After its approval by the USFDA in 1997,Sibutramine was widely used like an oral anorexiant to the pharmacological treatment of obesity.
Sibutramine belongs to a class of drugs known as monoamine reuptake inhibitors and most drugs of this class are prescribed for the treatment of depression: the effectiveness of these drugs is achieved by augmenting Central Nervous System concentrations of monoamine neurotasmitters, such as Dopamine, Norepinephrine and Serotonin (5-hydroxytryptamine). Sibutramine was ineffective in vivo as an antidepressant, but produced sustained weight loss by reducing food intake and increasing energy expenditure.
Sibutramine was originally developed and marketed by Knoll Pharmaceuticals and was more recently manufactured and marketed by Abbott Laboratories before its withdrawal from the market. It was sold under a variety of brand names including Reductil, Meridia and Sibutrex.
CHEMICAL AND PHARMACOLOGICAL DATA
Systematic name (IUPAC): (±)-dimethyl-1-[1-(4- chlorophenyl) cyclobutyl]-N,N,3-trimethylbutan- 1-amine
Molecular Formula: C17-H26-Cl-N
Molecular Weight: 279.85
Solubilities: in water 2.104 mg/L at 25°C.
Synthesis: The four-membered ring is prepared by removal of the benzylic protons of 4-chlorobenzyl cyanide with sodium hydride, followed by reaction with 1,3-dibromopropane. Reaction with isobutylmagnesium bromide, followed by reductive amination via the Leuckart reaction gives an amine. Methylation with formaldehyde in the Eschweiler-Clarke reaction gives the dimethylamino product, sibutramine.
Trade names: Meridia
Therapeutic Dosage: 10 mg once daily (usually in the morning), if this proves insufficient the dose may be increased to 15 mg daily after 4 weeks.
PHARMACOKINETICS AND PHARMACODYNAMICS
Sibutramine hydrochloride is a racemic compound that is structurally similar to other β-phenylethylamine drugs, such as metamphetamine and dexfenfluramine (it is suggested that the chlorine on the 4 position of the phenyl rings imparts affinity for the serotonin transporter). In vivo and in vitro data have demonstrated that sibutramine weakly inhibits monoamine uptake in human and rats tissue.
Sibutramine is metabolized in the liver principally by the cytochrome P450 (CYP3A4 ) isoenzyme, to desmethyl metabolites, M1 and M2 that are more potent monoamine inhibitors than the parent compound (in Vivo they are approximately equipotent for NA e 5HT inhibition with a inactive inhibition for DA). These active metabolites are further metabolized by hydroxylation and conjugation to pharmacologically inactive metabolites, M5 and M6.
M1 and M2 plasma concentrations reached steady-state within four days of dosing and were approximately two-fold higher than following a single dose. The elimination half-lives of M1 and M2, 14 and 16 hours, respectively, were unchanged following repeated dosing.
Absorption, Distribution and Excretion:
Sibutramine is rapidly absorbed from the GI tract (Tmax of 1.2 hours) following oral administration and undergoes extensive first-pass metabolism in the liver (oral clearance of 1750 L/hr and half-life of 1.1 hr) to form the pharmacologically active mono- and di-desmethyl metabolites M1 and M2. Peak plasma concentrations of M1 and M2 are reached within 3 to 4 hours and their half-life is 14 hours and 16 hours . On the basis of mass balance studies, on average, at least 77% of a single oral dose of sibutramine is absorbed.
Radiolabeled studies in animals indicated rapid and extensive distribution into tissues: highest concentrations of radiolabeled material were found in the eliminating organs, liver and kidney.
Approximately 85% (range 68-95%) of a single orally administered radiolabeled dose was excreted in urine and feces over a 15-day collection period with the majority of the dose (77%) excreted in the urine. Major metabolites in urine were M5 and M6; unchanged sibutramine, M1, and M2 were not detected. The primary route of excretion for M1 and M2 is hepatic metabolism (biliary) and for M5 and M6 is renal excretion.
