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Hindawi Publishing CorporationJournal of ObesityVolume 2011, Article ID 459263, 7 pagesdoi:10.1155/2011/459263 Research Article
Usage, Risk, and Benefit of Weight-Loss Drugs in Primary Care
Tomas Forslund,1 Pauline Raaschou,2 Paul Hjemdahl,2
Ingvar Krakau,3 and Bj¨orn Wettermark4

1 Gr¨ondal Primary Care Centre, P. O. Box 470 43, 100 74 Stockholm, Sweden2 Department of Clinical Pharmacology, Karolinska University Hospital, Solna, 141 86 Stockholm, Sweden3 Centre for Family and Community Medicine, Karolinska Institutet and Stockholm County Council, Huddinge, Sweden4 Drug Management and Informatics, 118 27 Stockholm, Sweden Correspondence should be addressed to Tomas Forslund, tomas.forslund@sll.se Received 31 December 2010; Accepted 12 April 2011 Academic Editor: Eliot Brinton Copyright 2011 Tomas Forslund et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.
Purpose. To investigate the use of the weight-loss drugs rimonabant, sibutramine, and orlistat in primary care and to characterizethe patients receiving the drugs. Methods. In this retrospective, descriptive study, 300 randomly selected patients having startedweight-loss drug treatment at 15 primary care centres were investigated using the patient's medical records and their complete drugpurchase data. Results. Even though 48% of the patients specifically demanded drug treatment, 77% continued treatment less thanone year. 28% of rimonabant patients and 32% of sibutramine patients had a history of depression or antidepressant treatment.
41% of sibutramine patients had a history of hypertension and/or cardiovascular disease. 36% had no documented weight aftertreatment initiation. Conclusions. These results suggest that weight-loss drug treatment was often initiated upon patient requestbut was of limited clinical benefit as it was managed in a large portion of Swedish primary carecenters.
October 2008 and sibutramine (Reductil, Reduxade, Zelium)in January 2010 due to safety concerns [5, 6]. Currently, orli- Obesity is a prevalent chronic condition which is associated stat is the only registered weight-loss drug on the European with significant morbidity and mortality [1]. The prevalence market, but new drugs are in the pipeline [7, 8].
is increasing rapidly in all countries, with WHO estimating In the metropolitan health region of Stockholm, Swe- 1.6 billion overweight adults and 400 million obese adults den, a model has been developed which includes horizon in 2005 [2]. Although not being one of the worst inflicted scanning (to prepare for drugs to come), forecasting of drug countries, the prevalence of obesity in Sweden has also in- utilization and expenditures, critical drug evaluation, and creased substantially over the last decades, and it has been structured programs for the introduction and followup of estimated that 10% of both men and women are obese, and new drugs [9]. When rimonabant was given the marketing a further 40% are overweight [3]. Consequently, there is an approval in 2006, the subsequent marketing activities led to urgent need for effective life-style interventions and often concerns about improper use and inappropriate increase in also pharmacological treatment.
expenditure. Rimonabant was, therefore, one of the drugs The development of antiobesity medicines has been selected for a structured introduction and followup program.
problematic and characterized by heavy marketing followed In 2006, the total expenditure for weight-loss drugs was 154 by withdrawals from the market after reports of safety prob- million SEK in Sweden [10].
lems, including pulmonary hypertension (aminorex), valvu- This study is a characterization of the use of weight- lar lesions (dexfenfluramine-phentermine), and addiction loss drugs in the primary health care setting of Stockholm (amphetamine) [4]. This pattern has continued in recent County. The aim was to analyse the utilization and effective- years with the withdrawal of rimonabant (Acomplia) in ness of the three weight-loss drugs rimonabant, sibutramine, Journal of Obesity Table 1: The three weight-loss drugs on the Swedish market in regarding the extraction of data documented in association with a specified term, but an additional manual analysis hadto be performed to include the missing medical data.
A total of 36 primary healthcare centres (PHCs) compris- Rimonabant (Acomplia) is a cannabinoid CB1-receptor earlierly ing the Southwest district of the Stockholm County Council registered in Europe for the treatment of overweight with risk were invited to participate in the study. 24 of them used factors (BMI over 27 with dyslipidemia or diabetes) or obesity(BMI over 30) in combination with lifestyle interventions. In electronic medical records adapted to the Rave3 software Sweden, the drug was reimbursed only if BMI was over 28 with and were thus able to participate. Among them, 15 practices dyslipidemia or diabetes, or if BMI was over 35 [11]. A agreed to participate and were included in the study.
meta-analysis has shown a placebo-adjusted weight loss of 4.3 kg Specific parameters as well as unformatted medical after one year of treatment [12]. Contraindications included record information from November 1, 2005 to February 28, ongoing depression or treatment with antidepressant drugs [11].
