GLP-1 agonists represent a new era in medicine. However, their optimal use requires an approach that balances excitement with caution, does not overlook lifestyle changes, and considers both patient safety and social equity.
In recent years, GLP-1 receptor agonists have emerged as one of the fastest-growing classes of drugs. Originally developed to treat type 2 diabetes, these drugs now sit at the heart of obesity treatment as well. Following the introduction of exenatide in 2005, molecules such as liraglutide, dulaglutide, and semaglutide arrived; subsequently, drugs like tirzepatide—which combine GLP-1 activity with GIP activity—further transformed the landscape. While weight-loss strategies once relied primarily on diet, exercise, behavioral changes, and drugs of limited efficacy, we now discuss pharmacological options capable of achieving weight loss of 15–20% (https://www.ncbi.nlm.nih.gov/books/NBK572151/).
The primary mechanism of these drugs is to mimic the effects of the GLP-1 hormone secreted by the intestine. GLP-1 stimulates insulin secretion, suppresses glucagon, slows gastric emptying, and enhances the sensation of satiety in the brain. Consequently, they are effective in both blood sugar control and appetite reduction. In type 2 diabetes, GLP-1 agonists significantly lower HbA1c levels and promote weight loss. Furthermore, cardiovascular studies involving semaglutide have demonstrated a reduction in cardiovascular events among high-risk patients with diabetes (https://www.nejm.org/doi/full/10.1056/NEJMoa1607141).
Data regarding obesity is even more striking. In the STEP-1 trial, adults with obesity or overweight who used 2.4 mg of semaglutide weekly experienced an average weight loss of 14.9% after 68 weeks, whereas the figure remained at 2.4% in the placebo group (https://www.nejm.org/doi/full/10.1056/NEJMoa2032183). Meanwhile, the SURMOUNT-1 trial involving tirzepatide reported weight loss ranging from approximately 16% to 22.5%, depending on the dosage (https://pubmed.ncbi.nlm.nih.gov/35658024/). Weight loss also yields positive effects on blood pressure, fatty liver, sleep apnea, joint load, and cardiometabolic risk. The SELECT trial further expanded this scope by demonstrating that semaglutide reduces major cardiovascular events in individuals without diabetes who have obesity or overweight and established cardiovascular disease (https://www.nejm.org/doi/full/10.1056/NEJMoa1607141).
There are also early indications that the effects of these drugs may extend beyond metabolism. Research is ongoing in areas such as addiction, fatty liver, polycystic ovary syndrome, Alzheimer’s disease, and depression. A recently published animal study suggested that liraglutide alleviates depressive behaviors by altering the gut microbiota—specifically through an increase in Lactobacillus delbrueckii—and by acting on the endocannabinoid system (https://www.eurekalert.org/news-releases/1130817). While this finding is exciting, it does not yet translate to a treatment for depression in humans. Nevertheless, it is noteworthy for demonstrating the potential importance of the gut-brain axis.
Of course, it is incorrect to present these drugs as “miracles.” Like most medications, they have side effects. The most common side effects include nausea, vomiting, diarrhea, constipation, and abdominal pain. Rarer but significant risks include pancreatitis, gallbladder disease, kidney problems due to fluid loss, increased heart rate, and—in some patients—worsening of diabetic retinopathy (https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/215256s033lbl.pdf). The risk of hypoglycemia may increase when used in combination with insulin or sulfonylureas. Furthermore, they should not be used by individuals with a history of medullary thyroid cancer or MEN2. There has been a long-standing debate regarding psychiatric side effects; however, recent FDA evaluations found no evidence that GLP-1 agonists cause suicidal thoughts (https://www.fda.gov/drugs/drug-safety-communications/update-fdas-ongoing-evaluation-reports-suicidal-thoughts-or-actions-patients-taking-certain-type).
Another issue is access and equity. Demand for these drugs has surged to such an extent that many countries experience periodic shortages, making it difficult for diabetic patients to obtain the medication. This situation brings the classic question of medicine back to the fore: When a treatment is effective, who should have access to it, to what extent, and on what grounds? (https://www.ema.europa.eu/en/news/eu-actions-tackle-shortages-glp-1-receptor-agonists)
GLP-1 agonists represent a new era in medicine. It is clear that they offer powerful tools for treating diabetes and obesity. However, the optimal approach will balance excitement with caution, avoid overlooking lifestyle changes, and consider patient safety and social equity in tandem.
