Drug Safety

, Volume 26, Issue 14, pp 1027–1048 | Cite as

A Benefit-Risk Assessment of Sibutramine in the Management of Obesity

Review Article


Obesity is a multifactorial, chronic disorder that has reached epidemic proportions in most industrialised countries and is threatening to become a global epidemic. Clinical management of obese patients is complex and serious doubts have arisen with regard to safety and efficacy of drug therapy. Following the withdrawal of fenfluramine and dexfenfluramine in 1997, interest has focused on novel anti-obesity drugs. Pharmacological approaches to the management of obesity can, in broad terms, use different distinct strategies: firstly, to reduce energy intake; secondly, to increase energy expenditure; and thirdly, to alter the partitioning of nutrients between fat and lean tissue.

Sibutramine is a serotonin-noradrenaline (norepinephrine) reuptake inhibitor indicated for the management of obesity in conjunction with a reduced calorie diet. The pharmacological mechanisms by which sibutramine exerts its weight loss effect are likely due to a combination of reduced appetite, feelings of satiety and possibly the induction of thermogenesis.

The efficacy of sibutramine for inducing initial weight loss and the subsequent maintenance of weight loss is well proven in short- and long-term clinical trials of up to 2 years’ duration. Most individual placebo-controlled trials and pooled estimates found that the drug produced statistically significant greater weight loss than placebo at all observed endpoints (weighted mean difference for weight change at 8 weeks: −3.4kg; mean difference range for weight change at 6 months: −4.0 to −9.1kg; and at 1 year: −4.1 to −4.8kg). The most frequent dosage regimen in these trials was 10–20mg daily. Findings suggested a dose-effect relationship in terms of weight loss. Sibutramine was also associated with better weight maintenance relative to placebo (statistically significant difference). Results from mainly small trials showed that sibutramine produced more favourable outcomes in terms of loss of fat mass, reduction in body mass index and loss of ≥5–10% of initial bodyweight.

The most commonly reported adverse effects of sibutramine are headache, constipation and nausea. Certain adverse events associated with the nervous system, including dizziness, dry mouth and insomnia, are reported by >5% of patients receiving sibutramine. Increases in blood pressure and heart rate were possible adverse effects that require regular monitoring especially in obese hypertensive patients. Neither left-sided cardiac valve disease nor primary pulmonary hypertension was associated with the use of sibutramine. The assessment of the benefit-risk profile of sibutramine remained positive, although the product must be kept under regular review.



Authors declare that Center for Study and Research on Obesity is partly funded by an educational grant by Abbott (Italy).


