Weight Management Pharmacotherapy

Weight management pharmacotherapy supports lifestyle change in adults with obesity (BMI 30 kg/m2 or more) or overweight (BMI 27 kg/m2 or more) with a weight-related complication. Lower BMI thresholds apply in people of Asian ancestry. Drugs are adjuncts to diet, activity and behavioural support, and weight is usually regained when treatment stops.

Mechanism. Orlistat inhibits gastric and pancreatic lipases, blocking absorption of about 30% of dietary fat. Naltrexone with bupropion acts on hypothalamic proopiomelanocortin neurons and reward circuits. Phentermine with topiramate combines noradrenergic appetite suppression with an anticonvulsant effect. Liraglutide, semaglutide and tirzepatide act on incretin receptors to reduce appetite and slow gastric emptying. Setmelanotide activates the melanocortin 4 receptor in rare genetic obesity.

Pharmacokinetics. Orlistat is minimally absorbed. Liraglutide is daily, semaglutide and tirzepatide weekly subcutaneous injections.

Others. Setmelanotide for POMC, PCSK1 or leptin receptor deficiency and Bardet-Biedl syndrome, under specialist care. Unregulated slimming products may contain withdrawn drugs such as sibutramine, thyroid hormone, amphetamines or diuretics.

• Choice: semaglutide or tirzepatide give the greatest weight loss and cardiometabolic benefit; they are preferred where cost and supply allow, especially in type 2 diabetes. Orlistat is the cheapest option and suits those with constipation or high fat intake.
• Orlistat practicalities: omit a dose if the meal has no fat or is missed; take a multivitamin containing fat-soluble vitamins at bedtime, at least 2 hours from orlistat.
• Response check: stop or change the drug if weight loss is under 5% after 12 to 16 weeks at the maintenance dose.
• Titration: hold at each step if nausea is troublesome; do not escalate faster than every 4 weeks for injectable agents.
• Escalation: refer for metabolic surgery with BMI 40 kg/m2 or more, or 35 kg/m2 or more with comorbidity (lower thresholds in type 2 diabetes and Asian ancestry).

Special groups. Pregnancy: stop all before conception; phentermine with topiramate is teratogenic (oral clefts). Breastfeeding: avoid. Children: liraglutide 3 mg and semaglutide 2.4 mg from 12 years, orlistat from 12 years, specialist use. Older adults: loss of lean mass, so combine with protein intake and resistance exercise. Kidney impairment: maximum naltrexone with bupropion 1 tablet twice daily in moderate disease.

Liver impairment: avoid naltrexone with bupropion in severe disease. Regional: rising urban obesity, high cost and limited supply; HIV-related weight change needs separate assessment.

Adverse effects. Orlistat: oily stools, urgency, flatulence, fat-soluble vitamin deficiency, oxalate nephropathy. Naltrexone with bupropion: nausea, insomnia, headache, raised blood pressure and heart rate, seizures, and mood effects. GLP-1 based agents: nausea, vomiting, diarrhoea, gallstones, pancreatitis, and loss of lean mass. Phentermine with topiramate: paraesthesia, cognitive slowing, raised heart rate, metabolic acidosis.

Contraindications. Pregnancy for all. Medullary thyroid carcinoma or multiple endocrine neoplasia type 2 for GLP-1 based agents. Naltrexone with bupropion: seizure disorders, uncontrolled hypertension, current opioid use, eating disorders, abrupt alcohol or benzodiazepine withdrawal, and MAO inhibitors within 14 days. Orlistat: chronic malabsorption and cholestasis.

Interactions. Orlistat reduces absorption of ciclosporin, levothyroxine, warfarin, antiepileptics and fat-soluble vitamins. Naltrexone blocks opioid analgesia; bupropion inhibits CYP2D6. GLP-1 based agents need insulin and sulphonylurea dose reductions of 10 to 25% to avoid hypoglycaemia, and tirzepatide reduces oral contraceptive exposure.

Monitoring. Weight and waist at each visit, blood pressure and heart rate, mood and suicidal thoughts (naltrexone with bupropion), glucose and lipids, vitamin levels with orlistat, and reassessment at 3 months and 12 months.

Referral and escalation. Early-onset severe obesity (possible monogenic cause), BMI thresholds for surgery, pancreatitis or gallbladder pain, mood deterioration, or inadequate response.