Skip to main content
Log in

Sibutramine

A Review of its Contribution to the Management of Obesity

  • Adis Drug Evaluation
  • Published:
Drugs Aims and scope Submit manuscript

Summary

Abstract

Sibutramine is an orally administered centrally acting weight management agent apparently devoid of amphetamine-like abuse potential. Its primary (M2; BTS 54 505) and secondary (M1; BTS 54 354) amine metabolites are pharmacologically active and are thought to induce the natural processes leading to enhancement of satiety and thermogenesis by inhibiting serotonin (5-hydroxytryptamine, 5-HT) and noradrenaline (norepinephrine) reuptake.

In clinical trials, once-daily sibutramine was administered at dosages of ≤30mg for ≤24 weeks and 10 or 15mg for 1 year in conjunction with reduced calorie intake, increased daily exercise and advice on eating behaviour. Dose-related bodyweight loss was greater with sibutramine than with placebo. Clinical effects were most commonly apparent at dosages ≥10 mg/day.

Weight loss of >1% within the first month of treatment appears indicative of good long term response with sibutramine. Weight loss was maintained during therapy for 1 year; longer term data are lacking. Weight regain occurred after treatment cessation in studies of ≤24 weeks’ duration; data from longer trials are unavailable.

Up to 15% of patients in ≤6-month studies did not respond to treatment irrespective of dose.

Obese patients with type 2 (non-insulin-dependent) diabetes or hypertension lost significantly more mean bodyweight with sibutramine than with placebo, although weight loss was less than that in obese patients without comorbidities. The effect of sibutramine on mean fasting blood glucose levels and plasma lipid levels was unclear..

Sibutramine, compared with placebo, statistically significantly increased blood pressure and heart rate in obese patients with or without hypertension when given for up to 12 months. However, after 12 weeks’ treatment in hypertensive obese patients, diastolic blood pressure was reduced by similar amounts with sibutramine or placebo.

Concerns over potential pressor effects with sibutramine are reflected in the manufacturer’s dosage and administration recommendations.

Although long term tolerability data are scarce, pooled data from 2952 patients in placebo-controlled trials (≤1 year) revealed that the drug was generally well tolerated. The most commonly reported adverse events were headache, dry mouth, anorexia, insomnia and constipation. Echocardiographs indicated that sibutramine therapy (⁈8 months) did not adversely affect cardiac valve function in obese patients.

Conclusion: Currently, there are few options for the long term management of obesity. Evidence, although limited, suggests that in selected obese patients, sibutramine may be considered a useful adjunct to traditional nonpharmacological therapy, to effect a sustained moderate weight loss during treatment which is greater than that with placebo. Concerns over potential pressor effects of sibutramine may be allayed by careful patient selection and subsequent monitoring.

Defining Obesity and Potential Treatment Strategies

A number of factors may contribute to the development of obesity, including genetic predisposition, endocrine factors, psychological make-up and level of physical activity. However, the most important factor remains that when energy intake exceeds energy output, bodyweight gain is inevitable.

The determination of a genetic association with obesity confirms that it should be classified as a disease. As a life-long disease, ideally, obesity requires long term management which should begin with nonpharmacological intervention such as diet, exercise and behavioural modifications.

Obesity is quite distinct from being overweight. It may be classified using several methods. For example, the phenotype may be recognised by the distribution of excess body fat and the severity by the individual’s body mass index (BMI) value; the latter method is endorsed by the WHO.

According to US-developed obesity management guidelines, a BMI of >25 kg/m2 is considered the point at which pharmacological intervention may be considered.

Drugs developed for the loss and maintenance of weight aim to cause appetite suppression, satiety enhancement, nutrient partitioning and/or alteration of thermogenic activity. Sibutramine is an orally administered agent that primarily acts to promote a sense of satiety; this is the result of serotonin (5 hydroxytryptamine; 5-HT) and noradrenaline (norepinephrine) reuptake inhibition effected by the drug. Sibutramine also has a moderate effect on energy expenditure by attenuating the decrease in energy output during rest. Increased satiety (i.e. decreased energy intake) combined with increased physical activity (i.e. increased energy output), which is encouraged during therapy, should lead to an overall decrease in bodyweight.

Pharmacodynamic Properties

Sibutramine is a centrally acting agent that dose-dependently inhibits serotonin and noradrenaline reuptake. The effect of sibutramine is largely attributable to its active primary (M2; BTS 54 505) and secondary (Ml; BTS 54 354) amine metabolites. The pharmacological activity of sibutramine does not appear to be a result of increased serotonin release; this differentiates it from the actions of dexfenfluramine, which predominantly releases serotonin, and dexamfetamine, which predominantly releases dopamine and noradrenaline. In in vitro studies as well as trials conducted in animals and humans, sibutramine and its metabolites also showed no significant potential for inducing dopamine release, unlike dexamfetamine. This may account for the lack of abuse potential with sibutramine as shown in rats and in healthy volunteers with histories of substance abuse.

The binding affinity and number of dopamine D1 or D2 receptors were not affected by sibutramine; additionally, sibutramine and its metabolites were stated to have low in vitro activity at central and peripheral muscarinic cholinoceptors, which suggests a lack of potential for sedative effects.

