Medical Treatment of Medical Treatment of ObesityObesity

F.Hosseinpanah,M.DF.Hosseinpanah,M.DEndocrine Research CenterEndocrine Research Center

Shahid Beheshti University of Medical Shahid Beheshti University of Medical SciencesSciences

2th Iranian congress of obesity2th Iranian congress of obesity29-30 Oct,200929-30 Oct,2009

TehranTehran

OutlineOutline• Introduction

• Sibutramine

• Orlistat

• Other drugs

• Critical appraisal

• Conclusion

Some important QuestionsSome important Questions

• Head-to-head comparisons of approved agents

• Long-term safety and efficacy of older drugs (e.g., phenteramine)

• Combination therapy

• Treatment of children and adolescents

• Treatment of elderly

• Identification of patients with a response to treatment

• Do drugs confer long-term, individual and population, reductions in morbid and mortal squeal of obesity

Outcome MeasuresOutcome Measures• Weight• Waist• W/H ratio• Lipid profile• BP , HR• Hb A1c , c peptide , Insulin• Conversion of IGT to DM

Measures of weight lossMeasures of weight loss

• Mean weight loss ( Kg )• Percentage weight loss• Percentage of individuals losing ≥

%5 or ≥ %10 of baseline weight• Maintenance of weight loss during

study• Absolute weight loss (i.e. in excess of

placebo )

Potential 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)

Obesity Guidance: Obesity Guidance: Efficacy CriteriaEfficacy 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 group

EMEA* 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

SibutramineSibutramineThe brand name is Meridia

Sibutramine induces weight loss primarily through its effects

on food intake and to a lesser degree through its effect on

metabolic rate. Sibutramine affects serotonin and

norepinephrine metabolism in the brain by stimulating satiety at the appetite centers in the brain.

Rapid absorption , peak plasma concentration are reached within one or two hours

• ARCH INTERN MED/VOL 164, MAY 10, 2004

Inclusion CriteriaInclusion 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

-5.06(-6.16to-3.96)

-4.45Kg(-5.29 to -3.62)

What About Side Effects?What About Side Effects?• Common side effects include:

– Dry mouth– Headache– Constipation– Insomnia– Increased blood pressure

THE LANCET • Vol 356 • December 23/30, 2000

%3 withdrawal in sibutramine group due to excessive BP increases

(J Clin Endocrinol Metab 90: 1460–1465, 2005)

• RCT• Sample size: 60 adolescents, aged

14–17 yr• F/U:6 months• Intervention: sibutramine (10 mg/d)

or matching placebo• Outcome: weight, waist, Hip, BP,

lipid profile, echocardiogram

Ann Intern Med. 2006;145:81-90.

• RCT• Participants: 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.

CautionsCautions

• Only 76% and 62% of the sibutramine and placebo recipients, respectively, completed the trial.

ImplicationsImplications

• Sibutramine plus behavioral therapy for 1 year can reduce weight and improve metabolic risk factors in some very obese adolescents.

OrlistatOrlistat

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

Orlistat meta analysisOrlistat meta analysis• 22 studies were pooled

• Average age , 48 years

• Average BMI , 36.7 Kg/m

• Seventy-three percent were women

Meta-Analysis: Pharmacologic Treatment of Obesity, Ann Intern Med. 2005;142:532-546

-2.75Kg (-3.31 to -2.20)

DIABETES CARE, VOLUME 27, NUMBER 1, JANUARY 2004

N = 3305 , BMI ≥ 30

F/U = 4 y

Diet + placebo VS DIET + orlistat ( 120 mg TDS )

Attrition rate = %54 in the orlistat and %34 in the placebo

What About Side Effects?What About Side Effects?• Gastrointestinal

symptoms– Increased flatus– Abdominal

discomfort– Oily spotting – Fecal Incontinence– More severe if

intake of fat is more than 100 grams.

• Nutritional concerns– Fat-soluble vitamins

may be malabsorbed.

