5/4/2014 WEIGHT MANAGEMENT: OBJECTIVES CASE 1 STATISTICS A TEAM APPROACH WHAT DO WE KNOW?

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1 OBJECTIVES 1. Evaluate the current guidelines for the management of overweight and obesity in adults. WEIGHT MANAGEMENT: A TEAM APPROACH Crystal Whitman, PharmD, BCACP Aleda E. Lutz VA Medical Center Saginaw, MI 2. Identify the components of a high-intensity, comprehensive-lifestyle intervention program. 3. Review treatment options that may aid patients in their weight loss goals. CASE 1 MK is a 32 y.o. hispanic female with body mass index (BMI) of 32. She has a diagnosis of hypertension (HTN) and hypothyroidism. She discusses her and her spouse s desire to become pregnant within the next year and her frustrations with her current weight. She reports trying really hard at home without success. What is your recommendation? A. phenteramine/topiramate (Qsymia) B. diethylpropion C. a comprehensive lifestyle intervention program D. bariatric surgery WHAT DO WE KNOW? HTN Cancer: endometrial, breast, Dyslipidemia prostate, and colon Sleep apnea & Type 2 respiratory diabetes problems (T2DM) Obesity and overweight increase the risk of morbidity from Coronary Osteoarthritis heart disease (CHD) Gallbladder Stroke disease Obesity Trends* Among U.S. Adults BRFSS, 1990, 2000, 2010 (*BMI 30, or about 30 lbs. overweight for 5 4 person) STATISTICS More than one-third of U.S. adults (35.7%) are obese Overweight (BMI>25)= 69% 35.7% 33.3% 31.0% Normal Overweight Obese The estimated annual medical cost of obesity in the U.S. was $147 billion in 2008 U.S. dollars $99.2 billion in 1995 The medical costs for people who are obese were $1,429 higher than those of normal weight No Data <10% 10% 14% 15% 19% 20% 24% 25% 29% 30% BRFSS: Behavioral Risk Factor Source Surveillance System NIH, NHLBI. Clinical Guidelines on the identification, evaluation, and treatment of overweight and obesity in Adults. The evidence report. NIH Publication No ,

2 WHO RESPONDED? National Heart, Lung, Blood Institute (NHLBI) in cooperation with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Identification, Evaluation, and Treatment of Overweight and Obesity In Adults (1998) Examined the evidence of benefits Assessment/classification: BMI, waist circumference Goals of weight loss and management (1-2 lbs/week) Strategies for weight loss and management Pharmacotherapy Bariatric Surgery Diet therapy (500 to 1000 kcal/d deficit) Physical Activity (30 min moderate intensity most days) TIME FOR AN UPDATE 2013 American Heart Association (AHA)/American College of Cardiology (ACC)/The Obese Society (TOS) Guideline for the Management of Overweight and Obesity in Adults 2008 NHLBI initiated June 2013 began collaboration with ACC/AHA Other ACC/AHA 2013 guidelines Assessment of cardiovascular (CV) risk Lifestyle modifications to reduce CV risk Blood cholesterol 2013 OVERWEIGHT/OBESITY GUIDELINES Differ from other ACC/AHA guidelines More limited in scope Focus on select critical questions (CQ) based on the highest quality evidence available Recommendations derived Randomized trials Meta-analyses Observational studies evaluated for quality Evidence not considered beyond OVERWEIGHT/OBESITY GUIDELINES Panel began with 23 possible CQ Excluded CQ Examples: genetics, binge, pharmacotherapy, cost effectiveness Panel s ultimate goal Develop evidence statements (ES) and recommendations for 5 CQs to assist clinicians in primary care Our goal today Discuss summary of recommendations Discuss 4 CQ and selected ES 2013 OVERWEIGHT/OBESITY GUIDELINES: CQ CQ1: address the expected health benefits of weight loss CQ2: (i) address the health risk of overweight and obesity (ii) determine if waist circumference/bmi cutpoints appropriate across all subgroups CQ3: which dietary intervention strategies are effective for weight loss efforts CRITICAL QUESTION 1 (CQ1) Among overweight and obese (O/O) adults, does achievement of reduction in body weight with lifestyle and pharmacological interventions affect cardiovascular disease (CVD) risk factors, CVD events, morbidity and mortality? Weight loss and risk of diabetes Weight loss and impact on cholesterol/lipid profile Weight loss and hypertension risk CQ4: determine the efficacy and effectiveness of a comprehensive lifestyle approach on weight loss and maintenance 2

