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Home , Cetilistat, Orlistat, Sibutramine, Tesofensine

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Comparative Efficiency and Safety of Pharmacological Approaches to the

VOJTECH HAINER, MD, PHD improved concentrations of HDL choles- terol and , whereas re- duced the incidence of diabetes and improved concentrations of total choles- besity and overweight are reaching and the presence of comorbidities (4). terol and LDL cholesterol (7). Norris et al. global epidemic proportions affect- Drugs used for the treatment of obesity (9) conducted a meta-analysis on the ef- O ficacy of orlistat and in obese ing more than 1.1 billion individu- in the past were associated with serious als worldwide. Excess weight is associated (psycho-stimulatory, depres- adults with and found with an increased mortality, chronic mor- sion, addiction, cardio-excitatory effects, only modest reductions of glycated he- bidity (including type 2 diabetes, arterial pulmonary , and valve dis- moglobin (0.4% with orlistat, 0.7% with hypertension, cardiovascular diseases, ease). Antiobesity agents that possess sibutramine). The improvement in lipid and certain cancers), decreased quality of cardio-excitatory and psycho-stimulatory profile in response to sibutramine and life, and considerable health care costs (1). effects (e.g., , , and orlistat is greater than can be expected Antiobesity drugs work through dif- mixture) have still been available from per se. A systemic re- ferent mechanisms either in the central for the short-term use in some countries view and a meta-analysis on attrition rate nervous system (CNS) or in the periph- (,3months). in trials with weight loss medications re- eral tissues. These mechanisms include: ported either similar total dropout rate 1) suppression of food intake in the CNS, SIBUTRAMINE AND ORLISTAT— for orlistat and sibutramine (10) or 2) decreased gut absorption of nutrients, Currently, only two drugs, sibutramine somewhat lower dropout rate on sibutr- and 3) increased energy expenditure or and orlistat, are prescribed for long-term (8). oxidation of nutrients. The efficacy of administration. The most important trial The sibutramine treatment favorably antiobesity drugs should be evaluated by evaluating the long-term efficacy of sibutr- affects inflammatory cytokines, serum their ability to reduce fat stores (preferen- amine was the Sibutramine Trial of Obesity hormonal levels (resistin, adiponectin), tially visceral adipose tissue), maintain Reduction and Maintenance (STORM) in and the transport of leptin through the weight loss, diminish obesity-related duration of 2 years (5), while the XENical blood-brain barrier. Antiobesity effects health risks, and thus decrease morbidity in the Prevention of Diabetes in Obese and adverse events are related to the and mortality, and improve quality of life. Subjects (XENDOS) study assessing orli- mechanisms of action of both drugs. An ideal antiobesity drug should be ad- stat efficacy in preventing type 2 diabetes Sibutramine selectively inhibits ministered orally, devoid of major side in obese subjects was carried out over of , , and partly effects, and distributed at affordable a 4-year period (6). Meta-analysis of ran- in the hypothalamus. This price. Treatment with antiobesity drugs domized trials revealed that sibutramine action results in an enhanced satiety and can be considered in obese patients who led to 4.2 kg and orlistat to 2.9 kg weight slightly increased thermogenesis (11). failed to achieve a sufficient weight loss reduction in comparison with placebo (7). Orlistat reduces dietary fat absorption to a program of lifestyle change, diet, Four of the seven studies comparing si- by inhibition of gastrointestinal and pan- and physical activity. However, the drug butramine and orlistat monotherapy creatic . The peripheral sympatho- treatment of obesity should be an integral showed that sibutramine was significantly mimetic activity of sibutramine leads to part of the comprehensive obesity treat- more efficacious for weight loss, and an increase in both systolic (sBP) and ment program that includes diet, , the remaining three studies showed equiva- diastolic (dBP) and pulse and cognitive behavioral intervention lent effects (8). Modest weight loss (5–10%) rate. However combined analysis of two (2,3). Treatment of obesity should be in- in response to antiobesity drug treatment placebo-controlled trials concluded that dividually tailored taking into account the wasassociatedwithanimprovementin sibutramine treatment is unlikely to degree and character of obesity, age, sex, lipid and glycemic profile. Sibutramine elicit a critical increase in blood pres- sure even in hypertensive patients with ccccccccccccccccccccccccccccccccccccccccccccccccc well-controlled hypertension. This is ex- From the Institute of Endocrinology, Obesity Management Center, Prague, Czech Republic. plained by the clonidine-like effect of si- Corresponding author: Vojtech Hainer, [email protected]. butramine, which is mediated through This publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in a Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were activation of central -2 adrenoreceptors made possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol- (12). A recent meta-analysis of long-term Myers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-La changes in blood pressure following Roche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pfizer. orlistat (12 trials including 5,540 patients) DOI: 10.2337/dc11-s255 © 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly and sibutramine (6 trials including 1,495 cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ patients) treatment in placebo-controlled licenses/by-nc-nd/3.0/ for details. trials of 12-months duration revealed a care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S349 Antiobesity drugs, efficiency, and safety modest decrease in both sBP (21.9 mmHg) IS THE interaction with fat micelles in the intes- and dBP (21.5 mmHg) in response to SUCCESSOR OF tine (25). orlistat treatment, whereas sibutramine SIBUTRAMINE?