Presentation on theme: "Medical Treatment of Obesity"— Presentation transcript:
1Medical Treatment of Obesity F.Hosseinpanah,M.DEndocrine Research CenterShahid Beheshti University of Medical Sciences2th Iranian congress of obesity29-30 Oct,2009Tehran
2Outline Introduction Sibutramine Orlistat Other drugs Critical appraisalConclusion
3Some important Questions Head-to-head comparisons of approved agentsLong-term safety and efficacy of older drugs (e.g., phenteramine)Combination therapyTreatment of children and adolescentsTreatment of elderlyIdentification of patients with a response to treatmentDo drugs confer long-term, individual and population, reductions in morbid and mortal squeal of obesity
6Outcome Measures Weight Waist W/H ratio Lipid profile BP , HR Hb A1c , c peptide , InsulinConversion of IGT to DM
7Measures of weight loss Mean weight loss ( Kg )Percentage weight lossPercentage of individuals losing ≥ %5 or ≥ %10 of baseline weightMaintenance of weight loss during studyAbsolute weight loss (i.e. in excess of placebo )
8Potential benefits of weight loss weight loss in overweight and obese patients - even as little as five to ten percent of initial body weight – is associated with an improvement in cardiovascular risk factors (Goldstein 1992; Blackburn 1995; Colditz 1995)
10Obesity Guidance: Efficacy Criteria US FDA criteria at the end of year 1:Mean placebo-subtracted weight loss > 5%Proportion of subjects who lose > 5% of baseline body weight is greater in drug- vs. placebo-treated groupEMEA* criteria at end of year 1:mean placebo-subtracted weight loss > 10%Proportion of patients who lose > 10% of baseline body weight is greater in drug- vs. placebo-treated group*Europeans Medicines Evaluation Agency
11Sibutramine The brand name is Meridia Sibutramine induces weight loss primarily through its effectson food intake and to a lesser degree through its effect onmetabolic rate.Sibutramine affects serotonin andnorepinephrine metabolism in the brain by stimulatingsatiety at the appetite centers in the brain.Rapid absorption , peak plasma concentration are reached within one or two hours
13Inclusion Criteria (1) randomized controlled trial (2) sibutramine, 10 to 20 mg/d, was administered(3) placebo controlled trial(4) overweight or obese subjects (BMI≥25)(5) subjects were aged 18 years or older(6) weight loss was assessed(7) 8-week duration or longer(8) 29 studies were pooled
29RCTParticipants: 498 participants 12 to 16 years of age with a body mass index (BMI) that was at least 2 units more than the U.S. weighted mean of the 95th percentile based on age and sex, to the upper limit of 44 kg/m2.Setting: 33 U.S. outpatient clinics.Interventions: Site-specific behavior therapy plus 10 mg of sibutramine or placebo. Blinded study medication dose was up titrated to 15 mg or placebo at month 6 if initial BMI was not reduced by 10%Length of F/U: 12 mo.Measurements: Body mass index, waist circumference, body weight, fasting lipid and glycemic variables, safety, and tolerability.
33CautionsOnly 76% and 62% of the sibutramine and placebo recipients, respectively, completed the trial.
34ImplicationsSibutramine plus behavioral therapy for 1 year can reduce weight and improve metabolic risk factors in some very obese adolescents.
35Orlistat The Brand name is Xenical Orlistat prevents the digestion of dietary fat.It inactivates pancreatic lipase that is involved with fat digestion , and about 30 percent less fat is absorbed.Less than %1 is absorbed . It does not alter the pharmacokinetics of digoxin , phenytoin , warfarin , glyburide ,ocp , alcohol , furosemide ,captopril , nifedipine , or atenolol
36Orlistat meta analysis 22 studies were pooledAverage age , 48 yearsAverage BMI , 36.7 Kg/mSeventy-three percent were womenMeta-Analysis: Pharmacologic Treatment of Obesity, Ann Intern Med. 2005;142:
43What About Side Effects? Gastrointestinal symptomsIncreased flatusAbdominal discomfortOily spottingFecal IncontinenceMore severe if intake of fat is more than 100 grams.Nutritional concernsFat-soluble vitamins may be malabsorbed.Daily multi-vitamin is recommended
44Side EffectsIn clinical trials, 1.1–6% of patients treated with orlistat and 0.6–1.3% of placebo recipients withdrew because of gastrointestinal adverse eventIn a large 2-year, double-blind, multicentre study, vitamin supplementation was required in 14.1% of orlistat treated patients and in 6.5% of placebo-treated patientsDrug Safety 2006; 29 (4):
46Participants: 539 obese adolescents aged 12-16 years ,BMI 2 units above the 95th percentile. F/U: 54 weeksSetting: 32 centers in the United States and CanadaInterventions: 120-mg dose of orlistat VS placeboOutcomes: BMI, Waist,Hip, glucose and insulin responses to oral glucose challenge ,Lipid profile , DEXASimilar proportions of participants in each treatment group completed the study (65% for orlistat and 64% for placebo).
50Generally mild to moderate gastrointestinal tract adverse events occurred in 9% to 50% of the orlistat group and in 1% to 13% of the placebo group.