2009 were centrally extracted with Rave3, anonymised, and Rimonabant was withdrawn from the market in October 2008 entered into a database for further analysis. Thus all patients due to the risk of psychiatric side effects [5].
could be evaluated during at least 15 months after the start of treatment. Data regarding diagnosis of depression, Orlistat (Xenical) is a gastrointestinal lipase inhibitor registered antidepressant treatment, or earlier treatment with orlistat in Europe and the US for the treatment of overweight with risk or sibutramine were also extracted back to the year 2000 factors (BMI over 27 with dyslipidemia or diabetes) or obesity in order to obtain some important characteristics of the (BMI over 30) in combination with diet interventions. In patients before November 1, 2005.
Sweden, the drug is reimbursed only if BMI is over 28 withdyslipidemia or diabetes, or if BMI is over 35 [13]. Ameta-analysis has shown a placebo-adjusted weight loss of 2.7 kg 2.2. Prescription Data. To assess to what extent the patients after one year of treatment [12]. Malabsorption is a redeemed their prescriptions, data from the medical records were linked to data on dispensed drugs in the Swedish Pre- scribed Drug register [17]. The National Board of Health andWelfare is responsible for keeping this register which contains Sibutramine (Reductil) is a serotonin, norepinephrine, anddopamine reuptake inhibitor earlierly registered in Europe for data on all prescription drugs dispensed in Sweden from the treatment of overweight with risk factors (BMI over 27 with 2005 and onwards, their amounts and dosages, expenditures dyslipidemia or diabetes) or obesity (BMI over 30) in and reimbursement, as well as the age, the gender and the combination with lifestyle interventions. In Sweden, the drug was unique identifier (personal identification number) of the reimbursed only if BMI was over 28 with dyslipidemia or patient. Using anonymised record linkage, we analysed the diabetes, or if BMI was over 35 [14]. A meta-analysis has shown a dispensing histories for all of patients' prescriptions between placebo-adjusted weight loss of 4.3 kg after one year of treatment November 1, 2005 and February 28, 2009 to assess all the [12]. Contraindications were among others cardiovascular drugs that the patients actually had purchased from the disease, psychiatric disease, ongoing treatment with pharmacy, regardless of the origins of the prescriptions. It antidepressant or antipsychotic drugs, and uncontrolled also permitted an analysis of the persistence of weight-loss hypertension [14]. Sibutramine was withdrawn from the market in January 2010 due to an increased risk of cardiovascularincidents [6].
The terminology and methodology used for measuring persistence varies across studies [18]. We defined persistenceas the total number of days on treatment measured by theamount of drugs purchased from the pharmacy divided by and orlistat (see Table 1) which were on the Swedish market the usual number of dosages for the drug. The reason for our in 2008. Rimonabant was withdrawn from the market toward choice is that weight-loss drugs have not been indicated for the end of the study period, which limits the possibility of long-term risk reduction but for a limited period of weight- conducting a 1-year evaluation for this drug. Sibutramine loss treatment. The duration of treatment is, thus, more was withdrawn after the study period, while orlistat still important in this case than for chronic treatment where remains on the market.
adherence is more interesting. Defined daily doses (DDD)were not used due to the availability of sibutramine in 2. Methods
both 10-mg and 15-mg compositions, which would haveoverestimated the treatment duration of this drug.
2.1. Medical Record Data. We conducted a retrospective, de-scriptive study based on data extracted from electronic med-ical records in primary healthcare. All data were extracted 2.3. Statistics. Standard descriptive statistics (numbers, pro- using Rave3 software (Medrave Software AB, Stockholm) portions, median, interquartile range, and range) were used [15, 16]. The Rave3 software extracts data from the medical to describe the study cohort and the utilization patterns. Data record database in a systematic way making it possible to link are presented with 95% exact binomial confidence intervals most of the recorded data such as diagnosis, laboratory (CI) for proportions, where appropriate.
