signalling in the brain, and altering enzymes involved in the production of amyloid‑beta.

“Whilst human studies demonstrating an impact on cognitive decline are still lacking, the current evidence points towards these drugs having a preventative effect, rather than in patients with established cognitive impairment.

“With more than three‑quarters of preclinical studies showing reductions in amyloid‑beta or tau, and early signals emerging from studies on humans, GLP‑1 drugs remain strong candidates for future Alzheimer’s prevention trials. Larger, early‑stage clinical trials are now needed to determine whether these promising signs actually translate into tangible benefits for patients.”

Journal

Molecular and Cellular Neuroscience

DOI

10.1016/j.mcn.2026.104091

Method of Research

GLP-1 drugs have long-term benefit for heart health

New research has shown that GLP‑1 weight-loss drugs deliver protection against heart attacks, strokes and premature death over a sustained period of time.

Researchers from Anglia Ruskin University (ARU) analysed data from more than 90,000 patients enrolled in large-scale international studies and found that people given glucagon-like peptide‑1 (GLP‑1) receptor agonists were significantly less likely to suffer major cardiovascular events than those given a placebo.

The review of 11 major cardiovascular outcome trials, published in the journal Cardiovascular Diabetology – Endocrinology Reports showed treatment with GLP‑1 receptor agonists reduced the risk of major adverse cardiovascular events, such as heart attack, stroke and cardiovascular death, by approximately 13% compared with placebo over an average follow‑up of almost three years.

The research is significant because it has focused on the long-term benefits of the drug – only studies with a minimum of one year follow-up were considered. The results are also independent of whether or not a patient is diabetic.

Patients taking the drugs were also less likely to die from any cause, and experienced lower rates of non‑fatal heart attacks, non‑fatal strokes and hospital admissions for heart failure.

The benefits were seen in people already at high cardiovascular risk, including those with type 2 diabetes, obesity or existing heart disease.

The review found no meaningful increase in serious safety concerns, such as severe hypoglycaemia or acute pancreatitis, compared with placebo. Gastrointestinal side effects, including nausea and vomiting, were more common, but are already well recognised.

GLP‑1 receptor agonists include medications such as semaglutide, liraglutide and dulaglutide, have attracted widespread attention in recent years because of their effectiveness in treating obesity.

Lead author Dr Simon Cork, Physiology lead at Anglia Ruskin University’s School of Medicine, said: “This is the most comprehensive review to date of long‑term cardiovascular outcome trials for GLP‑1 receptor agonists. We know that one of the factors that weighs on people’s minds when considering going onto these drugs is the potential long-term side effects.

“Our results show that, when taken over a prolonged period of at least one year, these medications do much more than help control blood sugar or weight. They significantly reduce the risk of heart attacks, strokes and premature death in people who are already vulnerable.

“We found the benefits to be consistent across different drugs, trial designs and patient groups. This has important implications for clinical practice and health policy, particularly given cardiovascular disease is the leading cause of death in the UK.

“These drugs have the potential to become a key part of healthcare strategies, especially for people with type 2 diabetes or established heart disease. Using them earlier and more widely across populations could help prevent thousands of serious cardiovascular events.”

Journal

Cardiovascular Diabetology – Endocrinology Reports

DOI

10.1186/s40842-026-00295-3

Popular weight loss, diabetes drugs linked to improved breast cancer survival

New research published today in JAMA Network Open offers illuminating evidence suggesting there is a positive association between GLP-1 agonists—drugs commonly used to treat obesity and diabetes—and better outcomes among breast cancer patients.

“This study suggests that GLP-1 drugs may offer protective benefits potentially improving survival and recurrence risk in some female patients with breast cancer – whether this is related to weight control, improve cardiovascular health or other mechanisms remains to be studied,” said study senior author Bernard F. Fuemmeler, Ph.D., MPH, associate director for population sciences and the Gordon D. Ginder, M.D., Chair in Cancer Research at VCU Massey Comprehensive Cancer Center.

The research findings
Through a retrospective cohort study examining the electronic health records of more than 840,000 breast cancer patients who were diagnosed between 2006 and 2023, the results suggest there is a potential link between GLP-1 RAs and improved outcomes among breast cancer patients who are also obese or have type 2 diabetes.

GLP-1 RA use was associated with an overall lower risk of death from any cause over a 10-year follow-up period among breast cancer patients. Additionally, breast cancer survivors who used GLP1-RAs for diabetes or obesity had a significantly lower risk of their cancer returning over 10 years following their initial treatment.