3 CQ1 (DM) Weight loss and risk of diabetes (DM) ES: O/O adults at risk for T2DM 2.5 to 5.5kg weight loss at > 2 years achieved w/ lifestyle intervention (+/- orlistat) reduced risk of developing T2DM by 30-60% ES: O/O adults with T2DM 2 to 5% weight loss in 1-4 years (lifestyle +/- orlistat) lowered HgbA1c by % 5-10% weight loss at 1 year (lifestyle +/- orlistat) associated with HgbA1c reductions of 0.6-1% and DM medications CQ1(DM)-MORTALITY ES: O/O adults with T2DM Intentional weight loss of 9 to13 kg had a 25% decrease in mortality rate vs. weight stable controls Observational cohort studies Strength of Evidence: High Strength of Evidence: Low CQ1(LIPID) Weight loss and impact on lipid profiles ES: O/O adults +/- elevated CVD risk Dose-response relationship between amount of weight loss (lifestyle) and the improvement in lipid profile Weight loss <3 kg: more modest/variable improvements in triglycerides (TG), high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol 3kg: decrease TG at least 15 mg/dl 5 kg to 8 kg Decrease LDL by ~5 mg/dl Increase HDL by 2 to 3 mg/dl CQ1(HTN) Weight loss and hypertension (HTN) risk ES: O/O adults with +CVD risk (including T2DM/HTN) Dose-response relationship between the amount of weight loss achieved at up to 3 years (lifestyle +/- orlistat) and the lowering of blood pressure (BP) 5% weight loss: mean reduction observed 3 mm Hg systolic BP 2 mm Hg diastolic BP <5% weight loss: more modest/variable BP reductions Strength of evidence: High Strength of evidence: High SUMMARY-CQ1 Counsel O/O adults with CV risk factors that lifestyle changes that produce even modest, sustained weight loss of 3%-5% produce clinically meaningful health benefits Greater weight losses = greater benefits NHLBI grade: A (strong) ACC/AHA: IA CRITICAL QUESTION 2 (CQ2) Are the current BMI cutpoint values for O/O vs. normal associated with CVD risk? Are the current waist circumference cutpoints associated with CVD risk? How do they compare** Are differences across population subgroups (in relation to BMI/waist circumference and CVD risk/mortality) sufficiently large to warrant different cutpoints? ** What are the associations between maintaining weight and weight gain with CVD risk in normal weight, overweight, and obese adults?** **Not enough evidence to answer 3

4 CLASSIFICATION OF OVERWEIGHT AND OBESITY BY BMI, WAIST CIRCUMFERENCE AND ASSOCIATED DISEASE RISK* BMI (kg/m2) Obesity Class Disease Risk* Relative to Normal Weight and Waist Circumference Men: < 102 cm (< 40 in) Women: < 88 cm (< 35 in) > 102 cm (> 40 in) > 88 cm (> 35 in) Underweight <18.5 Normal Overweight Increased High Obesity I High Very High Extreme Obesity * Disease risk for T2DM, HTN, and CVD II Very High Very High > 40 III Extremely High Extremely High CRITICAL QUESTION 2 (CQ2) ES: Current BMI cutpoint - O/O vs. normal Associated with risk of combined fatal and nonfatal coronary heart disease (CHD) Associated with risk of fatal CHD in both sexes ES: All-cause mortality The current category for overweight NOT associated with risk of all-cause mortality BMI at or above the current cutpoint for obesity IS associated with an risk of all-cause mortality vs. normal weight NIH, NHLBI. Clinical Guidelines on the identification, evaluation, and treatment of overweight and obesity in Adults. The evidence report. NIH