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Sibutramine
Sibutramine See also Anorectic drugs
GENERAL INFORMATION Sibutramine is an appetite suppressant that inhibits the reuptake of noradrenaline and serotonin. It was used in the adjunctive management of obesity in individuals with a body mass index (BMI) of 30 kg/m2 or more (and no associated co-morbidity) or in individuals with a BMI of 27 kg/m2 or more in the presence of other risk factors such as type 2 diabetes or hypercholesterolemia. Sibutramine was approved in Italy in April 2001, but it was taken off the market there on 6 March 2002, after 50 reports of adverse reactions (mainly tachycardia, hypertension, and dysrhythmias, in seven cases serious) and two deaths from cardiac arrest [1]. Subsequently, the Secretariat of the European Medicines Evaluation Agency began a comprehensive benefit to harm balance assessment of sibutramine, which remained on the market in several European countries; these included the UK (where there were 215 reports of 411 adverse events, 95 serious and 2 deaths) and France (where there were 99 reports of adverse events, 10 serious but no deaths). From February 1998 to September 2001, the Food and Drug Administration (FDA) in the USA received reports of 397 adverse events (143 cardiac dysrhythmias and 29 deaths, 19 due to cardiovascular causes, 10 involving people under 50 years of age, and three involving women under 30 years of age) [2]. In Canada, 28 adverse reactions (mainly hypertension and dysrhythmias, but no deaths) were reported from December 2000 to February 2002, including one case of chest pain, one of stroke, and two of eye hemorrhage; in three of these cases, the patients were concurrently taking a contraindicated antidepressant [3]. Tin 2009 the FDA listed the names of 69 products marketed for weight loss that had not been approved by the Agency and alerted consumers not to purchase or consume these products. They contained undeclared, active pharmaceutical ingredients that posed serious health risks (for example high blood pressure, seizures, tachycardia, palpitation, heart attacks, or strokes). These ingredients included sibutramine, rimonabant, phenytoin, phenolphthalein, and bumetanide, some in amounts that far exceed the FDA’s recommended doses [4]. The FDA also warned consumers not to take a product named Venom Hyperdrive 3.0, which was sold as a dietary supplement containing undeclared sibutramine [5]. The Swiss Agency for Therapeutic Products also issued a warning regarding the serious health risks of the slimming product “Zhen de Shou Fat Loss Capsules”, which contained sibutramine and had been sold via the internet [6]. Sibutramine was eventually withdrawn from the market in 2010 when it was discovered to be associated with an increased risk of cardiovascular events [7]. The European Medicines Agency (EMA) withdrew approval for sibutramine in January 2010, and the Food and Drugs Administration (FDA) restricted its licence based on concerns about the increased cardiovascular risk that was found in the Sibutramine Cardiovascular Outcome Trial (SCOUT) ã 2016 Elsevier B.V. All rights reserved.
[8,9]. Despite the fact that sibutramine is contraindicated in poorly controlled hypertension and cardiovascular disease, SCOUT only recruited patients aged over 55 years with known cardiovascular disease or type 2 diabetes plus at least one additional risk factor for cardiac disease; moreover, the patients were treated for 5 years, when the recommended period is 1 year [10]. After National Institute for Clinical Excellence (NICE) guidelines suggested that pharmacotherapy could be considered as useful adjuncts to behavioral weight loss interventions within a specialized service, prescribing of antiobesity drugs in adolescents increased dramatically [11]. It was argued that abrupt withdrawal of sibutramine in all age groups in Europe was an over-reaction, because it offered some hope of weight improvement in selected young people with profound obesity and no cardiovascular disease who have no other treatment options [12]. However, an editorial accompanying an original paper assessing cardiovascular responses to sibutramine in high-risk subjects during the 6-week lead-in period of SCOUT posed the question: “is SCOUT the new STORM on the horizon?” [13]. This turned out to be prescient [14].
