GLP-1 Agents’ Risks and Benefits Broader Than Previously Thought

An observational study of 175 health outcomes using Veterans Affairs (VA) data for nearly 2 million individuals uncovered new insights about possible risks and benefits of GLP-1 receptor agonists.

Over a median of 3.68 years, adults with type 2 diabetes who added a GLP-1 agent to their treatment plan had significantly decreased risks for 42 diverse outcomes, increased risks for 19 outcomes, and no association with 114 outcomes compared with usual care, reported Ziyad Al-Aly, MD, of Washington University in St. Louis, and colleagues.

“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 receptor agonists,” the researchers wrote in Nature Medicine.

GLP-1 agents “have an intricate web of various effects,” Al-Aly said in a press briefing. For example, the analysis showed that use of GLP-1 agonists was associated with a 5% risk reduction in neurocognitive disorders, driven by an 8% decreased risk of dementia and 12% lower risk for Alzheimer’s disease.

“It’s weak, but it’s not null,” Al-Aly said about the Alzheimer’s relationship, adding that this finding “is still welcome” given the limited number of treatments for the disease.

There also were decreases in other nervous system-related outcomes, including:

• Alcohol use disorders: HR 0.89 (95% CI 0.86-0.92)
• Cannabis use disorders: HR 0.88 (95% CI 0.83-0.93)
• Stimulant use disorders: HR 0.84 (95% CI 0.78-0.91)
• Opioid use disorders: HR 0.87 (95% CI 0.82-0.92)
• Suicidal ideation, attempt, or intentional self-harm: HR 0.90 (95% CI 0.86-0.94)
• Bulimia: HR 0.81 (95% CI 0.77-0.84)
• Schizophrenia and other psychotic disorders: HR 0.82 (95% CI 0.76-0.89)
• Seizures: HR 0.90 (95% CI 0.85-0.95)

Risks of severe infections, including a 12% reduced risk for bacterial infections, were lower in patients taking GLP-1 drugs. The researchers also found reduced risks for septicemia, pneumonia, pneumonitis, aspiration pneumonitis, postprocedural respiratory complications, pleural effusion, chronic obstructive pulmonary disease (COPD), and respiratory failure.

With risk reductions from 8% for coagulopathy and clotting disorders to 18% for pulmonary hypertension, GLP-1 drugs were also linked with a decreased risk for other conditions including acute pulmonary embolism, deep vein thrombosis, chronic phlebitis, and post-thrombotic sequelae.

As expected, use of GLP-1 agonists also was associated with a reduced risk of myocardial infarction by 9%, cardiac arrest by 22%, incident heart failure by 11%, ischemic stroke by 7%, and hemorrhagic stroke by 14%.

GLP-1 agonists also were tied to 12% reduced risk for acute kidney injury and 3% lower risk for chronic kidney disease. Other risk reductions with use of GLP-1 drugs extended to anemia, muscle pain, hepatic failure, inflammatory bowel disease, and liver cancer.

Al-Aly said the wide range of risk reductions were likely driven by two main mechanisms of action — the first being a reduction in obesity, “the mother of all ills,” he said. “When treating obesity effectively using GLP-1 receptor agonists, you see beneficial effects that are beyond reduction in BMI.”

GLP-1 agents may also suppress areas of the brain involved in impulse control and reward signaling, explaining some of the psychiatric benefits. They have anti-inflammatory properties and a stabilizing effect on endothelial function, which may be driving cardiovascular benefits, he added.

Beneficial outcomes associated with these agents can vary by dosage and formulation, Al-Aly said. “This field is very, very active and there’s a lot in the pipeline. Whether dual agonists [like tirzepatide] or even triple agonists could have a more potent effect remains to be seen.”

People without diabetes and obesity likely wouldn’t experience many of these benefits, he noted. The agents also come with significant side effects, he pointed out.

Many risks were gastrointestinal-related, including abdominal pain, nausea and vomiting, gastroesophageal reflux disease, gastritis, noninfectious gastroenteritis, gastroparesis, diverticulosis, and diverticulitis.

Other risks included hypotension, syncope, sleep disturbances, headaches, arthritis, arthralgia, tendinitis, and synovitis, interstitial nephritis, and nephrolithiasis. A target analysis of pancreatic disorders also found a 2.46-fold higher risk for drug-induced acute pancreatitis.

Data for the analysis came from VA electronic health records, which included 215,970 new users of GLP-1 drugs with type 2 diabetes and 1,203,097 patients who received usual diabetes care with non-GLP-1 antihyperglycemic agents from October 2017 through December 2023. The researchers didn’t examine within-class effects by comparing different GLP-1 agents.

The findings were based on military veterans who were older and mainly white, and may not apply to other populations.