Not Just For Weight Loss: GLP-1 Drugs May Affect Addiction And Dementia Risk

The team, led by senior author Dr Ziyad Al-Aly of Washington University in St Louis, mapped the association between GLP-1RAs and 175 different health outcomes, using data from a total of over 2 million people obtained from the US Department of Veterans Affairs. 

All the patients using GLP-1RAs in the study had been prescribed them for type 2 diabetes management, not to treat obesity.

Dr Al-Aly told a press briefing that this was the first comprehensive assessment of the risks and benefits, after the recent “explosion” in the use of these drugs around the world. 

A brief history of GLP-1RAs

GLP-1RAs have an intriguing origin story involving the only venomous lizard in the US, the Gila monster. A compound isolated from the reptile’s saliva was found to bind to human GLP-1 receptors, with the added perk that it was slow to break down in the body. This has the effect of simulating insulin production to help control blood sugar.

The first GLP-1RA to be approved, back in 2005, was called exenatide. Its use was limited to type 2 diabetes.

Research into the newest generation of GLP-1RAs demonstrated their potential for weight management. They work by decreasing appetite, and people using these drugs often speak of a reduction in “food noise” – they aren’t so focused on food, and consequently eat less. 

The big drug of the moment is semaglutide, marketed in slightly different formulations under a range of brand names, including Ozempic and Wegovy.

No one predicted that GLP-1RAs would have this other function, though that’s not an uncommon story with drugs. After they’re approved for one use and people start taking them in greater numbers, other side or “off-target” benefits – as well as risks – can start to emerge. It’s rare that a medication will do precisely one thing. As Dr Al-Aly put it, “Biology is too complex.”

More and more research is starting to emerge suggesting that GLP-1RAs could have a host of other medical uses. At the same time, clinicians are getting a clearer sense of the side effects, mild and severe. For Dr Al-Aly and the team, it was time to look at the bigger picture.

Discovery analysis: what did the study find?

The 175 health outcomes included in the study covered a whole range of medical conditions and bodily systems. GLP-1RAs were found to be associated with a surprising array of benefits. 

These included a decreased risk of acute and chronic kidney disease, infections, substance use disorders, psychotic disorders, clotting disorders, and dementia (including Alzheimer’s disease). 

At the same time, the study confirmed that GLP-1RAs are not without risks. Gastrointestinal problems are common, particularly when someone first starts taking the drug. As well as nausea and diarrhea, these can extend to more complex or longer-term problems, like gastroesophageal reflux disease, gastroparesis (paralysis of the stomach), and inflammation of the colon.

Beyond that, some other potential risks included sleep issues, low blood pressure (sometimes leading to fainting), kidney stones, arthritis, and acute pancreatitis.

The overall message is that GLP-1RAs do appear to be multiuse, or “pleiotropic” to use the technical term. 

“Future investigations should leverage the pleiotropy of GLP-1RAs to evaluate their effectiveness in treating multimorbidities, rather than focusing on a single health condition, particularly where obesity or other mechanistic pathways affected by GLP-1RAs are leading drivers,” the authors write in their paper.

They stressed that the findings are observational at this stage – we can’t say for certain from these data that the use of GLP-1RAs alone was directly responsible for any of the health outcomes. They also flag that the dataset they used contains predominantly older white males, so analysis in a more diverse cohort would be useful.

What do the results mean?

When asked about the results that particularly stood out, Dr Al-Aly highlighted the effect on substance use disorders. There have been suggestions recently that GLP-1RAs could help treat these conditions, but it was the consistency that was surprising – the same positive effect was seen across tobacco, cannabis, opioids, and alcohol.

The decreased risk of Alzheimer’s disease observed also merits further investigation. Dr Al-Aly put the risk reduction at 12 percent – though not exceptionally high, he suggested this is still welcome based on the lack of available treatments and preventatives. The findings could also push dementia drug research in new and fruitful directions.

For many of these health outcomes, though, it’s hard to know for sure if the drug is indirectly or directly causing them. The higher rate of kidney stones, for instance, might not be due to something the drug is doing but rather because people taking it have a lower appetite and struggle to drink enough fluids.

Some of the benefits, too, may be explained by the fact that people taking the drugs tend to lose weight, rather than the drugs themselves having a direct positive effect on a particular system or organ. Of course, that does also mean that people who do not have obesity may not see the same level of benefit from taking GLP-1RAs. A lot of these questions will need to be addressed in future studies.

What about people already taking these drugs?

Dr Al-Aly stressed that any conversations around the risks vs. benefits of taking GLP-1RAs should be a personal discussion between patient and care provider, taking into account their unique medical history. There’s still a lot we don’t know about these medications, and lots of research is underway.

“If you’re using GLP-1 medications, this study brings good news: these treatments may help in ways we didn’t fully realize before, like lowering the risks of certain diseases,” commented Dr Georgia Rigas, a Senior Bariatric Medical Practitioner and Obesity Doctor in Australia who was not involved in the study.

Others echoed the authors’ calls for caution. “This type of ‘big data’ research will generate lots of statistical associations, some of which will be spurious,” commented Professor David Henry of the Institute for Evidence-Based Healthcare at Bond University.

Any use of these drugs must take place under close medical supervision. Health authorities have warned about the dangers of fake semaglutide products on the black market. A recent study in JAMA Health Forum found that online advertising of compounded GLP-1RAs – containing the active drug and other inactive ingredients in different combinations – often includes misleading or incomplete information.

These compounded drugs are not approved by the US Food and Drug Administration, but this fact was not always included in online commercials.

The UK Medicines and Healthcare products Regulatory Agency issued a reminder in 2024 that health professionals should be making patients aware of the known side effects of GLP-1RAs, and reiterated the need for ongoing monitoring.

“This is the beginning of a journey,” Dr Al-Aly told the press briefing. The aim of this study was to build an atlas of the potential health risks and benefits of GLP-1RAs, some of which have not been explored before. It will be for future studies to dig deeper into this landscape and figure out the best possible uses of these doubtless transformative medicines.

The study is published in Nature Medicine.