DRUG STUDIES Placebo-controlled studies Sibutramine 10 mg/day in 109 obese patients (BMI over 30 kg/m2, ages 16–65 years) was evaluated in a doubleblind, placebo-controlled, parallel-group, prospective study over a period of 6 months [15]. There was a significant loss of body weight and significantly reduced BMI and waist measurement. There were 45 adverse events in 32 patients taking sibutramine; the most frequent were dry mouth (n ¼ 19), increased blood pressure (n ¼ 5), constipation (n ¼ 5), and tachycardia (n¼ 5); two patients withdrew owing to adverse events. There were 29 adverse events in 23 patients taking placebo, mainly increased blood pressure (n ¼ 11) and dry mouth (n ¼ 10). In contrast, in an earlier study [16] there was no significant increase in systolic or diastolic blood pressures or heart rate. In a 1-year placebo-controlled study in primary care, sibutramine 10 mg/day (n ¼ 122) or 15 mg/day (n ¼ 123) with dietary advice produced and maintained more weight loss than dietary advice alone [17]. None of the patients taking sibutramine or placebo (n ¼ 114) was withdrawn because of a raised blood pressure. There were comparable results in 44 patients who took sibutramine 10 mg/day for 12 months in a double-blind, placebo-controlled, crossover design [18]. After sibutramine withdrawal, the patients gained weight but did not reach baseline body weight. There were no significant adverse events of sibutramine withdrawal. Early sibutramine administration produced better effects than administration after a period of dieting. Other trials have confirmed the efficacy of sibutramine as a weight-loss agent in doses of 10–20 mg/day. The benefit of sibutramine is not only in its ability to induce weight loss, but also in its ability to maintain the weight loss effect for up to 2 years. However, after it is withdrawn, weight is commonly regained. Thus, sibutramine was considered effective in the management of obese patients who require
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pharmacotherapy as part of a multimodal approach to weight reduction [19]. In a multicenter, double-blind, randomized, parallelgroup, placebo-controlled trial in 22 European centers for specialist diabetes care over 6 months, sibutramine, in conjunction with moderate caloric restriction, enabled obese patients with type 2 diabetes taking sulfonylureas to achieve clinically significant weight loss [20]. This was associated with additional improvement in glycemic control in a limited number of patients who lost at least 10% of their baseline body weight. In a placebo-controlled study, sibutramine 10 mg/day for 6 months caused weight loss and a reduction in left ventricular mass in 86 obese hypertensive patients, with no changes in blood pressure or antihypertensive therapy [21]. Baseline investigations included echocardiography, 24-hour ambulatory blood pressure monitoring, and hepatic enzyme measurements. Compared with placebo, sibutramine produced a greater weight loss, an increase in heart rate, and a reduction in left ventricular mass/height index. The two groups had comparable increases in alkaline phosphatase activity and comparable adjustments in antihypertensive therapy. The most frequent adverse reactions associated with sibutramine were dry mouth and arthralgia; higher frequencies of insomnia and irritability, as suggested in other studies, were not found. The alterations reported in alkaline phosphatase may have been associated with mobilization of visceral adipose tissue [22] and could not be attributed to the use of sibutramine.
Systematic reviews In a systematic review of six randomized controlled studies of sibutramine in obese adolescents, the incidence of adverse reactions was similar with sibutramine and placebo, except for tachycardia (13% versus 6%) [23]. Other adverse events were dry mouth, constipation, dizziness, insomnia, and hypertension, all with a frequency of under 12%.
ORGANS AND SYSTEMS Cardiovascular Cardiovascular risk factors associated with obesity, including dyslipidemia, particularly raised triglyceride concentrations and reduced high-density lipoprotein concentrations, can be improved with weight loss during sibutramine treatment [17,18,24]. In general, improvements in serum lipids are proportional to the degree of body weight loss, whether that weight loss occurs with sibutramine or with placebo [24,25]. In a study of the efficacy and safety of sibutramine in obese white and African Americans with hypertension, the most common adverse event resulting in withdrawal among those taking sibutramine was hypertension (5.3% versus 1.4% of patients taking placebo) [26]. Sibutramine, which blocks the re-uptake of noradrenaline and serotonin and to a lesser extent dopamine [19], causes raised blood pressure [15,27]. Most studies have shown a positive relation between blood pressure and weight [28]. The failure of the blood pressure to fall with ã 2016 Elsevier B.V. All rights reserved.
weight loss in normotensive and hypertensive patients treated with sibutramine differed from the fall seen with orlistat [29–31] or weight loss induced by life-style modifications [32,33]. In the case of sibutramine, the potentially detrimental effect due to the failure of the blood pressure to fall with weight loss could be offset by the reductions in lipids, insulin, and uric acid that occur with weight loss [34]. The effects of sibutramine on weight loss, blood pressure, and pulse rate in hypertensive obese patients, whose blood pressure was well controlled with a beta-blocker either alone or with a thiazide diuretic, were evaluated in a 12-week, double-blind, placebo-controlled, parallelgroup, randomized study in 69 patients [35]. Sibutramine did not exacerbate pre-existing hypertension controlled with beta-blockers. Despite the presence of apparently effective beta-blockade, there were modest increases in pulse rate in those who took sibutramine, suggesting that mechanisms other than increased sympathetic tone may, at least in part, mediate this effect. In a 52-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 220 hypertensive patients with obesity (BMI 27–40 kg/m2), whose hypertension was well controlled with an angiotensin converting enzyme (ACE) inhibitor with or without a thiazide diuretic, sibutramine 20 mg/day achieved weight loss without compromising blood pressure control [36]. Blood pressure remained in the target range in patients who took sibutramine or placebo, although sibutramine was associated with a small mean increase in blood pressure and a modest increase in pulse rate. Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Program (IMMP) identified a case of QT interval prolongation and associated cardiac arrest in a patient who had taken sibutramine for 25 days [37]. There was a novel mutation in a cardiac potassium subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase the susceptibility to long QT intervals. Assessment of further IMMP reports identified five other patients who had palpitation associated with syncope or presyncopal symptoms, one of whom had a QTc interval at the upper limit of the reference range. Assessment of reports from the WHO database identified three reports of QT interval prolongation and one fatal case of torsade de pointes in a patient who was also taking cisapride. Sibutramine may cause potentially fatal dysrhythmias in patients with long QT syndrome or in those taking other medications known to prolong the QT interval. The Sibutramine Cardiovascular Outcomes (SCOUT) trial reported the effect of sibutramine 10 mg/day plus weight management on cardiovascular responses and weight loss in an initial single-blind, 6 week lead-in period [38]. Of 10 742 subjects, 97% had cardiovascular disease, 88% hypertension, and 84% type 2 diabetes. Body weight fell (median 2.2 kg; 95th percentile changes 6.2, 0.5); waist circumference was reduced by 2.0 cm (men: 8.5, 2.9; women: 9.0, 3.0), systolic blood pressure fell by 3 mmHg 24, 13) and diastolic by 1 mm Hg (14, 10). Pulse rate increased by 1.5/minute (11, 14). All changes were statistically significant. Two consecutive increases in blood pressure or pulse rate of >10 mmHg/bpm were observed in 4.7% and 3.5% of subjects respectively. Fifteen subjects died; 10 deaths were attributed to a
Sibutramine 373 cardiovascular cause, equivalent to 1.2 and 0.8 deaths per 100 years of exposure respectively. A further analysis of a subgroup in this trial showed that despite an initial lower body weight, older women with cardiovascular disease and diabetes mellitus appeared to lose as much weight as men. The adverse reactions profile of sibutramine in this older at risk population was similar to that previously observed in younger patients [39]. The SCOUT trial was a double-blind, randomized, placebo-controlled, parallel group trial conducted at 300 centers in 16 countries, predominantly in Europe [13]. The overall dropout rate due to adverse events was 6.8% during the lead-in phase. Cardiac disorders (0.6%) and blood pressure increases (0.2%) caused a minority of withdrawals, whereas others were due to previously reported and well-known adverse reactions to sibutramine. All these numbers are much lower than anticipated. Sibutramine had comparable effects in men and women, as well as in those taking or not taking beta-blockers. Although the authors of SCOUT study highlighted the potential of beta-blockers to protect against disadvantageous changes in blood pressure and heart rate, there are no ambulatory blood pressure data to support this claim. Identifying the subgroups that would particularly benefit from sibutramine might emerge when the complete trial results are available. The concomitant use of sibutramine and beta-blockers raised two conflicting problems. The Hypertension– Obesity–Sibutramine (HOS) study showed the effects of different antihypertensive regimens (felodipine þ ramipril versus trandolapril þverapamil versus metoprolol þ hydrochlorothiazide). Although the antihypertensive effects were not significantly different, those who took metoprolol þ hydrochlorothiazide had the greatest falls in blood pressure. More importantly, metoprolol þ hydrochlorothiazide attenuated the effect of sibutramine on weight loss and waist circumference. This treatment abrogated the improvement in glucose tolerance, as assessed by an oral glucose tolerance test, suggesting that this combination of antihypertensive drugs was associated with worsening of the metabolic syndrome [40]. Weight gain associated with beta-blockers, mostly due to an increase in body fat [41], was a disadvantage for combining them with sibutramine in patients with the metabolic syndrome and coronary artery disease. Two women developed myocardial infarctions with acute ST segment elevation associated with the use of sibutramine and phentermine [42]. The absence of cardiovascular risk factors and the negative results of other investigations suggested that the use of appetite suppressants may have been responsible. Acute myocardial infarction has been reported in a 24year-old man with a low risk of atherosclerosis, possibly associated with sibutramine [43]. Other causes were ruled out, including cocaine abuse, viral myocarditis, aortic dissection, hypercoagulable states, and autoimmune vasculitis. The cardiovascular effects of weight management with and without sibutramine were assessed in 10 744 overweight or clinically obese subjects, aged 55 years or older, with pre-existing cardiovascular disease, type 2 diabetes mellitus, or both [44]. The risk of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitation after cardiac arrest, or cardiovascular death) ã 2016 Elsevier B.V. All rights reserved.
was 11.4% with sibutramine and 10.0% with placebo (HR ¼ 1.16; 95% CI ¼ 1.03, 1.31). The rates of non-fatal myocardial infarction and non-fatal stroke were 4.1% and 2.6% with sibutramine and 3.2% and 1.9% with placebo (non-fatal myocardial infarction, HR ¼ 1.28; 95% CI ¼ 1.04, 1.57; for non-fatal stroke, HR ¼ 1.36; 95% CI ¼ 1.04, 1.77). The rates of cardiovascular death and death from any cause were not increased. Secondary causes of pulmonary arterial hypertension (PAH), including appetite suppressant drugs associated with PAH, have been reviewed [45]. Newer trends in the treatment of PAH, especially the status of prostacyclin analogues and endothelin-1 receptor antagonists, have been addressed.
