FDA-Approved Anti-Obesity Drugs and Their Mechanisms of Action

Criteria for Use

• BMI ≥ 30 (without comorbidities), or
• BMI ≥ 27 with at least one weight-related comorbidity (e.g., hypertension, type 2 diabetes, dyslipidemia)

1. GLP-1 Receptor Agonists (Incretins) - Tier 1 / First-Line

Semaglutide (Wegovy - injection; oral pill approved Dec 2025)

• MOA: Mimics endogenous GLP-1, activating GLP-1 receptors in the hypothalamus to reduce appetite and increase satiety. Also delays gastric emptying (promotes fullness during and after eating), reduces glucagon secretion, and enhances glucose-dependent insulin release.
• Weight loss: ~15-17% total body weight
• Dose: 2.4 mg SC once weekly
• Extra indications: Cardiovascular risk reduction (approved), MASH with liver fibrosis (approved Aug 2025)
• Side effects: Nausea, vomiting, diarrhea, pancreatitis risk, contraindicated in medullary thyroid carcinoma

Liraglutide (Saxenda)

• MOA: Same class as semaglutide - GLP-1 receptor agonist. Slows gastric emptying, suppresses appetite via hypothalamic GLP-1 receptors, reduces glucagon, increases satiety signals.
• Weight loss: ~5-8% total body weight
• Dose: 3 mg SC once daily
• Side effects: Nausea, vomiting, diarrhea, risk of pancreatitis

2. Dual GLP-1/GIP Receptor Agonist - Tier 1 / Highest Efficacy

Tirzepatide (Zepbound)

• MOA: First-in-class dual incretin agonist - simultaneously activates both GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptors in the brain. This dual action reduces appetite more powerfully than GLP-1 alone, increases satiety, delays gastric emptying, and improves insulin sensitivity. GIP receptor activation also contributes to energy expenditure in adipose tissue.
• Weight loss: 15-20.9% total body weight (highest of all approved agents); in the SURMOUNT-1 trial, the 15 mg dose achieved ~20.9% loss
• Dose: 5, 10, or 15 mg SC once weekly
• Extra indications: Obstructive sleep apnea (approved Dec 2024)
• Side effects: Nausea, vomiting, diarrhea (similar to GLP-1 class)

3. GI Lipase Inhibitor

Orlistat (Xenical - Rx; Alli - OTC)

• MOA: Reversibly inhibits pancreatic and gastric lipase in the GI lumen, preventing hydrolysis of dietary triglycerides into absorbable fatty acids and monoglycerides. Approximately 30% of dietary fat passes unabsorbed. Works locally in the gut with minimal systemic absorption.
• Weight loss: ~2.8-4.8% beyond placebo; ~37% of patients achieve ≥5% loss
• Dose: 120 mg (Rx) or 60 mg (OTC) TID with fat-containing meals
• Side effects: Steatorrhea (oily stools), flatulence with discharge, fecal urgency/incontinence, decreased absorption of fat-soluble vitamins (A, D, E, K) - take supplements at bedtime

4. Sympathomimetics (Short-term use only)

Phentermine (Adipex-P, Lomaira)

• MOA: Sympathomimetic amine (amphetamine analog) - stimulates norepinephrine (and to a lesser extent dopamine and serotonin) release in the CNS, particularly the hypothalamus, suppressing appetite.
• Weight loss: ~7-8.3% at 12 months
• Dose: Up to 37.5 mg/day orally; approved for short-term use only (≤12 weeks)
• Side effects: Elevated BP, tachycardia, arrhythmias, insomnia, anxiety, CNS agitation, prolonged QT interval
• Contraindicated in cardiovascular disease, uncontrolled hypertension

Diethylpropion, benzphetamine, phendimetrazine

• MOA: Similar to phentermine - sympathomimetic, CNS appetite suppressants via norepinephrine/dopamine release
• All approved for short-term use only; significant addiction potential

5. Combination Drugs

Phentermine + Topiramate (Qsymia)

• MOA (combined):
  • Phentermine: norepinephrine release in CNS → appetite suppression
  • Topiramate: exact mechanism in obesity unclear, but likely involves modulation of glutamate neurotransmission (AMPA receptor antagonism), GABA augmentation, and possibly effects on carbonic anhydrase - reduces food cravings and caloric intake
• Weight loss: ~9.8-10.9% at 12 months
• Dose: Max phentermine 15 mg/topiramate 92 mg orally daily
• Side effects: Paresthesias, dry mouth, constipation, upper respiratory infections; topiramate is a teratogen (Category X) - requires REMS program

Naltrexone + Bupropion (Contrave)

• MOA (combined):
  • Bupropion: dopamine and norepinephrine reuptake inhibitor → activates POMC (pro-opiomelanocortin) neurons in the hypothalamic arcuate nucleus, increasing melanocortin signaling → appetite suppression
  • Naltrexone: opioid receptor antagonist → blocks the auto-inhibitory feedback of beta-endorphin on POMC neurons, thus sustaining and amplifying bupropion's activation of the POMC/melanocortin pathway
  • Together they work on the hypothalamic reward-appetite circuit
• Weight loss: ~6.1-9.3% total body weight
• Dose: Max naltrexone 32 mg/bupropion 360 mg per day orally
• Side effects: Headache, nausea, dizziness, constipation; black box warning for suicidal ideation (from bupropion); contraindicated in seizure disorders

6. Physical/Mechanical Agent

Cellulose Hydrogel (Plenity)

• MOA: Cellulose-citric acid capsules dissolve in the stomach and expand as they absorb water, creating a large hydrogel matrix that occupies gastric volume, increasing the sensation of fullness and reducing food intake before and during meals.
• Works purely by physical displacement - no systemic pharmacologic effect
• Approved for adults with BMI 25-40 (including overweight)

7. Melanocortin-4 Receptor Agonist (Rare/Genetic Obesity)

Setmelanotide (Imcivree)

• MOA: Melanocortin-4 (MC4R) receptor agonist. Targets the hypothalamic leptin-melanocortin pathway. Approved specifically for severe obesity due to genetic deficiencies in POMC, PCSK1, or LEPR (leptin receptor) genes - conditions where the melanocortin pathway is deficient.
• Not approved for general obesity

Summary Table

Key Points

• Tirzepatide has the highest efficacy of any approved anti-obesity drug (~20% weight loss)
• Oral semaglutide (first oral GLP-1) was FDA-approved in December 2025 for weight management
• Orlistat is the only OTC-available option
• All drugs must be used alongside lifestyle modification (diet + exercise)
• Lorcaserin (5-HT2C agonist) was withdrawn in 2020 due to carcinogenicity concerns
• Sibutramine and rimonabant were also withdrawn - cardiovascular and psychiatric toxicities