Mechanism of Action:
The anorectic effects of sibutramine are principally due to its primary and secondary amine metabolites that inhibit reuptake (but do not cause release) of serotonin, norepinephrine, and, to a lesser extent, dopamine at the neuronal synapse, thus promoting a sense of satiety. Results of animal studies suggest that sibutramine also may increase energy expenditure through thermogenic effects. For example Sibutramine stimulates thermogenesis in rats, producing sustained (> 6 hr) increases in oxygen consumption of up to 30%. The thermogenic effect of sibutramine results from central activation of efferent sympathetic activity which, in turn, involves activation of beta 3-adrenoceptors. However, this has not been confirmed in humans to date.
Subatramine has several clinically significant interactions:
- In a double-blind, placebo-controlled, crossover study in 19 volunteers, administration of a single dose of ethanol (0.5 mL/kg) together with 20 mg of sibutramine resulted in no psychomotor interactions of clinical significance between alcohol and sibutramine.
- The rare, but serious, constellation of symptoms termed serotonin syndrome has also been reported with the concomitant use of selective serotonin reuptake inhibitors and agents for migraine therapy, such as Imitrex (sumatriptan succinate) and dihydroergotamine, certain opioids, such as dextromethorphan, meperidine, pentazocine and fentanyl, lithium, or tryptophan. The syndrome requires immediate medical attention and may include cognitive, autonomic and somatic symptoms like: excitement, hypomania, restlessness, loss of consciousness, confusion, disorientation, anxiety, agitation, motor weakness, myoclonus, tremor, hemiballismus, hyperreflexia, ataxia, dysarthria, incoordination, hyperthermia, shivering, pupillary dilation, diaphoresis, emesis, and tachycardia. Because sibutramine inhibits serotonin reuptake, in general, it should not be administered with other serotonergic agents.
- Potential pharmacologic interaction has been noticed when sibutramine is used with monoamine oxidase (MAO) inhibitors (phenelzine, selegiline); it could cause serotonin syndrome, potentially serious or fatal. Concomitant use is contraindicated; discontinue MAO inhibitors at least 2 weeks before starting sibutramine or discontinue sibutramine at least 2 weeks before starting MAO inhibitors.
- Concomitant use of Sibutramina and other agents that may raise blood pressure or heart rate have not been evaluated. These include certain decongestants, cough, cold, and allergy medications that contain agents such as ephedrine, or pseudoephedrine.
- Potential pharmacokinetic interaction (decreased sibutramine metabolism, altered serum concentrations of sibutramine and its metabolites) when sibutramine is used with inhibitors of cytochrome P-450 (CYP) isoenzyme 3A4, such as Ketoconazole and Erytromycina.
STUDIES DEMONSTRATING THE EFFECTIVENESS
The effectiveness of sibutramine in 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: -3.4 kg; mean difference range for weight change at 6 months: -4.0 to -9.1 kg; and at 1 year: -4.1 to -4.8 kg).
In one double-blind randomized trial, sibutramine at 5 mg or 20 mg once daily was compared with placebo in 3 groups of subjects. Notably, medications were administered over an 8-week period during the holiday season with Thanksgiving falling between week 2 and 3, Christmas between week 6 and 7, and New Year’s falling on weeks 7 and 8. Weight loss in the 5 mg sibutramine group (n = 18) was approximately 2% greater than in the placebo group (n = 19), while weight loss in the 20 mg sibutramine group (n = 18) was approximately 4% greater than in placebo.
Sibutramine in weight control: a dose-ranging, efficacy study.
In another multi-center double-blind randomized study using a wider dose range of sibutramine (6 doses between 1 and 30 mg once daily) in a large sample size (n = 1043) for a longer duration (24 weeks) the efficacy of sibutramine was further assessed. There was a dose-dependent relationship for weight loss with sibutramine over the trial. Doses of 1 mg or 5 mg produced an approximately 2% greater weight loss than in those individuals receiving placebo, while doses of 10 mg, 15 mg, 20 mg, and 30 mg produced an approximately 4% to 7% greater weight loss than in placebo. The categorical efficacy with 10 to 30 mg of sibutramine demonstrated that >58% of the population maintained 5% weight loss from baseline and >17% of the population maintained 10% weight loss from baseline over the 24 weeks. After the 24-week treatments there was a single-blind phase “washout” period of 6 weeks during which placebo was administered to all subjects. At the end of this period subjects regained weight, those losing the most during treatment regaining the most weight during the washout period.
