11/3/2014
Emerging Pharmacologic Treatments & Strategies in the Management of Obesity
W. Timothy Garvey, MD, FACE Professor and Chair, Department of Nutrition Sciences University of Alabama at Birmingham Director, UAB Diabetes Research Center
Outline • Rationale for long‐term therapy: obesity is a chronic disease • Pathophysiological mechanisms that necessitate long‐term medical therapy • Compare and contrast the safety and efficacy of emerging pharmacologic therapies in the management of obesity • Discuss the metabolic effects, adverse effects, and drug‐ drug interactions associated with anti‐obesity medications • Examine models of medical care for obese patients, evidenced‐based approaches for diagnosis and stratification of disease severity, and the utility of established obesity treatment guidelines
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Initializing Concepts: The AACE Position1
1. “It is the strong contention of AACE that the view of obesityThe American as a behavioral Medical decision Association is debunked designates by biomedical evidence.” obesity as a disease. 2. “…obesityJune is a18, primary 2013, AMA disease, House and of Delegates the full force of our medical knowledge should be brought to bear on the prevention and treatment of obesity as a primary disease entity.” 3. “…obesity is an altered physiological and metabolic state, with genetic, environmental, and behavioral determinants, which results in increased morbidity and mortality.”
1 Mechanick JI, Garber AJ, Handelsman Y, Garvey WT. Endocr Pract. 2012;18:642-8.
Is Obesity a Disease?
Concordance of Body Type between Dizygotic or Fraternal Twins
Concordance of Body Type between Monoygotic or Identical Twins
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Polygenic Diseases: Susceptibility Genes Interact with Each Other and the Environment
Gene 1 Gene 2
Individuals Environment with & Disease Behavior
5
Determinants of Body Weight
Genes Environment • Protective and at risk • Food availability alleles for weight gain • Food quality • Race (ancestral • Built environment admixture) • Socioeconomic status • Gene-Gene interactions • Education
Biological factors Behavior • In utero environment • Dietary preferences • Birth Weight • Physical activity • Gender • Psychological factors • Age • Cultural factors • Concurrent diseases • Diurnal life patterns
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Cause of Obesity: Abnormal Energy Balance
Body Weight
Increase Decrease
Human Energy intake being: Energy biological Ingestion of: expenditure and Proteins Basal metabolic rate behavioral Physical activity Fats interface Energy to Carbohydrates metabolized food
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AMA: Essential Criteria of a Disease
1. Characteristic signs or symptoms 2. Impairment in the normal functioning of some aspect of the body 3. Results in harm or morbidity
American Medical Association (AMA), Report 4 of the Council on Scientific Affairs (A-05). Recommendations for Physician and Community Collaboration on the Management of Obesity (Resolution 421, A-04), 2005
Available at: http://www.ama-assn.org/resources/doc/csaph/a05csa4-fulltext.pdf
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BMI = weight (kg)/height (m2)*
Normal weight BMI 18.5-24.9
Overweight BMI 25.0-29.9
Obesity class 1 BMI 30.0-34.9
Obesity class 2 BMI 35.0-39.9 Obesity class 3 BMI ≥40.0 (severe)
*World Health Organization defines overweight as BMI ≥25 kg/m2 and obese as BMI ≥30 kg/m2. http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed August 14, 2013.
Medical Complications of Obesity
Other BioMechanical Complications Obesity Complications Sleep Depression Apnea Dyslipidemia Hypertension Osteoarthritis
Prediabetic States Cancer Stress NAFLD PCOS Incontinence Diabetes GERD
Gallbladder CVD Dismobility/ Disease Disability Cardiometabolic Disease PCOS: Polycystic ovary syndrome; NAFLD: Non-alcoholic fatty liver disease Daniel S, Soleymani T, Garvey WT. Curr Opin Endocrinol Diabetes Obes, 20:377‐388, 2013
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Fat Tissue Inflammation
ABNORMAL LIPIDS in BLOOD SECRETION OF Dyslipidemia ADIPOCYTE FACTORS Central Adiposity
BLOOD VESSEL Hypertension Atherosclerosis
MUSCLE Insulin resistance Glucose intolerance Garvey WT, 2013
Insulin Resistance/Adipocyte Size Dysfibrinolysis • Free Fatty Acids • PAI-1 • Leptin • Adiponectin Vascular Reactivity • Resistin • Free Fatty Acids • Angiotensinogen (RAAS) • Inflammation
Lipids/Lipoproteins Inflammation • Acylation Stimulation Protein • TNF alpha • Cholesterol Ester Transfer Protein • IL-1, IL-6, IL-8, IL-10 • Phospholipid Transfer Protein • MCP-1 • MIF
RAAS, renin–angiotensin–aldosterone system; TNF, tumor necrosis factor; IL, interleukin; MCP-1, monocyte chemotactic protein-1; MIF, macrophage migration inhibiting factor.
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Late-phase Insulin Secretion
First-phase Insulin Secretion
Insulin Sensitivity
Fasting Glucose Pre-diabetic State Overt Diabetes
WT Garvey, 2011.
