What Do Sugar, Gila Monsters, and the Therapeutic Dance Have in Common With GLP-1RA, Stroke, and Dementia?

Mary Poppins famously asserted that "a spoonful of sugar helps the medicine go down," but this bon mot is likely wrong in almost every way.In fact, anecdotal and experimental data suggest health and longevity benefits to nutritional scarcity.The Western diet, with its heavy use of added sugars and high-fructose corn syrup in drinks and snacks, has contributed to the epidemics of type 2 diabetes (T2DM) and obesity, with adverse cardiometabolic effects and growing health consequences.1 Stroke remains a significant, growing public health burden in the United States. 2 The combined burden of Alzheimer disease and related dementias (ADRDs) is primarily driven by cardiometabolic morbidity.3 That spoonful of sugar causes a spike in blood glucose, disrupts homeostasis, and may have adverse consequences for the brain.The observations of Caro et al. 4 in this issue of Neurology ® and data from a host of sources are causing us to rethink how we can leverage glucose modulation for therapeutic benefit.5 Over nearly a century, we have come to understand the role that glucagon-like peptide-1 (GLP-1) and its receptor play in blood glucose regulation, ultimately leading to the development of GLP-1 receptor agonists (GLP-1RAs), first as treatment for diabetes and then for obesity.6 The first of these was derived from a GLP-1 analog in the venom of Gila monsters.In the 20+ years since their original release, evidence has emerged that these drugs may have cardiometabolic benefits beyond their original intent and independent of weight loss.A meta-analysis of 28 RCTs (74,148 patients) found a 27% reduction in ischemic stroke (RR 0.73; 95% CI 0.60-0.89) in treated patients with T2DM.7 The beneficial effects seem strongest for longacting GLP-1RAs, and the effect strengthens with longer periods of exposure.A target trial emulation in a population-based cohort study found that GLP-1RA use in T2DM was associated with a 33% lower risk of ADRDs compared with other glucose-lowering drugs.8 A metaanalysis of RCTs found that GLP-1RAs reduced odds of dementia/cognitive impairment by approximately 45%, a benefit not observed with other classes of drugs.9