– Daily multi-vitamin is recommended

Side EffectsSide Effects

• In clinical trials, 1.1–6% of patients treated with orlistat and 0.6–1.3% of placebo recipients withdrew because of gastrointestinal adverse event

• In 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 patients

Drug Safety 2006; 29 (4): 277-302

JAMA. 2005;293:2873-2883

• Participants: 539 obese adolescents aged 12-16 years ,BMI 2 units above the 95th percentile.

• F/U: 54 weeks• Setting: 32 centers in the United States and Canada• Interventions: 120-mg dose of orlistat VS placebo• Outcomes: BMI, Waist,Hip, glucose and insulin

responses to oral glucose challenge ,Lipid profile , DEXA

• Similar proportions of participants in each treatment group completed the study (65% for orlistat and 64% for placebo).

Generally 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.

phenterminephentermine

• six 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

Diethylpropion

• Nine 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 female

• Mean 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 of published randomized clinical trials. Int J Obes Relat Metab Disord. 2002;26:262-73

•Drug treatment in obese elderly adults

prevalenceprevalence• Seventy percent to 77% of adults

between the ages of 65 to 74 are overweight

• For 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 older

CDC, National Center for Health Statistics, National Health and Nutrition Examination Survey. Health, United States (Table 70); 2002.

Age<65 Age >65

Normal 23.7 (541) 33.3 (346)

Overweight 43.7 (998) 44.9 (467)

Obesity 32.6 (745) 21.8 (226)

Prevalence of excess weight in subjects aged 50 years and over in Tehran ( Tehran Lipid and Glucose Study)

The main issues in elderlyThe main issues in elderly

• Impaired gastric absorption and motility• The effects of altered body composition

on drug distribution• Impaired renal and hepatic function• High likelihood of concurrent

morbidities and use of polypharmacy , producing the possibility of drug interactions.

•Most of the trials , recruited patients under 65 years of age.

Continued..

• 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.

Pharmacologic 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.

• Eight 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 loss

• The weighted mean difference in weight loss was 2.2 kg (95% CI 0.5–3.9) favouring sibutramine.

• Three studies investigated orlistat and sibutramine as combination therapy, and two found it to be significantly better than orlistat alone, but not better than sibutramine alone

• No significant difference in dropout rate was seen, although the point estimate indicated a lower risk in sibutramine-treated patients

Drugs 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 diseases

• For patients with a BMI of 27 or above for those with concomitant risk factors or diseases (hypertension, dyslipidemia, CHD, type 2 diabetes, sleep apnea)

PharmacotherapyPharmacotherapy

Some important QuestionsSome important Questions

• Head-to-head comparisons of approved agents

• Long-term safety and efficacy of older drugs (e.g., phenteramine)

• Combination therapy

• Treatment of children and adolescents

• Treatment of elderly

• Identification of patients with a response to treatment

• Do drugs confer long-term, individual and population, reductions in morbid and mortal squeal of obesity

Critical appraisalCritical appraisal

• Methodological quality was moderate or good • blinding• High attrition rate• Run in period• Last observation carry forward analysis

(LOCF)• Younger and older people• Sex , ethnicity , social class• High risk vs low risk groups• Recruitment method

Critical appraisalCritical appraisal

• A 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.

ConclusionsConclusions• The most well-studied medications are sibutramine and orlistat• Mean weight loss was 2.8–5.7kg more for sibutramine 10–20 mg/day

than placebo• Mean weight loss was 1.3–4.2kg more for orlistat120mg three times

daily than placebo• Weight loss attributable to these medications are modest but still

may be clinically significant• The maximal duration of published treatment results is two years for

sibutramine and four years for orlistat• When drug therapy is discontinued , weight is regained• Near maximal weight loss is achieved by six months in most trials• There are no data on cardiovascular outcomes and mortality• For obese patients with HTN or dyslipidemia , orlistat can be

considered as first line • Pharmacologic 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.

• With 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

Thanks for your kind Thanks for your kind attentionattention