“Our findings align with emerging preclinical research and contribute to a growing body of literature related to GLP-1 RA use in oncology settings,” said study lead author Kristina L. Tatum, PsyD, MS, of the VCU School of Public Health.

What’s next?
Further studies are needed to understand the biological mechanisms, if any, between GLP-1 RAs and breast cancer outcomes. The research team intends to further evaluate these correlations through randomized clinical trials.

“Our study underscores the potential of GLP-1 RAs as an adjunct strategy for improving cancer-related outcomes among patients with breast cancer, although clinical trials are needed to inform effective therapeutic approaches and clinical decision making,” Fuemmeler said.

About breast cancer

The most common cancer among women in the US, except for skin cancer, accounting for nearly one-third of all female cancer cases.
The average risk of a woman in the US developing breast cancer sometime in her life is about 13%.

Breast cancer patients who are also obese or have type 2 diabetes experience more aggressive cancer growth and worse outcomes. Prior studies have shown that weight loss treatment and surgery following a breast cancer diagnosis are associated with improved heart health and increased survival.

What are GLP-1 drugs?

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs).
Approved to treat type 2 diabetes in 2005 and weight management in 2021.
Impacts on breast cancer survival and recurrence are still unclear.

Since 2020, the use of these drugs has increased dramatically, where approximately 12% of Americans have used GLP-1s for weight loss, according to a RAND report.

Journal

JAMA Network Open

DOI

10.1001/jamanetworkopen.2026.12133

Muscle mass preserved after obesity drug treatment

New research to be presented at the European Congress on Obesity (ECO2026) in Istanbul, Turkey (12–15 May) shows that following treatment with GLP-1 drugs for obesity, most weight loss is fat mass (80–85%) and relative muscle mass is preserved. The study is by Emilia Ida Frohner, Dr Alexander Jürets and Dr Bianca Karla-Itariu, Metabolism Center N°12 Antonigasse, Vienna, Austria and Medical University of Vienna, Austria.

Multiple clinical trials have shown glucagon-like peptide-1 (GLP-1)-based treatments (semaglutide/liraglutide) and GIP/GLP-1 (glucose-dependent insulinotropic polypeptide) dual agonists (tirzepatide) are safe and lead to weight reduction and decreased risk for adverse clinical outcomes. However, researchers are still trying to understand the relative effects on muscle and fat mass as a person loses weight using these drugs.

Bioelectrical Impedance Analysis (BIA) is a non-invasive, fast, and relatively inexpensive method for estimating body composition—including body fat, lean muscle mass, and water—by sending a low-level electrical current through the body. It relies on the principle that lean tissue conducts electricity better than fat.

Understanding changes in body composition, rather than weight alone, is essential to evaluate treatment quality and long-term functional outcomes using obesity drugs. In this new study, the authors analysed changes in skeletal muscle mass and fat mass during GLP-1RA or GIP/GLP-1RA therapy in adults with obesity using bioelectrical impedance analysis (BIA), and to evaluate the relationship between fat loss and muscle mass preservation over time.

This retrospective cohort study included 486 adult patients with obesity (18% male, 82% female; mean BMI 37.68 kg/m²; mean age 49.9 years) treated with GLP-1 receptor agonists or GIP/GLP-1 receptor agonists (liraglutide [8%], semaglutide [82%], or tirzepatide [8%]) at a specialised private obesity outpatient clinic in Vienna between 2022 and 2025. All patients received recommendations regarding physical exercise as per current guidelines. Body composition was assessed using bioelectrical impedance analysis (BIA), a non-invasive method for estimating fat and muscle mass.

Changes in absolute and relative skeletal muscle mass and fat mass from baseline to follow-up were analysed across different treatment durations (<6 months, 6–24 months, >24 months). If multiple measurements were available within a predefined time window, a single measurement per individual was selected based on the longest time since baseline. Computer modelling to adjust for repeated measurements was applied and adjusted for fat mass, time since treatment initiation, age, sex, and baseline BMI.

After a mean treatment duration of approximately 14 months, patients achieved a mean weight loss of 9.9%. Fat mass decreased by 9.0 kg (around 18%), while skeletal muscle mass decreased by only 1.2 kg (around 5%). Relative skeletal muscle mass was preserved or increased in more than 70% of patients. Statistical modelling showed that muscle mass remained stable over time when accounting for changes in fat mass, suggesting favourable body composition changes rather than clinically relevant muscle wasting.

