Obesity PharmacotherapyFariborz Farsad Pharm D , BCPS
OutlineCase PresentationDefinition, Prevalence, & Comorbidities of ObesityIndications for Drug TherapyFDA Approved Medicines for Obesity Treatmentsibutramine, phentermine, orlistatOther Medicines that Promote Weight LossDM medicines, antidepressants (SSRIs), anti-epilepticsInvestigational Medicines: RimonabantSummary and Case discussion
Case: DB49 y/o obese woman with the following concerns: Chronic bilateral knee pain not responding to anti-inflammatory medicationsInability to exercise due to painInability to loose weight despite food restriction
DB PMHMorbid obesityHTNHyperlipidemia TG, HDLOSA (Cant use CPAP)OADepressionInsulin resistanceHypothyroidismGERDs/p cholecystectomyDB MedicationsDiclofenacLasixPrevacidLevothyroxineSertralineBenazeprilDB Social HistoryDisabled/ MA+tobacco, no alcohol
DB ExamMorbidly obese285 lb, 52, BMI 52Knee exam difficult due to body habitus Diffuse tenderness ROM (0-100)No ligamentous laxity+Retropatellar crepitus
DB Imaging DataStanding Plain Films:Severe OA knees bilaterallyLateral compartment on RMedial compartment on L
DB Assessment & PlanMorbid obesity and severe bilateral OA of kneesReferred to OrthopedicsTKA is indicated, IF she can reduce weight below 180 lbs.Referred to Health ED for dietary counselingLast seen in September, several no shows. Referred for possible Bariatric surgery WI Medicaid coverage as of 2/05 Yes: Gastric bypass for qualified, low risk patients No: Gastric bandingDB asks whether there are any medications she could take to help her lose weight
When diet and exercise are not effective, or adequate exercise is not possible, are there medications to treat obesity that are safe and effective?How do I determine which medications are right for which patients?What about cost/ coverage by local insurance?Questions
Definition of ObesityBMI 25-29.9 (Grade 1, overweight)BMI 30-39.9 (Grade 2, obese)BMI > 40 (Grade 3, Morbidly obese)Increased visceral fatWaist > 94 cm in men (waist-to-hip > 0.95)Waist > 80 cm in women (waist-to-hip >0.8)
Obesity in the U.S.More than 97 million adults in US are overweight or obese (BMI >30)
19.9% of men 24.9% for women
Prevalence of ObesityMore than 30% of adults in the US are overweight or obese, and this percentage is rising.Percentage of people with BMI 30 in the US in 2005CDCs Behavioral Risk Factor Surveillance System.
Costs the US health-care system more than $99 billion each year Consumers also spend over $33 billion annually on weight-reduction products and servicesAnnual health-care costs for patients with BMIs of 20 to 24.9 were 20% lower than costs for patients with BMIs from 30 to 34.9 and almost 33% lower than for patients who had BMIs of 35 or more.
Costs of Obesity
Complications of Obesity
Obesity Related Comorbidities
HTN/ hyperlipidemiaCAD/CVADM IICancer (Breast, Colon, Prostate)Meralgia parestheticaGallbladder diseaseNASH/ NAFLDGERDVaricose veinsEndometrial Ca PCOS/ infertilitySurgical Risk/ post-op complicationsLE edema/ cellulitisDepressionOAPulmonary HTN/OSA
Does weight loss lead to improvement in outcome? 10kg loss leads to:Reduction in total cholesterol of 0.25mmol/lReduction in systolic BP of 6mmHgReduction in diastolic BP of 3mmHg
ANY weight loss in people with an obesity related illness leads to:In women - Reduced risk of death, CVD, cancer or diabetes related deathIn men Reduced risk of diabetes related death
Indications for Drug Therapy in ObesityFailure of diet and exercise aloneSignificant obesity related comorbidities even if BMI < 30 (ie 25-30).No contraindications to drug therapyMedication interactionsMedical conditions that may be adversely affected by the obesity drug
Snow, et al , Ann Intern Med, 2005.
Model of Obesity Care
Level 1: Public health initiatives. GP to signpost patients to community based lifestyle interventionLevel 2: 1+ practice based intervention, anti-obesity drugs, community dietitian, behaviour modificationLevel 3: (secondary care)Specialist dietitian, endocrinologist, psychologist, genetic screening, anti-obesity drugsLevel 4: (secondary care)Bariatric surgery with support from level 3 service
*Centrally-Acting Anorexigens Approved Post-193811947 Desoxyephedrine/methamphetamine (available pre-38)1956 Phenmetrizine (Preludin)1959 - Phendimetrazine (Bontril) 1959 - Phentermine (Fastin, Ionamin) W/D CPMP 20001959 - Diethylpropion (Tenuate)1960 - Benzphetamine (Didrex)1972 - Fenfluramine (Pondimin) W/D 1997 1973 - Mazindol (Sanorex)21995 Dexfenfluramine (Redux) W/D 19971997 Sibutramine (Meridia)
*Drugs Approved for Long-Term Treatment of Obesity1996 - Dexfenfluramine (Redux): w/d 97 1997 - Sibutramine (Meridia)1999 - Orlistat (Xenical)
Efficacy: Long-term indication drugsMean loss of 5.0 kg vs. placebo range of placebo-subtracted means across studies 1.5 to 6.0 kg
*Drug use data: 1991-2002Annual volume of antiobesity medications reported in the United States, 19912002, IMS HEALTH National Disease and Therapeutic Index. Data for 2002 are an estimate (E) based on January to March 2002 figures. HCl indicates hydrochloride. From: Stafford: Arch Intern Med, Volume 163(9).May 12, 2003.10461050
SibutramineMechanism of action:Inhibits norepinephrine and serotonin reuptakeDecreases food intake; ?Thermogenic effect?Dosing: 5 -15 mg po daily Schedule IV, but approved for long-term useCost: about $105 for a 30 day supply of 10 mg tabletsInsurance coverage: NC by Unity, PPlus, or Medicaid
Sibutramine: EfficacyMeta-analysis of healthy obese adults Exclusion: patients with CAD Concomitant lifestyle, dietary, and behavioral modificationPrimary outcome: weight lossSecondary outcomes: cardiovascular, metabolicArtburn, et al, Arch Intern Med, 2004.
