, Volume 56, Issue 6, pp 1093-1124
Date: 19 Sep 2012

Sibutramine

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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.