Publication No , Strength of Evidence: Moderate SUMMARY-CQ2 (IDENTIFY PATIENTS WHO NEED TO LOSE WEIGHT) Calculate BMI at least annually NHLBI grade: expert opinion ACC/AHA: IC Use current cutpoints: For O/O to identify adults who may be at risk of CVD Obesity to identify adults who may be at risk of mortality from all causes NHLBI grade: A (strong) ACC/AHA: IB SUMMARY CQ2 (IDENTIFY PATIENTS WHO NEED TO LOSE WEIGHT) Advise O/O adults that greater BMI= greater risk of CVD, T2DM, and all-cause mortality NHLBI grade: A (strong) ACC/AHA: IB Measure waist circumference at annual visits or more frequently in O/O adults Greater waist circumference= greater risk of CVD, T2DM, and all-cause mortality NHLBI grade: expert opinion ACC/AHA: IIB CRITICAL QUESTION 3 (CQ3) During weight loss or weight maintenance after weight loss, what are the comparative health benefits or harms of the above diets and other dietary weight loss strategies? SUMMARY: CQ3 (DIETS FOR WEIGHT LOSS) Prescribe a diet to achieve reduced calorie intake for O/O individuals who would benefit from weight loss, as part of a comprehensive lifestyle intervention. Prescribing options: In O/O adults, what is the comparative efficacy/effectiveness of diets of differing forms and structures OR other dietary weight loss strategies in achieving or maintaining weight loss? 1,200 1,500 kcal/d for women & 1,500 1,800 kcal/d for men 500 kcal/day or 750 kcal/day energy deficit Evidencebased diet that restricts certain food types NHLBI grade: A (strong) ACC/AHA: IB 4

5 SUMMARY: CQ3 (DIETS FOR WEIGHT LOSS) Prescribe a calorie-restricted diet, for O/O individuals based on the patient s preferences and health status and preferably refer to a nutrition professional for counseling Variety of dietary approaches = weight loss NHLBI grade: A (strong) ACC/AHA: IB CRITICAL QUESTION 4 (CQ4) Among O/O adults, what is the efficacy/effectiveness of a comprehensive lifestyle intervention program (CLIP) in facilitating weight loss or maintenance of lost weight? What characteristics of delivering comprehensive lifestyle interventions are associated with greater weight loss or weight loss maintenance? Frequency and duration of treatment Individual vs. group sessions Onsite vs. telephone/ contact CRITICAL QUESTION 4 (CQ4) ES: The principal components of an effective high-intensity, on-site CLIP include Physical activity >150 min/week min/week to maintain/minimize gain Increased physical activity Reduced calorie diet Behavioral therapy Food intake Physical activity Weight SUMMARY CQ4 (LIFESTYLE INTERVENTION AND COUNSELING) Advise O/O individuals to participate for 6 months in a CLIP that assists participants in adhering to the principal components NHLBI grade: A (strong) ACC/AHA: IA Prescribe on site, high-intensity CLIP in individual or group sessions by a trained interventionist (TI) NHLBI grade: A (strong) ACC/AHA: IB Strength of evidence: High Trained internationalist (reviewed studies) included mostly health professionals (ie. RN, psychologist, exercise specialists, or health counselors). SUMMARY CQ4 (LIFESTYLE INTERVENTION AND COUNSELING) SUMMARY CQ4 (LIFESTYLE INTERVENTION AND COUNSELING) Electronically delivered weight loss programs (+ telephone) that include personalized feedback from TI can be prescribed but may result in smaller weight loss vs. face-toface NHLBI grade: B (moderate) ACC/AHA: IIaA Some commercialbased programs that provide a CLIP can be prescribed, provided there is peer-reviewed published evidence of safety and efficacy NHLBI grade: B (moderate) ACC/AHA: IIaA Use a very low calorie diet (defined as <800 kcal/day) ONLY in limited circumstances ONLY when provided by trained practitioners in a medical care setting Medical supervision required (more discussion ahead) NHLBI grade: A (strong) ACC/AHA: IIA Advise O/O individuals who have lost weight to participate long-term ( 1 year) in a CLIP NHLBI grade: A (strong) ACC/AHA: IA 5

