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Sibutramine: possible cause of a reversible cardiomyopathy
International Journal of Cardiology 99 (2005) 481 – 482 www.elsevier.com/locate/ijcard
Letter to the Editor
Sibutramine: Possible cause of a reversible cardiomyopathy Tamer Sayin *, Muharrem Gu¨ldal Department of Cardiology, Heart Center, Ankara University, Ankara, Turkey Received 7 November 2003; accepted 18 November 2003 Available online 3 August 2004
Keywords: Sibutramine; Heart failure; Cardiomyopathy
1. Introduction Obesity is an ever increasing worldwide epidemic [1]. Treatment necessitates an interdisciplinary approach and there are not many choices for pharmacological treatment of obesity. Sibutramine, a drug used for treating obesity, acts centrally by inhibiting hypothalamic neuronal re-uptake of noradrenalin and serotonin. Frequent side effects include dry mouth, insomnia, asthenia and constipation. The drug produces small increases in blood pressure and pulse and that is why it is contraindicated in some individuals with heart disease.
2. Case presentation Thirty-six-year-old male, obese (125 kg body mass index of 38), physician patient was initiated sibutramine 15 mg/ day to treat obesity in May 2001. In October 2001, the patient reports an upper airway tract infection. In November 2001, the patient began to have progressively increasing fatigue, effort intolerance, weight gain, ankle edema and nocturnal dyspnea. In January 2002, the patient was admitted to our clinic with all signs and symptoms of heart failure. An echocardiographic study revealed a dilated left ventricle with diffuse hypokinesia. Ejection fraction was measured 22% with radionuclide ventriculography. A coronary angiography showed normal coronary arteries. Ceasing sibutramine, the patient was treated and discharged with furosemide, spironalactone, metoprolol, ¨ niversitesi Kalp Merkezi, 06100 * Corresponding author. Ankara U Cebeci, Ankara, Turkey. Tel.: +90 312 362 30 30/6744; fax: +90 312 363 22 89. E-mail address: [email protected] (T. Sayin). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.11.060
digoxine, low-dose aspirin and ramipril. The patient responded well to the treatment and both his clinical status and his echocardiographic measurements improved during the follow-up period. A control radionuclide ventriculography performed because of somewhat suboptimal echocardiographic studies revealed an ejection fraction of 47% (one year later than the initial radionuclide study). The patient has class 1 symptomatology since then. He has rare ventricular extrasystoles and a few hypokinetic segments with echocardiography.
3. Discussion We believe that, in our patient it is neither possible to prove or disprove a cause-and-effect relationship of sibutramine for the clinical picture. We have a history of 6 months of exposure to sibutramine just before symptom onset. Fenfluramine and dexfenfluramin, anorectic drugs, which act through different but somewhat similar ways, were drawn from the market because of some valvular abnormalities and increased risk of primary pulmonary hypertension (PPH) [2]. It was reported that fenfluramine and its derivatives, after an exposure of 3 months or more increased the risk of having PPH by 23 times [3]. The exact pathophysiological explanation for this important side effect is not clear. The point making the issue complex and unresolved is the anamnesis of upper airway tract infection 3 weeks before the onset of heart failure symptoms. We may have experienced a viral myocarditis with almost full recovery. However, viral myocarditis may still not be a valid explanation because we know that rate of biopsy proven myocarditis, in unexplained recent heart failure is less than 10% [4]. That is why we can claim that myocarditis is not so common in unexplained recent heart failure. Though we do not want to label sibutramine as potential cardiotoxic without strong
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T. Sayin, M. Gu¨ldal / International Journal of Cardiology 99 (2005) 481–482
data, we felt that it would not be prudent to totally ignore a possible causal relationship in this particular case. Furthermore, recently, there has been some warning reports for sibutramine about worsening of hypertension and cardiac arrhythmias [5,6] and the drug has now been banned in some European countries because of cardiac deaths which may have been due to this drug. It is difficult to make a meaningful pathophysiological explanation if the clinical picture was due to sibutramine. The same issues hold true for the historical anorectic drugs fenfluramine and dexfenfluramine. Since the drug inhibits neuronal re-uptake of norepinephrine, we can speculate that the drug might have caused a cathecholaminergic myocarditis picture. To our knowledge, this is the first case report of sibutramine for a reversible cardiomyopathy picture.
4. Conclusion Sibutramine might have a causal role for a reversible cardiomyopathy picture. As always, careful, watchful wait-
ing is necessary for recently or relatively recently marketed drugs. References [1] WHO. Obesity: preventing and managing the global epidemic. Report of A WHO Consultation on Obesity. Geneva: World Health Organization; 1997 June 3 – 5. [2] Van Gaal LF, Mertens IL, De Leeuw IH. Recent and Future Drugs for the Treatment of Obesity. In: Bjo¨rntorp P. editor. International Textbook of Obesity. Geneva: Wiley; 2002. pp. 451 – 69. [3] Abenheim L, Moride Y, Brenot F, et al. For the international primary pulmonary hypertension study group. Appetite-suppressant drugs and the risk of pulmonary hypertension. N Engl J Med 1996;335:609 – 16. [4] Chow LC, Dittrich HL, Shabetai R. Endomyocardial biopsy in patients with unexplained congestive heart failure. Ann Intern Med 1988;109: 535 – 9. [5] Deitel M. Sibutramine warning: hypertension and cardiac arrhythmias reported. Obes Surg 2002;12:422. [6] Wooltorton E. Obesity drug sibutramine (Meridia): hypertension and cardiac arrhythmias. CMAJ 2002;166:1307 – 8.
