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Phentermine-Topiramate (Qsymia): What It Is: Combination of appetite suppressant (phentermine) + anticonvulsant (topiramate) Phentermine: Sympathomimetic amine (stimulant) Topiramate: Originally approved for seizures, also affects appetite Effectiveness: Average Weight Loss: 7-9% of body weight CONQUER Trial: 9.3% loss with highest dose vs 1.6% placebo Third most effective after tirzepatide and semaglutide Dosing: Extended-release capsules taken once daily Dose escalation over 14 days Available in 4 dose combinations Highest: Phentermine 15 mg + Topiramate 92 mg Side Effects: Dry mouth Constipation Paresthesia (tingling in hands/feet) Insomnia Increased heart rate Mood changes Cognitive effects (brain fog reported) Contraindications: Pregnancy (topiramate causes birth defects) Glaucoma Hyperthyroidism Cardiovascular disease History of drug abuse (phentermine is controlled substance) Cost: $150-$250/month Generic versions available Some insurance coverage Who Should Consider: Cant use GLP-1s due to contraindications Need oral medication option Want lower cost than GLP-1s Dont mind daily medication No cardiovascular disease or substance abuse history Naltrexone-Bupropion (Contrave): What It Is: Combination of opioid antagonist (naltrexone) + antidepressant (bupropion) Works on brain reward and hunger centers Not a stimulant Effectiveness: Average Weight Loss: 4-5% of body weight COR Trials: 5.4% loss vs 1.3% placebo Among least effective FDA-approved options Dosing: Two tablets twice daily at full dose Gradual dose escalation over 4 weeks Taken with food Side Effects: Nausea (very common, 29-32%) Headache Constipation Dizziness Insomnia Dry mouth Contraindications: Uncontrolled hypertension Seizure disorders Eating disorders (anorexia, bulimia) Opioid use or withdrawal Use of MAO inhibitors Cost: $100-$250/month Limited insurance coverage Who Should Consider: Cant use GLP-1s Prefer oral medication Have depression (may benefit from bupropion component) Moderate weight loss goals Dont need maximum effectiveness Orlistat (Xenical, Alli): What It Is: Lipase inhibitor (blocks fat digestion) Prevents absorption of ~25% of dietary fat Available prescription (Xenical) and OTC (Alli) Effectiveness: Average Weight Loss: 3-5% of body weight Oldest and least effective option Requires strict low-fat diet Mechanism: Blocks enzyme that breaks down fat Undigested fat passes through intestines Must reduce fat intake or experience GI side effects Side Effects: Oily spotting Fecal urgency and incontinence Oily stools Increased bowel movements Flatulence with discharge Fat-soluble vitamin deficiency Side effects worsen with high-fat meals, essentially forcing dietary compliance through negative reinforcement

If you have genuinely exhausted optimization on tirzepatide, retatrutide (when available) offers additional receptor activation that may overcome the plateau

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