Reframing obesity as a chronic, multifactorial disease: Clinical implications of GLP-1–based therapies

Dear Editor, Obesity is increasingly recognized as a chronic, relapsing, multifactorial disease with strong biological drivers, rather than a simple consequence of individual behavior. While lifestyle factors remain essential components of care, advances in neuroendocrine science and clinical therapeutics have clarified that body weight regulation is tightly governed by complex hormonal and central pathways that defend energy stores. Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists have expanded therapeutic options by modulating appetite and satiety pathways, reducing energy intake, and improving cardiometabolic risk factors during ongoing therapy. Their clinical effects are best understood as supporting sustained weight reduction when treatment is maintained, rather than “resetting” a biological set point. In the STEP-1 trial, once-weekly semaglutide 2.4 mg produced a mean weight reduction of 14.9% at 68 weeks compared with 2.4% with placebo (between-group difference − 12.4 percentage points) 1. In SURMONT-1, tirzepatide achieved mean weight reductions of 15.0%, 19.5%, and 20.9% at 72 weeks across escalating doses (vs. −3.1% placebo) 2. These magnitudes approach outcomes seen with some bariatric procedures in selected populations; however, durability generally requires continued pharmacotherapy, and weight regain after discontinuation has been documented 3. Thus, these agents should be framed as chronic therapies within long-term weight-maintenance strategies. Beyond weight reduction, cardiovascular outcomes data have strengthened the clinical rationale for treatment. In SELECT, which enrolled 17,604 adults with overweight or obesity and established cardiovascular disease but without diabetes, semaglutide reduced the composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke by 20% (hazard ratio 0.80; 95% confidence interval: 0.72–0.90) over a mean follow-up of 39.8 months 4. These findings underscore that obesity pharmacotherapy may confer benefits extending beyond weight alone. At the same time, obesity management must remain comprehensive. Biological regulation interacts with environmental exposures, food systems, socioeconomic stressors, sleep patterns, mental health, and cultural factors. Pharmacotherapy complements – but does not replace – nutritional counseling, physical activity, behavioral support, and when appropriate, metabolic surgery. Treatment selection should reflect individual risk profiles, comorbidities, preferences, and access considerations 2. Safety and monitoring warrant balanced discussion. Gastrointestinal adverse effects (nausea, vomiting, diarrhea, and constipation) are common and often dose-dependent. Prescribing information also highlights important warnings, including risk of thyroid C-cell tumors observed in rodents (contraindicating use in patients with personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2), pancreatitis risk, gallbladder or biliary disease, and dehydration-related complications. Careful patient selection, gradual dose titration, counseling on symptoms requiring evaluation, and ongoing monitoring are essential components of responsible prescribing 1-3. Real-world implementation raises additional considerations: long-term adherence, cost, supply constraints, and equitable access across health systems. As with other chronic diseases, sustained benefit depends on continuity of care and integration into multidisciplinary frameworks. In summary, contemporary evidence supports describing obesity as a chronic, multifactorial disease with significant neuroendocrine contributions. GLP-1-based therapies provide clinically meaningful weight loss (approximately 15%–21% at 68–72 weeks in major trials) and, in selected populations, cardiovascular risk reduction. Their use should be embedded within comprehensive, patient-centered care models that acknowledge both biological regulation and broader determinants of health. Author’s contribution The author is solely responsible for the conception, drafting, and writing of the manuscript. Data availability statement Data will be available upon request. Financial support and sponsorship Not applicable. Conflict of interests No conflict of interests declared.