Monoamine oxidase activity was unaffected by sibutramine or its metabolites in vitro and in vivo.

In mice, sibutramine reduces postsynaptic more than presynaptic (X2-adrenoceptor activity. In addition, the number of cortical ß-adrenoceptors was reduced by 38% after 10 days’ sibutramine administration to rats, via exclusive reduction of β1-adrenoceptors. Indeed, sibutramine has a dose-related hypophagic effect in rats which is significantly inhibited by the serotonin antagonists metergoline, ritanserin and SB200646, the α1-adrenoceptor blocker prazosin and the β1-adrenoceptor blocker metoprolol, but not by the β2-adrenoceptor blocker ICI 118551 or the dopamine D2 receptor antagonist remoxipride.

Food intake (measured in both kilojoules and grams) was significantly reduced during therapy with sibutramine 10 to 30 mg/day compared with placebo in obese and non-obese volunteers who were not dieting (p < 0.05 for each dose vs placebo). aily intake of both fat and protein was significantly reduced by sibutramine in non-dieting obese women; the drug had no significant effect on daily carbohydrate intake. Overall, there were no significant effects on the proportions of macronutrients consumed by volunteers during sibutramine treatment. However, in diet-controlled obese patients, carbohydrate and protein intakes were increased (by 4.8 and 36%, respectively) and fat intake was reduced (by 7.8%) after 6 months’ treatment with once-daily sibutramine 10mg.

These results were supported by observations in animal feeding models. Compared with placebo, sibutramine or dexfenfluramine reduced food intake in rats by a maximum of 60.0 and 82.1%, respectively, up to 8 hours after administration. Sibutramine appears to enhance the natural development of satiety whereas dexamfetamine appears to interrupt the satiety sequence.

The minimum effective dose of sibutramine required to reduce food intake was lower in obese rats fed a high fat diet than in non-obese rats fed either a high carbohydrate or a normal diet. These data suggest that dietary composition may alter the effect of sibutramine on feeding behaviour.

Bodyweight gain was significantly reduced and the reduction was maintained during daily sibutramine administration in rats fed ad libitum. As expected, body-weight increased after sibutramine withdrawal; this also occurs in obese patients (see Therapeutic Efficacy summary). Fat but not lean body mass in rats was significantly decreased in relation to both the dose of sibutramine and duration of administration.

There is some evidence in both rats and humans that sibutramine has thermogenic activity.

In non-obese volunteers, single-dose sibutramine 60mg had no significant effect on supine stroke volume, cardiac output, systolic time intervals or cardiac parameters. However, systolic and diastolic blood pressure and heart rate were significantly increased (this has also been shown in obese individuals; see Tolerability summary); the addition of atenolol 50mg attenuated these effects.

Pharmacokinetic Properties

First-pass metabolism of sibutramine is extensive and results in the formation of pharmacologically active primary (M2) and secondary (Ml) amine metabolites. Pharmacokinetic data for sibutramine are limited to information from abstracts. However, age and bodyweight do not appear to significantly alter the pharmacokinetic parameters of the metabolites. The maximum plasma concentration (Cmax) values for each metabolite are dose related after single-dose administration of sibutramine 10 to 30mg; M2 values are approximately twice those of M1 values. Repeated administration did not affect the M1 Cmax value but the M2 value was approximately doubled.

Mean plasma M1 and M2 concentrations are also dose related (within the range 5 to 30 mg/day) after 24 weeks of therapy in 1047 obese patients. Steady-state plasma metabolite concentrations are maintained throughout 24 weeks of treatment.

Time to achieve Cmax, which is similar for both metabolites, ranges from 2.5 to 3.6 hours after single doses of sibutramine and is not significantly altered by repeated administration.

The area under the plasma concentration-time curve for each metabolite is dose related after administration of sibutramine and, in healthy volunteers, the bioavailability of the drug (10 to 30 mg/day) is not altered in the presence of food.

The elimination half-life (t1/2) of each metabolite is about 14 to 19 hours with sibutramine 10 to 30mg. In obese patients, the M2 t1/2 is not significantly altered by repeated administration. However, it is slightly, but not statistically significantly, increased in the elderly (mean age 70.3 years) compared with younger individuals (mean age 24 years).

Data from a small study in patients (BMI not stated) suggest that moderate hepatic impairment (not defined) does not clinically significantly affect the pharmacokinetics of the drug. However, use of sibutramine is contraindicated in patients with severe hepatic dysfunction (see Dosage and Administration summary).

Plasma concentrations of sibutramine and its active metabolites (M1 and M2) were unaffected by the presence of renal dysfunction in 18 non-obese patients.

Therapeutic Efficacy

In the trials reviewed, patients were clinically obese (i.e. had a BMI of 25 to 40 kg/m2 inclusive) but were without other medical complications unless stated otherwise. In most trials sibutramine was administered in conjunction with a reduced calorie intake and an increase in daily physical effort and advice on eating behaviour.