Sibutramine produces dose-related weight loss.
The greatest amount of weight loss with sibutramine appears to occur during the first 12 weeks of treatment, weight stabilizing or increasing slightly with longer treatment.
In a 12-month study, sibutramine showed potential benefit by improving biochemical risk factors associated with obesity, including plasma glucose, total cholesterol (−12.9%), low-density lipoprotein cholesterol (−18.5%), triglycerides (TG) (−15.8%), apolipoprotein B (−13.3%) and lipoprotein (a) (−13.3%) levels and elevation in high-density lipoprotein (HDL) cholesterol levels (1.2%).
An assessment of the safety and efficacy of sibutramine.
Sibutramine was also more effective at reducing body weight directly compared with another serotonergic drug used to treat obesity, dexfenfluramine. This comparison was only with a single dose of both drugs, rather than a range of doses. For this study, 2 groups of obese subjects received either sibutramine (10 mg once daily; n = 112) or dexfenfluramine (15 mg twice daily; n = 114) for 12 weeks. Because there was no placebo control group, weight loss was compared with baseline values within groups. Sibutramine treatment produced a 5.4% weight loss, dexfenfluramine a 4.2% weight loss.
A comparison of sibutramine and dexfenfluramine in the treatment of obesity.
In a meta-analysis that examined the data from 10 double-blind randomized control studies (n = 2623) it was revealed that long-term treatment (1 year or more) with sibutramine (10–20 mg once daily) lost 3.7% to 5.0% more weight than individuals receiving placebo.
In comparison, data from 13 studies (n = 4948) found that the FDA-approved gastrointestinal lipase inhibitor orlistat produced a weight loss 2.9% to 3.4% greater than in individuals receiving placebo, so orlistat has lower effects than Sibutramine.
Long term pharmacotherapy for obesity and overweight: updated meta-analysis
The most common, yet not serious, adverse effects of sibutramine include dry mouth, constipation, insomnia, headache, anorexia and nausea, most of which can be attributed to the anticholinergic action of this drug.
Several additional side effects have been reported in ≥1% of all patients who received sibutramine in controlled and uncontrolled pre-marketing studies. These include fever, diarrhoea, flatulence, gastroenteritis, tooth disorder, peripheral oedema, arthritis, agitation, leg cramps, hypertonia, abnormal thinking, bronchitis, dyspnoea, pruritus, amblyopia and menstrual disorders. Acute interstitial nephritis (confirmed by biopsy) was reported in one obese patient receiving sibutramine during pre-marketing studies. During pre-marketing testing, seizures were reported in <0.1% of sibutramine-treated patients.
Subatramine, modulating serotonin and noradrenaline neurotransmission, would also be expected to have effects on emotion including anxiety and depression via the modulation of multiple serotonin and noradrenaline receptors within the fronto-limbic circuitry. Indeed, serotonin and noradrenaline reuptake inhibitors are effective anxiolytic and antidepressant drugs.
For example, an open labeled study of sibutramine (15 mg) in obese patients showed a reduction in depression scores (assessed using the comprehensive psychopathological rating scale) over 6 months of treatment. In a more controlled trial with a comparison group (low calorie diet), 3 months’ treatment with sibutramine (10 mg) was associated with a decrease in depression scores as assessed by the Hamilton Depression Rating Scale (HAM-D) in obese and overweight subjects.
Taflinski was the first to report a psychiatric episode in a patient prescribed sibutramine in December 2000. A 19-year-old woman free of psychiatric history was admitted to hospital with acute paranoid symptoms 3 months after sibutramine initiation. The drug had not been well tolerated since the beginning of treatment, and psychiatric symptoms developed after 8 weeks of therapy when the dose of sibutramine increased. Discontinuation of the drug initially resulted in attenuation of the symptoms, but in the next 7 d the patient's mental state progressively deteriorated. Specifically, the patient experienced delusions of reference and auditory hallucinations, whereas clear signs of severe formal thought disorder were present.
