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GLP-1 Mimetic Benefits Are Broad, New Study Finds, But Risks Can't Be Ignored
Incretin-mimetics may have even broader application against disease than scientists can predict, but the risks are real, too, according to a study of 2 million.
The glucagon-like peptide-1 receptor agonists (GLP-1RA) and similar incretin-based medications have increasingly demonstrated positive and profound effects on a wide range of cardiometabolic diseases and more recently on behavioral conditions including substance use1,2 and neurocognitive disorders.2 A large-scale study from investigators at Washington University School of Medicine in St Louis, reports these widespread beneficial associations but also reveals a spectrum of adverse effects on the pancreas, kidneys, and other organ systems.3
Ziyad Al-Aly, MDCourtesy of Washington University School of Medicine
Recent research shows that 1 in 8 Americans has used or is currently using GLP-1 RAs including semaglutide, tirzepatide, and liraglutide, to treat type 2 diabetes, obesity, or cardiovascular disease. Writing in Nature Medicine, researchers led by Ziyad Al-Aly, MD, a clinical epidemiologist and nephrologist at Washington University, wrote that despite the “seemingly wide pleiotropic effects” of the class, there has yet been no systematic evaluation of their efficacy and risks in a comprehensive set of outcomes.”3
Their research analyzed 2.4 million de-identified health records culled from the US Department of Veteran’s Affairs databases. “Our approach has allowed us to build a comprehensive atlas mapping the associations of GLP-1RA spanning all organ systems,” Al-Aly said in a university press statement.4 “The study’s results provide insights into some known and previously unrecognized benefits and risks of GLP-1RA that may be useful to inform clinical care and guide research agendas.”4
In the Veteran’s Affairs health care archive, Al-Aly et al identified individuals with diabetes who began treatment with GLP-1RAs (n = 215,970), and with standard treatments for diabetes, ie, sulfonylureas (n = 159,465), DPP4 inhibitors (n = 117,989), SGLT2 inhibitors (n = 258,614) or a composite of the latter 3 antihyperglycemics (n = 536,068). A control group was created of 1,203,097 individuals who continued usual care with non-GLP-1 RA antihyperglycemics. Participants were enrolled between October 1, 2017 and December 31, 2023. After a median follow-up of 3.7 years the investigators compared 175 health outcomes between veterans who were treated for diabetes with GLP-1RAs and those who took more traditional medications.3
Pleiotropic Effects
When compared with usual care, Al-Aly and colleagues found GLP-1RAs were associated with reduced risk of neurocognitive disorders (dementia and Alzheimer disease), substance use disorders (alcohol, cannabis, stimulants opioids) and psychotic disorders (schizophrenia) as well as behavioral health conditions, such as suicidal ideation, attempted or intentional self-harm, and bulimia.3
“Interestingly, GLP-1RA drugs act on receptors expressed in brain areas involved in impulse control, reward, and addiction — potentially explaining their effectiveness in curbing appetite and addiction disorders,” Al-Aly said in the WashU Medicine statement. “These drugs also reduce inflammation in the brain and result in weight loss; both these factors may improve brain health.”4
Supporting existing research, the study confirmed the ability of the incretin-based drugs to reduce the risk of major adverse cardiovascular events and extended findings on anticonvulsant properties. Results of previous studies have shown an association with reduced risk of respiratory diseases, the authors note, which this team also reported, including lower risk of pneumonia, COPD, and respiratory failure.3
Risks: Pancreatitis, kidney problems, and GI issues
In tandem with the promise of their pleiotropic effects, the study did reveal risks including those known to be associated with the class, eg, gastrointestinal issues such as nausea, vomiting, and diarrhea, and more seriously, associations with rare but serious complications involving the pancreas and kidneys.3
“Our findings highlight important risks that should be carefully monitored in people taking these drugs,” Al-Aly said. “Physicians must remain vigilant for signs of pancreatitis and routinely monitor kidney function, as kidney problems often progress silently until they are at an advanced stage.”4
The future for GLP-1 mimetics is wide open, as suggested by the most recent approval of tirzepatide (Zepbound; Lilly) for treatment of sleep apnea.5 Ongoing clinical trials are exploring their potential efficacy for individuals with heart failure, kidney disease, and metabolic dysfunction-associated steatohepatitis (MASH), and Alzheimer's, among other indications.
“Altogether, our discovery approach confirms previous studies and clinical trials and also uncovers previously unreported benefits and risks of GLP-1RAs. 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-1RAs,” the team concluded.3