In adjusted linear mixed-effects models, time since treatment initiation was not independently associated with skeletal muscle mass after accounting for fat mass and other variables. Fat mass was strongly associated with absolute skeletal muscle mass, indicating proportional changes in body composition rather than disproportionate muscle loss.

The authors say: “In this real-world cohort, GLP-1RA or GIP/GLP-1 RA therapy was associated with substantial fat mass reduction while largely preserving skeletal muscle mass in relative terms. Our analyses indicate that skeletal muscle mass remains stable over time when accounting for changes in fat mass, supporting the concept that GLP-1RA-induced weight loss reflects favourable body composition changes rather than clinically relevant muscle wasting.”

The authors note that this is a retrospective real-world study with inherent limitations, including missing data, no placebo group, and a predominantly female study population. The findings apply to this specific treatment group and duration; larger prospective trials are needed to assess long-term effects.

GLP-1 class of obesity drugs significantly help people with asthma attacks

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New research presented at this year’s European Congress on Obesity in Istanbul, Turkey (12-15 May) shows the use of the new GLP-1 class of obesity drugs in people with asthma is associated with a 26% fall in the number of asthma exacerbations and a 14% drop in use of asthma inhaler reliever use. The study is by Simon Høj and Dr Kjell Erik Julius Håkansson Copenhagen University Hospital, Copenhagen Denmark and colleagues.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are now widely used to treat overweight, obesity and type 2 diabetes (T2DM), with growing evidence of benefits that extend beyond blood sugar control.

In asthma, where overweight, obesity and metabolic dysfunction can lead to increased severity of symptoms and adverse events such as acute exacerbations, the authors suggest that GLP-1 RAs may improve asthma outcomes through weight loss, modulation of airway inflammation, and improvements in metabolic functions. Reductions in occurrence of asthma exacerbations are likely to reduce systemic corticosteroid exposure (a common treatment for acute asthma exacerbations orally or intravenously) and thus may reduce the risk of corticosteroid exposure-associated adverse events such as osteoporosis or new-onset T2DM. As such, as the clinical use of GLP-1 RAs expands, reliable estimates of their impact on asthma control are needed for individuals living with both asthma and overweight, obesity or T2DM.

The researchers conducted a nationwide self-controlled cohort study using linked Danish health registers. Adult individuals with a prior asthma diagnosis or ≥2 asthma inhaler prescriptions redeemed within 12 months) were included on the date of their first GLP-1 RA dispensing (index date). Eligible individuals had continuous registration data for at least 12 months before and after the index date.

Individuals with COPD or patients with severe asthma treated with new and relatively expensive biologic drugs within 12 months before or after the index date were excluded. Overweight or obesity was defined using ICD-10 codes for those conditions. Those who had no evidence of T2DM - with no diagnosis recorded or no evidence of other first line diabetes drugs prescribed - were also placed in the with obesity/overweight group. Those with a T2DM diagnosis or prescriptions recorded for first line diabetes drugs such as metformin were placed in the T2DM group.

The primary outcome was exacerbations, defined as an inpatient asthma hospital contact(s) and/or systemic oral or intravenous corticosteroid course(s). Secondary outcomes were the use of rescue medication (inhaled short-acting β2-agonists), inhaled corticosteroid exposure, and chest infection events defined as redemption of antibiotics commonly used for lower airway infections

The cohort comprised 27,523 individuals (mean age 54 years, 66% female) with asthma and comorbid overweight or obesity (49%) or T2DM (61%) and 26% recorded as having both conditions. Around 50% of the GLP-1 prescriptions were liraglutide, 48% semaglutide, and 2% others (exenatide, dulaglutide, lixisenatide).

Compared with the year before GLP-1 RA treatment, GLP-1 RA treatment was associated with a 26% lower exacerbation rate overall; and 28% lower in men compared with 23% lower in women. When stratified according to GLP1 RA treatment indication, the analysis showed individuals with asthma and comorbid overweight or obesity and individuals with asthma and comorbid T2DM had similar effect estimates – a 22% reduction in those with overweight or obesity and a 26% reduction in those with T2D.