Respiratory In an open study in 87 middle-aged men with obesity (BMI ¼ 34 kg/m2) and symptomatic obstructive sleep apnea moderate weight loss (10%) with sibutramine and a weight loss program improved the severity of sleep apnea without increasing the blood pressure [46]. However, there was a small increase in resting heart rate. Given the high prevalence of hypertension in patients with sleep apnea, it is important first to establish whether concerns about the risks of using sibutramine are justified. Paradoxically, there was a tendency for the systolic blood pressure to fall during sibutramine therapy and then revert to baseline after drug washout. This finding was in keeping with the inhibitory clonidine-like effect of sibutramine on the central nervous system [47].
Psychiatric Two reports described three cases of psychosis probably induced by sibutramine that responded to antipsychotic drugs [48,49]. Sibutramine could have been a susceptibility factor for people vulnerable to psychosis [50].
Endocrine A 38-year-old woman took sibutramine and developed amenorrhea and galactorrhea with hyperprolactinemia [51]. Sibutramine was withdrawn, and her serum prolactin concentration returned to normal within 15 days; the amenorrhea and galactorrhea resolved.
Hematologic Evidence from postmarketing surveillance suggested a causal association between sibutramine and bruising/ ecchymosis. In an IMMP Cohort of 9532 patients who took sibutramine between February 2001 and November 2002, there were five reports of ecchymosis [52]. Search of the WHO-UMC database identified a further 89 reports, of which 39 were classified as ecchymosis. Of these 39 reports, 31 had sufficient information for causality assessment. In 11 of these 31 cases there was a positive dechallenge; of these, one patient had recurrence of ecchymosis on rechallenge. In the remaining 10 cases with a positive
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dechallenge, either the outcome of rechallenge was unknown or rechallenge was not performed. In two of these cases either aspirin or co-trimoxazole had also been used. The time to onset for these events was 1–86 days. Four patients developed bruising within 2 days of starting sibutramine. The case with a positive rechallenge developed ecchymosis 86 days after starting sibutramine. The incidence of ecchymosis in premarketing trials of sibutramine was under 1%. Although it appears that bruising/ecchymosis is not a common adverse reaction to sibutramine, a potential concern is that it may be associated with more serious hemorrhagic events.
SUSCEPTIBILITY FACTORS Genetic Patient selection based on candidate genes may enhance the response to sibutramine in obesity [53].
DRUG ADMINISTRATION Drug contamination A metabolite of sibutramine was identified in a urine sample of a 16-year-old girl by gas chromatography and mass spectrometry. Her parents had noticed a conspicuous mood change and her mother found a package labelled “LiDa Dai Dai Hua Jiao Nang”, a Chinese “pure herbal” weight loss product [54]. In another case a 20 year old woman developed severe headache, vertigo and numbness within 2 days after starting LiDa Dai Dai Hua Jiao Nang capsule. Sibutramine was identified in the urine, as well as in the capsule. Each capsule contained sibutramine base 27.4 mg [55]. A slimming product called “Green Coffee 800” was associated with hypomania in a 33-year-old woman and abnormal hepatic enzyme activities in a 44-year-old woman; it turned out to contain sibutramine [56].
DRUG–DRUG INTERACTIONS See also Ciclosporin; Selective serotonin re-uptake inhibitors (SSRIs); Yohimbine
Citalopram Hypomania in a unipolar depressed woman was attributed to concomitant use of sibutramine and citalopram [57]. The close temporal relation between the onset and the disappearance of hypomania with the introduction and withdrawal of sibutramine suggested a causal link. This report suggests that combining sibutramine with a serotonin re-uptake inhibitor could cause hypomania in people with unipolar major depressive disorder with a family history of bipolar disorder.
Finasteride Soon after the introduction of finasteride to treat alopecia, a 30-year-old man taking sibutramine developed paranoid psychotic behavior [58]. ã 2016 Elsevier B.V. All rights reserved.
Lorazepam Concurrent use of sibutramine 10 mg and lorazepam 2 mg resulted in hypoglycemic coma after less than 12 hours of fasting [59]. There was no other attributable cause, such as medication errors, ethanol ingestion, neoplasms, or liver disease.
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[51] Soares Leaes CG, Pereira-Lima JF, da Costa Oliveira M. A case of sibutramine-induced hyperprolactinemia. Neuro Endocrinol Lett 2011; 32(5): 616–8. [52] Conway CR, Ziaee L, Langenfeld SJ. Ephedrine-induced emergence of bipolar symptoms. Bipolar Disord 2006; 8: 204–5. [53] Grudell ABM, Sweetser S, Camilleri M, Eckert DJ, Vazquez-Rocque MI, Carlson PJ, Burton DD, Braddock AE, Clark MM, Graszer KM, Kalsy SA, Zinsmeister AR. A controlled pharmacogenetic trial of sibutramine on weight loss and body composition in obese and overweight adults. Gastroenterology 2008; 135: 1142–54. [54] Vidal C, Quandte S. Identification of a sibutraminemetabolite in patient urine after intake of a “pure herbal” Chinese slimming product. Ther Drug Monit 2006; 28: 690–2.
ã 2016 Elsevier B.V. All rights reserved.
