GLP-1 RAs Show Broad Health Benefits Alongside Some Risks

Credit: Adobe Stock/Konstantin Yuganov

A large-scale analysis using U.S. Department of Veterans Affairs data examined the health effects of GLP-1 receptor agonists (GLP-1 RAs) in people with diabetes compared with those of other common diabetes medications. Treatment with GLP-1 RAs was associated with multiple health benefits, including lower risks of neurocognitive disorders, psychotic disorders, cardiometabolic issues and more. However, they were also linked to higher risks of gastrointestinal disorders, hypotension and kidney stones, among others.

The use of GLP-1 RAs have been increasing in popularity and utilization, especially given their protective cardiovascular and renal properties and their effects on weight loss. Despite this, the efficacy and risk of this class of antihyperglycemics has not been comprehensively studied.

Investigators compared GLP-1 RA use with three other commonly used antihyperglycemic agents: dipeptidyl peptidase 4 (DPP4) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors and sulfonylureas. They also included a composite control group that was composed of equal proportions of patients with incident use of the three antihyperglycemics, as well as a group of controls who received usual care and did not receive GLP-1 RAs. The association between incident GLP-1 RA usage and the risk of 175 outcomes was evaluated.

A total of 1,955,135 individuals with diabetes were identified for inclusion and followed for an average of 3.68 years between October 2017 and December 2023. Among these patients, 215,970 were incident users of GLP-1 RAs, 159,465 received sulfonylureas, 258,614 were treated with SGLT2 inhibitors, and 117,989 received DPP4 inhibitors. Additionally, 1,203,097 were included as controls who continued usual care.

When compared with those receiving usual care, individuals treated with GLP-1 RAs were at a decreased risk of 42 outcomes — about 1 out of 4 — and an increased risk of 19 outcomes.

Patients receiving GLP-1 RAs had reduced risks of neurocognitive disorders (such as Alzheimer’s disease and dementia), psychotic disorders, seizures, cardiometabolic issues, infections (particularly bacterial pneumonia) and some respiratory conditions. The class of drug was linked to a reduced risk of alcohol, cannabis, opioid and stimulant use disorders, which aligns with previous research demonstrating the association between GLP-1 RAs and reduced risk of substance use disorders.

The drug also demonstrated lower risks of myocardial infarction, cardiac arrest, stroke, heart failure and chronic kidney disease. The risk of respiratory conditions, including chronic obstructive pulmonary disease (COPD) and respiratory failure were also reduced. Anemia, muscle pain, inflammatory bowel disease (IBD), liver cancer and hepatic failure were also at a decreased risk.

However, the drugs may increase the risk of gastrointestinal disorders including abdominal pain, nausea and vomiting, gastroesophageal reflux disease (GERD), noninfectious gastroenteritis and gastritis. They may also have an elevated risk of hypotension, syncope, arthritis, sleep disturbances, headaches, kidney stones, interstitial nephritis and drug-induced pancreatitis.

Using data from the U.S. Department of Veterans Affairs strengthened the study’s findings, according to investigators. Information from this database includes healthcare encounters, laboratory test results, medication use, sociodemographic information and more, while also offering comprehensive medical coverage to patients. This reduces the likelihood that the medications were prescribed based on the financial status of the individual. However, they noted the study included mostly White, older male patients, which may have limited the generalizability of the results.

“Altogether, our discovery approach confirms previous studies and clinical trials and also uncovers previously unreported benefits and risks of GLP-1 RAs,” investigators concluded. “The results may be useful for informing clinical care, enhancing pharmacovigilance and guiding the development of mechanistic and clinical research to evaluate the broad pleiotropic effects of GLP-1 RAs.”