The study, led by researchers at the Veterans Affairs St. Louis Health Care System, found that use of these GLP-1s, as they are classified, was associated with reduced risks of a number of health problems, including substance abuse disorders, suicidal ideation, schizophrenia and other psychotic disorders. Risk reduction was also found for neurocognitive disorders like Alzheimer’s and dementia, along with infections, liver cancer, and even life-threatening clotting disorders, like blood clots in the lungs.

How and why the drugs have such wide-ranging health benefits is subject to further research, and the GLP-1 drugs were found to increase risks of some conditions, including kidney stones and low blood pressure. On balance, though, the study’s results suggest a new frontier of potential benefits—subject, of course, to further investigation and the test of time.

“I think we need more data to help us understand whether these benefits are sustained over long periods of time, and we don’t know whether these medications carry serious long-term risks after five years or 10 years of use,” says Ziyad Al-Aly, who led the study and is director of the Clinical Epidemiology Center at VA St. Louis Health Care System. But given the evidence in total, Al-Aly says, “I’m more encouraged about the future of GLP-1 and its potential promise.”

A lower risk of dozens of diseases

The study included nearly 2 million patients, making it the largest ever conducted on this group of glucagon-like peptide-1 receptor agonists. All the participants, who were followed for a median of about three-and-a-half years, had type 2 diabetes. About 215,000 used GLP-1 drugs, while the rest were taking various other diabetes medications.

Though semaglutides like Ozempic and Wegovy dominate the market in the U.S., Al-Aly and his team included all GLP-1 drugs in the study. They evaluated the drugs’ effect on a comprehensive catalogue of 175 health outcomes and found that compared with usual care, where people continued use of their regular medications without a GLP-1 drug, GLP-1 use was associated with decreased risk of 42 outcomes (24%) and increased risk of 19 (11%).

Some of the results were unsurprising. Beyond glucose control and weight loss, benefits like a reduction in the risk of stroke, heart attacks, major cardiac events and kidney disease were expected, since some GLP-1 medicines have already been shown to be beneficial in reducing the incidence of these disorders in people with type 2 diabetes in clinical trials. But Al-Aly was particularly struck by the drugs’ apparent neurologic effects when compared with the care patients would normally receive—that is, without a GLP-1.

“There’s very clearly some neurotropic aspect to GLP-1, in the sense the drugs actually reduce risk of quite a number of neurologic conditions,” the researcher says. In the category of substance use disorders, for example, risk reductions were seen for alcohol, marijuana, stimulants and opioids.

GLP-1s may suppress the centers in the brain responsible for cravings—the same mechanism that could contribute to weight loss, says Al-Aly. In a similar vein, a study published this summer showed that patients taking semaglutide had a significantly lower risk of seeking medical care or counseling for tobacco use compared to those on other anti-diabetes medications.

Weight loss and reduced inflammation 

Like any study, there are limitations. The data are drawn from the VA database, which skews heavily male, white and older. (The large size of the study may reduce that effect somewhat.) And Al-Aly said this test, for so many health outcomes, might miss some weaker signals that could be detected by more narrowly focused studies of similar sample size.

The study found mild reductions in the risk for dementia (8%) and Alzheimer’s (12%)—not overwhelming, but still noteworthy. “It’s not the panacea,” Al-Aly says, but rather a sort of side benefit of GLP-1 agonists. The researcher likened the drug’s effect on those conditions to “a side gig. Nobody designed GLP-1s to reduce Alzheimer’s disease.”

Preclinical studies have highlighted the potential brain-protective effects of these drugs and the role they may have in treating various neurodegenerative diseases. Use of these in individuals with Alzheimer’s and Parkinson’s disease is already the subject of multiple trials.

Studies have shown that a GLP-1 drug, exenatide, sufficiently crosses the blood-brain barrier in rodent models of Parkinson’s disease, leading to improvements in motor performance, behavior, learning and memory. Human studies have seen more mixed results with respect to the drugs lowering the rate of Parkinson’s, slowing disease progression or improving motor function in affected individuals.

