A study by the United States Department of Veterans Affairs on the relationship between GLP-1 weight-loss drugs and 175 diseases and conditions supports a lot of what scientists already suspected about potential benefits, but contains a few surprises, too.
The findings, published in the journal Nature Medicine and based on an analysis of medical records from about 2.5m patients in the VA system, support the idea that the medications might be able to help patients with Alzheimer’s disease and those who are suffering from substance abuse involving alcohol, cannabis and narcotics.
The data included 215 970 individuals with diabetes who received these drugs in addition to usual care in the form of other blood-sugar lowering medications, as well as 1 203 097 individuals with diabetes who only received usual care. Participants were tracked for a median of about 3.5 years with the average body mass index above the threshold for obesity.
The “discovery” analysis of the drugs involves delving into data to look for connections and is not meant to establish causal relationships, but instead to generate hypotheses, reports The Washington Post.
The research is the first to attempt to comprehensively investigate the effects – both good and bad – of the drugs on the human body. It arrives at a time when anecdotal reports and small studies attesting to new effects of drugs sold under brand names such as Mounjaro, Ozempic, Wegovy and Zepbound emerge regularly.
“We tend to think of drugs as surgically designed to do only one thing. But the reality is almost never like this,” Ziyad Al-Aly, a co-author of the paper and chief of research for the VA St Louis Health Care System, said. In fact, Al-Aly said many medications result in an “intricate web of various effects”.
“We only studied people with diabetes but there is no biologic or clinical reason to think that the beneficial and risk profiles would be very different in people without diabetes.”
However, he said it was unlikely people without obesity would experience a similar range of potential benefits. He added that some of the positive associations might be linked to weight loss, while it was also important to consider the risks.
Usage of GLP-1 medications has exploded in recent years, rewriting the conversation around health and body image. The shots’ exorbitant price – roughly $1 000 a month – and spotty insurance coverage have raised uncomfortable questions about access and equity.
Novo Nordisk’s Ozempic is approved by the US Food and Drug Administration to treat Type 2 diabetes, obesity and cardiac risk. The company has said it intends to apply to update the drug’s label for use in patients with chronic kidney disease.
About one in eight US adults said they had tried or are using GLP-1 medications, according to a poll by KFF, a non-partisan healthcare research organisation.
Nora Volkow, director of the National Institute on Drug Abuse, called the findings fascinating and said the study “forces us to see that looking at a medicine in a comprehensive fashion could be very valuable and help advance the way we do medicine overall”.
The research compared diabetes patients on Ozempic and other GLP-1 drugs with people taking older treatments. The study also included subjects known as controls who did not have diabetes.
David Cummings, professor of medicine in the Division of Metabolism, Endocrinology and Nutrition at the University of Washington, said he liked to think of database dives such as this as fishing expeditions. Cast a wide net, and you’ll probably get some statistical blips that end up having no meaning even as you get some telling hits.
“The surprising ones are cool because that gives you a new avenue to pursue,” he said.
Among the expected results: GLP-1 was associated with a lower risk of cardiovascular, kidney and liver issues. On the negative side, it was linked to gastrointestinal issues such as reflux, headaches and pancreatitis.
Some unexpected findings include a suggestion that the drugs could help with blood clotting, respiration and infection.
“Those are very new, and I’d like to see more research there,” said Fatima Cody Stanford, an obesity medicine physician at Massachusetts General Hospital and an associate professor at Harvard Medical School.
The data also appeared to support recent studies that found suicidal thoughts were reduced by GLP-1 drugs rather than increased, as feared early on. Volkow said the signals suggesting a reduction in suicidality should be followed up, and wondered whether it might indicate that GLP-1 drugs dampen people’s stress responses, a finding in animal models.
The National Institutes of Health had been studying the impact of GLP-1 drugs on substance abuse even before the arrival of Ozempic, and Volkow said some clinicians have been prescribing them off-label already.
“The evidence is suggestive absolutely, but it’s not at the standard to very clearly say, ‘Let’s recommend this for a treatment’,” Volkow said.
The results reveal that, compared with usual care, GLP-1RAs were associated with a lower risk of 42 health outcomes, from clotting disorders to chronic kidney disease. More specifically, the risk was reduced by 13% for opioid-use disorders; 19% for bulimia; 18% for schizophrenia and other psychotic disorders; 10% for suicidal ideation, attempt or intentional self-harm; 12% for Alzheimer’s; and 12% for bacterial infections.
Some scientists were puzzled by an increased signal of arthritis among patients taking the drugs. Cummings called that “very strange” because weight loss should ease arthritis symptoms.
Stanford cautioned that the study should be viewed within the context of the VA population, which tends to be older, less diverse and more male than the US population as a whole. Because of their age, she said, the patients studied are likely to have multiple health conditions and be on multiple medications, which may have affected results.
The overarching takeaway for Cummings is that there were no new red flags in the data that should make people worry about GLP-1 drugs. To the contrary, he said, “every medicine has its pluses and minuses, and these are no exception”.
“But in this case, the plusses greatly outweigh the negative.”
It is not the first time GLP-1RAs have been linked to a host of potential health benefits: researchers are already exploring whether they could prove helpful in areas ranging from dementia to cancer.
Professor Naveed Sattar of the University of Glasgow, who was not involved in the study, told The Guardian that randomised trials were needed to explore new associations suggested by the study, but noted trials had already proved many of the potential benefits, such as a reduced risk of heart attacks.
“As more larger trials report, we will learn more about these classes of medicines, especially those that also give big weight loss, allowing us to better understand their net benefits and safety and potential widening their indications,” he said.
Study details
Mapping the effectiveness and risks of GLP-1 receptor agonists
Yan Xie, Taeyoung Choi & Ziyad Al-Aly.
Published in Nature Medicine on 20 January 2025
Abstract
Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are increasingly being used to treat diabetes and obesity. However, their effectiveness and risks have not yet been systematically evaluated in a comprehensive set of possible health outcomes. Here, we used the US Department of Veterans Affairs databases to build a cohort of people with diabetes who initiated GLP-1RA (n = 215,970) and compared them to those who initiated sulfonylureas (n = 159,465), dipeptidyl peptidase 4 (DPP4) inhibitors (n = 117,989) or sodium−glucose cotransporter-2 (SGLT2) inhibitors (n = 258,614), a control group composed of an equal proportion of individuals initiating sulfonylureas, DPP4 inhibitors and SGLT2 inhibitors (n = 536,068), and a control group of 1,203,097 individuals who continued use of non-GLP-1RA antihyperglycaemics (usual care). We used a discovery approach to systematically map an atlas of the associations of GLP-1RA use versus each comparator with 175 health outcomes. Compared to usual care, GLP-1RA use was associated with a reduced risk of substance use and psychotic disorders, seizures, neurocognitive disorders (including Alzheimer’s disease and dementia), coagulation disorders, cardiometabolic disorders, infectious illnesses and several respiratory conditions. There was an increased risk of gastrointestinal disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis and drug-induced pancreatitis associated with GLP-1RA use compared to usual care. The results provide insights into the benefits and risks of GLP-1RAs and may be useful for informing clinical care and guiding research agendas.
See more from MedicalBrief archives:
GLP-1 drugs may protect brain health – US review
Weight loss drug approved for heart disease prevention
FDA scrutiny for weight-loss drugs over suicidal thoughts