[55] Jung J, Hermanns-Clausen M, Weinmann W. Anorectic sibutramine detected in a Chinese herbal drug for weight loss. Forensic Sci Int 2006; 161: 221–2. [56] van Hunsel F, van Grootheest K. Bijwerkingen afslankmiddel, vervuild met sibutramine. [Adverse drug reactions of a slimming product contaminated with sibutramine.] Ned Tijdschr Geneeskd 2011; 155(42): A3695. [57] Benazzi F. Organic hypomania secondary to sibutramine citalopram interaction. J Clin Psychiatry 2002; 63(2): 165. [58] Sucar DD, Sougey EB, Neto JB. Psychotic episode induced by potential drug interaction of sibutramine and finasteride. Rev Bras Psiquiatr 2002; 24: 30–3. [59] Lin Y-Y, Hsu C-W, Chu S-J, Tsai S-H. Another dangerous combination for hypoglycemic coma: concurrent use of sibutramine and lorazepam. Q J Med 2008; 101: 243–4.
GENERAL INFORMATION Sibutramine is an appetite suppressant that inhibits the reuptake of noradrenaline and serotonin. It was used in the adjunctive management of obesity in individuals with a body mass index (BMI) of 30 kg/m2 or more (and no associated co-morbidity) or in individuals with a BMI of 27 kg/m2 or more in the presence of other risk factors such as type 2 diabetes or hypercholesterolemia. Sibutramine was approved in Italy in April 2001, but it was taken off the market there on 6 March 2002, after 50 reports of adverse reactions (mainly tachycardia, hypertension, and dysrhythmias, in seven cases serious) and two deaths from cardiac arrest [1]. Subsequently, the Secretariat of the European Medicines Evaluation Agency began a comprehensive benefit to harm balance assessment of sibutramine, which remained on the market in several European countries; these included the UK (where there were 215 reports of 411 adverse events, 95 serious and 2 deaths) and France (where there were 99 reports of adverse events, 10 serious but no deaths). From February 1998 to September 2001, the Food and Drug Administration (FDA) in the USA received reports of 397 adverse events (143 cardiac dysrhythmias and 29 deaths, 19 due to cardiovascular causes, 10 involving people under 50 years of age, and three involving women under 30 years of age) [2]. In Canada, 28 adverse reactions (mainly hypertension and dysrhythmias, but no deaths) were reported from December 2000 to February 2002, including one case of chest pain, one of stroke, and two of eye hemorrhage; in three of these cases, the patients were concurrently taking a contraindicated antidepressant [3]. Tin 2009 the FDA listed the names of 69 products marketed for weight loss that had not been approved by the Agency and alerted consumers not to purchase or consume these products. They contained undeclared, active pharmaceutical ingredients that posed serious health risks (for example high blood pressure, seizures, tachycardia, palpitation, heart attacks, or strokes). These ingredients included sibutramine, rimonabant, phenytoin, phenolphthalein, and bumetanide, some in amounts that far exceed the FDA’s recommended doses [4]. The FDA also warned consumers not to take a product named Venom Hyperdrive 3.0, which was sold as a dietary supplement containing undeclared sibutramine [5]. The Swiss Agency for Therapeutic Products also issued a warning regarding the serious health risks of the slimming product “Zhen de Shou Fat Loss Capsules”, which contained sibutramine and had been sold via the internet [6]. Sibutramine was eventually withdrawn from the market in 2010 when it was discovered to be associated with an increased risk of cardiovascular events [7]. The European Medicines Agency (EMA) withdrew approval for sibutramine in January 2010, and the Food and Drugs Administration (FDA) restricted its licence based on concerns about the increased cardiovascular risk that was found in the Sibutramine Cardiovascular Outcome Trial (SCOUT) ã 2016 Elsevier B.V. All rights reserved.
[8,9]. Despite the fact that sibutramine is contraindicated in poorly controlled hypertension and cardiovascular disease, SCOUT only recruited patients aged over 55 years with known cardiovascular disease or type 2 diabetes plus at least one additional risk factor for cardiac disease; moreover, the patients were treated for 5 years, when the recommended period is 1 year [10]. After National Institute for Clinical Excellence (NICE) guidelines suggested that pharmacotherapy could be considered as useful adjuncts to behavioral weight loss interventions within a specialized service, prescribing of antiobesity drugs in adolescents increased dramatically [11]. It was argued that abrupt withdrawal of sibutramine in all age groups in Europe was an over-reaction, because it offered some hope of weight improvement in selected young people with profound obesity and no cardiovascular disease who have no other treatment options [12]. However, an editorial accompanying an original paper assessing cardiovascular responses to sibutramine in high-risk subjects during the 6-week lead-in period of SCOUT posed the question: “is SCOUT the new STORM on the horizon?” [13]. This turned out to be prescient [14].