In double-blind placebo-controlled trials, once-daily sibutramine ≤30mg was given for up to 24 weeks and 10 or 15mg was given for 1 year. Weight loss was dose related and was commonly significantly greater in sibutramine ≥10 mg/day than placebo recipients. Patients receiving sibutramine 10 to 20 mg/day lost approximately 5 to 7.5kg bodyweight (5 to 9.5% of initial bodyweight) over an 8-to 12-week period; correspondingly, placebo recipients lost about 1.5 to 3.5kg (1.3 to 4.3%). In addition, a clinically significant 10% bodyweight loss was achieved after 24 weeks by 16 and 28%, respectively, of patients receiving sibutramine 10 and 15 mg/day compared with none of the placebo recipients. In the same study, women tended to lose a smaller percentage of their initial bodyweight than men.

Although actual weight loss appeared slightly greater with sibutramine than with dexfenfluramine in a comparative trial, the overall efficacy of the 2 treatments was considered equivalent, or not significantly different, after 12 weeks of treatment with once-daily sibutramine 10mg or twice-daily dexfenfluramine 15mg in a total of 278 obese patients.

Published data for long term use of sibutramine (≥1 year) are available from 2 trials. Weight loss was sustained for up to 1 year during sibutramine treatment. Sibutramine 10 or 15 mg/day compared with placebo significantly reduced body-weight in the 53% of obese patients who completed 12 months of once-daily treatment.

A second 1-year study showed that additional significant weight loss was possible with sibutramine 10 mg/day compared with placebo in obese patients who had already lost ≥6kg during a 4-week very low calorie run-in period.

Maximal weight loss was apparent after about 6 months of sibutramine in both 1-year studies. Bodyweight remained below baseline values thereafter, which suggests that significant weight loss may be maintained with continuous sibutramine treatment.

Waist circumference was significantly reduced in sibutramine compared with placebo recipients after 12 months; however, the effect of treatment on waist to hip ratio was not clear.

Non-response to treatment resulted in up to 15% withdrawal from therapy in ≤6-month studies; corresponding withdrawal rates for placebo recipients were not always available. An acute response to treatment (i.e. a decrease in baseline bodyweight of >1% within the first 4 weeks of therapy) may be indicative of good long term response with sibutramine treatment.

As may be expected, some weight regain was apparent after cessation of sibutramine therapy (8 to 52 weeks).

Moderate weight loss (⁈10%) has been shown to be beneficial in obese patients with concomitant diseases such as hypertension and diabetes mellitus. In obese patients with type 2 (non-insulin-dependent) diabetes or hypertension, mean weight loss was significantly greater in once-daily sibutramine 10 or 15mg than in placebo recipients after 12 weeks’ therapy with concurrent dietary control, although weight loss appeared to be less than that reported in obese patients without comorbidities. Weight loss was increased or maintained during 12-week nonblind extension periods in obese patients with hypertension or type 2 diabetes who previously received placebo or sibutramine for 12 weeks.

In obese patients with hypertension, reductions in standing and supine diastolic blood pressure of about 4mm Hg were observed after 12 weeks with sibutramine and of about 6mm Hg with placebo. Furthermore, an additional 12-week sibutramine treatment period caused similar reductions in supine and standing diastolic blood pressure (of about 6 to 7.5mm Hg).

Sibutramine may have beneficial effects on glucose control in patients with type 2 diabetes and on plasma lipid levels in patients with hyperlipidaemia, although further studies are required before this can be confirmed.

Tolerability

Published primary tolerability data from clinical trials of sibutramine in obese patients with or without comorbidities are scarce.

Pooled data from 2952 patients who received sibutramine or placebo (dosage and treatment duration details not available) indicate that the drug is generally well tolerated. The most commonly reported adverse events were headache, dry mouth, anorexia, insomnia and constipation.

In 173 obese patients, the incidence of adverse events significantly increased with increasing dosages of sibutramine. Pooled data from placebo-controlled trials revealed that 9% of 2068 sibutramine recipients and 7% of 884 patients who received placebo were withdrawn from studies because of adverse events (no further details provided).

Blood pressure and heart rate were statistically significantly increased in obese patients without hypertension who received sibutramine 10 or 15mg daily for 12 months compared with placebo (p < 0.01). In 2 separate studies, systolic and/or diastolic blood pressure were increased by up to 2.1mm Hg with sibutramine 10mg daily; there was a corresponding decrease of up to 1.4mm Hg in placebo recipients. Mean heart rates were increased by 6.3 and 3.5 beats/min with sibutramine 10 and 15mg daily and by 0.8 or 0.1 beats/min with placebo. In 1 of these studies, all blood pressure parameters decreased in sibutramine recipients (no further details provided) 4 weeks after drug cessation, and mean heart rate fell in sibutramine recipients.

In contrast, blood pressure and heart rate were not notably changed in 60 obese patients who received once-daily sibutramine 5 or 20mg or placebo for 8 weeks; no clinically significant abnormal electrocardiographic parameters were observed.

In obese patients with hypertension who were not reducing their calorie intake, mean arterial blood pressure was clinically and statistically significantly increased in the sibutramine 20 mg/day compared with the placebo group after 8 weeks (p < 0.05). Heart rates were significantly increased from baseline (by 4.5 to 25.8 beats/min) with sibutramine.

In a comparative study, 5% of sibutramine and 10% of dexfenfluramine recipients withdrew because of adverse events. The adverse event profiles of the 2 drugs were similar except that sibutramine 10mg once daily increased heart rate (by 3.4 beats/min) and dexfenfluramine 15mg twice daily slightly decreased it (by 1.3 beats/min).

