Sibutramine – Mildly Effective, But At A Great Risk

Use of serotonergic drugs (drugs that potentiate the actions of serotonin) has emerged as a new and exciting way of causing weight loss. Sibutramine is one such drug. Although used extensively, sibutramine was withdrawn from the market by the FDA because of cardiovascular toxicity.

Although, there is no doubt that sibutramine causes a mild degree of weight loss, there is great amount of disparity amongst researchers regarding the adverse effects profile of sibutramine – especially, the graver affective disorders like depression and suicidal tendencies. Currently, however, the evidence against sibutramine seems to be more convincing.

Today, Orlistat remains the only drug available for long-term treatment of obesity (Hauptman, Jeunet, & Hartmann, 1992; Williams, 2010; Araujo & Martel, 2012).

Recently, however, use of serotonergic drugs (drugs that potentiate the actions of serotonin) has emerged as a new and exciting way of causing weight loss. These drugs have been shown to reduce appetite and stimulate resting energy expenditure. Some of these are fluoxetine, sertraline, sibutramine, fluvoxamine, desipramine, imipramine and topiramate (Lam, Garfield, Marston, Shaw, & Heisler, 2010). All of these drugs have shown superiority over placebo in causing weight loss (Walsh et al., 1997).

Sibutramine, marketed as Meridia (by Abbott) – although used extensively and shown to be effective in causing mild degrees of weight loss was withdrawn from the market by the FDA because of cardiovascular toxicity (Goldenberg, 2012; Cello & Rogers, 2013; Doslikova et al., 2013; Connolly et al., 1997; Rucker, Padwal, Li, Curioni, & Lau, 2007; James et al., 2010; An, Sohn, & Chung, 2013).

Was sibutramine was really effective in reducing body weight? And, what were the adverse effects it caused? Let us have a look.

So, What is Sibutramine and How Does it Reduce Body Weight?

Sibutramine is a monoamine reuptake inhibitor (Cello & Rogers, 2013).

A monoamine, 5-Hydroxytryptamine (5-HT) – better known as serotonin – has been shown to be inherently linked to energy balance (Fernstrom & Wurtman, 1972; Tecott, 2007; Doslikova et al., 2013). Drugs or supplement ingredients that increase the level of 5-HT either by stimulating its release or suppressing reuptake of already secreted 5-HT have been shown to cause weight loss. As stated earlier, sibutramine belongs to this class of 5-HT (monoamine) reuptake inhibitors.

In addition to serotonin, other monoamines that are prevented from reuptake are noradrenaline (NA) and to a smaller extent, dopamine (DA) (An et al., 2013; Nisoli & Carruba, 2000).

Use of sibutramine with resultant increase in levels of 5-HT and NA potentiates the actions of these monoamines. This causes weight loss by the following mechanisms (An et al., 2013; Nisoli & Carruba, 2003; Halford, Wanninayake, & Blundell, 1998; Connoley et al., 1999):

  • Feeling of satiety,
  • Decreased food intake, and
  • Increased resting energy expenditure

What is the Recommended Dose of Sibutramine for Causing Weight Loss?

Recommended doses of sibutramine tended to vary. To test its effectiveness in causing weight loss, researchers have used doses from 10-20 mg/day either alone or in combination with dietary restriction and lifestyle changes (Wadden et al., 2005; Nisoli & Carruba, 2003).

It is of interest to note here that sibutramine with decreased calorie intake and lifestyle improvements have shown better results than sibutramine alone (see below).

Sibutramine was recommended to be taken as under:

  • 10-20 mg/day, in combination with
  • Dietary restriction, and
  • Lifestyle improvements

Was the Use of Sibutramine Associated with Adverse Effects?

Although it was mildly effectiveness in causing weight loss, FDA withdrew sibutramine from the market owing to the presence of adverse effects – especially, affective disorders like depression and suicidal ideation.

Adverse effects attributed to use of sibutramine (Berkowitz, Wadden, Tershakovec, & Cronquist, 2003; Berkowitz et al., 2006; Cello & Rogers, 2013; Nisoli & Carruba, 2003) are:

  • Headache,
  • Constipation,
  • Nausea,
  • Hypertension (raised blood pressure),
  • Tachycardia (elevated heart rate),
  • Cholelithiasis (formation of gall stones),
  • Depression , and
  • Suicidal ideation

What do Researchers Have to Say About the Effectiveness and Safety of Sibutramine?