—Tesofensine is treatment led to a modest increase in a recently discovered norepinephrine-, LEPTIN: TREATMENT OF sBP (+0.5 mmHg) and dBP (+1.7 dopamine-, and serotonin-reuptake inhib- RELATIVE LEPTIN mmHg) (13). It should be pointed out itor, which might have the potential to DEFICIENCY?—Obesity, metabolic, that the reduction of blood pressure in evoke a weight loss twice that of cur- neuroendocrine, and behavioral conse- patients with type 2 diabetes after orlistat rently approved drugs (22). A consider- quences of the rare congenital leptin de- treatment was less pronounced and the able effect of tesofensine on ficiency in humans are efficiently reversed increase in blood pressure after sibu- sensations and a moderate effect on en- by the treatment with recombinant leptin tramine was higher. A recent experience ergy expenditure at night can contribute (26). On the other hand, subjects with from the Sibutramine Cardiovascular to its strong weight-reducing effect (23). common obesity are hyperleptinemic Outcomes (SCOUT) trial clearly indi- The observed weight loss was mainly compared with normal weight individu- cated that sibutramine administration because of the loss of fat mass and was fi als and resistant to the central hypotha- should be strictly avoided in patients accompanied by a signi cant decrease lamic effects of endogenous leptin and with a history of , in anthropometric measures of abdomi- less sensitive to exogenous leptin (27). including those with uncontrolled hy- nal obesity as the waist circumference However, some obese subjects who have pertension (14,15). and the sagittal abdominal diameter. fi recently lost weight exhibit a relative lep- Ten years of experiences with sibu- Bene cial effects of tesofensine adminis- tin deficiency and reduced concentrations tramine and orlistat in the treatment of tration were demonstrated on the levels of that could be re- obesity and related conditions in both of total cholesterol, triglycerides, insu- versed by an administration of exogenous adults and adolescents were recently re- lin, adiponectin, and hemoglobin A1c. leptin (28). Further studies are needed to viewed (16–18). In addition to obesity, The most frequently observed adverse fi support the role of leptin administration the ef cacy and safety of both drugs in events (, dry mouth, constipa- for weight maintenance in subjects who the treatment of nonalcoholic fatty tion, and insomnia) are similar for teso- develop relative leptin deficiency in re- disease, polycystic ovary syndrome, and fensine and sibutramine. Increases in sponse to calorie deficit. binge were reported. Im- pulse rate, but no significant increases in provement in health-related quality of life sBP and dBP, were observed after was shown in sibutramine-treated pa- 24-weeks’ treatment with tesofensine MELANOCORTIN-4 — tients who achieved moderate weight in a dose of 0.25 or 0.50 mg. However, AGONISTS Incontrasttotherarecon- fi loss (19). Sibutramine treatment–induced these findings on the efficacy and safety of genital leptin de ciency, melanocortin-4 weight loss is associated with improvement tesofensine with regard to its potential receptor (MC4R) mutations are the most in eating attitudes as documented by in- adverse effects (cardiovascular and common causes of monogenic obesities. fi – creased dietary restraint and decreased CNS) need confirmationinphaseIIItri- MC4R de ciency is responsible for 0.5 dietary disinhibition and hunger scores als conducted in larger cohorts of obese 2.5% of severe obesities. Two novel MC4R fi (20). The weight loss with orlistat is not patients. agonists were recently identi ed that were related to eating behavior attitudes but able in vitro to activate mutated human is associated with personality traits such IS THE SUCCESSOR MC4R (29). However, clinical trials are fi fi as “order” and “deliberation” and thus, OF ORLISTAT?—The efficacy and required to con rm the ef ciency and in contrast to sibutramine, is more de- safety of cetilistat, a novel inhibitor of safety of these compounds in humans. manding and requires greater adherence gastrointestinal , was determined (21). in both obese nondiabetic (24) and di- : A SAFE Orlistat inhibits gastrointestinal and abetic (25) patients. Similar weight re- SUCCESSOR OF pancreatic lipase and thus the weight loss ductions were observed in patients ?—Dexfen- and favorable metabolic effects are mainly treated with cetilistat and orlistat (25). fluramine addressed serotoninergic hy- achieved by 30% reduction in dietary fat Weight reductions (from 23.3 kg to pothalamic appetite control mechanisms absorption. Because of the insignificant –4.3 kg) achieved by the treatment with and led to body weight loss, increased intestinal absorption and subsequent low different doses of cetilistat (60 mg t.i.d., adherence to a weight management pro- of orlistat, both its anti- 120 mg t.i.d., 240 mg t.i.d.) over a 12- gram, and favorably affected cardiome- obesity effects and side effects (steator- week period were statistically significant tabolic health risks in both obese rhoea, oily spotting, ) compared with placebo (24,25). The treat- nondiabetic (30) and diabetic (31) pa- are mediated via the . ment with cetilistat resulted in significant tients. However the mechanism of dex- The administration of orlistat is contra- reductions in total and LDL cholesterol fenfluramine action—stimulation of indicated in patients with levels in obese patients (24) and in an im- serotonin release, inhibition of its reup- syndrome and cholestasis. Until now, no proved glycemic control in obese patients take, and direct stimulation of postsyn- definite association between liver injury with diabetes (25). Cetilistat treatment aptic serotonin receptors—was also and orlistat administration has been es- was well tolerated and exhibited fewer associated with serious side effects such tablished. Orlistat blocks the absorption side effects compared with orlistat. Sig- as valve disease and pulmonary arterial of fat-soluble and b-carotene, nificantly reduced frequency of gastro- hypertension (32,33). In response to and thus their substitution is recommended intestinal adverse events after cetilistat these observations, fenfluramine and during the long-term administration of could be attributable to structural differ- dexfenfluramine were voluntarily with- orlistat. ences between the two molecules and their drawn from the market in 1997 (33).