There is no evidence for abuse potential with sibutramine.

Dosage and Administration

The recommended starting dose of sibutramine is 10mg once daily with or without food in persons with an initial BMI of ≥30 kg/m2, or ≥27 kg/m2 in the presence of risk factors including hypertension, diabetes mellitus or dyslipidaemia. Sibutramine should be used in conjunction with a reduced calorie diet. If a weight loss of 1.8kg (or >1% of initial bodyweight; see Therapeutic Efficacy summary) within the first 4 weeks of beginning drug therapy is not achieved, an increase in the dosage to 15mg once daily or discontinuation of sibutramine should be considered; dosages >15mg once daily are not recommended. In patients intolerant of sibutramine 10mg, the dosage may be reduced to 5mg once daily.

Sibutramine is contraindicated in patients with a history of coronary artery disease, congestive heart failure, arrhythmias, stroke, severe renal impairment or severe hepatic dysfunction.

Blood pressure monitoring is required before, and at regular intervals during, sibutramine therapy. If a sustained increase in blood pressure or heart rate is observed, either a reduction in dosage or withdrawal of the drug should be considered. Sibutramine should not be given to patients with poorly controlled or uncontrolled hypertension. It should be used with caution in patients with a history of hypertension or seizures (type not defined) and in those with narrow angle glaucoma.

Caution is advised when prescribing sibutramine to patients who may use decongestant agents (e.g. phenylpropanolamine, ephedrine, or pseudoephedrine). There may be potential for an interaction with drugs that inhibit cytochrome P450(3A4) metabolism.

Sibutramine 15mg daily for 28 days did not significantly alter the efficacy of combined oral contraceptives in healthy women and, in separate studies, did not attenuate the activity of atenolol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rossner S. Long-term intervention strategies in obesity treatment. Int J Obes 1995; 19 Suppl. 7: S29–33

    Google Scholar 

  2. Pisunyer. Guidelines for the approval and use of drugs to treat obesity -a position paper of the North American Association for the Study of Obesity. Obes Res 1995 Sep; 3: 473–8

    Google Scholar 

  3. National Task Force. Long-term pharmacotherapy in the management of obesity. JAMA 1996 Dec 18; 276(23): 1907–15

    Article  Google Scholar 

  4. Obesity: advances in understanding and treatment. Drug Mark Dev 1995 May 22; 6: 26-41

  5. Buttle LA. Anti-obesity drugs: on target for huge market sales. Expert Opin Invest Drugs 1996 Dec; 5: 1583–7

    Article  CAS  Google Scholar 

  6. Vanltallie TB. Worldwide epidemiology of obesity. Pharmacoeconomics 1994; 5 Suppl. 1: 1–7

    Article  Google Scholar 

  7. Seidell JC, Deerenberg I. Obesity in Europe: prevalence and consequence for use of medical care. Pharmacoeconomics 1994; 5 Suppl. 1: 38–44

    Article  PubMed  CAS  Google Scholar 

  8. Wilson CA, Stock MJ. Drugs for the treatment of obesity. Report on the Society for Drug Research Symposium held at the school of pharmacy, University of London, on 6 July 1989. Pharm Med 1990; 4: 249–59

    Google Scholar 

  9. Lean MEJ, Han TS, Morrison CE. Waist circumference as a measure for indicating need for weight management. BMJ 1995 Jul 15; 311: 158–61

    Article  PubMed  CAS  Google Scholar 

  10. Lissner L. Causes, diagnosis and risk of obesity. Pharmacoeconomics 1993; 5 Suppl. 1: 8–17

    Article  Google Scholar 

  11. National Heart L and BI. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults [online]. National Heart, Lung, and Blood Institute National Institutees of Health; 1998 June. Available from: URL: http://www.nihlbi.nih.gov/nhlbi/cardio/obes/prof/guidelns/obhome.htm [Accessed 1998 Aug 18]

  12. Kelly F, Jones SP, Lee IK. Sibutramine: weight loss on depressed patients [abstract]. Int J Obes 1995; 19 Suppl. 2: 145

    Google Scholar 

  13. Lean MEJ. Sibutramine -areview of clinical efficacy. Int J Obes 1997; 21: S30–6

    CAS  Google Scholar 

  14. Jackson HC, Bearham MC, Mazurkiewicz SE, et al. Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and NA uptake inhibitor sibutramine in the rat [abstract]. Br J Pharmacol 1996 Apr; 117 Proc. Suppl.: 168P

  15. Martin KF, Hannon SD, Czudek C, et al. Comparison of the effects of sibutramine and d-amphetamine on extracellular dopamine levels in rat nucleus accumbens: an in. vivo microdialysis study. Br J Pharmacol 1995; 114: 346

    Google Scholar 

  16. Luscombe GP, Hopcroft RH, Thomas PC, et al. The contribution of metabolites to the rapid and potent down-regulation of rat cortical beta-adrenoceptors by the putative antidepressant sibutramine hydrochloride. Neuropharmacology 1989 Feb; 28: 129–34