  1. Effectiveness
    • There is more than ample evidence to suggest that sibutramine may cause a mild degree of weight loss. However, it may not be as effective in the absence of calorie restriction.
    • According to Cello et al., the weight-reducing abilities of sibutramine are limited – use of sibutramine will allow for an extra weight loss of only 4-5 kilograms over the duration of a year – that too on a low calorie diet of 1500 calories per day (Cello & Rogers, 2013)
    • Wadden et al., in 2005, stated that weight loss caused by sibutramine alone was mild and combining sibutramine with calorie restriction and lifestyle improvement worked better (Wadden et al., 2005)
    • Many other studies have also supported the view that sibutramine was way more effective when combined with calorie restriction (Carvajal, Wadden, Tsai, Peck, & Moran, 2013; Hauptman, Lucas, Boldrin, Collins, & Segal, 2000; Poston et al., 2006)
  2. Adverse effects profile of sibutramine
    • Although banned by the FDA, there is some degree of disparity amongst researchers about the safety of sibutramine as a weight-reducing agent.
    • Although the FDA finds the risks associated with sibutramine too much for recommending its use, others say the benefits of sibutramine may yet outnumber risks (Nisoli & Carruba, 2000; Nisoli & Carruba, 2003). Notwithstanding their support for sibutramine, the authors of the studies quoted above were of the opinion that in view of dearth of information regarding long-term safety, sibutramine ‘must be kept under regular review’ (Nisoli & Carruba, 2003)
    • James et al., in 2010, suggested that patients with pre-existing cardiovascular disease are more likely to suffer from cardiovascular incidences like myocardial infarction and stroke after sibutramine use (James et al., 2010). However, it may of interest to note here that this study was conducted through funding by Abbott ( number, NCT00234832). Therefore, some degree of bias involved
    • Sibutramine may cause depression and other affective disorders, especially in those with a history of psychiatric illness (An et al., 2013)
    • Opinion is also divided regarding association of sibutramine with depression; some researchers saying there is a positive correlation (Perrio, Wilton, & Shakir, 2007; McElroy et al., 2007) while others reporting that sibutramine may, in fact, act as an antidepressant (Elfhag, Rossner, Barkeling, & Rooth, 2005; Kiortsis, Tsouli, Filippatos, Konitsiotis, & Elisaf, 2008)
    • Association of sibutramine with affective disorder, especially suicidal ideation, may be dose-dependent; further research to derive safer dosage regimen is likely to solve this problem (An et al., 2013)

So, What’s The Word on Sibutramine?

Although, there is no doubt that sibutramine causes a mild degree of weight loss, there is great amount of disparity amongst researchers regarding the adverse effects profile of sibutramine – especially, the graver affective disorders like depression and suicidal tendencies. Currently, however, the evidence against sibutramine seems to be more convincing.

Given that use of sibutramine can cause some serious effects, risk-benefit ratio of sibutramine seems to be stacked in favour of risks. Hence, we are of the opinion that sibutramine, in its current form, IS NOT WORTH TAKING THE RISK for!