6 SUMMARY CQ4 (LIFESTYLE INTERVENTION AND COUNSELING) For weight loss MAINTENANCE Prescribe face-to-face or programs that provide regular contact (> monthly) With a trained interventionist who Engage in high levels of physical activity minutes/week Monitor body weight regularly Weekly or more frequent Consume a reduced-calorie diet (maintain lower body wt) NHLBI grade: A (strong) ACC/AHA: IA COMPREHENSIVE LIFESTYLE + MEDICALLY SUPERVISED PROGRAMS Veteran s Administration MOVE!(Managing Overweight and/or Obesity for Veterans Everywhere). Evidence-based weight management program Largest/most comprehensive weight management program Individual, group, and activity sessions MOVE! Intensive Designed extreme obesity who have NOT been successful in MOVE! 12 day on-site program focus: diet, exercise and behavior Criteria BMI >35 w/ comorbid conditions or BMI >40 Failure to achieve/maintain a 5-10% weight loss with standard MOVE! Must be Independent with all ADL s Able to walk 100 feet unassisted Willing to complete health appraisal and sign behavioral agreement Team Dietician Nurse practitioner Pharmacist Physical therapist Behavioral psychologist Recreational therapist Chaplain Clearance by primary care provider (PCP) +/- Mental health Cardiac Pulmonary Hematology GI/liver Nephrology, etc Medication adjustments Diabetes Blood Pressure Additions Diet Exercise Behavior Discontinue Short acting insulin Orals causing hypoglycemia Cut in half Intermediate, longacting insulin Continue/adjust Metformin/DPP-4 Case-by-case GLP-1/TZDs ACE/ARB Discontinue Diuretics Discontinued Reduced in HF or excess fluid Multi-vitamin Constipation Non-rx 800 calorie diet Cooking Shopping Two 1-hour gym sessions daily Walking Tai Chi Wii fitness Journaling (sleep, emotions, etc.) Food Records Blood pressure/blood sugar records Group & individual therapy Health assessment Goal setting 6

7 % Body Weight Lost WEEK 1 MONDAY TUESDAY WEDNESDAY THURSDAY FRIDAY SATURDAY SUNDAY 6:00 AM Weigh In Weigh In Weigh In Weigh In Weigh In Weigh In 6:30 AM Walk/Wheel Walk/Wheel Walk/Wheel Walk/Wheel Walk/Wheel Walk/Wheel 7:00 AM Breakfast Breakfast Breakfast Breakfast Breakfast Breakfast Breakfast 7:30 AM Journaling Journaling Journaling Journaling Journaling Journaling Fitness Center Fitness Center Fitness Center Wii Games Wii Games 8:00 AM Orientation CLC Fitness Center 8:30 AM 9:00 AM Behavior Wii Games Behavior Change Nutrition Behavior Fitness Center Fitness Center Change Class: Change Counseling CLC1 9:30 AM Counseling CLC1 Counseling CLC1 Grocery DR DR Shopping DR 10:00 AM Educational Educational DVD Tour Wii Games Free Time Free Time Physical Therapy DVD Supersize Me Healthy Shopping 10:30 AM (room) 11:00 AM Diet Preview MOVE Free Time Educational DVD Educational DVD (room) Health Class Support Group ( rm 11:30 AM Pharmacy Free Time Enjoy Nutrition (1) Food Matters Review CLC1 DR 2315) 12:00 PM Lunch Lunch Lunch Lunch Lunch Lunch Lunch 12:30 PM 1:00 PM Nutrition Class- Educational Free Time Menu Planning Wii Games Wii Games DVD Chaplain 1:30 PM Control/Label Reading Overweight & Chapel Obesity Fitness 2:00 PM Fitness Center Center Fitness Center Fitness Center Fitness Center Fitness Center Free Time 2:30 PM Orientation CLC2 3:00 PM Dexascan Free Time Educational Free Time Educational DVD MyHealtheVet DVD Tai Chi CLC2 3:30 PM 4th floor Molly Forks over Enjoy Nutrition (2) Class (CLC 1) dining room Knives 4:00 PM Tai Chi (rm Free Time Free Time Home Exercise Tai Chi (rm 2315) Home Exercise 2315) 4:30 PM Video /Walk Video /Walk 5:00 PM Supper Supper Supper Supper Supper Supper Supper 6:00 PM Walking Walking Walking Walking Walking Walking Walking 8:00 PM Journaling Journaling Journaling Journaling Journaling Journaling Journaling 