Nigel Greig, who heads drug design and development within the National Institute on Aging at NIH, says that part of the apparent usefulness of a drug like Ozempic may lie in the fact that its intended target, the GLP-1 receptor, has wide distribution across the tissues of the body. That includes the heart, lung, pancreas, digestive tract, arteries and veins, brain, kidney, and more

“Equally important, numerous diseases are likely underpinned by common fundamental mechanisms—like inflammation, insulin resistance and oxidative stress—that GLP-1 based drugs can positively impact,” Greig says. Clearly, those mechanisms can extend well beyond diabetes control or weight loss promotion.

GLP-1s also reduced the risk of respiratory failure, sepsis, chronic obstructive pulmonary disease and pneumonia in Al-Aly’s Nature Medicine study. A previous review of 28 randomized control trials showed that GLP-1s lowered the incidence of respiratory diseases.

“I think the elephant in the room here is that GLP-1s reduce the risk of obesity–and it’s possible that obesity is kind of the mother of all ills,” Al-Aly says. “Obesity impairs metabolic health and leads to chronic low grade inflammation, affecting multiple body systems and making the immune system less efficient.” By assisting with weight loss, Ozempic or GLP-1s can improve that underlying immune response and reduce inflammation, among other things, the researcher says.

The future of GLP-1s

According to research by the Kaiser Family Foundation, about 1 in 8 adults in the U.S. has taken a GLP-1 drug to treat diabetes, promote weight loss or prevent heart attacks or strokes (in those with a history of heart disease). But nearly 60% quit within 12 weeks, before they’ve been on the drug long enough to meaningfully gauge its effectiveness for their condition.

There are many possible explanations for that, including side effects and the drug’s cost. According to a KFF analysis, the list price for GLP-1 drugs can range between $936 and $1,349 before insurance, manufacturer coupons or rebates. As the GLP-1 patients in Al-Aly’s study were all veterans, with full drug coverage, their retention rate was higher—roughly 70% after a year.

How the study’s results will be interpreted or acted upon remains to be seen. But “off-label” use of drugs, in which they’re prescribed to treat conditions for which they weren’t originally designed, has such a long history in the U.S. that it wouldn’t be uncommon for GLP-1s to find multiple uses over time. The Food and Drug Administration has approved semaglutide to reduce the risk of cardiovascular death, heart attack and stroke in adults with heart disease and obesity.

As for side effects, Al-Aly noted that the study found signals for drug-induced pancreatitis, arthritis, as well as interstitial nephritis, a disease characterized by inflammation within the kidneys. Other adverse effects include gastrointestinal issues like heartburn, vomiting or rare cases of stomach paralysis, although those were already well known with some GLP-1s.

The researchers also saw an increased risk of fainting spells and a higher risk of having episodes of low blood pressure. While, they don’t fully understand why, it’s possible, Al-Aly says, that when patients lose weight on the GLP-1s, their blood pressure improves—but their anti-hypertensive medications are never adjusted, so they faint or experience low blood pressure.

One thing researchers cannot yet answer is what would happen to patients who stopped taking a GLP-1. If they experienced enhanced protection against certain conditions while on the drug, would their risks increase again once the regimen ends?

“One thing we know is that for people who discontinue GLP-1s, their weight gain rebounds. We know that very, very clearly,” says Al-Aly. “I think we would need more data to help us understand whether the protective effect of these medicines (against certain conditions) is sustained.”

That, says Al-Aly “is the billion- or even trillion-dollar question.” A new frontier of possible uses for these drugs likely depends in part on the answer.

More on Ozempic and GLP-1s:

• Fake Ozempic and Wegovy are flooding the market. Here are 4 steps to avoid dangerous counterfeit weight loss drugs
• Zepbound vs. Wegovy: New clinical trial says this weight-loss medication sheds more pounds
• They lost weight on Wegovy. Here’s what happened when they stopped taking it
• How drugs like Ozempic and Wegovy work for weight loss: ‘Food tastes good, but I don’t want it’