DRUG STUDIES Placebo-controlled studies Sibutramine 10 mg/day in 109 obese patients (BMI over 30 kg/m2, ages 16–65 years) was evaluated in a doubleblind, placebo-controlled, parallel-group, prospective study over a period of 6 months [15]. There was a significant loss of body weight and significantly reduced BMI and waist measurement. There were 45 adverse events in 32 patients taking sibutramine; the most frequent were dry mouth (n ¼ 19), increased blood pressure (n ¼ 5), constipation (n ¼ 5), and tachycardia (n¼ 5); two patients withdrew owing to adverse events. There were 29 adverse events in 23 patients taking placebo, mainly increased blood pressure (n ¼ 11) and dry mouth (n ¼ 10). In contrast, in an earlier study [16] there was no significant increase in systolic or diastolic blood pressures or heart rate. In a 1-year placebo-controlled study in primary care, sibutramine 10 mg/day (n ¼ 122) or 15 mg/day (n ¼ 123) with dietary advice produced and maintained more weight loss than dietary advice alone [17]. None of the patients taking sibutramine or placebo (n ¼ 114) was withdrawn because of a raised blood pressure. There were comparable results in 44 patients who took sibutramine 10 mg/day for 12 months in a double-blind, placebo-controlled, crossover design [18]. After sibutramine withdrawal, the patients gained weight but did not reach baseline body weight. There were no significant adverse events of sibutramine withdrawal. Early sibutramine administration produced better effects than administration after a period of dieting. Other trials have confirmed the efficacy of sibutramine as a weight-loss agent in doses of 10–20 mg/day. The benefit of sibutramine is not only in its ability to induce weight loss, but also in its ability to maintain the weight loss effect for up to 2 years. However, after it is withdrawn, weight is commonly regained. Thus, sibutramine was considered effective in the management of obese patients who require
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pharmacotherapy as part of a multimodal approach to weight reduction [19]. In a multicenter, double-blind, randomized, parallelgroup, placebo-controlled trial in 22 European centers for specialist diabetes care over 6 months, sibutramine, in conjunction with moderate caloric restriction, enabled obese patients with type 2 diabetes taking sulfonylureas to achieve clinically significant weight loss [20]. This was associated with additional improvement in glycemic control in a limited number of patients who lost at least 10% of their baseline body weight. In a placebo-controlled study, sibutramine 10 mg/day for 6 months caused weight loss and a reduction in left ventricular mass in 86 obese hypertensive patients, with no changes in blood pressure or antihypertensive therapy [21]. Baseline investigations included echocardiography, 24-hour ambulatory blood pressure monitoring, and hepatic enzyme measurements. Compared with placebo, sibutramine produced a greater weight loss, an increase in heart rate, and a reduction in left ventricular mass/height index. The two groups had comparable increases in alkaline phosphatase activity and comparable adjustments in antihypertensive therapy. The most frequent adverse reactions associated with sibutramine were dry mouth and arthralgia; higher frequencies of insomnia and irritability, as suggested in other studies, were not found. The alterations reported in alkaline phosphatase may have been associated with mobilization of visceral adipose tissue [22] and could not be attributed to the use of sibutramine.
Systematic reviews In a systematic review of six randomized controlled studies of sibutramine in obese adolescents, the incidence of adverse reactions was similar with sibutramine and placebo, except for tachycardia (13% versus 6%) [23]. Other adverse events were dry mouth, constipation, dizziness, insomnia, and hypertension, all with a frequency of under 12%.
ORGANS AND SYSTEMS Cardiovascular Cardiovascular risk factors associated with obesity, including dyslipidemia, particularly raised triglyceride concentrations and reduced high-density lipoprotein concentrations, can be improved with weight loss during sibutramine treatment [17,18,24]. In general, improvements in serum lipids are proportional to the degree of body weight loss, whether that weight loss occurs with sibutramine or with placebo [24,25]. In a study of the efficacy and safety of sibutramine in obese white and African Americans with hypertension, the most common adverse event resulting in withdrawal among those taking sibutramine was hypertension (5.3% versus 1.4% of patients taking placebo) [26]. Sibutramine, which blocks the re-uptake of noradrenaline and serotonin and to a lesser extent dopamine [19], causes raised blood pressure [15,27]. Most studies have shown a positive relation between blood pressure and weight [28]. The failure of the blood pressure to fall with ã 2016 Elsevier B.V. All rights reserved.