Studies conducted with sibutramine indicate that it has a low risk profile for neuropsychiatric adverse effects.
There are however sporadic case reports of sibutramine induced neuropsychiatric adverse effects reported in the literature including panic attacks, psychotic episode, delusional disorder, hypomanic/manic episode and amnesia. Although the neural basis of these adverse effects is unclear from these single case reports, they have been linked to sibutramine treatment and may represent a real risk under certain environmental conditions (stress) and/or in patients that have a genetic predisposition (family history of psychiatric disorders).
These rare adverse events were also noted (one or two individual cases of each) in a large observational cohort study (in approximately 12,300 patients) using prescription event monitoring in England. This study also showed that depression (an incidence of 0.8%) and insomnia (an incidence of 0.7%) were two neuropsychiatric adverse events that led to patients stopping sibutramine within 3 months of treatment initiation. Overall, the risks of neuropsychiatric adverse effects following sibutramine treatment appear to be low, although the risks may be higher in patients who have a current diagnosis or a family history of psychiatric disorders. In fact, sibutramine was contraindicated in patients with severe depression or preexisting mania due to the concern that it may have the potential to cause greater adverse effects.
Sibutramine may also be associated with memory impairment. The IMMP received a report of amnesia in a 39-year-old woman who had been taking sibutramine for 1 month. Memory impairment progressively worsened until the patient's daily activities were severely impaired, whereas migraine accompanied by neck stiffness also occurred. Within 2 weeks of stopping sibutramine, amnesia improved and it completely resolved by the sixth week.
The "WHO": http://www.who.int/en/ international database contains 33 further reports of sibutramine-associated amnesia. In 25 of them, sibutramine was the only drug suspected to induce amnesia, while 10 patients recovered after sibutramine cessation. Memory impairment might be part of a cerebrovascular syndrome, but sibutramine may contribute directly to amnesia. Serotoninergic pathways play an important role in learning and memory, and antagonists of certain serotonin receptors prevent memory impairment. Therefore, sibutramine may contribute to memory impairment by increasing synaptic serotonin concentrations. It should be mentioned, however, that amnesia is listed as a reported event only during post-marketing surveillance of sibutramine and there is no published report of this adverse event in literature.
Neuropsychiatric Adverse Effects of Centrally Acting Antiobesity Drugs
Sibutramine may be associated with memory impairment
Subitamine’s action on the sympathetic nervous system is complex ad the drug might have opposing effects on peripheral and central sympathetic activity.
- Hypertension: the relation between sibutramine and blood pressure has been considered a therapeutic dilemma. Sibutramine treatment may somewhat dampen the classically observed reduction in arterial blood pressure resulting from weight loss as shown in several meta-analyses. Blood pressure changes following sibutramine administration can be viewed as a balance between sibutramine-direct increase in BP on the one hand and weight-loss-induced decrease of BP on the other hand. Usually, sibutramine-induced elevations in BP are observed during the initial phase of treatment. Most studies showed no or only minimal changes in systolic blood pressure, but a modest increase of diastolic blood pressure.
- Heart rate: Increased heart rate was another side effect of sibutramine that was observed in many studies. The reported effect of sibutramine, 10–20 mg/day, on heart rate was rather modest with a mean increase of 3–4 bpm. In the general population, elevated heart rate was associated with increased cardiovascular risk, but it is not clear whether the sibutramine-induced increase in heart rate was also harmful.
- QT prolongation and arrhythmias: Sibutramine has also been associated with cardiac arrhythmias, frequently followed by other cardiac-related symptoms. For Example the only New Zealand Intensive Medicines Monitoring Programme(200007/08)9:4%3C273::AID-PDS512%3E3.0.CO;2-T/abstract has reported 26 cases of palpitations, 20 cases of dizziness/faintness, 10 cases of tachycardia and six cases of chest pain/tightness or angina. Further reports included a case of circulatory collapse of unknown cause, a patient who suffered supra-ventricular tachycardia (SVT) 7 days after starting on sibutramine and a patient who experienced ventricular ectopic beats while taking sibutramine.