The Spectrum of Cardiometabolic Disease
Type 2 Prediabetic States 1. Prediabetes Diabetes Insulin i. IFG Resistance ii. IGT 2. Metabolic Syndrome •Waist • blood pressure Cardiovascular • fasting glucose • Triglycerides Disease • HDL-cholesterol
Obesity
Garvey WT, 2013
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Environment Genetics ↑Energy Intake ↓Energy Expenditure
Excess fat storage
INSULIN SENSITIVE INSULIN RESISTANT Osteo‐ increased fat mass Inflammation in Fat Diabetes arthritis Metabolic Sleep Syndrome Apnea Prediabetes
NAFLD Disability
HTN Urinary BIOMECHANICAL CARDIOMETABOLIC CVD Incontinence Complications Complications
Adapted from Bray GA. Obesity (Silver Spring). 2013;21:893‐9. Domenica M. Rubino, MD.
Higher Cortical Hypothalamic Pathways Peripheral Signals Centers Arcuate Nucleus PVN, LHA, DMN Orexigenic GHRELIN MCH1R Pathway GSHR Y1R LEPTIN LepR NPY Y5R MCH AGRP BDNF NTRK2
CCK LepR MC4R GLP-1 GLPR1 POMC/ PEPTIDE YY CART αMSH Y2R AMYLIN 5HT2c Anorexigenic μ-OR INSULIN Pathway
Courtesy of Dr. W. Timothy Garvey, 2013.
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It is difficult for patients to maintain their weight loss over time. 0 -1 -2 CHO/Pro/Fat -3 65/15/20% -4 55/25/20%
weight loss (kg) -5 45/15/40% -6 35/25/40% -7 0 6 12 18 24
months
Sacks FS. et al. NEJM 2009;360(9) 859-873.
Weight Loss Equilibrium Weight Baseline weight 250 lbs Weight Gain
↑ Ghrelin Increased ↓ Leptin, PYY, Appetite CCK, Amylin ↓ Resting energy Decreased expenditure Energy Out ↑ Hunger Increased ↑ Calorie-dense Energy In food preferences Garvey WT, 2014
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Chronic Disease Model (ie, obesity, diabetes, asthma, hypertension, lupus, etc.)
Genetics Genetics
Complications/ DISEASE Disease Severity
Environment Environment
The Faces of Obesity Obesity is not a lifestyle choice Obese persons face discrimination in …. • EMPLOYMENT • COLLEGE ADMISSION • ROMANCE • MEDICAL CARE • INCOME •AIRLINE SEATING
• >90% of obese persons have attempted to lose weight1 • >50% are currently trying to lose weight1
1. Harris Interactive/HealthDay. Many Obese Americans Struggle With Stigma, Discrimination: Poll. August 2012. Available at: http://www.healthday.com/press/healthday-harris- obese-discrimination.html
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Treatment Modalities for Overweight and Obese Patients?
Treatment of Obesity Medications
Lifestyle Modification in the Treatment of Obesity: evidence‐based essentials
• Reduced calorie diet – 500 kcal energy deficit//day • Healthy meal plan (e.g., low carb, low fat, DASH, Mediterranean) • Very Low Calorie Diets • Use of meal replacements (at least once a day) • Behavioral intervention (education, motivational interviewing, portion control, resolve psychological problems, etc.) • Increase voluntary physical activity; reduce sedentary behavior • Aspects associated with success in the National Weight Control Registry – self monitoring, – lots of physical activity, – low levels of sedentary behavior, – healthy eating patterns
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Intensification of Lifestyle Therapies to Achieve Weight Loss Goals Lifestyle Therapy • Simple advice to lose weight in doctor’s office INTENSIFICATION • Internet programs or self-help Impart skills and behavior books change to • Advice from dietitian induce and • Structured programs maintain weight loss (Weight Watchers, YMCA, tele- communication) • Multidisciplinary structured programs • Physician-driven individualized structured programs
Mean Weight Change in the Diabetes Prevention Program
0 Placebo -2 Metformin
-4 Lifestyle
-6 Weight change (kg) change Weight -8 01234 Years from Randomization
The DPP Research Group. N Engl J Med. 2002;346:393-403.
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All Participants
Placebo (n=1082) 40 Metformin (n=1073) Lifestyle (n=1079) 30 Risk reduction 31% by metformin 20 58% by lifestyle
10 Cumulative incidence (%) incidence Cumulative 0 01234 Years from randomization
The DPP Research Group. N Engl J Med. 2002;346:393-403.
Long‐term Weight Loss Is Difficult to Maintain DPP Outcomes Study (N=2766)
031 2 475 6 8109 Years
DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus. 26 DPP Research Group. Lancet. 2009;374:1677-1686.
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Weight Loss Reduces Long‐term Incidence of Type 2 Diabetes DPP Outcomes Study (N=2766)
Placebo Metformin Lifestyle
031 2 475 6 8109 Years
DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus. DPP Research Group. Lancet. 2009;374:1677-1686.
Look AHEAD Trial (N=5145) 0
-1.1% -2 Diabetes support and education P<0.0001
-4 Intensive lifestyle intervention -4.7%
-6 weight (%) weight Retention at 4 years:
Reduction in initial -8 ILI = 94.1% DSE = 93.1%
-10 012 3 4 Years
ILI, intensive lifestyle intervention; DSE, diabetes support and education. Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.