    Article  PubMed  CAS  Google Scholar 

  17. Luscombe GP, Slater NA, Lyons MB, et al. Effect on radiolabelled-monoamine uptake in vitro of plasma taken from healthy volunteers administered the antidepressant sibutramine HCl. Psychopharmacology 1990; 100(3): 345–9

    Article  PubMed  CAS  Google Scholar 

  18. Cheetham SC, Viggers JA, Slater NA, et al. Inhibition of [3H]-paroxetine binding by sibutramine, its metabolites and other antidepressants correlates with inhibition of [3H]-5-HT uptake [abstract]. Br J Pharmacol 1990 Nov; 101 Suppl.: 515

    Google Scholar 

  19. Martin KF, Heal DJ. The effects of sibutramine on serotonin release and metabolism in comparison to other anorectic drugs [abstract]. Soc Neurosci Abstr 1993; 19(1-3): 297

    Google Scholar 

  20. Heal DJ, Prow MR, Hearson M, et al. Efflux of [3H]-dopamine from superfused rat striatal slices: predictive value for detecting stimulant drugs of abuse [abstract 325P]. Br J Pharmacol 1996 Apr; 117 Proc. Suppl.

  21. Cheetham SC, Kettle CJ, Martin KF, et al. Dl receptor binding in rat striatum: modification by various Dl and D2 antagonists, but not by sibutramine hydrochloride, antidepressants or treatments which enhance central dopaminergic function. J Neural Transm Gen Sect 1995; 102: 35–46

    Article  PubMed  CAS  Google Scholar 

  22. Martin FK, Needham PL, Atkinson J, et al. Rat striatal and mesolimbic D1 receptor binding is not altered by antidepressant treatments including ECS and sibutramine HCL [abstract]. Br J Pharmacol 1988; 95: 896P

    Article  Google Scholar 

  23. Martin KF, Phillips I, Cheetham SC, et al. Dopamine D-2 receptors: a potential pharmacological target for nomifensine and tranylcypromine but not other antidepressant treatments. Pharmacol Biochem Behav 1995 Aug; 51: 565–9

    Article  PubMed  CAS  Google Scholar 

  24. Heal DJ, Prow MR, Gosden J, et al. A comparison of various antidepressant drugs demonstrates rapid desensitisation of alpha2-adrenoceptors exclusively by sibutramine hydrochloride. Psychopharmacology 1992 Jun; 107: 497–502

    Article  PubMed  CAS  Google Scholar 

  25. Heal DJ, Butler SA, Hurst EM, et al. Antidepressant treatments, including sibutramine hydrochloride and electroconvulsive shock, decrease beta -1-but not beta -2-adrenoceptors in rat cortex. J Neurochem 1989; 53(4): 1019–25

    Article  PubMed  CAS  Google Scholar 

  26. Rolls BJ, Shide DJ, Thorwart ML, et al. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 1998 Jan 1; 6: 1–11

    PubMed  CAS  Google Scholar 

  27. Stricker-Krongrad A, Souquet AM, Jackson HC, et al. Effect of various monoamine receptor antagonists on the decrease in food intake by sibutramine in the rat [abstract]. Br J Pharmacol 1996 Apr; 117 Proc. Suppl.: 167P

  28. Fantino M, Martel P, Souquet AM, et al. Decrease of food intake and weight loss induced by sibutramine in the rat [abstract]. Proceedings of pharmacologic treatment of obesity 7th ICO satellite, Sainte-Adele 1994: 41

  29. Burlet C, Stricker-Krongrad A, Souquet AM, et al. Effects of chronic sibutramine treatment on feeding behaviour and body weight in adult rats [abstract]. Proceedings of pharmacologic treatment of obesity 7th ICO satellite, Sainte-Adele 1994: 37

  30. Jackson HC, Hutchins LJ, Mazurkiewicz SE, et al. Comparison of the effects of sibutramine and other monamine reuptake inhibitors on food intake in the rat [abstract]. Br J Pharmacol 1996 Apr; 117 Proc. Suppl.: 323P

  31. Stricker-Krongrad A, Burlet C, Souquet AM, et al. Sibutramine effects on feeding behaviour: a dose-dependence and microstructural analysis [abstract]. Proceedings of pharmacologic treatment of obesity 7th ICO satellite, Sainte-Adele 1994: 53

  32. Haiford JCG, Heal DJ, Blundell JE. Effect in the rat of sibutramine on food intake and the behavioural satiety sequence [abstract]. Br J Pharmacol 1995 Apr; 114 Suppl.: 387P

  33. Connoley IP, Heal DJ, Stock MJ. A study in rats of the effects of sibutramine on food itake and thermogenesis [abstract]. Br J Pharmacol 1995 Apr; 114 Suppl.: 388P

  34. Gosden J, Buckett WR, Heal DJ. d-Amphetamine-cued drug discrimination in rats: predictive value for detecting stimulant drugs of abuse [abstract]. Br JPharmacol 1996 Apr; 117 Proc. Suppl.: 169P

  35. Cole JO, Friedman L, Kaiser PE, et al. Sibutramine hydrochloride: evaluation of abuse potential [abstract]. Psychopharmacol Bull 1995; 31(3): 557