weight loss in normotensive and hypertensive patients treated with sibutramine differed from the fall seen with orlistat [29–31] or weight loss induced by life-style modifications [32,33]. In the case of sibutramine, the potentially detrimental effect due to the failure of the blood pressure to fall with weight loss could be offset by the reductions in lipids, insulin, and uric acid that occur with weight loss [34]. The effects of sibutramine on weight loss, blood pressure, and pulse rate in hypertensive obese patients, whose blood pressure was well controlled with a beta-blocker either alone or with a thiazide diuretic, were evaluated in a 12-week, double-blind, placebo-controlled, parallelgroup, randomized study in 69 patients [35]. Sibutramine did not exacerbate pre-existing hypertension controlled with beta-blockers. Despite the presence of apparently effective beta-blockade, there were modest increases in pulse rate in those who took sibutramine, suggesting that mechanisms other than increased sympathetic tone may, at least in part, mediate this effect. In a 52-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study in 220 hypertensive patients with obesity (BMI 27–40 kg/m2), whose hypertension was well controlled with an angiotensin converting enzyme (ACE) inhibitor with or without a thiazide diuretic, sibutramine 20 mg/day achieved weight loss without compromising blood pressure control [36]. Blood pressure remained in the target range in patients who took sibutramine or placebo, although sibutramine was associated with a small mean increase in blood pressure and a modest increase in pulse rate. Post-marketing surveillance using prescription event monitoring in the New Zealand Intensive Medicines Monitoring Program (IMMP) identified a case of QT interval prolongation and associated cardiac arrest in a patient who had taken sibutramine for 25 days [37]. There was a novel mutation in a cardiac potassium subunit gene, KCNQ1, which is likely to prolong cardiac membrane depolarization and increase the susceptibility to long QT intervals. Assessment of further IMMP reports identified five other patients who had palpitation associated with syncope or presyncopal symptoms, one of whom had a QTc interval at the upper limit of the reference range. Assessment of reports from the WHO database identified three reports of QT interval prolongation and one fatal case of torsade de pointes in a patient who was also taking cisapride. Sibutramine may cause potentially fatal dysrhythmias in patients with long QT syndrome or in those taking other medications known to prolong the QT interval. The Sibutramine Cardiovascular Outcomes (SCOUT) trial reported the effect of sibutramine 10 mg/day plus weight management on cardiovascular responses and weight loss in an initial single-blind, 6 week lead-in period [38]. Of 10 742 subjects, 97% had cardiovascular disease, 88% hypertension, and 84% type 2 diabetes. Body weight fell (median 2.2 kg; 95th percentile changes 6.2, 0.5); waist circumference was reduced by 2.0 cm (men: 8.5, 2.9; women: 9.0, 3.0), systolic blood pressure fell by 3 mmHg 24, 13) and diastolic by 1 mm Hg (14, 10). Pulse rate increased by 1.5/minute (11, 14). All changes were statistically significant. Two consecutive increases in blood pressure or pulse rate of >10 mmHg/bpm were observed in 4.7% and 3.5% of subjects respectively. Fifteen subjects died; 10 deaths were attributed to a
Sibutramine 373 cardiovascular cause, equivalent to 1.2 and 0.8 deaths per 100 years of exposure respectively. A further analysis of a subgroup in this trial showed that despite an initial lower body weight, older women with cardiovascular disease and diabetes mellitus appeared to lose as much weight as men. The adverse reactions profile of sibutramine in this older at risk population was similar to that previously observed in younger patients [39]. The SCOUT trial was a double-blind, randomized, placebo-controlled, parallel group trial conducted at 300 centers in 16 countries, predominantly in Europe [13]. The overall dropout rate due to adverse events was 6.8% during the lead-in phase. Cardiac disorders (0.6%) and blood pressure increases (0.2%) caused a minority of withdrawals, whereas others were due to previously reported and well-known adverse reactions to sibutramine. All these numbers are much lower than anticipated. Sibutramine had comparable effects in men and women, as well as in those taking or not taking beta-blockers. Although the authors of SCOUT study highlighted the potential of beta-blockers to protect against disadvantageous changes in blood pressure and heart rate, there are no ambulatory blood pressure data to support this claim. Identifying the subgroups that would particularly benefit from sibutramine might emerge when the complete trial results are available. The concomitant use of sibutramine and beta-blockers raised two conflicting problems. The Hypertension– Obesity–Sibutramine (HOS) study showed the effects of different antihypertensive regimens (felodipine þ ramipril versus trandolapril þverapamil versus metoprolol þ hydrochlorothiazide). Although the antihypertensive effects were not significantly different, those who took metoprolol þ hydrochlorothiazide had the greatest falls in blood pressure. More importantly, metoprolol þ hydrochlorothiazide attenuated the effect of sibutramine on weight loss and waist circumference. This treatment abrogated the improvement in glucose tolerance, as assessed by an oral glucose tolerance test, suggesting that this combination of antihypertensive drugs was associated with worsening of the metabolic syndrome [40]. Weight gain associated with beta-blockers, mostly due to an increase in body fat [41], was a disadvantage for combining them with sibutramine in patients with the metabolic syndrome and coronary artery disease. Two women developed myocardial infarctions with acute ST segment elevation associated with the use of sibutramine and phentermine [42]. The absence of cardiovascular risk factors and the negative results of other investigations suggested that the use of appetite suppressants may have been responsible. Acute myocardial infarction has been reported in a 24year-old man with a low risk of atherosclerosis, possibly associated with sibutramine [43]. Other causes were ruled out, including cocaine abuse, viral myocarditis, aortic dissection, hypercoagulable states, and autoimmune vasculitis. The cardiovascular effects of weight management with and without sibutramine were assessed in 10 744 overweight or clinically obese subjects, aged 55 years or older, with pre-existing cardiovascular disease, type 2 diabetes mellitus, or both [44]. The risk of a primary outcome event (non-fatal myocardial infarction, non-fatal stroke, resuscitation after cardiac arrest, or cardiovascular death) ã 2016 Elsevier B.V. All rights reserved.
