Chapter 53: Weight Loss – Pharmacologic & Behavioral Therapies

The underlying causes of obesity are multifaceted, combining high heritability (40% to 70% of BMI predisposition), environmental factors like increased access to high-calorie, large-portion foods and decreased physical activity, psychological influences such as mood disorders and stress eating, and other factors including certain medications and sleep debt. Physiologically, maintaining weight loss is difficult due to biological adaptive responses and dysfunctional hormonal systems, which normally regulate appetite through signaling molecules like ghrelin (stimulant) and satiety hormones such as leptin and GLP-1. Clinically, obesity is most often classified using Body Mass Index (BMI ≥30 kg/m²), although waist circumference is also a critical measure for assessing increased cardiometabolic risk. The foundation of treatment is a comprehensive lifestyle intervention—including a reduced calorie diet, at least 150 minutes per week of aerobic physical activity, and behavior therapy—which is recommended for all patients and aims for a 5% to 10% weight loss, although even a 3% to 5% loss offers significant benefits in blood glucose and triglyceride reduction. Pharmacotherapy is initiated for those with a BMI ≥30 or ≥27 with comorbidities, serving to aid adherence to behavioral changes. Approved agents include short-term noradrenergic appetite suppressants (anorexiants) like phentermine, which mandate careful cardiac monitoring due to risks of increased heart rate and blood pressure; the non-systemic lipase inhibitor orlistat, which lowers fat absorption and requires dosing separation from fat-soluble vitamins and certain medications like levothyroxine; the GLP-1 receptor agonist liraglutide, which is preferred for patients with coexisting Type 2 diabetes or ASCVD but carries a boxed warning for medullary thyroid cancer; and combination medications like phentermine/topiramate (Qsymia), which necessitates a risk evaluation and mitigation strategy (REMS) due to teratogenicity risk, and naltrexone/bupropion (Contrave), which acts on both appetite and reward circuits but holds a boxed warning for suicidal ideation. All weight loss agents are contraindicated during pregnancy and breast-feeding, and treatment efficacy must be monitored monthly for the initial three months, with discontinuation advised if less than 5% body weight is lost.