S350 DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 care.diabetesjournals.org Hainer

In order to avoid adverse peripheral completed in 2009 (J.M. van Gerver, un- The addition of amylin (pramlantide) side effects, a new selective serotonin published results). to leptin (metreleptin) restores leptin re- agonist, lorcaserin, has recently been de- sponsiveness in subjects with common veloped. Lorcaserin selectively activates COMBINATION DRUGS—Ap- obesity and after 12-months’ treatment re- 5-HT2C receptors, which are located proaches with two drug combinations of sults in significant weight loss (211.5 kg), primarily in the hypothalamus, thalamus, decreased doses were recommended to reduction in triglycerides (28%), total cho- and limbic structures and are virtually increase both the safety and efficacy of lesterol (28%), fasting blood glucose (24 absent in peripheral tissues. This way, antiobesity treatment. However combina- mg/dL), insulinemia (222%), and insulin unfavorable cardiovascular side-events tions of sibutramine and orlistat exhibited resistance/homeostasis model assessment are avoided (34). The administration of no advantages over the monotherapy with (225%) (51). However, these combinations lorcaserin to obese subjects in both sibutramine alone (44,45). Combining fen- of antiobesity agents as well as other recently short-term (2 weeks) and long-term fluramine and phentermine was aimed to developed combinations— and (1-year and 2-year) trials resulted in achieve fewer adverse events and better ap- , phentermine and , decreased body weight and waist cir- petite control (46). This drug combination, pramlantide and sibutramine (52), cumference as well as in improved car- quite efficient in terms of weight loss and pramlantide and phentermine (52)— diometabolic risk profile and quality of thus widely prescribed (over 18 million require further long-term studies and a life (35–37). At 1-year follow-up, signif- prescriptions in the U.S. in 1996!), was careful evaluation with regard to their effi- icantly more patients lost 5% of their later shown to be associated with an in- cacy and potential adverse events (53). body weight in the lorcaserin group creased risk of valvular heart disease (32). Combination therapies using phentermine than in the placebo group (47.5 vs. Phentermine interferes with the clearance should consider that an administration of 20.3%, P , 0.001), corresponding to of serotonin, and this way a combination of phentermine is recommended for a short- an average weight loss of 5.8 6 0.2 kg fenfluramine and phentermine may poten- term period only. with lorcaserin and 2.2 6 0.1 kg with tiate the untoward effects of circulating se- placebo (37). No drug-related effects rotonin and result in valvular injury similar GUT HORMONES—Several hor- on heart valves, pulmonary artery pres- to that seen in patients with carcinoid syn- mones of the gastrointestinal tract such as sure, or depression and suicidal ideation drome (32). glucagon-like peptide 1 (GLP-1), cholecys- were recorded. Transient headache, Recently, several new drug combi- tikinin, amylin, pancreatic polypeptide, nausea, and dizziness were the most fre- nations were investigated. The antide- peptide YY (PYY3–36), quently reported side-effects (35,37). pressant bupropion, which acts as (OXM), and ghrelin have been found to norepinephrine and dopamine reuptake play important roles in energy balance DRUGS BLOCKING inhibitor and melanocortin pathways regulation, and some have recently been AND stimulator, was combined with the opi- investigated as pharmaceutical targets DOPAMINERGIC RECEPTORS— oid antagonist , which antag- for obesity (54). The administration of The blockade of cannabinoid CB1 recep- onized proopiomelanocortin neurons physiological doses of gut-derived appetite- tors (with or ) and inhibition by endogenous . A regulating agents is expected to be an dopaminergic D1/D5 receptors (with eco- sustained-release (SR) combination of efficient, specific, and thus a low side- pipam) exerted favorable effects on body naltrexone and bupropion was well tol- effect approach in the treatment of weight and cardiometabolic health risks erated and produced synergistic weight obesity. (38–41). However, because of the in- loss, which significantly exceeded that The GLP-1 is secreted from L-cells of creased risks of psychiatric adverse induced by placebo or by either drug the intestine in response to a meal. GLP-1 