Interestingly, sibutramine has been associated with four cases of long QT interval.
It would be prudent not to prescribe sibutramine to patients who present with long QT syndrome as well as to those taking medicine which prolong the QT interval (e.g. erythromycin, sparfloxacine).
- Myocardical Infarction: Several recent articles described the occurrence of acute myocardial infarction or acute coronary syndrome in young individuals receiving sibutramine. Although it is practically impossible to demonstrate a causal relation, the patient’s age, the absence of any attendant CVD risk factors, and/or the negative results of the other studies (including coronary angiography), together with the coincidence between the start of drug treatment for obesity, led to the conclusion that the use of sibutramine was probably responsible for the myocardial infarction, possibly as a result of coronary vasospasm.
Because of concerns that prolonged use of adrenergic or serotoninergic anti-obesity agents may induce pulmonary hypertension or valvular heart disease, two studies have evaluated the effects of sibutramine use on cardiac valve function and pulmonary artery pressure: a 24-week sibutramine treatment period did not affect heart valves and pulmonary artery pressure.
Effect of Sibutramine on Weight Loss and Blood Pressure
QT interval prolongation associated with sibutramine treatment
Since 2002, several cardiovascular adverse events (hypertension, tachycardia, arrhythmias, myocardial infarction) were reported in sibutramine-treated patients. This led to a contraindication of the use of this antiobesity agent in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias. In March 2002, sibutramine was temporarily withdrawn from the Italian market on the basis of 47 adverse event reports (primarily tachycardia, hypertension, and arrhythmias) and two deaths from CVD causes in our country. The EMEA began a comprehensive risk-benefit assessment of the drug, including in the U.K., where 215 reports of 411 adverse reactions (including 95 serious reactions and two deaths) were reported, and in France, where 99 adverse events were reported (including 10 serious adverse events but no deaths).
Therefore, upon a request of the EMEA, a long-term, large-scale prospective trial, SCOUT (Sibutramine Cardiovascular Outcome Trial), was designed to determine whether weight management with lifestyle intervention plus either sibutramine (10–15 mg/day) or placebo in cardiovascular high-risk overweight and obese patients would impact upon CVD end points.
To be eligible for inclusion, the patients had to meet the following key criteria: BMI 27–45 kg/m2 or BMI 25–27 kg/m2 with a waist circumference of ≥102 cm in males or ≥88 cm in females; and a history of documented coronary artery disease, cerebrovascular disease, or peripheral arterial occlusive disease, or with type 2 diabetes with at least one other risk factor. Exclusion criteria included heart failure symptoms; blood pressure >160/>100 mmHg; pulse >100 bpm; scheduled cardiac surgery or coronary angioplasty; and recent (<3 months) myocardial infarction, stroke, or transient ischemic attack.
A total of 10.724 subjects received 10-15 mg/day for a long-term treatment: 5 years.
The primary end point for SCOUT was the time-to-event analysis of the composite of primary outcome events: nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, and CVD death. The sibutramine group had a 16% increased risk relative to the placebo group.
Results from the analysis of the individual components of the primary end point showed that the increased risk was primarily attributed to the treatment difference for nonfatal events of myocardial infarction and stroke, with no apparent difference in risk for CVD death. No significant difference was observed between the treatment groups for all-cause mortality.
The review by the EMEA’s Committee for Medicinal Products for Human Use (CHMP ) was initiated because data from SCOUT showed an increased risk of serious, nonfatal cardiovascular events with sibutramine compared with placebo. The CHMP noted that the use of sibutramine was not in accordance with the prescribing information for most of the patients enrolled in SCOUT, as sibutramine is contraindicated in patients with known CVD. The treatment duration in the study was also longer than normally recommended. However, because obese and overweight patients are likely to have a higher risk of cardiovascular events, the CHMP was of the opinion that the data from SCOUT was relevant for the use of the medicine in clinical practice. The committee also noted that the data from available studies showed that the weight loss achieved with sibutramine was modest and may not be maintained after stopping. The CHMP concluded that the benefit of sibutramine as a weight loss aid does not outweigh the cardiovascular risks and recommended the suspension of marketing authorizations for sibutramine across the Europe.