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Look AHEAD Trial (N=5145)
At 1 year DSE ILI Weight loss (%) -0.7 -8.6 A1C (%) -0.14 -0.64* FPG (mg/dL) -7.2 -21.5*
% on diabetes medications 2.2 -7.8*
Systolic BP (mm Hg) -2.8 -6.8* Diastolic BP (mm Hg) -1.8 -3.0* LDL-C (mg/dL) -5.7 -5.2 HDL-C (mg/dL) 1.4 3.4* TG (mg/dL) -14.6 -30.3*
*P≤0.001, †P=0.01 vs customary support. BP, blood pressure; CV, cardiovascular; DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2DM, type 2 diabetes mellitus. Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383. Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.
Rationale for Using Medications
• Help patients who are struggling to achieve health benefits through weight loss. • Use as an adjunct to a lifestyle intervention program that includes a reduced calorie diet. • Addition of a weight‐loss medication consistently achieves greater weight loss than that achieved by the lifestyle intervention alone • Can help sustain weight loss. Obesity is a life‐long disease and requires long‐term treatment and follow‐up. • The ASBP, AACE and 2013 AHA/ACC/TOS Obesity Guidelines all advise use of medications for patients who have sufficient health risk, not for cosmetic reasons
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Obesity Medications: Prescribing Principles
• Indications: (i) BMI 25‐29.9 with at least one obesity related complication; (ii) BMI ≥ 30. • FDA “off‐ramp”: Discontinue medication if weight loss is <5% on maximal dose of drug after 12 weeks. • In the case of primary failure, can try another medication • Medications vary regarding efficacy, warnings, cautions, and side effect profile; this is important regarding individualization of therapy. • CVOTs pending • Additional data is required for optimal use of medications in long term treatment.
Agents Action Approval Previously available Phentermine • Sympathomimetic • 1959 Orlistat • GI lipase inhibitor • 1997 Recently Approved Phentermine/ • Sympathomimetic/Anticonvulsant • Approved, Topiramate ER (GABA receptor modulation?) Summer 2012
Lorcaserin • 5-HT2C serotonin receptor agonist • Approved, Summer 2012 NaltrexoneSR/ • Dopamine/noradrenaline reuptake • Approved, Bupropion SR inhibitor/Opioid receptor September 2014 antagonist Hopefully Available in Future (2014?) Liraglutide high • GLP-1 receptor agonist • Pending FDA dose (3 mg/day)) decision
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Decreased Appetite Arcuate Nucleus Paraventricular Nucleus
Phentermine GLP-1 R Higher Cortical POMC/ Centers μ-OR CART MC4R -MSH GABA? Dopamine/ NE reuptake 5-HT2C
Naltrexone Topiramate Lorcaserin Bupropion
Serotonergic Neurons MC4R, melanocortin 4 receptor. GABA, gamma-aminobutyric acid. POMC/CART, pro-opiomelanocortin/cocaine- and-amphetamine-regulated transcript. Courtesy of Dr. W. Timothy Garvey, 2013.
Approved by FDA 1998; 120 mg po tid with meals
Contraindications Pregnancy Malabsorption syndrome Cholestasis Warnings Drug interactions: cyclosporine, levothyroxine, warfarin Rare severe liver injury Oxalate renal stones Need to restrict dietary fat (<30% of calories) Need for daily vitamin (especially fat soluble) Risk of hypoglycemia with diabetes meds
US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Accessed August 7, 2014.
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Benefits of Medication Use: 4‐Year Randomized Controlled Trial of Orlistat as an Adjunct to Lifestyle for the Prevention of T2DM in Obese At‐risk Patients
0 “DPP-type” Placebo + lifestyle intervention –3 –3.0 kg P <0.001 Orlistat + –6 “DPP-type” intervention –9 Orlistat + lifestyle –5.8 kg
Change in Body Weight (kg) Weight Body in Change –12 0 52 104 156 208 Week
DPP=Diabetes Prevention Program. Torgerson JS et al. Diabetes Care. 2004;27(1):155–161.
Lorcaserin: Use in Clinical Practice Approved by FDA June 2012 10 mg po bid, schedule pending (IV)
Contraindications Pregnancy Warnings Coadministration with other serotonergic or antidopaminergic agents Valvular heart disease Cognitive impairment Psychiatric disorders (euphoria, suicidal thoughts, depression) Priapism Risk of hypoglycemia with diabetes meds
US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Accessed August 7, 2014.
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Lorcaserin 10 mg bid: BLOOM Study Weight Change Over Two Years
Smith SR et al. NEJM. 2010;363:245‐256.
Lorcaserin ─ BLOOM Study: Key Secondary Endpoints Endpoint Lorcaserin Placebo P value Waist circumference (cm) −6.8 −3.9 <0.001 SBP/DBP (mm Hg) −1.4/−1.1 −0.8/−0.6 0.04/0.01 Cholesterol (% Δ) Total −0.90 0.57 0.001 LDL 2.87 4.03 0.049 HDL 0.05 −0.21 0.72 Triglycerides (%) −6.15 −0.14 <0.001 HOMA‐IR −0.41 −0.17 <0.001 Safety HR (beats/min) −2.0 −1.6 0.049 Beck depression II −1.1 −0.9 0.26 Intention‐to‐Treat Analysis with LOCF Imputation HOMA‐IR, homeostasis model assessment of insulin resistance Smith SR et al. NEJM. 2010;363:245‐256.