events, i.e., depressed mood disorders, alone (47,48). Naltrexone SR/bupropion suppresses elevated glucagon secretion by anxiety, and suicidal ideation, rimona- SR (NB) combination therapy as an ad- pancreatic b-cells, enhances insulin se- bant was withdrawn from the obesity junct to behavior modification applied cretion, decreases apoptosis in pancreatic treatment (42), and pharmaceutical com- for 56 weeks induced significantly greater b-cells, increases satiety in the brain, and panies discontinued clinical trials with weight loss compared with behavior mod- delays gastric emptying. Postprandial taranabant and as antiobesity ification alone (9.3 6 0.4% vs. 5.1 6 0.6%, GLP-1 secretion is reduced in diabetic pa- agents (40,41). Rimonabant positively P , 0.001) (49). NB treatment was as- tients compared with nondiabetic pa- influenced dyslipidemia and insulin resis- sociated with improvements in body fat tients. GLP-1 receptor agonists such as tance not only by decreasing the food in- distribution, lipid profile, glucose homeo- liraglutide and exenatide represent a take in the brain but also by blocking stasis, and quality of life (49). The most new treatment option for patients with peripheral CB1 receptors. CB1 blockade frequent adverse event in response to NB diabetes, and especially those who are favorably affects lipogenesis in fat stores treatment was nausea. NB combination obese. A recent review of randomized and liver, glucose uptake in skeletal mus- treatment was not associated with in- controlled trials evaluated six trials with cle, and adiponectin secretion in adipose creased depression and attempts. exenatide and six trials with liraglutide tissue. Moreover, those using NB combination that were administered either alone or Knowledge of peripheral targets of treatment exhibited fewer adverse psychi- combined with oral antidiabetic drugs CB1 antagonists led to the development atric events than those using its compo- (55). Both drugs improved glycemic con- of a new CB1 antagonist, TM38837, which nents given separately (48,50). Transient trol, induced comparable weight losses, specifically acts in the peripheral tissues increases in both sBP and dBP during the and reduced blood pressure (55). The because of the lowered propensity to pass initial phase of NB treatment should how- most frequent side effects were transient the blood-brain barrier (43). The phase I ever be carefully evaluated in future stud- mild nausea and minor hypoglycemia, with TM38837 was successfully ies (48,50). which were less common with liraglutide care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S351 Antiobesity drugs, efficiency, and safety than with exenatide (56). Antibodies devel- been available (61). The less frequent available agents both with regard to their oped with a lesser frequency in liraglutide- nausea after administration of OXM efficacy and safety (68). However, it will treated subjects than in those treated by than after GLP-1 agonists encourages fur- be necessary for medical authorities to exenatide, likely because of its greater ther clinical studies. To improve clinical persuade not only physicians and patients structural similarity with human GLP-1 usefulness of treatment, the breakdown- but also the drug-regulating agencies (and (97 vs. 52%). However, it is encouraging resistant analogs of OXM and intranasally their committees) that the drug treatment that the development of antibodies does administered analogs of PYY3–36 have of obesity (de facto obesities) must eval- not affect the drug efficacy. Combining been developed. A recently published uate antiobesity drugs just as they do GLP-1 analogs with in obese study suggested that the effect those for other complex diseases (such patients with diabetes seems a reasonable of PYY3–36 and OXM can be additive (63). as hypertension) and take into account approach, as both drugs possess the Coadministration of PYY3–36 and OXM their specific pathogenesis and character, weight-lowering properties (57,58). The intravenously reduced energy intake by age of a patient, and presence of comor- disadvantage of GLP-1 agonists is a need 42.7% in comparison with saline control. bidities (69). for parenteral administration—once daily This energy intake reduction after com- with liraglutide and twice daily with bined hormone administration was — exenatide. A recent study demonstrated more pronounced than during infusions ADDENDUM On October 8, 2010, the following