Sibutramine in cardiovascular disease: is SCOUT the new STORM on the horizon?
Sibutramine on Cardiovascular Outcome
IMPORTANCE OF SEROTONERGIC SYSTEM IN THE LONG TERM TREATMENT OF OBESITY.
The 5HT-Containing neurons are organized into nine nuclei (B1-B9) and are located in the midbrain and hindbrain areas. The dorsal raphe (B7), in particular, has distinct projections to hypothalamic nuclei and other feeding-related forebrain areas. Obesity (by genetic or diet-iduced) has been demonstrated to alter 5HT dorsal raphe neurons and 5HT terminals regions.
The assortment of central and peripheral biological action of 5HT is mediated by at least 14 different classified receptors that are differentiated based on structure, function and intracellular signaling. The two receptors most critically involved in the control of feeding behaviour and body weight homeostasis are the 5HT1B e 5HT2C receptors.
- 5HT1B receptor is a G protein couple receptor that negatively couples to adenylyl cyclase to inhibit cAMP formation; it has a high affinity for 5HT. Located on the nerve terminals, the 5HT1B receptor functions as an autoreceptor to inhibit the release of 5HT from serotoninergic neurons or as heteroreceptors to inhibit the release of other neurotransmitters. The involvement of the 5HT1B receptor in feeding behaviour was initially implicated using antagonists with affinity for the receptor to block the anorectic action of DEXFENFLURAMIDE; while the selective agonist reduced meal size and decreased feeding duration. Further evidence was demonstrated with the generation of the 5HT1B receptor knockout mouse.
In the arcuate nucleus (ARC) of the hypothalamus there are two different populations of neurons: the first expresses neuropeptide Y and Agouti-related peptide ; the second expresses the precursor pro-opiomelacortin (POMC) to the anorectic peptide α-MSH . αMSH acts on melanocortin MC3/MC4 receptors to downstream effects that reduce food intake and increase energy expenditure. Reciprocally, increases in food intake and reduction in energy expenditures are demonstrated following activation of adjacent NPY/AgRP neurons: while NPY acts on a distinct set of receptors, AgRP is an endogenous antagonist for MC3/"MC4":http://en.wikipedia.org/wiki/Melanocortin_4_receptor receptors.
5HT1B receptors are expressed on AgRP neurons and 5HT terminals are in close proximity to ARC neurons that contain AgRP. Furthermore, it was demonstrated that CPP 94235, a selective 5HT1B receptor agonist, reduces the membrane potential ( hyperpolarizes) of ARC neurons that express NPY/AgRP and reduces the inhibitory inputs on POMC neurons.
- 5HT2C receptor is a GPCR with cellular excitatory activation that leads to the accumulation of inositol phosphates and downstream activation of phospholipase C. Similar to 5HT1B, the role of the 5HT2C receptor was implicated in feeding by several experiments using preferential and selective agonist and antagonists. Experiments utilizing 5HT2C receptor knockout mice have demonstrated hyperphagia and an obese phenotype; these mice more over are less responsive to anorectic properties of dexfenfluramine. It has been shown that the 5HT2C receptor mediates the activity of ARC neurons: 5HT2C receptor was found in up to 80% of POMC neurons and the activation of this receptor increased the firing rate of POMC neurons.
Using selective 5HT2C ligands, it was demonstrated that 5HT2C receptors compounds improved glucose homeostasis in obese animals suggesting 5HT2C receptors activation alters sympathetic outflow. A similar mechanisms in speculated to account for the hyperthermic effects noted with several selective 5HT2C receptor agonist, but this has not been experimentally determined.
Reversal of sibutramine-induced anorexia with a selective 5-HT receptor antagonist.
The use of serotonergic drugs to treat obesity