    Google Scholar 

  36. Wynne RD, Braybrooke RM, Brown T, et al. A single-dose, placebo-controlled, Comparative evaluation of the cardiovascular effects of sibutramine and amitriptyline in normal volunteers. Int J Pharm Med 1997; 11: 65–70

    Google Scholar 

  37. Silverstone T. Appetitie suppressants: areview. Drugs 1992 Jun; 43: 820–36

    Article  PubMed  CAS  Google Scholar 

  38. Thomas DR, Nelson DR, Johnson AM. Biochemical effects of the antidepressant paroxetine, a specific 5-hydroxytriptamine uptake inhibitor. Psychopharmacology 1987; 93: 193–200

    Article  PubMed  CAS  Google Scholar 

  39. Cheetham SC, Viggers JA, Slater NA, et al. [(3)H]paroxetine binding in rat frontal cortex strongly correlates with [(3)H]5-HT uptake: effect of administration of various antidepressant treatments. Neuropharmacology 1993; 32(8): 737–43

    Article  PubMed  CAS  Google Scholar 

  40. 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: 303–9

    Article  CAS  Google Scholar 

  41. Stock MJ. Sibutramine: a review of the pharmacology of a novel anti-obesity agent. Int J Obes 1997; 21 Suppl. 1: S25–9

    CAS  Google Scholar 

  42. Mahony MT, Evans CA, Hall JM, et al. The effects of sibutramine on acetylcholine-and carbachol-evoked responses in the rat hippocampus and guinea-pig ileum [abstract]. Br J Pharmacol 1988; 95: 885P

    Google Scholar 

  43. Mahony MT, Dennison L, Holden A, et al. The effects of sibutramine HC1 and its metabolites on histamine-evoked responses in the guinea-pig ileum [abstract]. Br J Pharmacol 1989 Dec; 98 Suppl.: 877

    Google Scholar 

  44. Buckett WR, Thomas PC, Luscombe GP. The pharmacology of sibutramine hydrochloride (BTS 54 524), a new antidepressant which induces rapid noradrenergic down-regulation. Prog Neuropsychopharmacol Biol Psychiatry 1988; 12: 575–84

    Article  PubMed  CAS  Google Scholar 

  45. Chapelot D, Marmonier C, Himaya A, et al. Modalities of the food intake-reducing effect of sibutramine [abstract no. P661]. Int J Obes 1998 Aug; 22 Suppl. 3: S270

    Google Scholar 

  46. Saris WHM, STORM study group. Sibutramine trial of obesity reduction and maintenance -Lifestyle and diet during the 6-month run-in phase [abstract no. P665]. Int J Obes 1998 Aug; 22 Suppl. 3: S271

    Google Scholar 

  47. Davis R, Faulds D. Dexfenfluramine: an updated review of its therapeutic use in the management of obesity. Drugs 1996; 52(5): 696–724

    Article  PubMed  CAS  Google Scholar 

  48. Jackson HC, Needham AM, Hutchins LJ, et al. Comparison of the effects of sibutramine and other monoamine reuptake inhibitors on food intake in the rat. Br J Pharmacol 1997; 121: 1758–62

    Article  PubMed  CAS  Google Scholar 

  49. Jackson HC, Cheetham SC, Hutchins LJ, et al. Involvement of 5-HT2C receptors in the hypophagic effects of sibutramine and D-fenfluramine in rats [abstract no. 571.1]. Soc Neurosci Abstr 1995; 21(1-3): 1459

    Google Scholar 

  50. Stricker-Krongrad A, Souquet AM, Burlet C. Effects of sibutramine on feeding behaviour in dietary-induced obesity: role of dietary constituents [abstract]. Int J Obes 1995; 19 Suppl. 2: 145

    Google Scholar 

  51. Souquet AM, Courcier S, Stricker-Krongrad A, et al. Effects of chronic sibutramine treatment on body composition in adult rats [abstract]. Proceedings of pharmacologic treatment of obesity 7th ICO satellite, Sainte-Adele 1994: 51

  52. Stock MJ, Hansen L, Toubro S, et al. Sibutramine targets both sides of the energy balance in humans [abstract no. P656]. Int J Obes 1998 Aug; 22 Suppl. 3: S269

    Google Scholar 

  53. Walsh K, Lean MEJ. The effects of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females with dyslipidaemia [abstract no. P658]. Int J Obes 1998 Aug; 22 Suppl. 3: S269

    Google Scholar 

  54. Connoley IP, Frost I, Heal DJ, et al. Role of beta-adrenoceptors in mediating the thermogenic effects of sibutramine [abstract]. Br J Pharmacol 1996 Apr; 117 Proc. Suppl.: 170P

  55. Liu YL, Kashani SMZ, Heal DJ, et al. Effect of sibutramine on tissue glucose utilisation in the rat [abstract]. Br J Pharmacol 1996 Apr; 117 Proc. Suppl: 324P

  56. 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: 65–81

    PubMed  Google Scholar 

  57. Schuh L, Mendel C, Rowe E, et al. The novel antiobesity agent, sibutramine (Meridia/Reductil) lacks significant abuse potential [abstract no. P655]. Int J Obes 1998 Aug; 22 Suppl. 3: S269