statement was released by that a long-term version of exenatide ad- of either hormone alone. “ ministered once weekly produced sus- the Abbott Laboratories: Abbott believes sibutramine has a positive risk/benefit tained glycemic control and weight loss DURATION OF TREATMENT fi over 52 weeks (59). Other recently devel- WITH ANTIOBESITY DRUGS— pro le in the approved patient pop- ulation, but will comply with the FDA’s oped GLP-1 agonists with prolonged half- Long-term administration of antiobesity ’ lives such as taspoglutide and albiglutide drugs should be indicated according to [Food and Drug Administration s] request and will voluntarily withdraw MeridiaÒ may also allow weekly dosing. the weight loss achieved in response to an ” Several trials evaluating the use of initial 3-months’ therapy (64,65). A meta- (sibutramine) from the U.S. market. GLP-1 agonists as antiobesity drugs have analysis of sibutramine studies revealed been in progress. Only a few of the results that a weight loss of 4 kg at 3 months — . Acknowledgments This study was partly have been published. A small-scale study predicted weight loss 5% at 12 months supported by a grant from the Czech Ministry conducted in overweight nondiabetic (65). The drug administration should be of Health (IGA NR/7800-4). V.H. participated women with polycystic ovary syndrome discontinued in patients who do not re- as an investigator in the SCOUT Study sup- demonstrated that a combination of ex- spond to 3-months’ drug treatment. It has ported by the Abbott Laboratories. No other enatide with metformin favorably influ- been demonstrated that intermittent potential conflicts of interest relevant to this enced body weight, insulin sensitivity, treatment with some antiobesity drugs article were reported. and menstrual cyclicity. These beneficial (phentermine, sibutramine) may be as effects were more pronounced with com- effective as their continuous administra- bination treatment than with administra- tion and may diminish both the side ef- References tion either of exenatide or metformin fects and costs (66,67). On the other 1. World Health Organization. Obesity: Pre- alone (60). hand, the long-term replacement of an- venting and Managing the Global Epidemic. Report of a WHO Consultation.Geneva, Other gut hormones (e.g., amylin, tiobesity drugs with placebo is followed World Health Org., 2000 (Tech. Rep. Ser., OXM, PYY3–36) as potential antiobesity by weight regain as demonstrated in the no. 894) drugs are currently being investigated studies with sibutramine, lorcaserin, 2. Expert Panel on the Identification, Eval- (61). Amylin is cosecreted with insulin and rimonabant conducted over a uation, and Treatment of Overweight in by pancreatic b-cells in response to meal 2-year period (5,37,39). It therefore Adults. Clinical guidelines on the identi- intake. Amylin inhibits food intake in the should be considered that future drug fication, evaluation, and treatment of area postrema via specific amylin recep- treatment of obesity should be indicated overweight and obesity in adults: execu- tors, regulates gastric emptying, and sup- for lifelong administration as in treating tive summary 1–3: Expert Panel on the fi presses inappropriate postprandial other complex diseases. Identi cation, Evaluation, and Treatment of Overweight in Adults. Am J Clin Nutr glucagon secretion. Sustained weight – — 1998;68:899 917 loss of 7.2 kg in response to a 12-month CONCLUSIONS Currently avail- 3. Tsigos C, Hainer V, Basdevant A, et al.; treatment with synthetic amylin analog able antiobesity drugs result in only Obesity Management Task Force of the pramlintide (360 mg twice daily) was modest weight loss accompanied by re- European Association for the Study of demonstrated in obese and relatively ductions of cardiometabolic health risks. Obesity. Management of obesity in adults: healthy subjects (62). The most common Adverse events related to existing anti- European clinical practice guidelines. Obes side effect with pramlintide treatment was obesity drugs however, call for careful Facts 2008;1:106–116 fi fi mild nausea. Both OXM and PYY3–36 are assessment of the risk/bene tprole in 4. Hainer V, Toplak H, Mitrakou A. Treatment cosecreted with GLP-1 from intestinal each new agent designed to treat obesity. modalities of obesity: what fits whom? Diabetes Care 2008;31(Suppl. 