Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), such as semaglutide (Ozempic, Wegovy) and liraglutide, alongside dual GIP/GLP-1 agonists like tirzepatide (Mounjaro), represent a paradigm shift in the management of type 2 diabetes (T2D) and obesity. Pharmacologically, these agents are engineered for extended half-lives—achieved in semaglutide through albumin binding facilitated by a fatty di-acid moiety—allowing for once-weekly administration. They function by mimicking incretin hormones to stimulate insulin secretion, inhibit glucagon release, and delay gastric emptying, thereby improving glycemic control.
"Food Noise" and Neurobiology Beyond metabolic regulation, GLP-1 RAs profoundly impact the central nervous system, particularly reward circuits. A key emergent concept is the reduction of "food noise"—persistent, intrusive, and dysphoric thoughts about food that burden cognitive function. By modulating the default mode network and dopamine pathways in the brain, these medications reduce maladaptive prospection and craving. This neurobiological effect may explain why GLP-1 RAs are currently being investigated for treating substance use disorders, including alcohol and cocaine addiction, with observational data showing reduced incidence of substance use disorders in patients treated with semaglutide.
Expanded Indications: Cardiovascular and Neurodegenerative Health The therapeutic scope of GLP-1 RAs has expanded significantly. The SELECT trial demonstrated that semaglutide reduces major cardiovascular events (stroke, myocardial infarction) by 20% in adults with overweight or obesity and established cardiovascular disease (CVD), even without diabetes. Furthermore, these drugs exert anti-inflammatory effects and are under investigation for neuroprotective potential in Alzheimer’s and Parkinson’s diseases, with clinical trials like EVOKE currently underway.
Safety Profile and Adverse Events While effective, GLP-1 RAs carry specific risks. Gastrointestinal side effects (nausea, vomiting) are pervasive. More severe concerns include an increased risk of pancreatitis and gastroparesis ("stomach paralysis"). Although rodent studies initially raised concerns regarding thyroid C-cell tumors, recent large-scale human studies suggest that observed associations with thyroid cancer may stem from detection bias rather than direct causation. Additionally, rapid weight loss associated with these drugs raises concerns regarding sarcopenia (loss of muscle mass) and reduced bone density, potentially increasing fracture risk in older adults if not managed with resistance training and adequate protein intake.
Discontinuation and "Obesogenic Memory" A critical limitation of GLP-1 therapy is the rapid weight regain observed upon discontinuation. The STEP 1 trial extension revealed that participants regained two-thirds of their lost weight within one year of stopping semaglutide. Recent research identifies an "obesogenic memory" retained in adipose tissue via epigenetic changes; adipocytes maintain transcriptional alterations even after weight loss, priming the body for rapid lipid accumulation upon re-exposure to excess calories. This supports the classification of obesity as a chronic, relapsing disease requiring long-term treatment.
Economic Considerations The high cost of GLP-1 RAs challenges healthcare systems. Cost-effectiveness analyses indicate that at current US list prices, semaglutide exceeds standard willingness-to-pay thresholds for CVD prevention unless significant rebates are applied or usage is targeted toward high-risk populations