51phenterminesix placebo controlled RCTs contributed data to the pooled analysis.The duration of treatment with phenteramine varied from 2 to 24 weeks.Mean Weight Change in Treated Patients Compared with Placebo (95% CI) was 3.6 kg ( 0.6 to 6.0 kg)Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized clinical trials. Int J Obes Relat Metab Disord. 2002;26:262-73
52DiethylpropionNine Placebo controlled RCTs contributed data to the pooled analysis.The duration of treatment with diethylpropion varied from 6 to 52 weeks.More than 80% of enrolled individuals were femaleMean Weight Change in Treated Patients Compared with Placebo (95% CI ) was 3.0 kg ( 1.6 to 11.5 kg)Pharmacotherapy for obesity: a quantitative analysis of four decades ofpublished randomized clinical trials. Int J Obes Relat Metab Disord. 2002;26:262-73
55prevalenceSeventy percent to 77% of adults between the ages of 65 to 74 are overweightFor adults 75 years and older, the incidence is 60% to 66%The occurrence of obesity among older adults ranges from 33% to 39% for those 65 to 74 years of age and 20% to 25% for those 75 years and olderCDC, National Center for Health Statistics, National Health and Nutrition Examination Survey. Health, United States (Table 70); 2002.
56Age<65 Age >65 Normal 23.7 (541) 33.3 (346) Overweight Prevalence of excess weight in subjects aged 50 years and over in Tehran ( Tehran Lipid and Glucose Study)Age<65Age >65Normal23.7 (541)33.3 (346)Overweight43.7 (998)44.9 (467)Obesity32.6 (745)21.8 (226)
57The main issues in elderly Impaired gastric absorption and motilityThe effects of altered body composition on drug distributionImpaired renal and hepatic functionHigh likelihood of concurrent morbidities and use of polypharmacy , producing the possibility of drug interactions.
58Most of the trials , recruited patients under 65 years of age.
61Segal KR, Lucas C, Boldrin M, et al Segal KR, Lucas C, Boldrin M, et al. Weight loss efficacy of orlistat in obese elderly adults. J Obes Research 1999;7(Suppl 1):26.Hind ID, Mangham JE, Ghani SP, et al. Sibutramine pharmacokinetics in young and elderly healthy subjects. Eur J Clin Pharmacol 1999;54(11):847– 9.
65Pharmacologic therapy has not been sufficiently studied in adults older than 65 years of age, so weight loss medications are usually not recommended. If a clinician suspects a patient who has obesity may improve with drug therapy and wishes to start an agent, orlistat may be a better choice than sibutramine or phentermine.
67Eight such studies were found comparing weightloss of orlistat and sibutramine Four of the seven studies comparing sibutramine and orlistat mono-therapy showed that sibutramine was significantly more efficacious for weight lossThe weighted mean difference in weight loss was 2.2 kg (95% CI 0.5–3.9) favouring sibutramine.
68Three studies investigated orlistat and sibutramine as combination therapy, and two found it to be significantly better than orlistat alone, but not better than sibutramine aloneNo significant difference in dropout rate was seen, although the point estimate indicated a lower risk in sibutramine-treated patients
71PharmacotherapyDrugs approved for long-term use by the FDA may be used as part of a comprehensive weight loss program including diet and physical activity. Evidence Category B.For patients with a BMI of 30 or above with no concomitant risk factors or diseasesFor patients with a BMI of 27 or above for those with concomitant risk factors or diseases (hypertension, dyslipidemia, CHD, type 2 diabetes, sleep apnea)If after at least 6 months on a weight loss regimen of an LCD, increased physical activity, and behavior therapy, pharmacotherapy can be considered as part of a comprehensive program for the following patients:Patients with a BMI 30 who have not lost the recommended 1lb/week on lifestyle therapy.Other patients with a BMI of 27 to 29.9 if they have hypertension, dyslipidemia, CHD, type 2 diabetes, or sleep apnea.There are few long-term studies evaluating the safety or effectiveness of many currently approved weight loss medications. At present, sibutramine and orlistat are the only drugs available for long-term use.Weight loss medications should be used only by patients who are at increased medical risk because of their weight and should not be used for cosmetic weight loss.
72Some important Questions Head-to-head comparisons of approved agentsLong-term safety and efficacy of older drugs (e.g., phenteramine)Combination therapyTreatment of children and adolescentsTreatment of elderlyIdentification of patients with a response to treatmentDo drugs confer long-term, individual and population, reductions in morbid and mortal squeal of obesity
73Critical appraisal Methodological quality was moderate or good blindingHigh attrition rateRun in periodLast observation carry forward analysis (LOCF)Younger and older peopleSex , ethnicity , social classHigh risk vs low risk groupsRecruitment method
74Critical appraisalA careful assessment of the safety of antiobesity medications may be more important than for drugs used to treat other conditions , in which the drugs are less liable to misused.Obesity is a chronic condition. In light of this, longer-term data on the effectiveness and safety would be helpful.
75ConclusionsThe most well-studied medications are sibutramine and orlistatMean weight loss was 2.8–5.7kg more for sibutramine 10–20 mg/day than placeboMean weight loss was 1.3–4.2kg more for orlistat120mg three times daily than placeboWeight loss attributable to these medications are modest but still may be clinically significantThe maximal duration of published treatment results is two years for sibutramine and four years for orlistatWhen drug therapy is discontinued , weight is regainedNear maximal weight loss is achieved by six months in most trialsThere are no data on cardiovascular outcomes and mortalityFor obese patients with HTN or dyslipidemia , orlistat can be considered as first linePharmacologic therapy can be offered to obese patients who have failed to achieve their weight loss goals through diet and exercise alone. However, there needs to be a doctor–patient discussion of the drugs’ side effects, the lack of long-term safety data, and the temporary nature of the weight loss achieved with medications before initiating therapy.
76With better understanding of complexity of energy balance regulation Ultimately , goal must be to use this understanding to develop more effective strategies not only for treatment , but also for the primary prevention of obesity