    Google Scholar 

  58. Barry H. Classification of drugs according to their discriminable effects in rats. Fed Proc 1974 Jul; 33(7): 1814–24

    PubMed  CAS  Google Scholar 

  59. Kaiser PE, Hinson JL. Sibutramine: dose response and plasma metabolite concentrations in weight loss [abstract]. J Clin Pharmacol 1994 Oct; 34: 1019

    Google Scholar 

  60. Garratt CJ, Hind ID, Haddock RE. Sibutramine metabolite kinetics in young and elderly subjects [abstract]. J Clin Pharmacol 1995 Sep; 35: 928

    Google Scholar 

  61. Garratt CJ, Hind ID, Haddock RE. Single/repeat dose kinetics of sibutramine metabolites in obese subjects [abstract]. J Clin Pharmacol 1995 Sep; 35: 928

    Google Scholar 

  62. Garratt CJ, Hind ID, Haddock RE. Sibutramine metabolite bioavailability: effect of dose level and food [abstract]. J Clin Pharmacol 1995 Sep; 35: 927

    Google Scholar 

  63. Meridia® (sibutramine hydrochloride monohydrate) Product information. Knoll Pharmaceutical Company, 1997

  64. Johnson F, Velagapudi R, Hind I, et al. Effects of renal dysfunction on the pharmacokinetics of sibutramine and its metabolites [abstract no. 31]. J Clin Pharmacol 1997; 37: 865

    Google Scholar 

  65. Weintraub M, Rubio A, Golik A, et al. Sibutramine in weight control: a dose-ranging, efficacy study. Clin Pharmacol Ther 1991 Sep; 50: 330–7

    Article  PubMed  CAS  Google Scholar 

  66. Bray GA, Ryan DH, Gordon D, et al. Double-blind randomized placebo-controlled trial of sibutramine. Obes Res 1996 May; 4: 263–70

    PubMed  CAS  Google Scholar 

  67. Drouin P, Hanotin C, Courcier S, et al. A dose-ranging study: efficacy and tolerability of sibutramine in weight loss [abstract no. 0232]. Int J Obes 1994; 18 Suppl. 2: 60

    Google Scholar 

  68. Jones SP, Newman BM, Romanec FM. Sibutramine hydrochloride: weight loss in overweight subjects [abstract no. 0234]. Int J Obes 1994; 18 Suppl. 2: 61

    CAS  Google Scholar 

  69. Heath MJ, Fitchet M. Initial weight los as predictor of long-term weight loss with sibutramine [abstract]. Int J Obes 1996; 20(4): 156

    Google Scholar 

  70. Jones SP, Smith IG, Kelly F, et al. Long-term weight loss with sibutramine [abstract]. Int J Obes 1995; 19 Suppl. 2: 41

    Google Scholar 

  71. Study number SB1047UK. Federal Drug Administration, New Drug Approval package [online]. Federal Drug Administration; 1998 Available as Adobe Acrobat (PDF) files from: URL: http://www.fda.gov/cder/foi/nda/index97.htm [accessed 1998 May]

  72. Study number SB 1049. Federal Drug Administration, New Drug Approval package [online]. Federal Drug Administration; 1998 Available as Adobe Acrobat (PDF) files from: URL: http://www.fda.gov.cder/foi/nda/index97.htm [accessed 1998 May]

  73. Hazenberg BP, Johnson SG, Kelly F. Sibutramine in the treatment of obese subjects with hypertension [abstract]. Int J Obes 1996; 20(4): 156

    Google Scholar 

  74. Kelly F, Wade AG, Jones SP, et al. Sibutramine hydrochloride vs dexfenfluramine: weight loss in obese subjects [abstract no. 0235]. Int J Obes 1994; 18 Suppl. 2: 61

    Google Scholar 

  75. Drouin P, Hanotin C, Thomas F, et al. Efficacy and tolerability if sibutramine versus dexfenfluramine in obese patients [abstract]. Int J Obes 1995; 19 Suppl. 2: 144

    Google Scholar 

  76. Apfelbaum M, Vague P, Ziegler O, et al. Long-term maintenance of weight loss after a very-low-calorie diet: efficacy and tolerability of sibutramine versus placebo. Am J Med. In press

  77. Kelly F, Shepherd G. Sibutramine induced weight loss is not influenced by baseline BMI in obese patients [abstract no. P663]. Int J Obes 1998 Aug; 22 Suppl. 3: S271

    Google Scholar 

  78. National Task Force. Weight cycling. JAMA 1994 Oct 19; 272(15): 1196–202

    Article  Google Scholar 

  79. Zanchetti A, Chalmers JP, Gyarfas I, et al. Prevention of hypertension and associated cardiovascular disease: a 1995 statement. Conclusions from a joint WHO/ISH meeting. Clin Exp Hypertens 1996 Apr-May; 18: 581–93

    Article  Google Scholar 

  80. Goldstein DJ. Beneficial health effects of modest weight loss [abstract]. Int J Obes 1992 Jun; 16(6): 397–415

    CAS  Google Scholar 

  81. Griffiths J, Brynes AE, Frost G, et al. Sibutramine in the treatment of overweight non-insulin dependent diabetics [abstract]. Int J Obes 1995; 19 Suppl. 2: 41

