Is Tesofensine (a serotonin-norepinephrine-dopamine reuptake inhibitor) effective and safe for weight loss?

Tesofensine for Weight Loss: Efficacy and Safety

Tesofensine, a triple monoamine reuptake inhibitor (inhibiting noradrenaline, dopamine, and serotonin reuptake), is not currently FDA-approved for weight loss and cannot be recommended as a first-line treatment for obesity based on available evidence and guidelines.

Efficacy of Tesofensine

• Tesofensine has shown promising results in clinical trials, with weight loss approximately twice that of currently approved medications, producing 9.2% weight loss with the 0.5mg dose over 24 weeks compared to 2% with placebo 1
• In short-term studies (2 weeks), tesofensine induced a 1.8kg weight loss above placebo, with increased ratings of satiety and fullness 2
• The weight loss effects appear to work through multiple mechanisms including appetite suppression and modest increases in energy expenditure during night periods (4.6%) 2
• Animal studies suggest tesofensine may normalize dopamine levels in the brain that are reduced in obesity, potentially addressing the neurochemical basis for overeating 3

Safety Concerns

• Common adverse effects include dry mouth, nausea, constipation, hard stools, diarrhea, and insomnia 1
• Cardiovascular effects include increased heart rate (7.4 beats per minute with 0.5mg dose), though no significant increases in blood pressure were noted at the 0.25mg and 0.5mg doses in the 24-week trial 1
• Long-term safety data (beyond 24 weeks) is lacking, which is a significant concern for chronic weight management therapy 4

Current Guideline Recommendations

• Current guidelines do not include tesofensine among recommended weight loss medications 4
• FDA-approved medications for long-term weight management include orlistat, phentermine-topiramate, naltrexone-bupropion, liraglutide, and semaglutide 4
• Guidelines emphasize that pharmacotherapy should be considered only after failure of lifestyle modifications (diet and exercise) 4
• Weight loss medications generally produce modest results (<5kg at 1 year) and lack evidence for long-term mortality benefits 4

Comparison to Other Agents

• In animal studies, tesofensine (2.5mg/kg) produced greater sustained weight loss (9.9%) compared to sibutramine (7.6%) and rimonabant (transient effect only) 5
• Tesofensine's 9.2% weight loss at 24 weeks exceeds the typical 3-5kg weight loss seen with other pharmacotherapies over 6 months 1, 6
• Unlike some other agents, tesofensine appears to improve glycemic control beyond what would be expected from weight loss alone in animal models 5

Clinical Approach

• First-line therapy for obesity should always be lifestyle modification through diet and exercise 4
• Pharmacotherapy should only be considered for patients with BMI ≥30 kg/m² or ≥27 kg/m² with obesity-related comorbidities who have failed lifestyle interventions 4
• If considering pharmacotherapy, FDA-approved medications should be used first 4
• Efficacy of weight loss medications should be assessed after 3 months; if <5% weight loss is achieved, the medication should be discontinued 4

Conclusion

While tesofensine shows promise with potentially greater weight loss than currently available medications, it lacks FDA approval and long-term safety data. Until more comprehensive safety data and regulatory approval are available, established FDA-approved weight loss medications should be preferred for pharmacological management of obesity.