findings, and text registered in the medical record. A vali-dation was done confirming that the extracted data was in 2.4. Ethics. The study was approved by the regional ethics agreement with the medical records. Rave3 performed well Journal of Obesity 3. Results
not been analysed. 58% of rimonabant patients and 56%of sibutramine patients had signs of psychiatric problems in 3.1. Population. The 15 PHCs included were responsible for their medical history (anxiety, sleeping disorder, stress disor- a total of 205, 440 patients in 2008. Rave3 identified a total ders, professional burnout, eating disorder, or treatment for of 876 patients who had commenced treatment with weight- such conditions). Psychiatric disease was a contraindication loss drugs at these primary care centres between November 1, for sibutramine. Patients treated with orlistat had a slightly 2006 and November 30, 2007, that is, a period of 13 months.
higher frequency of both depression or treatment of depres- 370 patients (42%) had received rimonabant, 230 patients sion and other psychiatric problems, but such patients can be (26%) had received orlistat, and 276 patients had received treated with the drug without additional risk.
sibutramine (32%). The number of unique patients was829 due to the fact that an individual patient could havestarted treatment with different weight-loss drugs during 3.6. Initiative to Treat. In 48% of the cases, it was clearly this time period. The present analysis was limited to 100 stated in the medical file that the patient asked for treatment randomly chosen patients for each weight-loss drug, that is, with weight-loss drugs, often with the wish for a specific 300 patients in total. The number of unique patients analysed drug. It was unclear whether the patient or the prescribing physician had taken the initiative to drug treatment in 50%of the cases. In only 2% of the cases, it was clearly stated thatthe physician had proposed treatment with the weight-loss 3.2. Selection Bias. In order to detect possible selection bias, we characterized the participating PHCs and compared themto the nonincluded centres. The participating centres weremore often publicly managed and had more patients than the 3.7. Prescription of Other Weight-loss Drugs. In total, 40% nonparticipating centres. The proportion of older patients, of the patients had tried one or both of the other weight- the number of visits per patient, the average drug expen- loss drugs during the study period 48% of those receiving diture per patient, and the proportion of prescriptions rimonabant, 46% of those receiving sibutramine, and 27% of for weight-loss drugs compared to the total amount of those receiving orlistat.
prescriptions were similar. The population-base living nextto the centres was also similar, as evaluated by age spans, 3.8. Weight Change. In 51% of all 300 patients, Rave3 found unemployment, beneficiaries of social aid, immigrants, as no documentation of the patient's weight under the right well as levels of education and proportions of low- and heading in the electronic medical record. We therefore also high-income households. Thus, the comparison revealed no conducted a manual evaluation of the case records. We potentially important differences between PHCs who partic- limited this analysis to patients having been prescribed the ipated in the study and those who did not (data not shown).
weight-loss drug for at least one year since a meaningfuleffect on weight requires a long period of treatment. Among 3.3. Diabetes and/or Dyslipidemia. Of the patients who initi- the 300 manually analysed patient records, 100 patients had ated weight-loss drug treatment, 65% had a diagnosis of dia- been prescribed the drug for one year or longer 48 had had betes and/or dyslipidemia, treatment for such a diagnosis, or rimonabant, 31 sibutramine, and 21 orlistat. These patients laboratory tests indicating such a condition (see Table 2). The were further analysed regarding the last documented weight incidence was evenly distributed among the three weight-loss after at least 9 months of treatment. In 62 patients the data drugs. 32% had treatment for diabetes and/or dyslipidemia.
were insufficient to evaluate changes in weight. 28 patientshad lost weight, and 10 patients had an unchanged weight.
3.4. Cardiovascular Disease. Cardiovascular disease or un- Only 18 out of the 300 patients, that is, 6% had the drug controlled hypertension was contraindications for treatment prescribed for at least one year and a confirmed clinically with sibutramine. 41% of the patients who started treatment relevant weight-loss of at least 5% after at least 9 months of with sibutramine had at least one diagnosis or treatment treatment (see Figure 1). Whether the weight loss achieved consistent with hypertension and/or other cardiovascular depended on the drug treatment or other factors cannot be disease (see Table 2). The first or last blood pressure during concluded in this study, and possible long-term changes in the study period was above 140/90 mm Hg in another 7% of weight among other patients could not be deduced from the the patients.
medical records.