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Lorcaserin: Adverse Events Reported by 5% or More in Any Group
Lorcaserin Placebo N (%) (N=3195) (N=3185) Headache 537 (16.8) 321 (10.1) Dizziness 270 (8.5) 122 (3.8) Nausea 264 (8.3) 170 (5.3) Constipation 186 (5.8) 125 (3.9) Fatigue 229 (7.2) 114 (3.6) Dry mouth 169 (5.3) 74 (2.3)
US FDA CDER Lorcaserin NDA 022529 May 2, 2014.
Phentermine/Topiramate ER: Use in Practice Approved by FDA in July 2012, schedule IV • Initiation X 2 weeks: phentermine 3.25mg/topiramate ER 23 mg • Treatment dose daily: phentermine 7.5 mg/topiramate ER 46 mg • Maximum dose daily: phentermine 15 mg/ topiramate ER 92 mg Contraindications Pregnancy, glaucoma, hyperthyroidism, MAOIs Warnings Fetal toxicity Increased heart rate Suicide and mood and sleep disorders Acute myopia and glaucoma Cognitive impairment Metabolic acidosis Creatinine elevations Hypoglycemia with diabetes medications US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA. Accessed August 7, 2014.
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Effect of Phentermine/Topiramate ER on Weight Loss in Obese Adults Over 2 Years: SEQUEL Study 0 ‐2 (kg) ‐4 loss ‐6 ‐8 weight ‐10 ‐12 mean
LS ‐14 ‐16 0 8 1216 20 24 28 32 3640 44 48 52 56 6064 68 72 76 80 8488 92 96 100 104 108 LOCF Weeks: Placebo n: 227 227 227 208 197 227 PHEN/TPM CR 7.5/46 n: 153 152 153 137 129 153 PHEN/TPM CR 15/92 n: 295 295 295 268 248 295 Placebo PHEN/TPM CR 7.5/46 PHEN/TPM CR 15/92
Garvey WT et al. Am J Clin Nutr. 2012;95(2):297‐308.
Phentermine/Topiramate ER Effect on Risk Factors: CONQUER Study
Phentermine 7.5 mg/ Topiramate Variable 46 mg ER Placebo P value Waist circumference (cm) ‐7.6 ‐2.4 <0.0001 Systolic BP (mm Hg) ‐4.7 ‐2.4 0.0008 Diastolic BP (mm Hg) ‐3.4 ‐2.7 0.1281 Triglycerides (%) ‐8.6 4.7 <0.0001 LDL–C (%) ‐3.7 ‐4.1 0.7391 HDL–C (%) 5.2 1.2 <0.0001 CRP (mg/L) ‐2.49 ‐0.79 <0.0001 Adiponectin (µg/mL) 1.40 0.33 <0.0001 Changes from baseline to week 56 in secondary endpoints Garvey WT et al. Am J Clin Nutr. 2012;95(2):297‐308.
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Phentermine/Topiramate ER: EQUIP and CONQUER ─ Most Commonly Reported Treatment Emergent Adverse Events Occurring More Commonly In Patients Receiving Medication
Adverse Event PHEN/TPM PHEN/TPM PHEN/TPM (%) (N=3749) Placebo ER Low ER Mid ER Top Paresthesia 1.9 4.2 13.7 19.9 Dry mouth 2.8 6.7 13.5 19.1 Constipation 6.1 7.9 15.1 16.1 Dysgeusia 1.1 1.3 7.4 9.4 Nasopharyngitis 8.0 12.5 10.6 9.4 Insomnia 4.7 5.0 5.8 9.4
US FDA CDER Phentermine/Topiramate ER (NDA) 022580 May 2, 2014.
Effect of Weight Loss Induced by Phentermine/Topiramate ER on the Prevention of Diabetes in Patients With Metabolic Syndrome and/or Prediabetes: SEQUEL Study
12 Placebo 11 PHEN/TPM ER 7.54/46 10 PHEN/TPM ER 15/92 9 8 Diabetes 7 2 Incidence
6 Type
5 of 4
Cumulative 3 Rate 2 1 0 04 12 20 28 36 44 52 60 68 76 84 92 100 108 Weeks Garvey WT et al. Diabetes Care. 2014;37:912‐921.
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Naltrexone ER/Bupropion ER: Use in Practice
Approved by FDA Sept 2014 Initiation: Begin with 1 pill each AM and escalate dose over 4 weeks to 2 pills bid Treatment: 2 pills bid, each containing 8 mg naltrexone/90 mg bupropion Contraindications Pregnancy Uncontrolled HTN Seizure disorder Chronic opioid use MAOIs Warnings Angle closure glaucoma Suicidal behavior/ideation Increased BP and HR Seizures Risk of hypoglycemia with diabetes medications Note: high fat meal increases blood levels
US FDA CDER. Naltrexone; Bupropion NDA 200063 Label. October 3, 2014.