9:00 PM Snack Snack Snack Snack Snack Snack Snack Discharge 1200 calorie diet Group or individual classes (dietician) With most current medication adjustments Follow-up within 2 weeks clinical pharmacist/pcp PHARMACOLOGY Data (8/2012-4/2014) Average BMI: Average MOVE! IOP % Body Weight Lost Post-IOP (n=104) 1 month (n=94) 3 month (n=83) 6 month (n=81) 9 month (n=55) 12 month (n=65) 18 month (n=15) Time 4.82 Fenfluramine (Pondimin,1973) Dexfenfluramine (Redux, 1996) Provider-initiated reports of valvular heart disease Withdrawn September 1997 Off-label use of Fen-phen Withdrawn Sibutramine (Meridia,1997) SCOUT trial: 16% in risk of major adverse CV events Withdrawn: October 2010 Still hanging on Diethylpropion HCL and ER (Tenuate, 1960) Indication (C-IV) Short-term adjunct (diet) for weight loss Contraindications (CI) Pulmonary HTN Advanced arteriosclerosis Hyperthyroidism Glaucoma Severe HTN Agitated states History drug abuse MAOI within 14 days PHARMACOLOGY PHARMACOLOGY: THE NEW KIDS ON THE BLOCK Still hanging on Still hanging on Phentermine/Topiramate (Qsymia) Locaserin (Belviq) Phentermine (Adipex-P, 1959) Indication (C-IV) Short-term adjunct (exercise/diet/behavior) for weight loss CI CVD (uncontrolled HTN, CVA, arrhythmias, CHF) Hyperthyroidism Glaucoma Agitated states History of drug abuse MAOI within 14 days Pregnancy/lactation Drug interaction (DI) SSRI: coadministration NOT recommended Orlistat (Alli, Xenical, 1999) Indication Weight loss AND maintenance with diet Reduce the risk for weight regain after prior weight loss CI Pregnancy Chronic malabsorption syndrome Cholestasis MVI indicated +/- 2hrs of dose DI: levothyroxine (+/- 4hrs) cyclosporine (3hrs after) 7

8 PHENTERMINE/TOPIRAMATE (QSYMIA) THE HISTORY reports: providers writing phentermine in am + topiramate bedtime New Drug Application (NDA) 12/2009 phentermine/topiramate (Qnexa) July 2010 reviewed by FDA committee No efficacy issues cited 2 safety concerns Teratogenic potential Detailed plan/strategy to evaluate and mitigate risk Provide evidence that heart rate (hr), 0.6 to 1.6 beats/min (bpm), does not increase the risk for major adverse cardiovascular events (MACE) Results from SEQUEL PHENTERMINE/TOPIRAMATE (QSYMIA) THE HISTORY... SEQUEL 1-year extension study to look at a second year of exposure of obese subjects with obesity-related comorbidities 676 subjects enrolled Mean exposure: days Results 1.6 bpm hr (high dose) mmhg decrease in systolic BP (SBP) Clinical relevance unknown (1 2 bpm increase in HR) NO increase in MACE composite hazard ratios vs. placebo Approved July postmarketing studies mandated Potential name confusion PHENTERMINE/TOPIRAMATE (QSYMIA) PHENTERMINE/TOPIRAMATE (QSYMIA) Indication (C-IV) Adjunct (diet/exercise) for chronic weight management with BMI >30 or 27+ comorbidity Dose titration < 3% not achieved: dose < 5% not achieved: d/c CI Pregnancy MAOI within 14 days Glaucoma Hyperthyroidism Caution/Consideration Cardiac/CV disease Not studied in HF Excluded stroke/mi/unstable CV disease in previous 6 mo. Elderly: >65 y.o. only 7% of subjects On topiramate Oral carbonic anhydrase inhibitor (avoid use) CNS effects Renal/hepatic impairment Safety The FDA-approved REMS program Purpose Increase awareness of congenital malformations Prescriber Requirements Encouraged to undergo the training Counsel women of childbearing potential Fax/mail universal form + prescription to certified pharmacy Pharmacy Requirements Certified to dispense Staff must receive training Medication guide + risk of birth defects brochure Maintain a list of prescribers Monitoring BP, glucose, blood chemistry, mood LOCASERIN (BELVIQ) THE HISTORY LOCASERIN (BELVIQ) THE HISTORY NDA December completed Phase III trials in non-diabetic (>7000 pts) Phase III trial (BLOOM-DM) was ongoing October 2010 FDA responded siting 4 main