GLP-1 Receptor Agonists Come With Broad Array of Benefits, Risks

Glucagon-like peptide-1 (GLP-1) receptor agonists used in patients with diabetes are associated with reduced risks of dozens of outcomes—as well as increased risks of others—when compared with other antihyperglycemic medications, according to a new study highlighting the potential pleiotropic effects of this popular drug class.

Compared with usual care, initiation of a GLP-1 receptor agonist was tied to lower risk for 42 of 175 outcomes examined in the study, including coagulation and cardiometabolic disorders, infectious diseases, various substance use and psychotic disorders, neurocognitive conditions like Alzheimer’s disease and dementia, and others. Lead author Yan Xie, MD (VA St. Louis Health Care System and Washington University School of Medicine, St. Louis, MO), and colleagues reported their findings in a paper published online Monday in Nature Medicine.

Another 19 outcomes, including a variety of GI disorders and hypotension, among others, occurred at higher rates in new users of the GLP-1 drugs versus other medications.

“What we found was that GLP-1 receptors agonists have a wide array of beneficial effects . . . but not without risks,” senior author Ziyad Al-Aly, MD (VA St. Louis Health Care System and Washington University School of Medicine), said during a briefing with reporters.

The risks and benefits are important to consider for each individual patient, he added. “Patients would need to discuss them with their individual providers to see whether in their case—given their metabolic profile and other risk factors and age and other considerations—the potential benefits really outweigh the risk.”

An ‘Atlas of Associations’

The study was inspired by the skyrocketing use of GLP-1 receptor agonists over the past several years—driven by effects on weight loss and protection against cardiovascular and renal disease—and the anecdotal reports of various off-target effects, both positive and negative.

“GLP-1 receptor agonists are new drugs on the market, or fairly new,” said Al-Aly. “We wanted to really build an atlas of associations . . . and we wanted, literally, to map the landscape of benefits and risks.”

The investigators used US Department of Veterans Affairs databases to perform a “discovery analysis” assessing risks of 175 outcomes across 12 diagnostic categories—blood and blood-forming organs; circulatory system; digestive system; endocrine; nutritional and metabolic system; genitourinary system; infectious and parasitic diseases; mental health; musculoskeletal system; neoplasms; nervous system; and respiratory system and symptoms.

The observational analysis included 215,970 patients with diabetes who initiated a GLP-1 receptor agonist between October 2017 and December 2023, 159,465 who started a sulfonylurea, 117,989 who started a dipeptidyl peptidase-4 (DPP-4) inhibitor, and 258,614 who initiated a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

After inverse probability weighting to balance baseline characteristics, the researchers compared GLP-1 receptor agonist users to those taking each of those other antihyperglycemic medication classes separately, to a control group of 536,068 patients taking any of those three, and to a group of more than 1.2 million patients who continued with usual care during the study period. Follow-up lasted a median of 3.68 years.

Across comparisons between GLP-1 receptor agonists and the multiple control groups, results varied “but consistently showed effectiveness and risks that extended beyond those currently recognized,” the researchers report.

For instance, when compared against a control group consisting of patients started on sulfonylureas, DPP-4 inhibitors, or SGLT2 inhibitors, GLP-1 receptor agonists were associated with lower risks of 34 outcomes, with the strongest relationships seen for pneumonia, alcohol use disorders, respiratory failure, chronic obstructive pulmonary disease, and suicidal ideation. There also were greater risks of 17 outcomes, with the strongest associations observed for nausea and vomiting, gastroesophageal reflux disease, abdominal pain, nephrolithiasis, and sleep disturbances.

GLP-1 receptor agonists were associated with significantly lower risks of coagulopathy and clotting disorders, thromboembolic disorders, acute pulmonary embolism, deep vein thrombosis, chronic phlebitis, postthrombotic sequelae like pulmonary hypertension, MI, cardiac arrest, incident heart failure, ischemic stroke, and hemorrhagic stroke, with hazard ratios ranging from 0.78 to 0.93.

Outcomes that were increased in users of GLP-1 receptor agonists included GI disorders, hypotension, syncope, arthritic disorders, nephrolithiasis, interstitial nephritis, and drug-induced pancreatitis.

Balancing the Benefits and Risks

Asked why GLP-1 receptor agonists would influence such a diverse set of medical conditions, Al-Aly said a few different mechanisms might be at play.

For one, it could be that addressing obesity by reducing body weight also reverses many of the problems, like heart and kidney disease, that are associated with excess weight, he said, noting that “you can sort of conceptualize obesity as the mother of all ills.”

Secondly, there are GLP-1 receptors throughout the body, including in parts of the brain involved in impulse control and reward signaling, he said. That could be “why these drugs may also be effective in reducing the risk of addiction disorders like alcohol use disorders, cannabis use disorders, stimulant use disorders, opioid use disorders, etc.”

The GLP-1 drugs may be providing benefits through a stabilizing effect on endothelial function as well, and “there’s been quite a bit of research suggesting that they also reduce the propensity for clot formation and also reduce inflammation, including neural inflammation,” Al-Aly said.

Overall, he said, “there’s sort of an intricate web of various effects.”

In addition to helping inform clinical practice, the researchers say these new data can help enhance pharmacovigilance and guide the development of mechanistic and clinical research that will allow them to evaluate the broad pleiotropic effects of the drug class.