Stopping Ozempic may raise heart attack and stroke risk

 GLP-1 drugs such as semaglutide (Ozempic and Wegovy) and tirzepatide (Mounjaro and Zepbound) have surged in popularity for treating diabetes and helping people lose weight. About one in eight U.S. adults now use these medications, which are also known to provide cardiovascular benefits. But new research suggests that those heart benefits may fade quickly when treatment is stopped.

Researchers at Washington University School of Medicine in St. Louis tracked more than 333,000 U.S. veterans with type 2 diabetes for three years. They found that interrupting or stopping GLP-1 treatment for as little as six months was associated with a meaningful increase in the risk of major cardiovascular events compared with remaining on the medication.

The longer patients stayed off treatment, the greater the increase in risk. After two years without GLP-1 therapy, the risk of heart attack, stroke and death was up to 22% higher than among people who continued treatment, largely wiping out the cardiovascular protection gained while taking the drugs.

The findings, published in BMJ Medicine, suggest that stopping GLP-1 medications may have consequences that extend well beyond weight regain. They also point to the importance of uninterrupted treatment for maintaining heart protection.

"There is enormous exuberance about starting GLP-1 drugs, but not nearly enough attention to what happens when people stop," said senior author Ziyad Al-Aly, MD, a WashU Medicine clinical epidemiologist and chief of the Research and Development Service at the VA Saint Louis Health Care System. "Many quit after a few months because of cost, side effects or shortages. When they stop, it's not just weight that comes back; they experience a resurgence in inflammation, blood pressure, and cholesterol. Weight regain is visible; the metabolic reversal is not."

"Our data suggest this metabolic whiplash is detrimental to heart health," Al-Aly added. "Restarting the medication helped restore some protection, but only partially, showing that discontinuation leaves a lasting scar."

Heart protection depends on continued GLP-1 use

GLP-1 medications include the semaglutide drugs Ozempic and Wegovy and the tirzepatide drugs Mounjaro and Zepbound. After observing that about half of users stop taking GLP-1 drugs not long after beginning treatment, Al-Aly set out to examine what happens to cardiovascular health after therapy is discontinued.

The study focused on major adverse cardiovascular events, including heart attack, stroke and death. Researchers analyzed data from 333,687 veterans with type 2 diabetes. Of those, 132,551 had been prescribed GLP-1 drugs, while 201,136 had been prescribed sulfonylureas, another class of diabetes medications.

Sulfonylureas include glipizide (Glucotrol), glimepiride (Amaryl), and glyburide (Diabeta and others). Participants were followed for up to three years.

Researchers reassessed GLP-1 treatment status every six months. During the study, 26% of GLP-1 users stopped taking the medication altogether. Another roughly 23% experienced a treatment gap lasting at least six months before eventually restarting therapy.

Continuous treatment produced the greatest benefit

The clearest cardiovascular benefit appeared among people who remained on GLP-1 medications throughout the full three-year study period.

Compared with participants taking sulfonylureas, those who consistently stayed on GLP-1 therapy had an 18% lower risk of major cardiovascular events. That translated to about four fewer major cardiovascular events for every 100 people over three years.

Participants who stayed on GLP-1 treatment for two years or two-and-a-half years before stopping for the rest of the study also saw meaningful reductions in risk, at 7% and 15%, respectively.

By contrast, people who discontinued GLP-1 therapy before reaching 18 months showed no significant reduction in cardiovascular risk compared with those taking sulfonylureas by the end of the study.

Treatment gaps weakened heart protection

Interrupting treatment and then restarting it also appeared to reduce the cardiovascular benefit.

People who remained on GLP-1 drugs continuously for three years had an 18% reduction in risk, while those who stopped temporarily and later resumed treatment saw an average reduction of 12%.

Even a six-month interruption before restarting therapy was enough to weaken the benefit. Compared with continuous use, those treatment gaps were associated with a 4% to 8% increase in cardiovascular risk.

Longer periods off the drugs were linked to even greater losses of protection. People who stopped GLP-1 treatment for one year without restarting had a 14% higher risk of cardiovascular events compared with continuous users. After two years off treatment, that increase reached 22%.

The pattern suggests that cardiovascular benefits accumulated during GLP-1 treatment can be lost relatively quickly once the medication is discontinued.

Restarting may not fully restore lost benefits

The findings reinforce the importance of continuous treatment if patients and clinicians want to preserve the cardiovascular effects of GLP-1 therapy. They also suggest that reducing treatment interruptions could help maximize the drugs' protective effects on the heart.