Dose# trialsDurationPatients10-15 mg78-12 wks54612 (4-5-3)16-24 wks1079544-54 wks2188
Results: Mean Difference in Weight LossSubgroup A used late-observation-carried-forward analysis and had >70% follow upSubgroup B analyzed only participants who completed the trialSubgroup C had follow up rates less than 70%ABCArtburn, et al, Arch Intern Med, 2004.2.783.434.45
Secondary OutcomesModest increase in BP and HRSmall improvements in TG, HDL, & glycemic controlNo evidence of improvement of morbidity & mortalityNo dose effect for weight loss.1 trial showed weight loss maintained at 2 yrs2 trials showed regain of 50% of weight at 6-12 months after stopping medicine.Artburn, et al, Arch Intern Med, 2004.
Cochrane Review:Sibutramine Long-term Efficacy Meta-analysis of RCTs, Sibutramine vs. placebo 3 trials -- weight loss at more than 1 year follow up 2 trials -- weight maintenance at 2 yearsInclusion: adults BMI>30 or BMI>27 + comorbiditiesExclusion: patients with DM or uncontrolled HTNResults: 4.3 kg (3.6-4.9) more wt loss with sibutramine27% more patients maintained 80% of original weight loss at 2 years with sibutramineAdverse effects: Small increase in HR and BPPadwal, et al. Cochrane Database of Systematic Reviews, 2003.
Sibutramine with & without Lifestyle ChangesWadden TA et al. NEJM, 2005.224 obese adults randomized to the following for 1 year:15 mg sibutramine daily (PCP 8 visits, no counseling)Lifestyle modification alone (30 group sessions, 90 minutes, psychologist)Sibutramine + lifestyle modification (30 group sessions)Sibutramine + brief lifestyle modification (PCP 8 visits, brief counseling)All prescribed diet 1200-1500 kcal per day and exercise regimen
Adverse EffectsContraindicationsIncrease BP, HRHistory of CAD, CHF, CVA, glaucoma Palpitations, prolong QTTachyarrhythmia (rare)History of arrhythmiaThrombocytopeniaPredisposition to bleedingP450 metabolismSevere liver or renal diseaseSerotonin syndromeMAOIs, SSRIsHA, insomnia, Sz (rare)History of seizureGI disturbance
Phentermine and DiethylpropionMechanism of action: Stimulate NE release and inhibit re-uptakeDosing (short-term use only -- < 12 weeks)18.75 to 37.5 mg once daily or in divided dosesSchedule IVCost: about $34 for a month supply of 37.5 mg tabletsInsurance coverage: NC by Unity, PPlus, or Medicaid
Phentermine: Efficacy and SafetyMeta-analysis: Included 6 RCTsDuration: 2-24 wksDose: 15-30 mg per dayResults: 3.6kg (0.6-6.0) more wt loss with phentermine No data on side effects or adverse events reported
Haddock et al, J Obes Relat Metabolic Disord, 2002.
Adverse EffectsHTN, tachyarrhythmiaHeart valve disorder (rare)PPH (rare)GI disturbancePsychosis, agitationHA, insomnia, tremor, AMS, dizzinessDecreased libidoAffect insulin needs in DM
ContraindicationsCAD, HTN, glaucomaHyperthyroidismMAOI, SSRIHistory of drug/etoh abusePsychiatric disease
Orlistat Mechanism of ActionInhibits pancreatic lipases preventing hydrolysis of ingested fatLess than 1% absorbedDosing: 60 120 mg prior to each meal.Lower dose OTC (My Alli)Cost: about $224 for a 1 month supply of 120 mg doseInsurance coverage: NC by Unity, PPlus, or MedicaidGI side effects: diarrhea, cramping, flatus, oily discharge, malabsorption of fat soluble vitamins.Only drug interaction: CSA
Orlistat: EfficacyMeta-analysis, 29 RCTs included12 trials with 6 months follow upMean of 2.59 kg (1.74-3.46) more wt loss with orlistat22 trials with 12 months follow upMean of 2.89 kg (2.27-3.51) more wt loss with orlistatRR diarrhea 3.40, flatus 3.10, and dyspepsia 1.48No difference between 6 and 12 monthsCochrane