  1. 1.
    World Health Organization. Obesity: preventing and managing the global epidemic. Geneva, Switzerland: Report of a WHO Consultation: Technical Report Series 894, 2000Google Scholar
  2. 2.
    Pi-Sunyer FX. Medical hazards of obesity. Ann Intern Med 1993; 119: 655–60PubMedGoogle Scholar
  3. 3.
    Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 2003; 348: 1625–38PubMedCrossRefGoogle Scholar
  4. 4.
    Hill JO, Wyatt HR, Read GE, et al. Obesity and the environment: where do we go from here? Science 2003; 299: 853–5PubMedCrossRefGoogle Scholar
  5. 5.
    Manson JE, Willett WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl J Med 1995; 333: 677–85PubMedCrossRefGoogle Scholar
  6. 6.
    US Department of Health and Human Services. The Surgeon General’s call to action to prevent and decrease overweight and obesity 2001. Rockville (MD): US Department of Health and Human Services, Public Health Service, Office of the Surgeon General, 2001Google Scholar
  7. 7.
    Deckelbaum RJ, Williams CL. Childhood obesity: the health issue. Obes Res 2001; 9Suppl. 4: 239S–43SPubMedCrossRefGoogle Scholar
  8. 8.
    Ogden CL, Flegal KM, Carroll MD, et al. Prevalence and trends in overweight among US children and adolescents, 1999-2000. JAMA 2002; 288: 1728–32PubMedCrossRefGoogle Scholar
  9. 9.
    Strauss RS, Pollack HA. Epidemic increase in childhood overweight, 1986-1998. JAMA 2001; 286: 2845–8PubMedCrossRefGoogle Scholar
  10. 10.
    Jackson MY. Height, weight, and body mass index of American Indian schoolchildren, 1990-1991. J Am Diet Assoc 1993; 93: 1136–40PubMedCrossRefGoogle Scholar
  11. 11.
    Wang G, Dietz WH. Economic burden of obesity in youths aged 6 to 17 years: 1979-1999. Pediatrics 2002; 109: E81–2PubMedCrossRefGoogle Scholar
  12. 12.
    Williamson DF, Pamuk E, Thun M, et al. Prospective study of intentional weight loss and mortality in never-smoking US white women aged 40-64 years. Am J Epidemiol 1995; 141: 1128–41PubMedGoogle Scholar
  13. 13.
    Gregg EW, Gerzoff RB, Thompson TJ, et al. Intentional weight loss and death in overweight and obese US adults 35 years of age and older. Ann Intern Med 2003; 138: 383–9PubMedGoogle Scholar
  14. 14.
    Hill JO, Peters JC. Environmental contributions to the obesity epidemic. Science 1998; 280: 1371–4PubMedCrossRefGoogle Scholar
  15. 15.
    Woods SC, Seeley RJ, Porte Jr D, et al. Signals that regulate food intake and energy homeostasis. Science 1998; 280: 1378–83PubMedCrossRefGoogle Scholar
  16. 16.
    Blackburn L, Miller D, Chan S. Pharmaceutical treatment of obesity. Nurs Clin North Am 1997; 32: 831–48PubMedGoogle Scholar
  17. 17.
    Tuck ML, Sowers J, Dornfeld L, et al. The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients. N Engl J Med 1981; 304: 930–3PubMedCrossRefGoogle Scholar
  18. 18.
    Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr 1992; 56: 320–8PubMedGoogle Scholar
  19. 19.
    UK prospective study on maturity onset diabetes. Effect of diet and sulphonylurea, insulin or biguainide therapy on fasting plasma glucose and body weight over a year: a multicentre study. Diabetologia 1983; 24: 404–11Google Scholar
  20. 20.
    Bosello O, Armellini F, Zamboni M, et al. The benefits of modest weight loss in type 2 diabetes. Int J Obes Relat Metab Disord 1997; 21Suppl. 1: S10–3PubMedGoogle Scholar
  21. 21.
    Tuomilehto J, Lindström J, Eriksson JG, et al. for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–50PubMedCrossRefGoogle Scholar
  22. 22.
    US Department of Health and Human Services. Diet and exercise dramatically delay type 2 diabetes: diabetes medication metformin also effective. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Available from URL: www.niddk.nih.gov/welcome/release/8_9_01.htm [Accessed 2002 Mar 12]Google Scholar
  23. 23.
    National Task Force on the Prevention and Treatment of Obesity. Long-term pharmacotherapy in the management of obesity. JAMA 1996; 276: 1907–15Google Scholar
  24. 24.
    National Heart, Lung, and Blood Institute Obesity Education Initiative. The practical guide identification, evaluation, and treatment of overweight and obesity in adults. Rockville (MD): US Department of Health and Human Services; Public Health Service; National Institutes of Health; National Heart, Lung, and Blood Institute; 2000 Oct. NIH Publication Number 00-4084Google Scholar