Reliever medication use fell by 14% overall, suggesting fewer symptoms despite daily inhaled corticosteroid exposure also decreasing by 23% (inhaled corticosteroids are used to prevent exacerbations and treat symptoms in asthma). Furthermore, pneumonia events were reduced by 10%. People also living with allergic rhinitis saw similar decreases (23%) in exacerbations to those living without allergic rhinitis (28%). The authors are also working on updated analyses to show differences between men and women for these specific outcomes.

The authors conclude: “In this nationwide cohort of over 27,000 individuals with asthma and also overweight, obesity or type 2 diabetes, use of GLP-1 drugs was associated with significant reductions in exacerbation burden as well as reliever use, exposure to inhaled corticosteroids and pneumonia events, irrespective of whether the drugs were being used to treat obesity or type 2 diabetes.”

The authors explain that their study did not have access to clinical records (just if people had used GLP-1 and hospital admissions), so data on BMI and weight loss for participants were not available.

But Dr Håkansson says: “There's a high chance that the weight loss is a major contributor to these results. A common symptom in both asthma and obesity is shortness of breath, and the presence of excess fatty tissue creates a pro-inflammatory state in the body in general. There's also evidence from other studies suggesting that the inflammation caused by excess adipose tissue is distinct from the ‘classic’ asthma inflammation which often is driven by allergies or cells called eosinophils.”

And he adds: “As the use of GLP-1 therapies increase, researchers are finding an increasing number of effects outside of weight loss.”

Extending healthspan via GLP-1 receptor agonist

Aging is characterized by chronic inflammation, oxidative stress, and mitochondrial dysfunction. Glucagon‑like peptide‑1 receptor agonists (GLP‑1 RAs), developed for type 2 diabetes and obesity, may modulate the hallmarks of aging. This review summarizes mechanistic and therapeutic evidence that GLP‑1 RAs improve mitochondrial function, reduce oxidative stress, enhance autophagy, and attenuate inflammaging. Preclinical and clinical data indicate neuroprotective, cardioprotective, and metabolic benefits. GLP‑1 RAs affect all 12 hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, insulin resistance, and dysbiosis. Although long‑term safety requires further evaluation, GLP‑1 RAs are promising gerotherapeutics with potential to extend healthspan.

Introduction
Aging involves progressive physiological decline and increased chronic disease risk. The twelve hallmarks of aging provide a framework for understanding molecular mechanisms. GLP‑1 is an incretin hormone that enhances insulin secretion, suppresses glucagon, and delays gastric emptying. GLP‑1 RAs resist DPP‑4 degradation and have shown benefits beyond glycemic control, including cardiovascular and neuroprotective effects. This review explores how GLP‑1R signaling may influence aging pathways and promote healthy aging.

GLP‑1R Signaling in Healthy Aging
GLP‑1R is a G‑protein‑coupled receptor in pancreas, brain, gut, and other tissues. Activation triggers cAMP/PKA, Epac/PI3K/Akt, and ERK/MAPK pathways. These pathways enhance mitochondrial biogenesis, autophagy, cell survival, and stress resistance. GLP‑1R also modulates sirtuins (SIRT1), NAD⁺ metabolism, and the HPA axis, linking metabolic health to neuroendocrine resilience. Cardiovascular benefits include improved endothelial function, reduced arterial stiffness, and lower MACE risk (~14% reduction in meta‑analyses).

GLP‑1 RAs and the Hallmarks of Aging
GLP‑1 RAs affect all twelve hallmarks:

Genomic instability: Reduce oxidative DNA damage via AMPK and enhance DNA repair.
Telomere attrition: May preserve telomere length by reducing metabolic stress and upregulating SIRT1.
Epigenetic alterations: Reverse aberrant DNA methylation of the GLP‑1R gene and influence histone modifiers.
Loss of proteostasis: Enhance autophagy (AMPK/mTOR pathway) to clear misfolded proteins.
Deregulated nutrient sensing: Improve insulin sensitivity, suppress mTOR overactivation, and mimic caloric restriction effects.
Mitochondrial dysfunction: Promote biogenesis (PGC‑1α), increase respiration, and reduce ROS.
Cellular senescence: Lower oxidative stress and inflammation, reducing senescent cell burden.
Stem cell exhaustion: Protect stem cell function via reduced inflammation and improved vascular niche.
Altered intercellular communication: Reduce inflammatory cytokines (TNF‑α, IL‑6) and improve endothelial function.
Inflammaging: Decrease systemic and neuroinflammation.
Dysbiosis: Modify gut microbiota composition, increasing beneficial bacteria and reducing gut permeability.
Disabled macroautophagy: Restore autophagic flux.