2):S269– L-cells. OXM inhibits food intake in the Further studies evaluating the effect of hypothalamus by binding to three differ- antiobesity drugs on morbidity and mor- S277 5. James WP, Astrup A, Finer N, et al. Effect ent receptors (GLP-1 receptor, glucagon tality end points in appropriate target of sibutramine on weight maintenance after receptor, and independent OXM recep- populations are needed. It is expected weight loss: a randomised trial. STORM tor). Only preliminary data on energy in- that the new compounds, which have Study Group. Sibutramine Trial of Obesity take, energy expenditure, and weight loss recently been tested in clinical trials, will Reduction and Maintenance. Lancet 2000; in humans after OXM and PYY3–36 have possess more advantages over the currently 356:2119–2125

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6. Torgerson JS, Hauptman J, Boldrin MN, 20. Hainer V, Kunesova M, Bellisle F, Hill M, with fenfluramine-phentermine. N Engl J Sjöström L. XENical in the prevention of Braunerova R, Wagenknecht M. Psycho- Med 1997;337:581–588 Diabetes in Obese Subjects (XENDOS) behavioral and nutritional predictors of 33. Gardin JM, Schumacher D, Constantine G, study: a randomized study of orlistat as an weight loss in obese women treated with Davis KD, Leung C, Reid CL. Valvular adjunct to lifestyle changes for the pre- sibutramine. Int J Obes (Lond) 2005;29: abnormalities and cardiovascular status vention of type 2 diabetes in obese pa- 208–216 following exposure to dexfenfluramine or tients. Diabetes Care 2004;27:155–161 21. Elfhag K, Finer N, Rössner S. Who will lose phentermine/fenfluramine. JAMA 2000; 7. Rucker D, Padwal R, Li SK, Curioni C, Lau weight on sibutramine and orlistat? Psycho- 283:1703–1709 DC. Long term pharmacotherapy for logical correlates for treatment success. Di- 34. Thomsen WJ, Grottick AJ, Menzaghi F, obesity and overweight: updated meta- abetes Obes Metab 2008;10:498–505 et al. Lorcaserin, a novel selective human analysis. BMJ 2007;335:1194–1199 22. Astrup A, Madsbad S, Breum L, Jensen TJ, 5-hydroxytryptamine2C agonist: in vitro 8. Neovius M, Johansson K, Rössner S. Kroustrup JP, Larsen TM. Effect of teso- and in vivo pharmacological character- Head-to-head studies evaluating efficacy fensine on bodyweight loss, body compo- ization. J Pharmacol Exp Ther 2008;325: of pharmaco-therapy for obesity: a sys- sition, and quality of life in obese patients: 577–587 tematic review and meta-analysis. Obes a randomised, double-blind, placebo- 35. Smith SR, Prosser WA, Donahue DJ, Rev 2008;9:420–427 controlled trial. Lancet 2008;372:1906– Morgan ME, Anderson CM, Shanahan WR; fi 9. Norris SL, Zhang X, Avenell A, et al. Ef - 1913 APD356-004 Study Group. Lorcaserin cacy of pharmacotherapy for weight loss 23. Sjödin A, Gasteyger C, Nielsen AL, et al. (APD356), a selective 5-HT()agonist, in adults with type 2 diabetes mellitus: The effect of the triple monoamine reup- reduces body weight in obese men and a meta-analysis. Arch Intern Med 2004; take inhibitor tesofensine on energy me- women. Obesity (Silver Spring) 2009;17: – 164:1395 1404 tabolism and appetite in overweight and 494–503 10. Fabricatore AN, Wadden TA, Moore RH, moderately obese men. Int J Obes (Lond) 36. Anderson CM, Smith SR, Sanchez M, – et al. Attrition from randomized con- 2010;34:1634 1643 Stubbe S, Shanahan WR. Lorcaserin treat- trolled trials of pharmacological weight 24. Kopelman P, Bryson A, Hickling R, et al. ment was associated with improvements in loss agents: a systematic review and anal- Cetilistat (ATL-962), a novel lipase in- – cardiovascular risk factors and weight loss ysis. Obes Rev 2009;10:333 341 hibitor: a 12-week randomized, placebo- in the BLOOM trial. Obesity (Silver Spring) 11. Hansen DL, Toubro S, Stock MJ, controlled study of weight reduction in 2009;17(Suppl. 2):S52 Macdonald IA, Astrup A. The effect of obese patients. Int J Obes (Lond) 2007;31: – 37. Smith SR, Weissman NJ, Anderson CM, sibutramine on energy expenditure and 494 499 Shanahan WR; the Behavioral Modifi- appetite during chronic treatment with- 25. Kopelman P, Groot GdeH, Rissanen A, cation and Lorcaserin for Overweight out dietary restriction. Int J Obes Relat et al. Weight loss, HbA1c reduction, and and Obesity Management (BLOOM) Study Metab Disord 1999;23:1016–1024 tolerability of cetilistat in a randomized, Group. Multicenter, placebo-controlled trial 12. Jordan J, Scholze J, Matiba B, Wirth A, placebo-controlled phase 2 trial in obese of lorcaserin for weight mnagement. N Engl Hauner H, Sharma AM. Influence