Spotlight on GLP-1 RA risks in older patients

Two retrospective studies and a recently published opinion piece analyzed risks of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients ages 65 years and older.

The first study, published by the Journal of General Internal Medicine on May 20, looked at risk of migraine in patients ages 66 years or older who initiated the medications. It used 2016 to 2020 Medicare data to match patients with type 2 diabetes who were newly prescribed either a GLP-1 RA or a sodium-glucose cotransporter-2 (SGLT-2) inhibitor. A total of 27,545 matched pairs were included. The study found GLP-1 RAs were significantly associated with an increased risk of incident migraine (hazard ratio [HR], 1.23; 95% CI, 1.07 to 1.42). The results were similar in a per protocol analysis (HR, 1.39; 95% CI, 1.11 to 1.73). Risk of any type of headache was also higher in the GLP-1 RA group than in the patients taking SGLT-2 inhibitors (HR, 1.08; 95% CI, 1.03 to 1.14). The results “contrast with previous mechanistic studies suggesting potential beneficial effects of GLP-1RAs on the central nervous system, particularly in alleviating central sensitization in chronic migraine,” said the study authors, who called for additional research on this question, ideally with studies that control for body mass index and hypoglycemia.

The second study, published by JAMA Ophthalmology on June 5, assessed rates of neovascular age-related macular degeneration (nAMD) in older patients taking GLP-1 RAs. The retrospective study matched each of 46,334 patients who were ages 66 years or older and took a GLP-1 RA for diabetes to two controls who had not taken the medications. Over a follow-up period of three years, the patients on GLP-1 RAs had significantly higher incidence of nAMD (0.2% vs. 0.1%; crude hazard ratio [HR], 2.11 [95% CI, 1.58 to 2.82]; adjusted HR, 2.21 [95% CI, 1.65 to 2.96]). “These findings expand upon the growing body of literature raising concerns regarding the potential ocular safety of systemic GLP-1 RA use in patients with diabetes. However, it is also important to note that these findings demonstrate associations rather than cause and effect,” said the study authors, who noted the need for more research. An accompanying editorial called for studies to look for risk factors for nAMD on GLP-1 RAs and to assess whether risk for the condition varies by diabetes status or by specific GLP-1 RA.

Finally, an Ideas and Opinions article published by Annals of Internal Medicine on June 10 raised concerns about the risk of older adults losing skeletal muscle mass (SMM) during treatment with GLP-1 RAs. The authors noted that people ages 65 years and older lose SMM from natural aging and are at risk for additional reductions with any weight loss treatment; “although this phenomenon is not unique to GLP-1 RAs, it is increasingly recognized as a potential issue given the medications' profound effect on weight loss and widespread use,” the authors said. They recommended “focusing on functional capacity when assessing response to GLP-1 RAs in older adults” and highlighted resistance exercise training, aerobic training, and adequate protein intake (1.6 to 1.8 g/kg of body weight per day over three meals containing 0.6 g/kg of high-quality protein and 5 g of leucine) as strategies to potentially combat this risk. “Certain cases may require dose adjustment or reconsideration of GLP-1 RA medication,” they concluded.