Clinical trials (STEP, SURMOUNT, SELECT) show GLP‑1 RAs induce weight loss, improve cardiovascular outcomes, and reduce all‑cause mortality. However, lean mass loss occurs (2–4 kg in major trials), necessitating protein intake (1.0–1.2 g/kg/day) and resistance exercise, especially in older adults. The SEMALEAN study found improved muscle function despite initial lean mass loss.

Emerging Hypotheses and Limitations
GLP‑1R activation may have organ‑specific effects due to differential aging rates (e.g., brain, kidney, heart). Individual variability in aging trajectories requires personalized dosing and monitoring. Chronic use may lead to receptor desensitization or gastrointestinal adverse events. Long‑term safety data in healthy, non‑obese older adults are lacking. Evidence for healthspan extension beyond metabolic benefits remains indirect; functional endpoints (frailty, cognition, mobility) need more study.

Clinical Uses and Obesity Link
Obesity accelerates aging via inflammation and metabolic dysfunction. GLP‑1 RAs reduce weight, improve insulin sensitivity, and lower biological age (epigenetic clocks). In HIV‑associated lipohypertrophy, semaglutide slowed epigenetic aging. Tirzepatide reduced left ventricular mass in heart failure. Ongoing trials are evaluating physical function and frailty outcomes.

Future Directions

Standardize biomarkers of aging (epigenetic, proteomic clocks).
Conduct long‑term RCTs in older adults with functional endpoints (cognition, gait speed, frailty).
Develop precision medicine approaches based on organ‑specific aging profiles.
Investigate combination with exercise and nutritional support to preserve lean mass.
Address global access and health equity.

Conclusions
GLP‑1 RAs exert pleiotropic effects across all 12 hallmarks of aging. They improve mitochondrial function, reduce inflammation, enhance autophagy, and support metabolic and cardiovascular health. While long‑term safety and efficacy in healthy aging populations require further validation, current evidence positions GLP‑1 RAs as promising gerotherapeutics to extend healthspan and mitigate age‑related decline.

Full text:

https://www.xiahepublishing.com/2472-0712/ERHM-2025-00036

The study was recently published in the Exploratory Research and Hypothesis in Medicine.

GLP-1 use linked to lower breast cancer incidence in large cohort study

A retrospective analysis of more than 110,000 women between the ages of 45 and 80 found that those who took GLP-1 medications were about 30 percent less likely to develop breast cancer than those who did not take GLP-1 medications, according to research presented today at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting (Abstract 10506) by Elizabeth McDonald, MD, PhD, a professor of Radiology in the University of Pennsylvania Perelman School of Medicine and a practicing breast radiologist at Penn’s Abramson Cancer Center. The findings were also published today in JCO Oncology Practice.

“While our study was observational and does not definitively confirm an association between GLP-1 medications and reduced breast cancer incidence, it does add to the growing body of evidence suggesting that it’s worth investigating these weight-loss drugs as potential cancer prevention tools,” McDonald said.

GLP‑1 medications are a class of drugs that mimic a natural hormone in the body called glucagon‑like peptide‑1, which helps regulate blood sugar and appetite. Originally used to treat type 2 diabetes, GLP‑1 medications are now also widely used for weight management. A handful of recent observational studies have linked GLP-1s to lower cancer risks and/or improved outcomes in cancer survivors, but prospective data—the gold standard in clinical research—is lacking. Now, McDonald and collaborators are actively working to stand up a multisite clinical trial to assess whether GLP-1 medications can lower breast cancer incidence among women at high-risk, including those with a history of breast cancer.

“GLP-1 medications are intriguing from a cancer research perspective because they weren’t designed for cancer therapy, but they do affect many different targets and pathways associated with cancer development, so we’re eager to study them in this context,” McDonald said.

Statistically significant reduced incidence seen across multiple large cohorts

For this analysis, the researchers looked at health records from 111,646 women ages 45 to 80 with a body mass index (BMI) of 25 or above (the “overweight” threshold) who had breast imaging and a documented outcome in the Penn Medicine EHR between January 2022 and June 2025. Of those women, 15,264 (13.7 percent) had documented GLP-1 medication prescriptions, and 96,382 (86.3 percent) had no documented exposure to GLP-1 medications.