of diabetics: comparison with orlistat (Xenical). J Med 2010;363:245–256 sibutramine on blood pressure: evidence Obesity (Silver Spring) 2010;18:108– 38. Van Gaal LF, Rissanen AM, Scheen AJ, from placebo-controlled trials. Int J Obes 115 Ziegler O, Rössner S; RIO-Europe Study (Lond) 2005;29:509–516 26. Farooqi IS, Jebb SA, Langmack G, et al. Group. Effects of the cannabinoid-1 re- 13. Johansson K, Sundström J, Neovius K, Effects of recombinant leptin therapy in a Rössner S, Neovius M. Long-term changes child with congenital leptin deficiency. N ceptor blocker rimonabant on weight re- in blood pressure following orlistat and Engl J Med 1999;341:879–884 duction and cardiovascular risk factors sibutramine treatment: a meta-analysis. 27. Myers MG, Cowley MA, Münzberg H. in overweight patients: 1-year experience – from the RIO-Europe study. Lancet 2005; Obes Rev 2010;11:777 791 Mechanisms of leptin action and leptin – 14. Scheen A. Sibutramine on cardiovascular resistance. Annu Rev Physiol 2008;70: 365:1389 1397 outcome. Diabetes Care 2011;34(Suppl. 2): 537–556 39. Pi-Sunyer FX, Aronne LJ, Heshmati HM, S114–S119 28. Rosenbaum M, Goldsmith R, Bloomfield Devin J, Rosenstock J; RIO-North America 15. James WPT, Caterson ID, Coutinho W, D, et al. Low-dose leptin reverses skeletal Study Group. Effect of rimonabant, a et al.; SCOUT Investigators. Effect of muscle, autonomic, and neuroendocrine cannabinoid-1 receptor blocker, on weight sibutramine on cardiovascular outcomes adaptations to maintenance of reduced and cardiometabolic risk factors in over- in overweight and obese subjects. N Engl weight. J Clin Invest 2005;115:3579– weight or obese patients: RIO-North America: J Med 2010;363:905–917 3586 a randomized controlled trial. JAMA – 16. Tziomalos K, Krassas GE, Tzotzas T. The 29. Roubert P, Dubern B, Plas P, et al. Novel 2006;295:761 775 use of sibutramine in the management of pharmacological MC4R agonists can ef- 40. Aronne LJ, Tonstad S, Moreno M, et al. A fi obesity and related disorders: an update. ficiently activate mutated MC4R from clinical trial assessing the safety and ef - Vasc Health Risk Manag 2009;5:441–452 obese patient with impaired endogenous cacy of taranabant, a CB1R inverse ago- 17. Drew BS, Dixon AF, Dixon JB. Obesity agonist response. J Endocrinol 2010;207: nist, in obese and overweight patients: management: update on orlistat. Vasc 177–183 a high-dose study. Int J Obes (Lond) Health Risk Manag 2007;3:817–821 30. Guy-Grand B. Clinical studies with dex- 2010;34:919–935 18. Coutinho W. The first decade of sibutr- fenfluramine: from past to future. Obes 41. Astrup A, Greenway FL, Ling W, et al.; for amine and orlistat: a reappraisal of their Res 1995;3(Suppl. 4):491S–496S the Ecopipam Obesity Study Group. Ran- expanding roles in the treatment of obe- 31. Chow CC, Ko GT, Tsang LW, Yeung VT, domized controlled trials of the D1/D5 an- sity and associated conditions. Arq Bras Chan JC, Cockram CS. Dexfenfluramine tagonist ecopipam for weight loss in obese Endocrinol Metabol 2009;53:262–270 in obese Chinese NIDDM patients: a placebo- subjects. Obesity (Silver Spring) 2007;15: 19. Samsa GP, Kolotkin RL, Williams GR, controlled investigation of the effects on 1717–1731 Nguyen MH, Mendel CM. Effect of mod- body weight, glycemic control, and cardio- 42. Christensen R, Kristensen PK, Bartels EM, erate weight loss on health-related quality vascular risk factors. Diabetes Care 1997;20: Bliddal H, Astrup A. Efficacy and safety of of life: an analysis of combined data from 4 1122–1127 the weight-loss drug rimonabant: a meta- randomized trials of sibutramine vs pla- 32. Connolly HM, Crary JL, McGoon MD, analysis of randomised trials. Lancet 2007; cebo. Am J Manag Care 2001;7:875–883 et al. Valvular heart disease associated 370:1706–1713 care.diabetesjournals.org DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011 S353 Antiobesity drugs, efficiency, and safety