  25. 25.
    Manson JE, Faich GA. Pharmacotherapy for obesity: do the benefits outweigh the risks. N Engl J Med 1996; 335: 659–60PubMedCrossRefGoogle Scholar
  26. 26.
    Royal College of Physicians of London. Clinical management of overweight and obese patients with particular reference to the use of drugs. London: A report of the Royal College of Physicians of London; 1998 DecGoogle Scholar
  27. 27.
    Silverstone T. Appetite suppressants: a review. Drugs 1992; 43: 820–36PubMedCrossRefGoogle Scholar
  28. 28.
    Kernan WN, Viscoli CM, Brass LM, et al. Phenylpropanolamine and the risk of hemorrhagic stroke. N Engl J Med 2000; 343: 1826–32PubMedCrossRefGoogle Scholar
  29. 29.
    Gardin JM, Schumacher D, Constantine G, et al. Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or phentermine/fenfluramine. JAMA 2000; 283: 1703–9PubMedCrossRefGoogle Scholar
  30. 30.
    Goran MI, Treuth MS. Energy expenditure, physical activity, and obesity in children. Pediatr Clin North Am 2001; 48: 931–53PubMedCrossRefGoogle Scholar
  31. 31.
    Spruijt-Metz D, Lindquist CH, Birch LL, et al. Relation between mothers’ child-feeding practices and children’s adiposity. Am J Clin Nutr 2002; 75: 581–6PubMedGoogle Scholar
  32. 32.
    Robinson TN. Reducing children’s television viewing to prevent obesity: a randomized controlled trial. JAMA 1999; 282: 1561–7PubMedCrossRefGoogle Scholar
  33. 33.
    Heal D, Aspley S, Prow MR, et al. Sibutramine: a novel antiobesity drug: a review of the pharmacological evidence to differentiate it from d-amphetamine and d-fenfluramine. Int J Obes 1998; 22Suppl. 1: S18–28Google Scholar
  34. 34.
    Casado A, Rodriguez VM, Portillo MP, et al. Sibutramine decreases body weight gain and increases energy expenditure in obese Zucker rats without changes in NPY and orexins. Nutr Neurosci 2003; 6(2): 103–11PubMedCrossRefGoogle Scholar
  35. 35.
    Levin BE, Dunn-Meynell AA. Sibutramine alters the central mechanisms regulating the defended body weight in diet-induced obese rats. Am J Physiol Regul Integr Comp Physiol 2000; 279(6): R2222–8PubMedGoogle Scholar
  36. 36.
    McNeely W, Goa KL. Sibutramine: a review of its contribution to the management of obesity. Drugs 1998; 56: 1093–124PubMedCrossRefGoogle Scholar
  37. 37.
    Knoll Limited, Nottingham. (Data on file)Google Scholar
  38. 38.
    Fantino M. Decrease of food intake and weight loss induced by sibutramine in the rat [abstract]. Obes Res 1995; 3Suppl. 4: S628Google Scholar
  39. 39.
    Stricker-Krongrad A, Burlet C, Souquet AM, et al. Sibutramine effects on feeding behaviour: a dose-dependence and microstructural analysis [abstract]. Obes Res 1995; 3Suppl. 4: 631SGoogle Scholar
  40. 40.
    Stricker-Krongrad A, Souquet AM, Burlet C. Effects of sibutramine on feeding behaviour in obese and lean Zucker rats [abstract]. Int J Obes 1995; 19Suppl. 2: P399Google Scholar
  41. 41.
    Stricker-Krongrad A, Souquet AM, Burlet C. Effects of sibutramine on feeding behaviour in dietary-induced obesity: a role of dietary components [abstract]. Int J Obes 1995; 19Suppl. 2: P398Google Scholar
  42. 42.
    Halford JCG, Wanninayake SC, Blundell JE. Behavioral satiety sequence (BSS) for the diagnosis of drug action on food intake. Pharmacol Biochem Behav 1998; 61: 159–68PubMedCrossRefGoogle Scholar
  43. 43.
    Connoley IP, Liu YL, Frost I, et al. Thermogenic effect of sibutramine and its metabolites. Br J Pharmacol 1999; 126: 1487–95PubMedCrossRefGoogle Scholar
  44. 44.
    Stock MJ. Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Int J Obes 1997; 21Suppl. 1: S25–9Google Scholar
  45. 45.
    Rolls BJ, Shide DJ, Thorwart ML, et al. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 1998; 6: 1–11PubMedGoogle Scholar
  46. 46.
    Danforth Jr E. Sibutramine and thermogenesis in humans. Int J Obes 1999; 23: 1007–8CrossRefGoogle Scholar
  47. 47.
    Hansen DL, Toubro S, Stock MJ, et al. Thermogenic effects of sibutramine in humans. Am J Clin Nutr 1998; 68: 1180–6PubMedGoogle Scholar
  48. 48.
    Walsh KM, Leen E, Lean MEJ. The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females. Int J Obes 1999; 23: 1009–15CrossRefGoogle Scholar
  49. 49.
    Hansen DL, Toubro S, Stock MJ, et al. The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. Int J Obes 1999; 23: 1016–24CrossRefGoogle Scholar