The researchers then looked at whether women were diagnosed with a new breast cancer in two different cohorts: the full group of 111,646 women and a smaller cohort of 30,528 women, including one-to-one controls for each of the 15,264 GLP-1 cases, matched across age, race, ethnicity, BMI, breast density, and diabetes status to limit bias and potential confounding. The lower incidence of breast cancer was seen across both cohorts: 35.1 percent lower odds in the full analysis and 30.5 percent lower odds in the matched cohort.

The study did not account for type of GLP-1 medication or length of use, genetic risk factors, or cancer stage or type at diagnosis. Further analyses are planned to address some of these variables.

The need for better breast cancer prevention strategies

GLP-1 medications are highly effective at helping people lose weight, and maintaining a healthy weight has long been recommended as part of breast cancer prevention strategies because being overweight or obese, particularly after menopause, is a known risk factor for breast cancer. Researchers have also long suspected that low-grade inflammation may play a role in breast cancer development. GLP-1s reduce systemic inflammation through several different pathways and have other metabolic and epigenetic effects that could inhibit tumor growth. The researchers currently hypothesize that these multiple effects of GLP-1 medications inhibit breast cancer development.

Beyond breast cancer screening via mammography or MRI, medical or surgical interventions to reduce breast cancer risk are limited and potentially life-altering. Prophylactic mastectomy is recommended for some people with genetic mutations that significantly raise the lifetime risk of breast cancer. And while tamoxifen is highly effective at reducing breast cancer incidence in high-risk patients, uptake among eligible patients is limited, due to the drug’s known side effects. Meanwhile, GLP-1 medications are widely used by millions of Americans.

“Ultimately, we want to find better options to prevent breast cancer,” McDonald said. “It’s been encouraging to see the survival rates for breast cancer improve over recent decades, and we’d love to see the same gains in prevention.”

The study was supported by the American College of Radiology Center for Research and Innovation, the Pennsylvania Breast Cancer Coalition, and the Abramson Cancer Center.

###

Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service.

The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.

The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with more than $588 million awarded in the 2024 fiscal year. Home to a proud history of “firsts,” Penn Medicine teams have pioneered discoveries that have shaped modern medicine, including CAR T cell therapy for cancer and the Nobel Prize-winning mRNA technology used in COVID-19 vaccines.

The University of Pennsylvania Health System cares for patients in facilities and their homes stretching from the Susquehanna River in Pennsylvania to the New Jersey shore. UPHS facilities include the Hospital of the University of Pennsylvania, Penn Presbyterian Medical Center, Chester County Hospital, Doylestown Health, Lancaster General Health, Princeton Health, and Pennsylvania Hospital—the nation’s first hospital, chartered in 1751. Additional facilities and enterprises include Penn Medicine at Home, GSPP Rehabilitation, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is a $13.7 billion enterprise powered by more than 50,000 talented faculty and staff.

Journal

JCO Oncology Practice

DOI

10.1200/OP-26-00485R1

Semaglutide postpones several molecular signs of aging, potential of all GLP‑1 receptor agonists

Glucagon-like peptide-1 (GLP-1) receptor agonist medications have gained widespread attention for effectively treating obesity, lowering blood sugar and decreasing the risk of cardiovascular disease. Some researchers have proposed that these drugs may also influence the biology of aging, but direct evidence in humans has remained limited. Now, a new study provides the first randomized, placebo-controlled clinical evidence that semaglutide, a widely used GLP-1 drug, slows down the accumulation of biological aging markers in the DNA of adults with HIV. The study is published in Nature Communications.

Researchers at the University of California San Diego and several partner institutions analyzed data from a previously published clinical trial of 108 adults with HIV‑associated lipohypertrophy, a condition in which excess fat builds up around the abdomen. About half of the participants received weekly injections of semaglutide, with the rest receiving placebo injections.

The team used a set of biological “epigenetic clocks” to track cellular aging over the 32-week treatment period. These clocks detect DNA methylation, chemical marks on DNA that help regulate how genes are turned on or off without changing the genetic sequence itself. By measuring changes in these marks, the team could assess whether the treatment was associated with a slower or faster biological aging pattern.