43. Receveur JM, Murray A, Linget JM, et al. approach to obesity pharmacotherapy. of single and combined treatment with Conversion of 4-cyanomethyl-pyrazole- Obesity (Silver Spring) 2009;17:1736– exenatide and metformin on menstrual 3-carboxamides into CB1 antagonists with 1743 cyclicity in overweight women with poly- lowered propensity to pass the blood- 52. Aronne LJ, Halseth AE, Burns CM, Miller S, cystic ovary syndrome. J Clin Endocrinol brain-barrier. Bioorg Med Chem Lett 2010; Shen LZ. Enhanced weight loss follow- Metab 2008;93:2670–2678 20:453–457 ing coadministration of pramlintide with 61. Chaudhri OB, Wynne K, Bloom SR. Can 44. Wadden TA, Berkowitz RI, Womble LG, sibutramine or phentermine in a multi- gut hormones control appetite and prevent Sarwer DB, Arnold ME, Steinberg CM. center trial. Obesity (Silver Spring) 2010; obesity? Diabetes Care 2008;31(Suppl. 2): Effects of sibutramine plus orlistat in obese 18:1739–1746 S284–S289 women following 1 year of treatment by 53. Klonoff DC, Greenway F. Drugs in the 62. Smith SR, Aronne LJ, Burns CM, Kesty sibutramine alone: a placebo-controlled pipeline for the obesity market. J Diabetes NC, Halseth AE, Weyer C. Sustained trial. Obes Res 2000;8:431–437 Sci Tech 2008;2:913–918 weight loss following 12-month pram- 45. Sari R, Balci MK, Cakir M, Altunbas H, 54. Field BC, Chaudhri OB, Bloom SR. Obe- lintide treatment as an adjunct to lifestyle Karayalcin U. Comparison of efficacy of sity treatment: novel peripheral targets. Br intervention in obesity. Diabetes Care sibutramine or orlistat versus their com- J Clin Pharmacol 2009;68:830–843 2008;31:1816–1823 fi bination in obese women. Endocr Res 55. White J. Ef cacy and safety of incretin 63. Field BC, Wren AM, Peters V, et al. PYY3-36 2004;30:159–167 based therapies: clinical trial data. J Am and oxyntomodulin can be additive in their 46. Weintraub M, Hasday JD, Mushlin AI, Pharm Assoc (2003) 2009;49(Suppl. 1): effect on food intake in overweight and Lockwood DH. A double-blind clinical trial S30–S40 obese humans. Diabetes 2010;59:1635– in weight control: use of fenfluramine and 56. Buse JB, Rosenstock J, Sesti G, et al.; 1639 phentermine alone and in combination. LEAD-6 Study Group. Liraglutide once a 64. Toplak H, Ziegler O, Keller U, et al. Arch Intern Med 1984;144:1143–1148 day versus exenatide twice a day for type 2 X-PERT: weight reduction with orlistat 47. Greenway FL, Whitehouse MJ, Guttadauria diabetes: a 26-week randomised, parallel- in obese subjects receiving a mildly or M, et al. Rational design of a combination group, multinational, open-label trial moderately reduced-energy diet: early re- medication for the treatment of obesity. (LEAD-6). Lancet 2009;374:39–47 sponse to treatment predicts weight main- Obesity (Silver Spring) 2009;17:30–39 57. DeFronzo RA, Ratner RE, Han J, Kim DD, tenance. Diabetes Obes Metab 2005;7: 48. Greenway FL, Fujioka K, Plodkowski RA, Fineman MS, Baron AD. Effects of ex- 699–708 et al.; COR-I Study Group. Effect of nal- enatide (exendin-4) on glycemic control 65. Finer N, Ryan DH, Renz CL, Hewkin AC. trexone plus bupropion on weight loss and weight over 30 weeks in metformin- Prediction of response to sibutramine in overweight and obese adults (COR-I): treated patients with type 2 diabetes. Di- therapy in obese non-diabetic and diabetic a multicentre, randomised, double-blind, abetes Care 2005;28:1092–1100 patients. Diabetes Obes Metab 2006;8: placebo-controlled, phase 3 trial. Lancet 58. Nauck M, Frid A, Hermansen K, et al.; 206–213 2010;376:595–605 LEAD-2 Study Group. Efficacy and safety 66. Munro JF, MacCuish AC, Wilson EM, 49. Wadden TA, Foreyt JP, Foster GD, et al. comparison of liraglutide, glimepiride, Duncan LJ. Comparison of continuous and Weight loss with naltrexone SR/bupropion and placebo, all in combination with met- intermittent anorectic therapy in obesity. SR combination therapy as an adjunct to formin, in type 2 diabetes: the LEAD BMJ 1968;1:352–354 behavior modification: the COR-BMOD (liraglutide effect and action in diabetes)-2 67. Wirth A, Krause J. Long-term weight loss trial. Obesity (Silver Spring) 2011;19:110– study. Diabetes Care 2009;32:84–90 with sibutramine: a randomized controlled 120 59. Buse JB, Drucker DJ, Taylor KL, et al.; trial. JAMA 2001;286:1331–1339 50. Astrup A. Is cardiometabolic risk improved DURATION-1 Study Group. DURATION-1: 68. Astrup A. Drug management of obesity— by weight-loss drugs? Lancet 2010;376: exenatide once weekly produces sustained efficacy versus safety. N Engl J Med 2010; 567–568 glycemic control and weight loss over 52 363:288–290 51. Ravussin E, Smith SR, Mitchell JA, et al. weeks. Diabetes Care 2010;33:1255–1261 69. Dvorak RV, Sharma AM, Astrup A. Anti- Enhanced weight loss with pramlintide/ 60. Elkind-Hirsch K, Marrioneaux O, Bhushan obesity drugs: to be or not to be? Obes Rev metreleptin: an integrated neurohormonal M, Vernor D, Bhushan R. Comparison 2010;11:833–834

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