    Google Scholar 

  82. Vargas R, McMahon FG, Jain AK. Effects of sibutramine vs. placebo in NIDDM [abstract]. In: 95th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics; 1994: 188

  83. Study number SB2059. Federal Drug Administration, New Drug Approval package [online]. Federal Drug Administration; 1998 Available as Adobe Acrobat (PDF) files from: URL: http://www.fda.gov.cder/foi/nda/index97.htm [accessed 1998 May]

  84. Study number SB3068. Federal Drug Administration, New Drug Approval package [online]. Federal Drug Administration; 1998 Available as Adobe Acrobat (PDF) files from: URL: http://www.fda.gov.cder/foi/nda/index97.htm [accessed 1998 May]

  85. Griffiths J, Bloom SR, Finer N, et al. Body composition changes following weight loss induced by sibutramine [abstract]. Int J Obes 1995; 19 Suppl. 2: 144

    Google Scholar 

  86. Fujioka K, Weinstein SP, Rowe E, et al. Sibutramine induces weight loss and improves glycemic control in obese patients with type 2 diabetes mellitus [abstract no. 832]. Diabetologia 1998 Aug; 41 Suppl. 1: A215

    Google Scholar 

  87. Study number SB3051. Federal Drug Administration, New Drug Approval package [online]. Federal Drug Administration; 1998 Available as Adobe Acrobat (PDF) files from: URL: http://www.fda.gov.cder/foi/nda/index97.htm [accessed 1998 May]

  88. Study number SB3069. Federal Drug Administration, New Drug Approval package [online]. Federal Drug Administration; 1998 Available as Adobe Acrobat (PDF) files from: URL: http://www.fda.gov.cder/foi/nda/index97.htm [accessed 1998 May]

  89. Lean MEJ, Campbell S, Walsh K, et al. Sibutramine in the treatment of obese patients with dyslipidaemia [abstract no. P662]. Int J Obes 1998 Aug; 22 Suppl. 3: S270

    Google Scholar 

  90. Fitchet M, Shepherd G, Kelly F Sibutramine: a meta-analysis of changes in fasting serum lipds in placebo controlled studies [abstract no. 151]. Int J Obes 1997; 21 Suppl. 2: S53

    Google Scholar 

  91. Knoll’s Sibutramine rejected by US panel. Marketletter 1996 Oct 7; 23: 18

  92. Knoll meridia blood pressure elevation screen should be created; BP concerns outweigh weight loss benefit for 39%–50% patients, FDA Committee concludes. FDC Pink 1996 Sep 30; 58: 10-2

  93. Study number BPI855. Federal Drug Administration, New Drug Approval package [online]. Federal Drug Administration; 1998 Available as Adobe Acrobat (PDF) files from: URL: http://www.fda.gov.cder/foi/nda/index97.htm [accessed 1998 May]

  94. Holliday SM, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression. Drugs 1995; 49(2): 280–94

    Article  PubMed  CAS  Google Scholar 

  95. Bach DS, Rissanen AM, Mendel CM, et al. Absence of cardiac valve dysfunction in obese patients treated with sibutramine [abstract no. 0275]. Int J Obes 1998: S76

  96. Back DJ, Fearn R, Oliver S, et al. Lack of effect of sibutramine on the efficacy of oral contraceptive steroids in healthy women. Int J Pharm Med 1997; 11: 71–6

    Google Scholar 

  97. McMahon FG, Weinstein SP, Rowe E, et al. Sibutramine induces weight loss without significant BP increase in obese hypertensive patients taking beta-blockers [abstract no. P659]. Int J Obes 1998 Aug; 22 Suppl. 3

  98. Pi-Sunyer X. The NAASO position paper on approval and use of drugs to treat obesity. Obes Res 1995 Sep; 3: 471–2

    PubMed  CAS  Google Scholar 

  99. US antiobesity drug guidelines slimmed. Inpharma 1995 Feb 4; 972: 22

  100. Bower H. Guidelines tackle tidal wave of obesity. BMJ 1996 Nov 16; 313: 1225

    Article  PubMed  CAS  Google Scholar 

  101. Hutton J. The economics of treating obesity. Pharmacoeconomics 1994; 5 Suppl. 1: 66–72

    Article  PubMed  CAS  Google Scholar 

  102. Gorstein J, Grosse RN. The indirect costs of obesity to society. Pharmacoeconomics 1994; 5 Suppl. 1: 58–61

    Article  PubMed  CAS  Google Scholar 

  103. Enzi G. Socioeconomic consequences of obesity. The effect of obesity on the individual. Pharmacoeconomics 1994; 5 Suppl. 1: 54–7

    CAS  Google Scholar 

  104. Knoll meridia studies continue after redux, pondimin withdrawal; lawsuits call for Wyeth to fund medical monitoring of patients exposed to drugs. From: The news this week (Sept 22); delivery via SandPoint Hoover, contents from F-D-C reports, inc, 1997

  105. “Fen-phen” now liked to 82 cases of heart valve disease. Scrip Mag 1997 Sept 5; 2264: 20

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Karen L. Goa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

McNeely, W., Goa, K.L. Sibutramine. Drugs 56, 1093–1124 (1998). https://doi.org/10.2165/00003495-199856060-00019

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.2165/00003495-199856060-00019

Keywords

Navigation