What oral drug can be recommended for appetite suppression in a patient with potential cardiovascular disease, glaucoma, or hyperthyroidism?

Oral Appetite Suppressants: Recommendations for Patients with Cardiovascular Disease, Glaucoma, or Hyperthyroidism

Avoid phentermine and phentermine-containing combinations in patients with cardiovascular disease, glaucoma, or hyperthyroidism, as these are absolute contraindications. 1 Instead, use orlistat, liraglutide 3.0 mg, semaglutide, or tirzepatide, which do not carry sympathomimetic risks. 2, 3

Contraindications to Phentermine-Based Medications

Phentermine and phentermine/topiramate ER are absolutely contraindicated in the following conditions: 1, 2

• Cardiovascular disease (coronary artery disease, stroke, arrhythmias, congestive heart failure, uncontrolled hypertension) 1
• Hyperthyroidism 1, 2
• Glaucoma 1, 2
• History of drug abuse 1
• During or within 14 days of MAOI use 1
• Pregnancy and breastfeeding 1

The mechanism underlying these contraindications is phentermine's potent noradrenergic activity—it promotes norepinephrine release while blocking reuptake, causing sympathomimetic effects including elevated heart rate and blood pressure. 4, 3

Recommended Alternatives Based on Comorbidities

For Patients with Cardiovascular Disease

Prioritize GLP-1 receptor agonists (liraglutide 3.0 mg, semaglutide, tirzepatide), which provide superior weight loss without sympathomimetic cardiovascular risks: 5, 3

• Semaglutide: 11.4% greater weight loss versus placebo (5 RCTs, 4421 participants) 3
• Tirzepatide 15 mg: 12.4% greater weight loss versus placebo (6 RCTs, 1972 participants) 3
• Liraglutide 3.0 mg: 4.7% greater weight loss versus placebo (18 RCTs, 6321 participants) 3

These medications work through nutrient-stimulated hormone pathways that modify central appetite regulation without activating the sympathetic nervous system. 3 Common adverse effects include nausea (28%-44%), diarrhea (21%-30%), and constipation (11%-24%). 3

Orlistat is the safest cardiovascular option if GLP-1 agonists are unavailable or unaffordable, as it works peripherally by inhibiting gastrointestinal lipases rather than affecting the sympathetic nervous system: 5, 2

• 3.1% greater weight loss versus placebo (52 RCTs, 16,964 participants) 3
• Dosing: 120 mg three times daily with meals 2
• Side effects: steatorrhea, fecal urgency, oily spotting (>25% of patients) 2, 3
• Requires fat-soluble vitamin supplementation 2

For Patients with Glaucoma

Use orlistat or GLP-1 receptor agonists, as phentermine's sympathomimetic effects can trigger acute angle-closure glaucoma. 1, 2 The same alternatives recommended for cardiovascular disease apply. 5, 3

For Patients with Hyperthyroidism

Avoid phentermine completely due to additive sympathomimetic effects with thyroid hormone excess. 1, 2 Use orlistat or GLP-1 receptor agonists instead. 5, 3

Alternative Appetite Suppressants Without These Contraindications

Lorcaserin (Note: Withdrawn from Market)

While previously approved, lorcaserin was voluntarily withdrawn in 2020 due to cancer concerns identified in long-term cardiovascular outcome trials. 2 Do not prescribe lorcaserin. This medication is mentioned only for historical context.

Naltrexone ER/Bupropion ER

This combination is an option for patients with cardiovascular contraindications to phentermine, though it requires caution: 2, 3

• 4.1% greater weight loss versus placebo (6 RCTs, 9,949 participants) 3
• Mechanism: opioid receptor antagonist combined with dopamine/norepinephrine reuptake inhibitor 2
• Contraindications: uncontrolled hypertension, seizure history, eating disorders, current opioid use 2
• Common side effects: nausea, constipation, headache (approximately 20%) 3
• Monitor blood pressure, as bupropion can elevate it 2

Clinical Decision Algorithm

Step 1: Screen for absolute contraindications to phentermine 1, 2

• Cardiovascular disease? → Yes = Avoid phentermine
• Glaucoma? → Yes = Avoid phentermine
• Hyperthyroidism? → Yes = Avoid phentermine
• Any other contraindication from FDA label? → Yes = Avoid phentermine

Step 2: If any contraindication present, select alternative 5, 3

• First choice: GLP-1 receptor agonist (semaglutide > tirzepatide > liraglutide based on efficacy) 3
• Second choice: Orlistat (if cost is prohibitive or GLP-1 agonists unavailable) 5, 2
• Third choice: Naltrexone/bupropion (if no seizure history or uncontrolled hypertension) 3, 2

Step 3: Counsel on mechanism and side effects 3, 2

• GLP-1 agonists: expect nausea initially, improves with time 3
• Orlistat: requires low-fat diet to minimize GI side effects 2
• Naltrexone/bupropion: monitor blood pressure 2

Common Pitfalls to Avoid

Do not confuse phentermine monotherapy with "fen-phen" (phentermine-fenfluramine), which was withdrawn due to valvular heart disease and pulmonary hypertension—these risks were attributed to fenfluramine, not phentermine. 5 However, this historical context does not change the absolute contraindications for phentermine in cardiovascular disease, glaucoma, and hyperthyroidism. 1

Do not prescribe phentermine/topiramate ER to patients with glaucoma, as both components carry this contraindication—phentermine due to sympathomimetic effects and topiramate due to risk of acute angle-closure glaucoma. 2

Do not assume all appetite suppressants work through the same mechanism. Orlistat works peripherally in the GI tract, GLP-1 agonists work through hormone pathways, and phentermine works through noradrenergic sympathetic activation—only the latter is contraindicated in these specific conditions. 2, 3, 4