Residency · Residency · Internal Medicine

Obesity Medicine: Pharmacotherapy and the GLP-1 Revolution

Introduction

Obesity is a chronic, relapsing, multifactorial disease affecting over 40% of US adults. It is a major driver of type 2 diabetes, cardiovascular disease, obstructive sleep apnea, NAFLD, and numerous cancers. The arrival of highly effective GLP-1 receptor agonists and dual incretin agonists has transformed obesity medicine, achieving weight loss previously attainable only through bariatric surgery. Internal medicine residents must understand the pathophysiology of obesity, available pharmacotherapies, and an evidence-based approach to long-term management.

Pathophysiology

• Obesity results from a complex interplay of genetic susceptibility, neurohormonal regulation, environment, and behavior
• The hypothalamus integrates signals from leptin (adipose tissue), ghrelin (stomach), GLP-1 and GIP (gut), and insulin (pancreas) to regulate energy balance
• After weight loss, metabolic adaptation occurs: decreased resting energy expenditure, increased ghrelin, decreased leptin and satiety hormones, driving weight regain
• This biological defense of a higher body weight set point explains why sustained weight loss requires ongoing treatment

Assessment and Diagnosis

• Body mass index (BMI): >= 30 kg/m2 defines obesity; >= 25 kg/m2 defines overweight
• BMI limitations: does not account for body composition, muscle mass, fat distribution, or ethnicity (lower thresholds for Asian populations: >= 27.5 for obesity)
• Waist circumference: abdominal obesity (> 102 cm men, > 88 cm women) correlates with cardiometabolic risk independent of BMI
• Assess for weight-related complications: diabetes, hypertension, dyslipidemia, OSA, NAFLD, GERD, osteoarthritis, depression, infertility

Lifestyle Intervention: The Foundation

• Caloric deficit: 500-750 kcal/day deficit targeting 5-10% weight loss over 6 months
• Physical activity: >= 150 min/week moderate-intensity; 200-300 min/week for weight maintenance
• Behavioral strategies: self-monitoring (food diaries, apps), stimulus control, cognitive restructuring
• Intensive behavioral therapy: >= 14 sessions in 6 months is the evidence-based standard (CMS-covered)
• Lifestyle alone produces 3-5% weight loss on average; insufficient for most patients with obesity-related complications

Anti-Obesity Pharmacotherapy

When to Initiate

• BMI >= 30 or BMI >= 27 with weight-related comorbidity
• Pharmacotherapy should be considered when lifestyle intervention alone is insufficient
• Treat obesity as a chronic disease requiring long-term medication, analogous to hypertension or diabetes

GLP-1 Receptor Agonists

Semaglutide 2.4 mg (Wegovy)

• Weekly subcutaneous injection; dose-escalated over 16 weeks
• STEP 1: 14.9% weight loss vs. 2.4% placebo at 68 weeks
• STEP 5: weight loss maintained at 12.6% at 2 years with continued use; regain upon discontinuation
• SELECT trial: 20% reduction in MACE in patients with obesity and established CVD (without diabetes)
• Most common side effects: nausea, vomiting, diarrhea (dose-dependent, typically transient)

Liraglutide 3.0 mg (Saxenda)

• Daily subcutaneous injection
• SCALE trial: 8% weight loss vs. 2.6% placebo at 56 weeks
• Now largely superseded by semaglutide due to greater efficacy

Dual Incretin Agonists

Tirzepatide (Zepbound)

• GIP/GLP-1 receptor agonist; weekly subcutaneous injection
• SURMOUNT-1: 20.9% weight loss at highest dose (15 mg) vs. 3.1% placebo at 72 weeks
• SURMOUNT-2 (patients with T2DM): 14.7% weight loss and HbA1c reduction of 2.4%
• Represents the most effective non-surgical weight loss therapy available
• Side effect profile similar to GLP-1 RAs; dose-escalate gradually

Oral Semaglutide (Higher Doses)

• OASIS-1: oral semaglutide 50 mg achieved 15.1% weight loss at 68 weeks
• May improve access and patient preference over injectable formulations

Other FDA-Approved Agents

• Phentermine-topiramate ER (Qsymia): 9-10% weight loss; contraindicated in pregnancy (topiramate teratogenicity), glaucoma, hyperthyroidism
• Naltrexone-bupropion (Contrave): 5-6% weight loss; avoid in seizure disorders, uncontrolled hypertension, opioid use
• Orlistat (Xenical/Alli): 3-4% weight loss; GI side effects limit adherence; minimal role in current practice

Bariatric and Metabolic Surgery

• Indications: BMI >= 40, or BMI >= 35 with obesity-related comorbidity (ASMBS/IFSO 2022: consider at BMI >= 30 with metabolic disease)
• Roux-en-Y gastric bypass: 25-30% total body weight loss; gold standard for diabetes remission
• Sleeve gastrectomy: 20-25% weight loss; most commonly performed procedure
• Superior to medical therapy for long-term weight loss and diabetes remission (STAMPEDE trial at 5 years)
• Long-term nutritional monitoring required: B12, iron, calcium, vitamin D

Emerging Therapies

• Retatrutide (triple agonist: GIP/GLP-1/glucagon): up to 24% weight loss in Phase 2 trials
• Orforglipron: oral non-peptide GLP-1 RA; does not require fasting for absorption
• CagriSema: combination cagrilintide (amylin analog) + semaglutide; up to 22% weight loss
• Bimagrumab: anti-activin type II receptor antibody; promotes lean mass preservation during weight loss

Managing Weight Regain

• Weight regain is the norm after discontinuing pharmacotherapy (STEP 1 extension: two-thirds of lost weight regained within 1 year of stopping semaglutide)
• Long-term pharmacotherapy is essential, similar to treating any chronic disease
• Combination approaches (medication + behavioral + surgical) may offer the most durable results

Key Clinical Pearls

• Obesity is a chronic disease driven by neurohormonal dysregulation, not a failure of willpower; treat it accordingly with long-term pharmacotherapy
• Tirzepatide produces the greatest weight loss of any non-surgical intervention, approaching the efficacy of sleeve gastrectomy
• Semaglutide (SELECT trial) is the first anti-obesity medication to demonstrate cardiovascular mortality benefit
• Weight regain after medication discontinuation is expected and should be discussed upfront with patients

References

1. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205-216.
2. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002.
3. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes (SELECT). N Engl J Med. 2023;389(24):2221-2232.
4. Mechanick JI, Apovian C, Brethauer S, et al. Clinical Practice Guidelines for the Perioperative Management of Bariatric Surgery Patients. Obesity. 2020;28(4):O1-O58.

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