What are the considerations and recommendations for prescribing Phentermine (Phentermine)-topiramate to a patient with a history of cardiovascular disease and potential risk for kidney stones for weight loss?

Phentermine-Topiramate in Cardiovascular Disease and Kidney Stone Risk

Phentermine-topiramate should be avoided in patients with a history of cardiovascular disease, and caution is warranted in those with significant kidney stone risk. 1, 2, 3, 4

Cardiovascular Disease: Absolute Contraindication

The FDA drug label explicitly contraindicates phentermine in patients with a history of cardiovascular disease, including coronary artery disease, stroke, arrhythmias, congestive heart failure, or uncontrolled hypertension. 4 The 2022 AGA Clinical Practice Guidelines reinforce this position, stating that phentermine-topiramate ER "should be avoided in patients with a history of cardiovascular disease or uncontrolled hypertension." 1, 2

Why This Matters for Morbidity and Mortality

• Phentermine is a sympathomimetic amine that activates the adrenergic system, causing increases in heart rate and blood pressure through norepinephrine elevation in the central nervous system 1, 2
• These hemodynamic effects increase myocardial oxygen demand, which can exacerbate underlying coronary artery disease and precipitate adverse cardiovascular events 2
• No large cardiovascular outcome trials exist for long-term phentermine-topiramate use, leaving safety in cardiovascular disease patients unestablished 1, 2
• In the pivotal CONQUER trial, while blood pressure generally declined with treatment, there was a modest increase in heart rate at higher doses 1, 5

Alternative Options for Cardiovascular Disease Patients

For patients with cardiovascular disease requiring weight loss pharmacotherapy, GLP-1 receptor agonists (semaglutide 2.4 mg or liraglutide 3.0 mg) represent safer alternatives with demonstrated cardiovascular benefits. 6 Orlistat may also be considered as it works through gastrointestinal lipase inhibition rather than sympathetic nervous system activation. 2, 6

Kidney Stone Risk: Relative Contraindication Requiring Caution

Topiramate has carbonic anhydrase inhibitor properties that induce metabolic acidosis, elevated urine pH, hypercalciuria, and hypocitraturia—all of which increase kidney stone risk, particularly with higher doses and prolonged exposure. 1

Clinical Approach to Kidney Stone History

• Caution is advised in patients with a history of significant nephrolithiasis 1
• A 2025 retrospective cohort study of over 1.1 million participants found that topiramate or zonisamide users had significantly higher hazard of symptomatic stone events compared to nonusers (HR 1.58 in commercial insurance cohort, HR 1.22 in Medicare cohort) 7
• The unadjusted cumulative incidence of symptomatic stone events between 3 months and 3 years was 2.9% among topiramate/zonisamide users versus 1.2% among nonusers 7
• The hazard of symptomatic stone events increased with higher topiramate doses 7

Monitoring Strategy If Prescribed Despite Risk

If phentermine-topiramate is considered in a patient with remote or minor kidney stone history (which should only occur after careful risk-benefit assessment):

• Periodic monitoring of serum bicarbonate levels should be implemented for patients on long-term therapy 1
• Counsel patients on adequate hydration to minimize stone formation risk 1
• Consider lower maintenance dose (7.5 mg/46 mg) rather than maximum dose (15 mg/92 mg) to reduce topiramate exposure 1
• Maintain high index of suspicion for new stone formation and discontinue if symptomatic stones develop 1

Dosing Algorithm When Appropriate

When phentermine-topiramate ER is appropriate (i.e., no cardiovascular disease history and acceptable kidney stone risk):

• Start with 3.75 mg/23 mg once daily for 14 days 1
• Escalate to maintenance dose of 7.5 mg/46 mg daily 1
• After 12 weeks, if <3% body weight loss achieved, either discontinue or escalate dose 1
• For dose escalation: titrate to 11.25 mg/69 mg daily for 14 days, then to maximum maintenance dose of 15 mg/92 mg daily 1
• If <5% weight loss after 12 weeks on maximum dose, discontinue with gradual taper (one capsule every other day for at least 1 week to minimize seizure risk) 1
• Take early in the day to minimize insomnia risk 1

Critical Monitoring Requirements

For any patient on phentermine-topiramate (when appropriately prescribed):

• Blood pressure and heart rate monitoring at every visit 1, 6, 3
• Monthly pregnancy tests for women of childbearing potential (topiramate is teratogenic) 1, 3
• Periodic serum bicarbonate levels for long-term users 1
• Baseline and periodic assessment for mood changes, anxiety, and cognitive effects 8, 9

Common Pitfalls to Avoid

• Do not confuse phentermine monotherapy with the discontinued "fen-phen" combination (phentermine-fenfluramine)—the valvular heart disease and pulmonary hypertension risks were attributed to fenfluramine, not phentermine 6, 4
• Do not prescribe within 14 days of MAOI use due to hypertensive crisis risk 3, 4
• Do not use in untreated hyperthyroidism due to arrhythmia and seizure concerns 1, 3, 4
• For patients requiring general anesthesia, be aware of potential perioperative complications including hypertensive crises, hypotension, bradycardia, and hyperthermia due to phentermine's sympathomimetic effects 1