"Clinicians should treat adherence to GLP-1 treatment as an important outcome in its own right -- not an afterthought," Al-Aly said. "Health systems need plans in place to help people continue their medication indefinitely, recognizing that GLP-1s treat chronic conditions. That includes proactive management of side effects, candid conversations about the long-term nature of treatment, infrastructure to identify and support patients at risk of stopping and addressing the cost barriers that make GLP-1 therapy unsustainable for many."

Al-Aly noted that this is especially important because cardiovascular protection from GLP-1 treatment appears to accumulate gradually but disappear much more quickly.

For study participants, spending only one year off the medication was enough to lose benefits that had taken years of continuous treatment to build. Restarting the drug restored some of that protection, but not all of it.

The research was funded by the United States Department of Veterans Affairs. The funders had no role in considering the study design or in the collection, analysis, interpretation of data, writing of the report, or decision to submit the article for publication. The contents do not represent the views of the US Department of Veterans Affairs or the US Government.

Source: ScienceDaily

Hidden gut defect that may explain why IBD keeps coming back

 Researchers have identified early molecular warning signs of inflammatory bowel disease that may appear before symptoms and remain active even when patients seem to be doing well.

The study, led by WEHI in partnership with the Royal Melbourne Hospital, uncovered a hidden defect in intestinal cells that can make them vulnerable to damage. The problem was still detectable in some patients whose disease appeared to be well controlled.

Published in Science, the findings may help explain why people with inflammatory bowel disease can experience sudden flare-ups even after reaching remission.

Key findings

WEHI researchers identified a 'smoldering' molecular defect in gut cells from people with inflammatory bowel disease.

The defect involves abnormal cell death and could be detected even in patients whose disease was under good control.

The work, carried out through a broad collaboration with the Royal Melbourne Hospital, could eventually lead to earlier prediction of flare-ups, more precise monitoring and treatment tailored more closely to individual patients.

A hidden problem in intestinal cells

Inflammatory bowel disease (IBD), which includes conditions such as Crohn's disease and ulcerative colitis, is a chronic condition that affects around 180,000 Australians.

People with IBD can experience serious symptoms including rectal bleeding, abdominal pain, diarrhea, fatigue, and weight loss.

Modern therapies can help many patients achieve remission, but diagnosing and managing IBD remains challenging.

The disease often alternates between periods when symptoms are controlled and sudden flare-ups that can become severe enough to require hospital care.

Study co-author Dr. Andre Samson said the researchers discovered that intestinal cells could remain vulnerable even when patients felt well, and their disease appeared stable.

"Once you've got the diagnosis, IBD doesn't go away. Even if you become symptom-free on the current treatments, we know there's a likelihood you're going to have a flare or relapse," said Dr. Samson.

"What we found in patient samples was that intestinal cells are primed to die. Even in patients with essentially no symptoms, there's still this persistent problem sitting there."

Cell death may help drive IBD

The results challenge the assumption that cell death in IBD is simply damage caused by inflammation. Instead, the researchers say abnormal cell death may be involved in helping drive the disease itself.

The defect was already present during the earliest stages of disease activity, including in patients with clinically mild IBD. Detecting it required detailed molecular analysis.

Study co-author Professor James Murphy said the discovery revealed a 'smoldering' molecular problem and encouraged the researchers to focus more closely on what happens at the beginning of the disease process.

"Most people have been focusing on the major clinical problem, when someone comes to hospital with severe gut inflammation," Prof Murphy, a WEHI deputy director and lab head, said.

"We've gone to the other end of the spectrum and looked at gut tissue that doesn't have clear signs of active disease. What we're finding is this molecular defect happening very early in disease progression - one of the first dominoes to fall."

Human tissue reveals clues to future flare-ups

The research relied entirely on human tissue and patient-derived organoids.

Working with clinicians from the Royal Melbourne Hospital, the team collected around 900 biopsies from 80 people with and without IBD. Researchers used those samples to grow organoids, lab-grown tissues derived from patients, allowing them to investigate the disease directly in human cells.

Study co-author Professor Edwin Hawkins, head of the Colonial Foundation Diagnostics Center where samples were analyzed, said the size and nature of the patient group were important strengths of the research.

"While cell death has been implicated in IBD for a long time, how it arises in humans has remained unclear, probably because most studies rely on mouse models which often do not accurately mimic the human condition," Prof Hawkins, a WEHI lab head, said.