  50. 50.
    Di Chiara G, Acquas E, Tanda G, et al. Drugs of abuse: biochemical surrogates of specific aspects of natural reward? Biochem Soc Symp 1993; 59: 65–81PubMedGoogle Scholar
  51. 51.
    Heal DJ, Frankland AT, Gosden J, et al. A comparison of the effects of sibutramine hydrochloride, bupropion and methamphetamine on dopaminergic function: evidence that dopamine is not a pharmacological target for sibutramine. Psychopharmacology (Berl) 1992; 107: 303–9CrossRefGoogle Scholar
  52. 52.
    Cole JO, Levin A, Beake B, et al. Sibutramine: a new weight loss agent without evidence of the abuse potential associated with amphetamines. J Clin Psychopharmacol 1998; 18: 231–6PubMedCrossRefGoogle Scholar
  53. 53.
    Foltin RW, Fischman MW. Assessment of the abuse liability of stimulant drugs in humans: a methodological survey. Drug Alcohol Depend 1991; 28: 3–48PubMedCrossRefGoogle Scholar
  54. 54.
    Schuh LM, Schuster CR, Hopper JA, et al. Abuse liability assessment of sibutramine, a novel weight control agent. Psychopharmacology (Berl) 2000; 147: 339–46CrossRefGoogle Scholar
  55. 55.
    Nisoli E, Carruba M. An assesssment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action. Obes Rev 2000; 1: 127–39PubMedCrossRefGoogle Scholar
  56. 56.
    Bray GA. Drug treatment of obesity. Rev Endocr Metab Disord 2001; 2: 403–18PubMedCrossRefGoogle Scholar
  57. 57.
    Luque CA, Rey JA. The discovery and status of sibutramine as an anti-obesity drug. Eur J Pharmacol 2002; 440: 119–28PubMedCrossRefGoogle Scholar
  58. 58.
    O’Meara S, Riemsma R, Shirran L, Mather L, ter Riet G, The clinical effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology assessment. Health Technol Assess 2002; 6(6): 1–97PubMedGoogle Scholar
  59. 59.
    James WPT, Astrup A, Finer N, et al. for the STORM Study Group. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000; 356: 2119–25PubMedCrossRefGoogle Scholar
  60. 60.
    Apfelbaum M, Vague P, Ziegler O, et al. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med 1999; 106: 179–84PubMedCrossRefGoogle Scholar
  61. 61.
    Knoll. Submission to National Institute for Clinical Excellence (NICE); 2000. Report No. SB1047 (Smith IG, 1994) Nottingham: Knoll LimitedGoogle Scholar
  62. 62.
    Knoll. Submission to National Institute for Clinical Excellence (NICE); 2000. (Rissanen AM, 1998) Nottingham: Knoll Limited. Report No. SB5078Google Scholar
  63. 63.
    Knoll. Submission to National Institute for Clinical Excellence (NICE); 2000. (Williams G, 1999) Nottingham: Knoll Limited. Report No. SB6085Google Scholar
  64. 64.
    McNulty SJ, Ur E, Williams G. A randomized trial of sibutramine in the management of obese type 2 diabetic patients treated with metformin. Diabetes Care 2003; 26(1): 125–31PubMedCrossRefGoogle Scholar
  65. 65.
    Bray GA, Blackburn GL, Ferguson JM, et al. Sibutramine produces dose-related weight loss. Obes Res 1999; 7: 189–98PubMedGoogle Scholar
  66. 66.
    Fanghanel G, Cortinas L, Sanchez Reyes L, et al. A clinical trial of the use of sibutramine for the treatment of patients suffering essential obesity. Int J Obes 2000; 24: 144–50CrossRefGoogle Scholar
  67. 67.
    Cuellar GEM, Ruiz AM, Monsalve MCR, et al. Six-month treatment of obesity with sibutramine 15mg: a double-blind, placebo-controlled monocenter clinical trial in a Hispanic population. Obes Res 2000; 8: 71–82PubMedCrossRefGoogle Scholar
  68. 68.
    Fujioka K, Seaton TB, Rowe E, et al. Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus. Diabetes Obes Metab 2000; 2: 175–87PubMedCrossRefGoogle Scholar
  69. 69.
    Gokcel A, Karakose H, Ertorer EM, et al. Effects of sibutramine in obese female subjects with type 2 diabetes and poor blood glucose control. Diabetes Care 2001; 24(11): 1957–60PubMedCrossRefGoogle Scholar
  70. 70.
    Serrano-Rios M, Melchionda N, Moreno-Carretero E. Role of sibutramine in the treatment of obese type 2 diabetic patients receiving sulphonylurea therapy. Diabet Med 2002; 19(2): 119–24PubMedCrossRefGoogle Scholar
  71. 71.
    Hanotin C, Thomas F, Jones SP, et al. A comparison of sibutramine and dexfenfluramine in the treatment of obesity. Obes Res 1998; 6: 285–91PubMedGoogle Scholar
  72. 72.
    Finer N, Bloom SR, Frost GS, et al. Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised, double-blind, placebo-controlled study. Diabetes Obes Metab 2000; 2: 105–12PubMedCrossRefGoogle Scholar