Letter to the Editor
Sibutramine: Possible cause of a reversible cardiomyopathy Tamer Sayin *, Muharrem Gu¨ldal Department of Cardiology, Heart Center, Ankara University, Ankara, Turkey Received 7 November 2003; accepted 18 November 2003 Available online 3 August 2004
Keywords: Sibutramine; Heart failure; Cardiomyopathy
1. Introduction Obesity is an ever increasing worldwide epidemic [1]. Treatment necessitates an interdisciplinary approach and there are not many choices for pharmacological treatment of obesity. Sibutramine, a drug used for treating obesity, acts centrally by inhibiting hypothalamic neuronal re-uptake of noradrenalin and serotonin. Frequent side effects include dry mouth, insomnia, asthenia and constipation. The drug produces small increases in blood pressure and pulse and that is why it is contraindicated in some individuals with heart disease.
2. Case presentation Thirty-six-year-old male, obese (125 kg body mass index of 38), physician patient was initiated sibutramine 15 mg/ day to treat obesity in May 2001. In October 2001, the patient reports an upper airway tract infection. In November 2001, the patient began to have progressively increasing fatigue, effort intolerance, weight gain, ankle edema and nocturnal dyspnea. In January 2002, the patient was admitted to our clinic with all signs and symptoms of heart failure. An echocardiographic study revealed a dilated left ventricle with diffuse hypokinesia. Ejection fraction was measured 22% with radionuclide ventriculography. A coronary angiography showed normal coronary arteries. Ceasing sibutramine, the patient was treated and discharged with furosemide, spironalactone, metoprolol, ¨ niversitesi Kalp Merkezi, 06100 * Corresponding author. Ankara U Cebeci, Ankara, Turkey. Tel.: +90 312 362 30 30/6744; fax: +90 312 363 22 89. E-mail address: [email protected] (T. Sayin). 0167-5273/$ - see front matter D 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2003.11.060
digoxine, low-dose aspirin and ramipril. The patient responded well to the treatment and both his clinical status and his echocardiographic measurements improved during the follow-up period. A control radionuclide ventriculography performed because of somewhat suboptimal echocardiographic studies revealed an ejection fraction of 47% (one year later than the initial radionuclide study). The patient has class 1 symptomatology since then. He has rare ventricular extrasystoles and a few hypokinetic segments with echocardiography.
3. Discussion We believe that, in our patient it is neither possible to prove or disprove a cause-and-effect relationship of sibutramine for the clinical picture. We have a history of 6 months of exposure to sibutramine just before symptom onset. Fenfluramine and dexfenfluramin, anorectic drugs, which act through different but somewhat similar ways, were drawn from the market because of some valvular abnormalities and increased risk of primary pulmonary hypertension (PPH) [2]. It was reported that fenfluramine and its derivatives, after an exposure of 3 months or more increased the risk of having PPH by 23 times [3]. The exact pathophysiological explanation for this important side effect is not clear. The point making the issue complex and unresolved is the anamnesis of upper airway tract infection 3 weeks before the onset of heart failure symptoms. We may have experienced a viral myocarditis with almost full recovery. However, viral myocarditis may still not be a valid explanation because we know that rate of biopsy proven myocarditis, in unexplained recent heart failure is less than 10% [4]. That is why we can claim that myocarditis is not so common in unexplained recent heart failure. Though we do not want to label sibutramine as potential cardiotoxic without strong
482
T. Sayin, M. Gu¨ldal / International Journal of Cardiology 99 (2005) 481–482
data, we felt that it would not be prudent to totally ignore a possible causal relationship in this particular case. Furthermore, recently, there has been some warning reports for sibutramine about worsening of hypertension and cardiac arrhythmias [5,6] and the drug has now been banned in some European countries because of cardiac deaths which may have been due to this drug. It is difficult to make a meaningful pathophysiological explanation if the clinical picture was due to sibutramine. The same issues hold true for the historical anorectic drugs fenfluramine and dexfenfluramine. Since the drug inhibits neuronal re-uptake of norepinephrine, we can speculate that the drug might have caused a cathecholaminergic myocarditis picture. To our knowledge, this is the first case report of sibutramine for a reversible cardiomyopathy picture.
4. Conclusion Sibutramine might have a causal role for a reversible cardiomyopathy picture. As always, careful, watchful wait-
ing is necessary for recently or relatively recently marketed drugs. References [1] WHO. Obesity: preventing and managing the global epidemic. Report of A WHO Consultation on Obesity. Geneva: World Health Organization; 1997 June 3 – 5. [2] Van Gaal LF, Mertens IL, De Leeuw IH. Recent and Future Drugs for the Treatment of Obesity. In: Bjo¨rntorp P. editor. International Textbook of Obesity. Geneva: Wiley; 2002. pp. 451 – 69. [3] Abenheim L, Moride Y, Brenot F, et al. For the international primary pulmonary hypertension study group. Appetite-suppressant drugs and the risk of pulmonary hypertension. N Engl J Med 1996;335:609 – 16. [4] Chow LC, Dittrich HL, Shabetai R. Endomyocardial biopsy in patients with unexplained congestive heart failure. Ann Intern Med 1988;109: 535 – 9. [5] Deitel M. Sibutramine warning: hypertension and cardiac arrhythmias reported. Obes Surg 2002;12:422. [6] Wooltorton E. Obesity drug sibutramine (Meridia): hypertension and cardiac arrhythmias. CMAJ 2002;166:1307 – 8.