"Our study is based on human tissue and patient biopsies."

Researchers then tracked the patients for more than two years. They found that people showing stronger intestinal cell death signaling were also more likely to experience a relapse.

Toward earlier IBD detection

IBD can behave very differently from one person to another, making it difficult to know who will respond to a particular treatment or who is most likely to relapse.

Study co-author Dr. Jiyi Pang said the newly identified molecular signals could eventually help scientists develop more precise tools for monitoring patients and selecting treatments based on the biology of an individual's disease.

"The causes of IBD are largely unknown and quite variable," Dr. Pang said.

"Using mini-intestinal organoids grown in a dish and by working alongside a diverse team of researchers and clinicians, we uncovered the inflammatory signals responsible for this cell death response."

"We now have the hallmarks of what underlies disease at the molecular level. The question is which of those are therapeutically actionable and whether they might help us to better match treatments to patients, based on how their disease behaves at a molecular level."

More personalized treatment could follow

Study co-author Dr. Aysha Al-Ani cautioned that the findings are unlikely to produce a new diagnostic test or therapy immediately. However, they provide a foundation for future research into better forecasting tools and potential treatments.

"It opens new avenues for different prognostic tools, using more sophisticated and refined methods than are currently used clinically," Dr. Al-Ani said.

"The ethos behind IBD therapy is to reduce the frequency and severity of flares, halting disease progression and improving patients' lives. More sensitive molecular detection may help us keep patients in deep remission for longer and introduce new treatments."

Source: ScienceDaily

Scientists solve a 50-year mystery and discover a new human blood group

 More than half a century after scientists first encountered a mysterious marker on human red blood cells, researchers finally traced it to its genetic source. The breakthrough established MAL as a human blood group system and gave doctors a new way to identify the exceptionally rare people whose blood lacks the AnWj antigen.

The work was led by scientists at NHS Blood and Transplant in Bristol, including researchers from the International Blood Group Reference Laboratory (IBGRL), together with colleagues at the University of Bristol. Their findings solved a puzzle dating back to 1972 and could help prevent dangerous transfusion reactions in a small number of patients.

Although most people are familiar with the ABO and Rh blood groups, those are only part of a much larger biological system. Red blood cells carry hundreds of different molecules on their surfaces. Many of these molecules act as antigens, markers that the immune system can recognize.

For most transfusions, ABO and Rh compatibility receive the most attention. But in patients with unusual antibodies or rare blood types, matching some of these lesser-known antigens can become crucial.

A Blood Marker Found in More Than 99.9% of People

The AnWj antigen was discovered in 1972, but for decades scientists did not know which gene produced it or which protein carried it on red blood cells.[1]

More than 99.9% of people are AnWj positive. For the tiny minority who are AnWj negative, however, the distinction can matter enormously.

If an AnWj negative person develops antibodies against AnWj and then receives AnWj positive blood, those antibodies can attack the transfused red blood cells. In some circumstances, that can trigger a potentially serious transfusion reaction.

There are also two very different reasons someone can lack the antigen. In most cases, AnWj expression appears to be suppressed because of an underlying hematological disorder or certain cancers.[2] Much more rarely, a person is born without the antigen because of an inherited genetic change.

Only a handful of people with this inherited form had ever been identified, making the mystery especially difficult to investigate.

The Genetic Clue Was Hidden in MAL

To find the source, the researchers turned to whole exome sequencing. This technique examines the portions of DNA that contain instructions for making proteins, allowing scientists to search across thousands of genes for unusual variants shared by affected individuals.

The analysis pointed unexpectedly to the MAL gene.

The researchers found that people with the inherited AnWj negative phenotype carried homozygous deletions affecting MAL. Homozygous means that the relevant change was present in both copies of the gene, one inherited from each parent.

The MAL gene produces a small membrane protein called Mal. When the team examined red blood cells, people who were AnWj positive produced the full-length Mal protein on their cells, while it was missing from AnWj negative cells.

Five genetically AnWj negative individuals were included in the investigation, including members of an Arab Israeli family.[3] The samples also included blood donated in 2015 by the woman who had been the first AnWj negative person identified in the 1970s.

The researchers did not stop at finding a genetic association. They needed to demonstrate that Mal really was responsible for the antigen.

When scientists introduced the normal MAL gene into laboratory cells, the cells became reactive with AnWj antibodies. Introducing the altered form did not produce the same response. Additional experiments showed that Mal was both necessary and sufficient for expression of the AnWj antigen.

Source: ScienceDaily