Naltrexone SR/Bupropion SR: Observed Change in Body Weight Over 56 Weeks (COR‐I)
Weeks 0 4 8 12 16 20 24 28 32 36 4 0 44 48 52 56 0 ‐1 ‐1.3% Placebo ‐2 * (%)
* ‐3 * * Baseline ‐4 * *
From ‐5 * * * ‐6 * * * Naltrexone SR 16 * * Change * * * ‐5.6% * mg/bupropion SR ‐7 * 360 mg *
Weight ‐8 ‐6.1% Naltrexone SR 32 * * * * * * mg/bupropion SR ‐9 * * 360 mg ‐10
MITT, LOCF analysis Greenway F, et al. Lancet. 2010;376:595‐605.
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Naltrexone/Bupropion ER Effect on Risk Factors: COR‐I Study Variable Naltrexone/ Placebo P Value Bupropion ER 32/360 mg Waist (cm) ‐6.2 ‐2.5 < 0.0001
SBP (mm Hg) ‐0.1 ‐1.9 0.0008 DBP (mm Hg) 0 ‐0.9 0.0217 Pulse rate (bpm) 0.4 -1.0 < 0.05 TG (%) ‐12.7 ‐3.1 < 0.0001 LDL‐c (%) ‐2.0 ‐0.5 0.4838 HDL‐c (%) 8.0 0.8 < 0.0001 CRP (%) ‐29.0 ‐16.7 < 0.0076 Fasting insulin (%) ‐17.1 ‐4.6 < 0.0007 Changes from baseline to week 56 in secondary endpoints Greenway F, et al. Lancet. 2010;376:595-605.
Naltrexone/Bupropion ER: COR‐I Study ─ Most Commonly Reported Treatment‐ Emergent Adverse Events
Adverse Event (%) (N = Naltrexone/Bupropion 573) Placebo 32/360 mg Nausea 5.3 29.8 Headache 9.3 13.8 Constipation 6.1 7.9 Dizziness 2.6 9.4 Vomiting 2.5 9.8 Dry mouth 1.9 7.5 Hot flush 1.2 5.2
Greenway F, et al. Lancet. 2010;376:595-605. 48
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On the Horizon: Medications Considered for US Approval in 2014
Agents Site of Action Phase 3 Studies Approval/Phase
Liraglutide3,4 • GLP-1 receptor SCALE- • NDA submitted agonist Maintenance • Panel review in 2014 • 3 mg qd SCALE-Sleep Apnea SCALE-DM SCALE-Obesity and Pre-DM
Clinicaltrials.gov. http://clinicaltrials.gov/ct2/results?term=SCALE+liraglutide&Search=Search. Accessed August 7, 2014
Ability of Liraglutide 3 mg to Maintain and Promote Additional Weight Loss After Low‐calorie Diet: SCALE Maintenance Study
S Run-in Treatment period F Liraglutide: n = 207 n = 181 n = 156 n = 153 Placebo: n = 206 n = 168 n = 144 n = 141
6
4
2 99.6 ± 21.0 kg 0 Placebo
-2 -4 Liraglutide 3.0 -6 mg Change in Body Change in (%) Body Weight -8
-14 -10 -6-4-2 0 2 4 6 10 14 18 22 26 30 34 38 44 50 56 60 64 68 Time (weeks) Mean ± SD weight at run-in (week -12): 105.9 ± 22.1 kg F = follow‐up period; S = screening period. 50 Wadden TA et al. Int J Obes (Lond). 2013;37(11):1443–1451.
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Comparative Efficacy of Weight‐Loss Medications All data placebo‐subtracted, maximal dose, ITT‐LOCF, 1 year, unless otherwise indicated year
10 1
9 after
8 7 6 baseline
5 from
4
loss 3
2 1 weight
% 0 Phentermine/ Liraglutide* Naltrexone/ Lorcaserin Orlistat Phentermine Topiramate 3 mg Bupropion*
*Not approved for the treatment of obesity. Garvey WT. Endocr Pract. 2013;19(5):864‐874. Sep 6:1–31. Wadden TA et al. Int J Obes (Lond). 2013;37(11):1443‐1451.
Surgical Options
Gastric Restriction Metabolic Procedures Procedures
Laparoscopic Adjustable Laparoscopic Sleeve Roux‐en‐Y Gastric Gastric Band (LABG) Gastrectomy (LSG) Bypass (RYGB)
Gastric Plication Biliopancreatic Diversion 52
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Weight Regain After Bariatric Surgery SOS Study: Mean Percent Weight Over 15 Years
0 Control
‐10 Banding (%)
Vertical‐banded Weight ‐20
in gastroplasty
Gastric bypass Change ‐30
0 1 2 3 4 6 8 10 15 No. patients Years Control 2037 1768 1660 1553 1490 1281 982 886 190 Banding 376 363 357 328 333 298 267 237 52 Vertical-banded gastroplasty 1369 1298 1244 1121 1086 1004 899 746 108 Gastric bypass 265 245 245 211 209 166 92 58 10
SOS, Swedish obese subjects. Reprinted with permission from Massachusetts Medical Society. Sjostrom L, et al. N Engl J Med. 2007;357:741-752.