3.5. Psychiatric Disease. Contraindications for rimonabant 3.9. Documentation of Weight. 26% of the patients who had and sibutramine included ongoing depression or treatment been prescribed the weight-loss drug for at least one year with antidepressants. 28% of the patients who started treat- lacked documentation of his/her initial weight or weight ment with rimonabant and 32% of the patients with sibu- within 3 months prior to the prescription. 36% lacked tramine had a diagnosis of depression and/or antidepressant a followup weight on any occasion after the initiation of treatment during the study period (see Table 2). Whether treatment. For these reasons, it was impossible to draw the depression and/or antidepressant treatment was present any conclusions regarding treatment efficacy in 45% of the before the initiation of weight-loss drug treatment, occurred patients. This indicates that the management and followup during the treatment, or occurred after the treatment, has of patients treated with weight-loss drugs was inadequate.
Journal of Obesity Table 2: Patient characteristics (Values within parentheses are 95% Confidence Intervals (CI). CIs around medians calculated by binomialmethod, and around relative frequencies by exact binomial method.).
Rimonabant patients Sibutramine patients Orlistat patients Body Mass Index BMI <28 kg/m2 BMI 28–35 kg/m2 BMI >35 kg/m2 Concomitant diseases and treatments Diabetes, and/or dyslipidemia Treatment for diabetes Treatment for dyslipidemia Treatment for diabetes and/or dyslipidemiaCardiovascular disease and/or hypertensionDepression and/or antidepressant Psychiatric problems Pain and other musculoskeletal problems The weight-loss process ients 200patof 150er Weight loss Conclusive after weight change after >9 months >9 months after >9 months Figure 1: The weight loss process.
3.10. Treatment Persistence. Although 33% of the 300 pa- 3.11. Treatment Discontinuation. Most commonly, no reason tients in the present study had been prescribed drug for discontinuation was documented (65% of the patients).
treatment for at least one year, it appears that 23% of them The most common cause for discontinuation of rimonabant actually purchased the drugs for at least one year of treatment was prescription until, or past, the date of market withdrawal 32% on rimonabant, 25% on sibutramine, and 13% on which is reported under "Other" (see Table 3). Other orlistat (see Figure 2). Among the 300 patients, 6% never common reasons included side effects reported by 15% filled the first prescription at the pharmacy.
and dissatisfaction with the effect reported by 11%. The Journal of Obesity for weight-loss drugs in Sweden showed similar results witha frequent history of use of other weight-loss drugs and antidepressant drugs, and with many patients who were noton drug treatment for diabetes and/or dyslipidemia [10].
Needless to say, the management of overweight patientsmight vary between different units and prescribers.
The present results suggest that many patients were prescribed weight-loss drugs despite possible or definite contraindications. It is remarkable that information about the key variable of interest, that is, body weight, was so oftenlacking in the medical records. All three weight loss drugs were only licensed for weight-loss treatment in combination with a structured weight loss program including exercise and diet. Regular followup including weight measurementsboth before and during such a program is essential and should be a mainstay in the treatment of overweight. The moderate weight loss seen in clinical trials of these drugs[12] is not generally applicable to short-term treatments without followup. Frequent prescriptions for patients with contraindications or other conditions prompting for caution Duration of treatment (years) are an important safety aspect. Both rimonabant and sibu- tramine have been withdrawn from the market. The present data support the wisdom of these withdrawals.
Even though advertising for prescription drugs is illegal in the European Union, it was often stated in the medical Figure 2: Percentage of patients left on treatment.
records that the reason for consulting the doctor was toobtain weight-loss drug treatment, often with the wish fora specific drug. Safety and efficacy concerns normally appear most commonly documented causes for discontinuation for to have a major influence on the use of new drugs in primary patients having received sibutramine were dissatisfaction care [19]. However, denying treatment to a patient who with the effectiveness of the drug and side effects reported by through media, friends, the Internet, or other sources has 11% each. 7% of the patients having received orlistat stopped got the impression that there are effective drugs for losing treatment due to dissatisfaction with the effectiveness, and weight is a delicate task and requires knowledge on the behalf 4% quitted due to side effects.
of the prescriber in order to motivate his/her decision totreat or not to treat with a drug. Additional possibilities to advertise directly to patients would probably further increasethe problems described in this article [20, 21].