was 11.4% with sibutramine and 10.0% with placebo (HR ¼ 1.16; 95% CI ¼ 1.03, 1.31). The rates of non-fatal myocardial infarction and non-fatal stroke were 4.1% and 2.6% with sibutramine and 3.2% and 1.9% with placebo (non-fatal myocardial infarction, HR ¼ 1.28; 95% CI ¼ 1.04, 1.57; for non-fatal stroke, HR ¼ 1.36; 95% CI ¼ 1.04, 1.77). The rates of cardiovascular death and death from any cause were not increased. Secondary causes of pulmonary arterial hypertension (PAH), including appetite suppressant drugs associated with PAH, have been reviewed [45]. Newer trends in the treatment of PAH, especially the status of prostacyclin analogues and endothelin-1 receptor antagonists, have been addressed.
Respiratory In an open study in 87 middle-aged men with obesity (BMI ¼ 34 kg/m2) and symptomatic obstructive sleep apnea moderate weight loss (10%) with sibutramine and a weight loss program improved the severity of sleep apnea without increasing the blood pressure [46]. However, there was a small increase in resting heart rate. Given the high prevalence of hypertension in patients with sleep apnea, it is important first to establish whether concerns about the risks of using sibutramine are justified. Paradoxically, there was a tendency for the systolic blood pressure to fall during sibutramine therapy and then revert to baseline after drug washout. This finding was in keeping with the inhibitory clonidine-like effect of sibutramine on the central nervous system [47].
Psychiatric Two reports described three cases of psychosis probably induced by sibutramine that responded to antipsychotic drugs [48,49]. Sibutramine could have been a susceptibility factor for people vulnerable to psychosis [50].
Endocrine A 38-year-old woman took sibutramine and developed amenorrhea and galactorrhea with hyperprolactinemia [51]. Sibutramine was withdrawn, and her serum prolactin concentration returned to normal within 15 days; the amenorrhea and galactorrhea resolved.
Hematologic Evidence from postmarketing surveillance suggested a causal association between sibutramine and bruising/ ecchymosis. In an IMMP Cohort of 9532 patients who took sibutramine between February 2001 and November 2002, there were five reports of ecchymosis [52]. Search of the WHO-UMC database identified a further 89 reports, of which 39 were classified as ecchymosis. Of these 39 reports, 31 had sufficient information for causality assessment. In 11 of these 31 cases there was a positive dechallenge; of these, one patient had recurrence of ecchymosis on rechallenge. In the remaining 10 cases with a positive
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dechallenge, either the outcome of rechallenge was unknown or rechallenge was not performed. In two of these cases either aspirin or co-trimoxazole had also been used. The time to onset for these events was 1–86 days. Four patients developed bruising within 2 days of starting sibutramine. The case with a positive rechallenge developed ecchymosis 86 days after starting sibutramine. The incidence of ecchymosis in premarketing trials of sibutramine was under 1%. Although it appears that bruising/ecchymosis is not a common adverse reaction to sibutramine, a potential concern is that it may be associated with more serious hemorrhagic events.
SUSCEPTIBILITY FACTORS Genetic Patient selection based on candidate genes may enhance the response to sibutramine in obesity [53].
DRUG ADMINISTRATION Drug contamination A metabolite of sibutramine was identified in a urine sample of a 16-year-old girl by gas chromatography and mass spectrometry. Her parents had noticed a conspicuous mood change and her mother found a package labelled “LiDa Dai Dai Hua Jiao Nang”, a Chinese “pure herbal” weight loss product [54]. In another case a 20 year old woman developed severe headache, vertigo and numbness within 2 days after starting LiDa Dai Dai Hua Jiao Nang capsule. Sibutramine was identified in the urine, as well as in the capsule. Each capsule contained sibutramine base 27.4 mg [55]. A slimming product called “Green Coffee 800” was associated with hypomania in a 33-year-old woman and abnormal hepatic enzyme activities in a 44-year-old woman; it turned out to contain sibutramine [56].
DRUG–DRUG INTERACTIONS See also Ciclosporin; Selective serotonin re-uptake inhibitors (SSRIs); Yohimbine
Citalopram Hypomania in a unipolar depressed woman was attributed to concomitant use of sibutramine and citalopram [57]. The close temporal relation between the onset and the disappearance of hypomania with the introduction and withdrawal of sibutramine suggested a causal link. This report suggests that combining sibutramine with a serotonin re-uptake inhibitor could cause hypomania in people with unipolar major depressive disorder with a family history of bipolar disorder.
Finasteride Soon after the introduction of finasteride to treat alopecia, a 30-year-old man taking sibutramine developed paranoid psychotic behavior [58]. ã 2016 Elsevier B.V. All rights reserved.
Lorazepam Concurrent use of sibutramine 10 mg and lorazepam 2 mg resulted in hypoglycemic coma after less than 12 hours of fasting [59]. There was no other attributable cause, such as medication errors, ethanol ingestion, neoplasms, or liver disease.
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