Bariatric Surgery Reduces Mortality in Severely Obese Patients Swedish Obese Subjects Study (N=4047) Fatal CV Events Total CV Events Control (49 events) Control (49 events) Surgery (28 events) Surgery (28 events) 0.035 HR, 0.56; 95% CI, 0.35‐0.88; Log‐ 0.16 HR, 0.83; 95% CI, 0.69‐1.00; Log‐ rank P = 0.01 rank P = 0.05 0.030 0.14 0.025 0.12 0.10 incidence incidence
0.020 0.08 0.015 0.06 0.010 0.04 Cumulative Cumulative 0.005 0.02 0 0 0 6 12 18 0 6 12 18 No. at risk Years Years Control 2037 1993 1423 405 2037 1945 1326 361 Surgery 2010 1970 1557 412 2010 1921 1468 375
BMI entry criteria: ≥34 kg/m2 men, ≥38 kg/m2 women. 54 Sjostrom L, et al. JAMA. 2012;307:56‐65.
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Dr. Garvey, are you nuts? 35% of America is obese and another 35% is overweight. We can’t pay for treatment for all these folks? We will go broke !!!
How Do We Use Available Treatment Modalities for Overweight and Obese Patients?
• Balance efficacy, safety, and cost Treatment of Obesity
• Optimize benefit: risk ratio
• Achieve best outcomes
• Cost-effectiveness of care Medications
56
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NHLBI Obesity Treatment Guidelines
A Guide to Selecting Treatment BMI Category Treatment 25–26.9 27–29.9 30–34.9 35–39.9 ≥40
Diet, physical Appropriate activity, and NHLBI behavior Guidelines ++++
With Pharmacotherapy No comorbidities +++
No With Surgery* No No LAGB only comorbidities +
*Bariatric surgeries require lifestyle medical follow‐up. ⱡFDA approved gastric band surgery for patients with BMI ≥30 and one weight related medical condition (February 2011). LAGB, laparoscopic adjustable gastric banding Pi‐Sunyer FX, et al. Available at http://www.nhlbi.nih.gov/guidelines/obesity/ob_gdlns.htm
AACE Complication‐Centric Model for Care of the Overweight/Obese Patient
Garber AJ et al. Endocr Pract. 2013;19:327‐336.
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Therapeutic Weight Loss OBESITY % weight loss required COMPLICATION for therapeutic benefit Notes References
Diabetes Prevention 3% to 10% Maximum benefit 10% DPP (Lancet, 2009) SEQUEL (Garvey et al, 2013) Hypertension 5% to >15% BP still decreasing >15% Look AHEAD (Wing, 2011)
TG still decreasing at >15% Look AHEAD (Wing, 2011) Dyslipidemia 3% to >15%
HbA1c still decreasing at Look AHEAD (Wing, 2011) HbA1c 3% to >15% >15% Improves steatosis, Assy et al, 2007; inflammation, mild fibrosis Dixon et at, 2004; NAFLD 10% Anish et al, 2009
Little benefit at ≤ 5% Sleep AHEAD (Foster, 2009) Sleep Apnea (AHI) 10% Winslow et al, 2012
Improves symptoms and Christensen et al, 2007 Osteoarthritis 5-10% joint stress mechanics Felson et al, 1992; Aaboe et al, 2011
Burgio et al, 2007 Stress Incontinence 5-10% Leslee et al, 2009 5-10% women Singh et al, 2013 GERD Tutujian R, 2011 10% men 5-15% (>10% Lowers androgens, Panidis D et al, 2008 PCOS improves ovulation, Norman et al, 2002 optimal) increases insulin sensitivity Moran et al, 2013
The Spectrum of Cardiometabolic Disease
Type 2 Prediabetic States 1. Prediabetes Diabetes Insulin i. IFG Resistance ii. IGT 2. Metabolic Syndrome •Waist • blood pressure Cardiovascular • fasting glucose • Triglycerides Disease • HDL-cholesterol
Obesity
Garvey WT, 2013
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Prevalence of Metabolically Healthy Obese vs. Insulin Resistant Obese as a Function of Weight Class
Men Women (%) (%)
100 100 90 90 78.9 80 70.8* 80 69.9 64.6* 70 70 57.0 60 48.8 51.2* 60 50 50 43.0* 35.4 40 30.1 29.2 40
Prevalence 30 Prevalence 30 21.1 20 20 10 10 0 0 Normal Overweight Obese Normal Overweight Obese Weight Weight Metabolically healthy Metabolically abnormal
Wildman RP et al. Arch Intern Med. 2008;168(15):1617–1624.
Insulin Resistance Is a More Important Contributor than Obesity to Cardiovascular Risk
BMI Metabolic Status Status N 1 Overweight Normal 120 0.95 Obese Normal 77 0.9 Normal Normal 132 Patients
MACE
0.85
of Obese Dysmetabolic 250
0.8 Overweight Dysmetabolic 149 From
0.75 Normal Dysmetabolic 52 Free 0.7 Proportion 0.65 0.6 1 Year 2 Year 3 Year
MACE = death, nonfatal MI, stroke, congestive heart failure. Kip KE et al. Circulation. 2004;109(6):706–713.