In this retrospective, descriptive study, prescription routines In our earlier analysis of the national prescription data, for 300 randomly selected patients having started weight-loss we found that only 1/3 of the patients who started treatment drug treatment at 15 primary care centres were investigated with rimonabant during its first six weeks on the market using patients' electronic medical records and their complete continued the treatment after 6 months [10]. A Canadian drug purchase data from the Swedish National Board of Wel- evaluation of the treatment persistence with sibutramine and fare. Generally, patients who received weight-loss drugs had orlistat showed that less than 10% of the patients remained a poor health status with cardiovascular disease, diabetes, on treatment after one year, and less than 2% continued dyslipidemia, depression, and other psychiatric problems.
treatment after 2 years [22]. Maintaining the patients on Many had attempted treatment with other weight-loss drugs, treatment has been a problem also in the clinical trials [12, and a significant proportion had listed contra-indications 23]. For example, the drop-out rate in the clinical trials of to the prescribed drug. Even though the patients often spe- rimonabant was 35–50% during the first year [24–27]. Lack cifically demanded weight-loss drug treatment from the doc- of persistence with treatment was a major problem in this tor, 77% continued treatment for less than one year. A large study as well. Lack of efficacy or adverse events are the likely proportion of the patients were not weighed prior to major causes of premature discontinuation of treatment.
treatment initiation and not followed within the context of However, the reasons are seldom clearly stated in the medical a structured lifestyle intervention.
Prescription of weight-loss drugs was the most common in the Stockholm County Council than elsewhere in thecountry [10]. Our results are thus not generally applicable 4.1. The Future. It is likely that the trend of informed throughout Sweden but suggest problems that probably patients actively seeking medical treatment for lifestyle- exist to varying degrees at many primary care centres.
related conditions will increase. It might be problematic to However, our earlier analysis of national prescription data achieve a rational use of drugs which are seldom prescribed Journal of Obesity Table 3: Reasons for discontinuation.
Neurological Psychiatric Gastrointestinal Cardiovascular (N = 100)Sibutramine (N = 100)Orlistat by the average general practitioner, especially if the treatment [7] "Lorcaserin hydrochloride APD-356 for obesity or overweight is new on the market. Unbiased continued medical education people with at least one co-morbidity," National Horizon about new drugs appears to be important, and electronic tools for prospective data collection could possibly improve the quality regarding both initiation of therapy and followup of particularly sensitive and/or expensive drug treatments.
APD-356 .pdfk.
These results show the importance of prioritizing the devel- [8] A. Astrup, S. Madsbad, L. Breum, T. J. Jensen, J. P. Kroustrup, and T. M. Larsen, "Effect of tesofensine on bodyweight loss, opment of such assistance.
body composition, and quality of life in obese patients: a ran-domised, double-blind, placebo-controlled trial," The Lancet, vol. 372, no. 9653, pp. 1906–1913, 2008.
[9] B. Wettermark, M. E. Persson, N. Wilking et al., "Forecasting In conclusion, this observational study suggests that the drug utilization and expenditure in a metropolitan health treatment with weight-loss drugs was of limited clinical ben- region," BMC Health Services Research, vol. 10, p. 128, 2010.
efit the way they were used in a large proportion of Swedish [10] B. Wettermark, P. Raaschou, T. Forslund, and P. Hjemdahl, primary care. Also, our results indicate that effective models "Fortsatta fr˚agetecken kring bantningsmedlet rimonabant," are needed to evaluate the risks and benefits of treatment L¨akartidningen, vol. 104, no. 51-52, pp. 3879–3881, 2007.
with life-style drugs in the everyday clinical setting.
[11] "Summary of product characteristics, Acomplia," EMEA, http://www.ema.europa.eu/docs/en GB/document li- brary/EPAR - Product Information/human/000666/WC500- Conflict of Interests
[12] D. Rucker, R. Padwal, S. K. Li, C. Curioni, and D. C. W.
The authors declare that they have no conflict of interest.
Lau, "Long term pharmacotherapy for obesity and overweight:updated meta-analysis," The British Medical Journal, vol. 335, no. 7631, pp. 1194–1199, 2007.
[13] "Summary of product characteristics, Xenical," eMC, 2011, We gratefully acknowledge Anders Sundstr¨om, Ph.D. at the Centre for Pharmacoepidemiology, Karolinska Institutet for valuable statistical advice.
[14] "Summary of product characteristics, Reductil," eMC, 2010, [15] P. Engfeldt, C. Popa, P. Bergensand et al., "Kvalitetsarbete kring l¨akemedelsf¨orskrivning i prim¨arv˚arden. Nytt databaspro-gram underl¨attar uppf¨oljning av l¨akemedelsbehandling," [1] D. W. Haslam and W. P. T. James, "Obesity," Lancet, vol. 366, L¨akartidningen, vol. 98, no. 50, pp. 5767–5771, 2001.
no. 9492, pp. 1197–1209, 2005.