  73. 73.
    Hanotin C, Thomas F, Jones SP, et al. Efficacy and tolerability of sibutramine in obese patients: a dose-ranging study. Int J Obes 1998; 22: 32–8CrossRefGoogle Scholar
  74. 74.
    Weintraub M, Rubio A, Golik A, et al. Sibutramine in weight control: a dose-ranging, efficacy study. Clin Pharmacol Ther 1991; 50: 330–7PubMedCrossRefGoogle Scholar
  75. 75.
    Seagle HM, Bessesen DH, Hill JO. Effects of sibutramine on resting metabolic rate and weight loss in overweight women. Obes Res 1998; 6: 115–21PubMedGoogle Scholar
  76. 76.
    Scheen AJ, Ernest P. New antiobesity agents in type 2 diabetes: overview of clinical trials with sibutramine and orlistat. Diabetes Metab 2002; 28: 437–45PubMedGoogle Scholar
  77. 77.
    Berkowitz RI, Wadden TA, Tershakovec AM, et al. Behavior therapy and sibutramine for the treatment of adolescent obesity: a randomized controlled trial. JAMA 2003; 289: 1805–12PubMedCrossRefGoogle Scholar
  78. 78.
    Bach DS, Rissanen AM, Mendel CM, et al. Absence of cardiac valve dysfunction in obese patients treated with sibutramine. Obes Res 1999; 7: 363–9PubMedGoogle Scholar
  79. 79.
    Fitzgerald LW, Burn TC, Brown BS, et al. Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol 2000; 57: 75–81PubMedGoogle Scholar
  80. 80.
    Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–16PubMedCrossRefGoogle Scholar
  81. 81.
    Fishman AP. Appetite suppressant drugs and pulmonary hypertension [letter]. N Engl J Med 1997; 336: 511PubMedGoogle Scholar
  82. 82.
    Cortijo J, Marti-Cabrera M, Bernabeu E, et al. Characterization of 5-HT receptors on human pulmonary artery and vein: functional and binding studies. Br J Pharmacol 1997; 122: 1455–63PubMedCrossRefGoogle Scholar
  83. 83.
    Perchenet L, Hilfiger L, Mizrahi J, et al. Effects of anorexinogen agents on cloned voltage-gated K(+) channel hKv1.5. J Pharmacol Exp Ther 2001; 298(3): 1108–19PubMedGoogle Scholar
  84. 84.
    Van Gaal LF, Wauters MA, De Leew IH. Anti-obesity drugs: what does sibutramine offer? An analysis of its potential contribution to obesity treatment. Exp Clin Endocrinol Diabetes 1998; 106Suppl. 2: 35–40PubMedCrossRefGoogle Scholar
  85. 85.
    European Agency for the Evaluation of Medicinal Products. Committee for Proprietary Medicinal Products Meeting of 25-27 June 2002 [press release; online]. Available from URL: http://www.emea.eu.int/htms/hotpress/h306502.htm. [Accessed 2002 Nov 1]Google Scholar
  86. 86.
    Lean MEJ. Sibutramine: a review of clinical efficacy. Int J Obes 1997; 21: S30–6Google Scholar
  87. 87.
    Sharma AM. Sibutramine in overweight/obese hypertensive patients. Int J Obes Relat Metab Disord 2001; 25Suppl. 4: S20–3PubMedCrossRefGoogle Scholar
  88. 88.
    Product Information: Meridia®, sibutramine capsules. Knoll Pharmaceutical Company, Mount Olive (NJ), (PI revised 11/1999) reviewed 3/2002Google Scholar
  89. 89.
    King DJ, Devaney N. Clinical pharmacology of sibutramine hydrochloride (BTS 54524), a new antidepressant, in healthy volunteers. Br J Clin Pharmacol 1988; 26: 607–11PubMedCrossRefGoogle Scholar
  90. 90.
    Hazenberg BP. Randomized, double-blind, placebo-controlled, multicenter study of sibutramine in obese hypertensive patients. Cardiology 2000; 94(3): 152–8PubMedCrossRefGoogle Scholar
  91. 91.
    FDC reports: The Pink Sheet. 1996 Sep 30; 10–12Google Scholar
  92. 92.
    Birkenfeld AL, Schroeder C, Boschmann M, et al. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation 2002; 106(19): 2459–65PubMedCrossRefGoogle Scholar
  93. 93.
    Lean MEJ. How does sibutramine work? Int J Obes 2001; 25Suppl. 4: S8–S11CrossRefGoogle Scholar
  94. 94.
    Singh RB, Rastogi SS, Verma R, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. BMJ 1992; 304(6833): 1015–9PubMedCrossRefGoogle Scholar
  95. 95.
    Pi-Sunyer FX. Guidelines for the approval and use of drugs to treat obesity: a position paper for the Study of Obesity. Obes Res 1995; 3: 473–8Google Scholar

Copyright information

© Adis Data Information BV 2003

Authors and Affiliations

  1. 1.Center for Study and Research on Obesity, Department of Preclinical SciencesUniversity of Milan, LITA Vialba, Luigi Sacco HospitalMilanItaly
  2. 2.Istituto Auxologico ItalianoMilanItaly

Personalised recommendations