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Approaches for Staging Cardiometabolic Disease Risk in Obesity Clinically identifiable Risk States • Prediabetes1 • Metabolic Syndrome2 Indices • Framingham Risk Score3 • Reynolds Risk Score4 • ADA Diabetes Risk Score5 Commercial Diagnostic Products • PreDX® (Tethys Bioscience)6 • LP‐IR score® (Liposcience)7 • Quantose IR (Metabolon) Clinical Staging Paradigms • Edmonton Obesity Staging System (EOSS)8 • Cardiometabolic Disease Staging (CMDS)9
1. Diabetes Care. 2013;36 Suppl 1:S67‐74. 2. Circulation. 2009;120(16):1640‐1645. 3. Circulation. 2008;117(6):743‐753. 4. JAMA. 2007;297(6):611‐619. 5. Diabetes Care 2003;26(3):725‐731 6. PloS one. 2011;6(7):e22863. 7. Metab Syndr Relat Disord. 2012;10(4):244‐251. 8. Int J Obes 33:289, 2009. 9. Endocr Pract 2013, abstract, In Press
Cardiometabolic Disease Staging (CMDS) 8 Stage Criteria Rationale 0 No Risk Factors Healthy Obese 1 1 1or 2 Risk Factors Metabolic Syndrome has low sensitivity (waist, blood pressure, for CMD, and 1 or 2 risk factors elevates triglycerides, HDL‐c) risk of future T2DM and CVD 2,3 2 Metabolic Syndrome OR Both Metabolic Syndrome and Prediabetes Prediabetes confer increased risk of (i) Metabolic Syndrome alone, T2DM and CVD 3,4 OR (ii) IFG, OR (iii) IGT 3 Metabolic Syndrome plus Risk of future T2DM is double in Prediabetes patients with both Metabolic Syndrome 2or more out of 3: Metabolic and Prediabetes compared with either Syndrome, IFG, IGT alone 3‐6 4 End‐Stage Cardiometabolic T2DM is CVD risk equivalent 7 Disease Type 2 Diabetes and/or CVD
1. Wildman, Arch Intern Med 168:1617, 2008. 2. Liao, Diabetes Care 27:978, 2004. 3. Wilson, Circulation 112: 3066, 2005. 4. Lakka JAMA. 2002;288:2709, 2002. 5. Lorenzo, Diabetes Care 26:3153, 2003. 6. De Vegt JAMA 285:2109, 2001. 7. Haffner, N Engl J Med 339:229, 1998. 8. Guo F, Moellering DR, Garvey WT, Obesity, In Press, 2013
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Cumulative Diabetes Incidence as a Function of Increasing CMDS Risk Stage: CARDIA Study Cohort
50 Stage 0, Metabolically healthy Stage 1 Stage 2 40 Stage 3
30
20
10 Cumulative diabetes incidence (%) Cumulative diabetes
0
0 2 46810 12 Guo F, Moellering DR, Garvey WT. Follow-up time (years) Obesity, In Press, 2013
Survival Probability as a Function of Increasing CMDS Risk Stage: NHANES
1.0
0.9
0.8
0.7 Stage 0, Metabolically healthy Stage 1 Stage 2 0.6 Stage 3 Survival Probability Stage 4
0.5
0 40 80 120 160 200 Follow-up time (month)
Guo F, Moellering DR, Garvey WT. Obesity, In Press, 2013
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Pre‐diabetes Algorithm*: AACE Comprehensive Diabetes Algorithms
*No drugs are currently approved for the treatment of pre‐diabetes. Garber AJ et al. Endocr Pract. 2013;19(2):327–336.
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Spectrum of Obesity Guidelines BMI Centric Complications‐Centric 1. Treatment indications based on 1. Treatment indications based on risk, BMI presence, and severity of obesity 2. Goal of therapy is to lose a given related complications amount of weight (e.g., 5‐10%) 2. Goal of therapy is to treat or prevent the complication
NHLBI AHA/ACC/TOS ASBP AACE
More aggressive treatments All patients treated who targeted to those patients who meet BMI criteria will derive highest benefit
Low benefit/risk High benefit/risk
Low cost effectiveness High cost effectiveness
Garvey WT, 2014
Paradox
We have more effective tools to treat obesity than ever before, Yet: • Overweight, Obesity, and the resulting suffering and social costs of the disease are mounting • There is limited availability and access to many effective therapies
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AACE Consensus Conference on Obesity Building an Evidence Base for Comprehensive Action March 23‐24, 2014 Washington, DC Four Pillars 5 Questions 1. What is obesity? Concerted Action Plan 2. What options are available for for Obesity obesity management? 3. What is the optimal use of therapeutic modalities? 4. Can the optimal framework be cost‐effective? 5. What are the knowledge gaps and how can they be filled?
Biomedical Government/ Healthcare Organizations/ Regulatory Industry Research/ Education
AACE Consensus Conference on Obesity. https://www.aace.com/sites/all/files/consensus/obesity/slides/Dr-W-Timothy-Garveys-Welcome.pdf. Accessed October 7, 2014.