[16] C. Norman, R. Zarrinkoub, J. Hasselstr¨om, B. Godman, F.
[2] World Health Organization (WHO). Obesity and overweight.
Granath, and B. Wettermark, "Potential savings without com- Fact sheet No 311, 2010, http://www.who.int/mediacentre/ promising the quality of care," International Journal of Clinical Practice, vol. 63, no. 9, pp. 1320–1326, 2009.
[3] M. Neovius, A. Janson, and S. R¨ossner, "Prevalence of obesity [17] B. Wettermark, N. Hammar, C. M. Fored et al., "The new in Sweden," Obesity Reviews, vol. 7, no. 1, pp. 1–3, 2006.
swedish prescribed drug register—opportunities for pharma- [4] G. A. Bray, Contemporary Diagnosis and Management of Obe- coepidemiological research and experience from the first six sity and the Methabolic Syndrome, Handbooks in Health Care, months," Pharmacoepidemiology and Drug Safety, vol. 16, no.
Newtown, Pa, USA, 3rd edition, 2003.
7, pp. 726–735, 2007.
[5] "Questions and answers on the recommendation to sus- [18] P. A. Caetano, J. M. C. Lam, and S. G. Morgan, "Toward pend the marketing authorisation of Acomplia (rimona- a standard definition and measurement of persistence with bant),," EMEA, 2008, http://www.ema.europa.eu/humandocs/ drug therapy: examples from research on statin and antihy- pertensive utilization," Clinical Therapeutics, vol. 28, no. 9, pp.
[6] "European medicines agency recommends suspension of 1411–1424, 2006.
marketing authorisation for sibutramine," EMEA, 2010, [19] A. Mason, "New medicines in primary care: a review of influ- ences on general practitioner prescribing," Journal of Clinical and events/news/2010/01/news detail 000985.jsp.
Pharmacy and Therapeutics, vol. 33, no. 1, pp. 1–10, 2008.
Journal of Obesity [20] M. R. Law, S. R. Majumdar, and S. B. Soumerai, "Effect of illicit direct to consumer advertising on use of etanercept, mometa-sone, and tegaserod in Canada: controlled longitudinal study,"The British Medical Journal, vol. 337, p. a1055, 2008.
[21] S. Gilbody, P. Wilson, and I. Watt, "Benefits and harms of direct to consumer advertising: a systematic review," Qualityand Safety in Health Care, vol. 14, no. 4, pp. 246–250, 2005.
[22] R. Padwal, A. Kezouh, M. Levine, and M. Etminan, "Long- term persistence with orlistat and sibutramine in a popula-tion-based cohort," The International Journal of Obesity, vol.
31, no. 10, pp. 1567–1570, 2007.
[23] K. Johansson, K. Neovius, S. M. Desantis, S. R¨ossner, and M.
Neovius, "Discontinuation due to adverse events in random-ized trials of orlistat, sibutramine and rimonabant: a meta-analysis," Obesity Reviews, vol. 10, no. 5, pp. 564–575, 2009.
[24] J. P. Despr´es, A. Golay, L. Sj¨ostr¨om, and Rimonabant in Obesity-Lipids Study Group, "Effects of rimonabant on met-abolic risk factors in overweight patients with dyslipidemia,"The New England Journal of Medicine, vol. 353, no. 20, pp.
2121–2134, 2005.
[25] L. F. Van Gaal, A. M. Rissanen, A. J. Scheen, O. Ziegler, and S. R¨ossner, "Effects of the cannabinoid-1 receptor blockerrimonabant on weight reduction and cardiovascular risk fac-tors in overweight patients: 1-Year experience from the RIO-Europe study," Lancet, vol. 365, no. 9468, pp. 1389–1397, 2005.
[26] A. J. Scheen, N. Finer, P. Hollander, M. D. Jensen, and L. F. Van Gaal, "Efficacy and tolerability of rimonabant in overweight orobese patients with type 2 diabetes: a randomised controlledstudy," Lancet, vol. 368, no. 9548, pp. 1660–1672, 2006.
[27] F. X. Pi-Sunyer, L. J. Aronne, H. M. Heshmati, J. Devin, and J.
Rosenstock, "Effect of rimonabant, a cannabinoid-1 receptorblocker, on weight and cardiometabolic risk factors in over-weight or obese patients: RIO-North America: a randomizedcontrolled trial," The Journal of the American Medical Associa-tion, vol. 368, no. 9548, pp. 1660–1672, 2006.

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