issues + updated safety (particularly valvulopathy) Mammary tumor findings in female rats Astrocytoma in male rats A request to include data from BLOOM-DM Assessment of abuse potential (2 rodent experiments) April 2012 briefing document submitted to FDA Mammary tumor Pathology work group established tumor related to high dose (24x human exposure) Astrocytoma Extrapolated data: exposure in rat brain at dose level revealing NO astrocytoma was ~70x estimated level that 10mg bid would produce Abuse potential Repeated animal studies Package insert Human abuse potential study in recreational drug abusers, doses of lorcaserin (40 and 60 mg) 2- to 6-fold increases on measures of High, Good Drug Effects, Hallucinations and Sedation vs. placebo Similar to those produced by zolpidem and ketamine 8

9 LOCASERIN (BELVIQ) THE HISTORY Briefing (continued) Safety update (valvulopathy) Lorcaserin n=1278 Approved June 2012 BLOOM BLOSSOM BLOOM-DM Placebo n=1191 Lorcaserin n= postmarketing studies mandated Placebo n=1153 Lorcaserin n=210 Placebo n=209 Valvulopathy, n (%) 34 (2.7) 28 (2.4) 24 (2.0) 23 (2.0) 6 (2.9) 1 (0.5) Rel. Risk (95% CI) 1.13 (0.69, 1.85) 1.00 (0.57, 1.75) 5.97 (0.73, 49.17) Pooled Rel. Risk 1.16 (0.81, 1.67) LOCASERIN (BELVIQ) Mechanism of action: serotonin 2C receptor agonist Believed to decrease food consumption and promote satiety Indication (C-IV) Adjunct (diet/exercise) for chronic weight management with BMI >30 or 27+ comorbidity Dose: 10 mg twice daily (max) 5% of baseline body weight not lost by week 12 = discontinue LOCASERIN (BELVIQ) HOW DO THEY STACK UP? CI DI Pregnancy SSRI/SNRI excluded 2D6 substrate caution Safety No REMS Monitoring BP, glucose, mood Caution/Consideration Serotonin syndrome or neuroleptic malignant syndrome Valvular heart disease Not studied CHF Cognitive impairment; psychiatric disorders Priapism Elderly (2.5% >65 y.o. studied) kg weight loss more than placebo diethylpropion phentermine orlistat lorcaserin lorcaserin2 Qsymia 7.5/46 Qsymia 15/92 CASE 1 QUESTIONS? MK is a 32 y.o. hispanic female with body mass index (BMI) of 33. She has a diagnosis of hypertension (HTN) and hypothyroidism. She discusses her and her spouse s desire to become pregnant within the next year and her frustrations with her current weight. She reports trying really hard at home without success. What is your recommendation? A. phenteramine/topiramate (Qsymia) B. diethylpropion C. a comprehensive lifestyle intervention program D. bariatric surgery 9

10 REFERENCES 1. Smith SR, Weissman NJ, Anderson CM, et al. Multicenter, placebo-controlled trial of lorcaserin for weight management. N Engl J Med 2010;363: O Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in type 2 diabetes mellitus: The BLOOM-DM study. Obesity 2012;20: Fidler MC, Sanchez M, Raether B, et al. A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: The BLOSSOM trial. J Clin Endocrinol Metab 2011;96: BELVIQ (lorcaserin hydrochloride) package insert. June Li Z, Maglione M, Tu W, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med 2005; 142: Allison DB, Gadde KM, Garvey WT, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized control trial (EQUIP). Obesity 2011;20: Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomized, placebo-controlled, phase 3 trial. Lancet 2011;377: Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012;95: Jensen MD, Ryan DH, Apovian CM, et. al. Circulation Nov AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. 10. FDA. FDA Briefing Document (Accessed 30 Apr 2014) 11. FDA. FDA Briefing Document committee/ucm pdf (Accessed 30 Apr 2014) 12. Micromedex. [Internet]. Greenwood Village: Truven Health Analytics. [cited 2014 Apr 30]. Available from: duct/evidencexpert/duplicationshieldsync/0e5775/nd_pg/evidencexpert/nd_b/evidencexpert/nd_p/evidencexpert/pfa ctionid/pf.homepage 10