Useful References

  • An, H., Sohn, H., & Chung, S. (2013). sibutramine and affective disorders. Clin Psychopharmacol.Neurosci., 11, 7-12. Online Reference
  • Araujo, J. R. & Martel, F. (2012). Sibutramine effects on central mechanisms regulating energy homeostasis. Curr.Neuropharmacol., 10, 49-52. Online Reference
  • Berkowitz, R. I., Fujioka, K., Daniels, S. R., Hoppin, A. G., Owen, S., Perry, A. C. et al. (2006). Effects of sibutramine treatment in obese adolescents: a randomized trial. Ann Intern.Med, 145, 81-90.
  • Berkowitz, R. I., Wadden, T. A., Tershakovec, A. M., & Cronquist, J. L. (2003). Behavior therapy and sibutramine for the treatment of adolescent obesity: a randomized controlled trial. JAMA, 289, 1805-1812. Online Reference
  • Carvajal, R., Wadden, T. A., Tsai, A. G., Peck, K., & Moran, C. H. (2013). Managing obesity in primary care practice: a narrative review. Ann N Y.Acad.Sci., 1281, 191-206. Online Reference
  • Cello, J. P. & Rogers, S. J. (2013). Morbid obesity-the new pandemic: medical and surgical management, and implications for the practicing gastroenterologist. Clin Transl.Gastroenterol., 4, e35. Online Reference
  • Connoley, I. P., Liu, Y. L., Frost, I., Reckless, I. P., Heal, D. J., & Stock, M. J. (1999). Thermogenic effects of sibutramine and its metabolites. Br.J Pharmacol., 126, 1487-1495. Online Reference
  • Doslikova, B., Garfield, A. S., Shaw, J., Evans, M. L., Burdakov, D., Billups, B. et al. (2013). 5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: an effect mediated via increased proportion of pro-opiomelanocortin neurons activated. J Neurosci., 33, 9800-9804. Online Reference
  • Elfhag, K., Rossner, S., Barkeling, B., & Rooth, P. (2005). Sibutramine treatment in obesity: initial eating behaviour in relation to weight loss results and changes in mood. Pharmacol.Res., 51, 159-163.
  • Fernstrom, J. D. & Wurtman, R. J. (1972). Brain serotonin content: physiological regulation by plasma neutral amino acids. Science, 178, 414-416. Online Reference
  • Goldenberg, M. M. (2012). Pharmaceutical approval update. P.T., 37, 668-708. Online Reference
  • Halford, J. C., Wanninayake, S. C., & Blundell, J. E. (1998). Behavioral satiety sequence (BSS) for the diagnosis of drug action on food intake. Pharmacol.Biochem.Behav., 61, 159-168.
  • Hauptman, J., Lucas, C., Boldrin, M. N., Collins, H., & Segal, K. R. (2000). Orlistat in the long-term treatment of obesity in primary care settings. Arch.Fam.Med, 9, 160-167.
  • Hauptman, J. B., Jeunet, F. S., & Hartmann, D. (1992). Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18-0647 (tetrahydrolipstatin). Am J Clin Nutr., 55, 309S-313S.
  • James, W. P., Caterson, I. D., Coutinho, W., Finer, N., Van Gaal, L. F., Maggioni, A. P. et al. (2010). Effect of sibutramine on cardiovascular outcomes in overweight and obese subjects. N Engl J Med, 363, 905-917.
  • Kiortsis, D. N., Tsouli, S., Filippatos, T. D., Konitsiotis, S., & Elisaf, M. S. (2008). Effects of sibutramine and orlistat on mood in obese and overweight subjects: a randomised study. Nutr.Metab Cardiovasc.Dis., 18, 207-210.
  • Lam, D. D., Garfield, A. S., Marston, O. J., Shaw, J., & Heisler, L. K. (2010). Brain serotonin system in the coordination of food intake and body weight. Pharmacol.Biochem.Behav., 97, 84-91.
  • McElroy, S. L., Frye, M. A., Altshuler, L. L., Suppes, T., Hellemann, G., Black, D. et al. (2007). A 24-week, randomized, controlled trial of adjunctive sibutramine versus topiramate in the treatment of weight gain in overweight or obese patients with bipolar disorders. Bipolar.Disord, 9, 426-434.
  • Nisoli, E. & Carruba, M. O. (2000). An assessment of the safety and efficacy of sibutramine, an anti-obesity drug with a novel mechanism of action. Obes Rev, 1, 127-139.
  • Nisoli, E. & Carruba, M. O. (2003). A benefit-risk assessment of sibutramine in the management of obesity. Drug Saf, 26, 1027-1048.
  • Perrio, M. J., Wilton, L. V., & Shakir, S. A. (2007). The safety profiles of orlistat and sibutramine: results of prescription-event monitoring studies in England. Obesity (Silver.Spring), 15, 2712-2722. Online Reference
  • Poston, W. S., Haddock, C. K., Pinkston, M. M., Pace, P., Reeves, R. S., Karakoc, N. et al. (2006). Evaluation of a primary care-oriented brief counselling intervention for obesity with and without orlistat. J Intern.Med, 260, 388-398. Online Reference
  • Rucker, D., Padwal, R., Li, S. K., Curioni, C., & Lau, D. C. (2007). Long term pharmacotherapy for obesity and overweight: updated meta-analysis. BMJ, 335, 1194-1199. Online Reference
  • Tecott, L. H. (2007). Serotonin and the orchestration of energy balance. Cell Metab, 6, 352-361.
  • Wadden, T. A., Berkowitz, R. I., Womble, L. G., Sarwer, D. B., Phelan, S., Cato, R. K. et al. (2005). Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med, 353, 2111-2120. Online Reference
  • Walsh, B. T., Wilson, G. T., Loeb, K. L., Devlin, M. J., Pike, K. M., Roose, S. P. et al. (1997). Medication and psychotherapy in the treatment of bulimia nervosa. Am J Psychiatry, 154, 523-531. Online Reference
  • Williams, G. (2010). Withdrawal of sibutramine in Europe. BMJ, 340, c824. Online Reference

Have Your Say

Get the conversation started by leaving your comments using the form above.

Add your comment

We'd love to get your opinion. Please keep it clean and stay on topic, no spamming. Comments are moderated before being made live. Your email address will not be published.
We cannot give advice about medical conditions or prescription drugs. Please direct specific medical questions to your doctor.

This site uses Akismet to reduce spam. Learn how your comment data is processed.