People with HIV often experience accelerated aging, even if it is well-controlled with antiretroviral therapy, according to first author Michael Corley, PhD, associate professor at UC San Diego School of Medicine and the Stein Institute for Research on Aging. However, the study found compared to the placebo group:

Participants treated with semaglutide exhibited a broad pattern of slower biological aging across epigenetic clocks linked to inflammation and blood, brain, heart, kidney, liver and metabolic health.
The drug slowed the pace of biological aging by 9 %, as measured by the DunedinPACE epigenetic clock.
The drug significantly slowed biological processes associated with the risk of all‑cause mortality and age-related disease, as measured by the PCGrimAge epigenetic clock.

Research suggests there are several mechanisms by which semaglutide may influence biological aging. By reducing inflammation and metabolic stress, GLP-1 drugs decreased chronic immune activation, a primary driver of accelerated aging in people with HIV. They also reduce visceral and ectopic fat that accumulates around the abdomen and organs, which may help curb the inflammatory and metabolic signals that promote aging.

“Emerging data also suggest that GLP-1 drugs may reprogram certain cells in different organs, which could help explain why we see effects across multiple aging clocks,” said Corley.

While the study focused on people with HIV‑associated lipohypertrophy, Corley says it may also offer lessons for the wider population.

“Many of the biological processes we study in HIV are also central to aging in the general population,” he said. “Because these processes can emerge earlier or be more pronounced in people with HIV, this community can help us identify interventions that may improve healthspan more broadly.”

In a related pilot study published in npj Aging last month, Corley and another team of researchers found that taking semaglutide for 24 weeks:

Reduced the rate of biological aging for 42% of participants with HIV and metabolic dysfunction-associated steatotic liver disease (MASLD) — also known as fatty liver disease — as measured by the DunedinPACE epigenetic clock. Those participants also had a greater reduction in liver fat compared with participants whose pace of aging sped up.
Slowed aging associated with the risk of all‑cause mortality in 34% of participants as measured by the PCGrimAge epigenetic clock.
Increased the length of telomeres — repetitive DNA sequences at the ends of chromosomes that protect genetic material — in nearly 49 % of participants as measured by the PCDNAmTL epigenetic clock. Those participants also tended to walk faster after treatment, suggesting better physical function.

Together, these studies add to growing evidence that GLP-1 drugs may influence pathways involved in biological aging.

“We are not saying that semaglutide reverses aging or makes people younger,” said Corley. “What we are seeing is a signal that it may slow some of the biological processes associated with aging. With newer GLP-1–based therapies now emerging, the field has an opportunity to test whether different drugs in this class have distinct effects on aging biology and to identify which patients may benefit most.”

Larger clinical trials are needed to confirm the findings, determine how long treatment effects last, and establish optimal dosing and treatment duration for both people with HIV and the broader population. Future studies will also be needed to test whether the effects of GLP-1 effects on aging biology are enhanced when combined with lifestyle interventions such as diet, exercise and sleep optimization.

The Stein Institute for Research on Aging plans to translate these results into individualized “aging dashboards” to track biological aging with epigenetic clocks, enabling clinicians to design personalized therapies that target the underlying mechanisms of aging and help prevent age‑related diseases.

Additional co-authors on the Nature Communications study include: Alina P. S. Pang at UC San Diego;  Varun Dwaraka and Ryan Smith at TruDiagnostic; Danielle Labbato and Grace A. McComsey at University Hospitals Cleveland Medical Center; Allison Ross Eckard at the Medical University of South Carolina; and Grace A. McComsey at Case Western Reserve University. The study was funded, in part, by the National Institutes of Health (grants P30 AI036214, R01DK121619 and UM1TR004528) and the James B. Pendleton Charitable Trust.

Additional co-authors on the npj Aging study include: Alina P. S. Pang at UC San Diego; Douglas W. Kitch and Amy Kantor at Harvard T.H. Chan School of Public Health; Fred Sattler at University of Southern California Keck School of Medicine; Pablo F. Belaunzaran‑Zamudio at the National Institute of Allergy and Infectious Diseases. Todd T. Brown at Johns Hopkins University School of Medicine; Alan Landay at the University of Texas Medical Branch; Jordan E. Lake at UTHealth Houston; and Kristine M. Erlandson at University of Colorado Anschutz Medical Campus. The study was funded, in part, by the National Institutes of Health (grants P30 AI036214, UM1 AI068634, UM1 AI068636, UM1 AI106701) and the James B. Pendleton Charitable Trust.

Corley serves as a scientific advisor for TruDiagnostic.

Journal

Nature Communications

DOI

10.1038/s41467-026-72861-3