AACE Consensus Conference on Obesity Comprehensive Plan for Treatment/Prevention of Obesity
Primary • Prevent obesity
Secondary • Treat obesity to prevent disease complications
Tertiary • Treat obesity to ameliorate disease complications
Garvey WT, et al. Endocr Pract. 2014;20:977-989.
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AACE Consensus Conference on Obesity: Diagnosis Must Integrate 2 Components
Indication of DIAGNOSIS BMI the Impact on Health
Anthropo‐ Presence and DIAGNOSIS metric Severity of Measure of Obesity‐ Adiposity related Complications
Garvey WT, et al. Endocr Pract. 2014;20:977-989.
Advanced Framework for a New Diagnosis of Obesity as a Chronic Disease DIAGNOSIS ANTHROPO‐ CLINICAL Prevention/ METRIC COMPONENT Treatment COMPONENT Normal BMI < 25 Primary Overweight BMI 25‐29.9 No obesity Related Complications Obesity BMI ≥ 30 No obesity Related Secondary Complications
Obesity BMI ≥ 25 Presence of one or more Stage 1 mild‐moderate obesity related complications Tertiary Obesity BMI ≥ 25 Presence of one or more Stage 2 severe obesity related complications Garvey WT et al. AACE/ACE Advanced Framework for a New Diagnosis of Obesity. Endocrine Practice, In Press, 2014
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Garvey WT, et al. Endocr Pract. 2014;20:977-989.
Obesity Management: Intensity Based on Disease Severity
Chronic Primary Secondary Tertiary Disease Treatment/ Treatment/ Treatment/ Management Prevention Prevention Prevention
Garvey WT, et al. Endocr Pract. 2014;20:977-989.
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Rationale for a Complications‐Centric Model as opposed to decisions based primarily on BMI level 1.Nearly 70% of American Adults are overweight or obese, and it is not safe or fiscally feasible to treat everyone with medications or surgery. 2.Risk staging and assessment of obesity‐related complications (presence and severity) can identify those patients who will most benefit from weight loss therapy 3.Emphasize medical rather than cosmetic outcome because medications +lifestyle often achieve ~10% weight loss. 4.10% weight loss is sufficient to improve insulin sensitivity, glucose homeostasis, lipid levels, blood pressure, diabetes prevention, CVD risk factors, and glucose & blood pressure control in T2DM. 5.Benefit/risk and cost effectiveness are increased when medical and surgical interventions are targeted to obese patients with complications. 6.Optimal benefit / risk occurs when weight loss is used as a tool to treat the complications of obesity.
THANK YOU
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RESERVE SLIDES
Liraglutide Dose‐Response Effect on Body Weight Over 20 Weeks: Nondiabetic Obese Adults
0
–1
–2
–3
–4 Weeks
–5
Screening Orlistat –6 Randomization Liraglutide 1.2 mg
Mean Weight Loss (kg) Mean Weight –7 Liraglutide 1.8 mg Liraglutide 2.4 mg –8 Liraglutide 3.0 mg –9 –5 –3 0 5 10 15 20 Weeks Astrup A et al. Lancet. 2009;374(9701):1606–1616.
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New Obesity Diagnosis: Staging for Cardiometabolic Disease ATP III Risk Factors Evaluated: Waist, BP, HDL, TG, Fasting Glucose STAGE CRITERIA
Stage 0 No Risk Factors
Stage 1 1 or 2 risk factors
• Metabolic Syndrome Stage 2 • Prediabetes • Type 2 Diabetes
Obesity Diagnosis: Staging of Diabetes Risk: 10 year incident diabetes in the ARIC study
35
Stage 0 Advanced Framework 28 Stage 1 Obesity Diagnosis 2
Stage 2 Obesity
21
Stage 14
Diabetes (%) 1
7
0 0
0 4 8121620 Follow up (Year)
Guo F and Garvey WT, unpublished data, 2014.
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The 2013 TOS/AHA/ACC 1. Evaluation: BMI ≥25 Guidelines 2. Treat complications up front “regardless of weight loss efforts” Include a 3. Assess lifestyle choices and Treatment readiness to change, and set weight‐ Algorithm loss goals with patient 4. Comprehensive lifestyle intervention with goal of 5‐10% weight loss 5. If weight loss is not ≥5%, add The Chronic medications Care Model 6. Consider bariatric surgery 7. Long‐term follow‐up of Weight Management by PCPs
Prediabetes Algorithm
FPG, fasting plasma glucose; GLP-1 RA, long-acting glucagon-like peptide 1 receptor agonist; PG, plasma glucose; TZD, thiazolidinedione. Reprinted with permission from American Association of Clinical Endocrinologists. Garber AJ, et al. Endocr Pract. 2013;19:327-336.
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Glycemic Control Algorithm
Reprinted with permission from American Association of Clinical Endocrinologists. Garber AJ, et al. Endocr Pract. 2013;19:327-336.
CMDS Predicts T2DM Independent of BMI in CARDIA
Risk level Hazard ratio
Stage 3 21.9 (11.2-43.0)
Stage 2 9.73 (5.17-18.3)
Stage 1 Model 1 3.32 (1.80-6.15) Metabolically No Adjustment for BMI Healthy 1[Reference]
01020304050
Risk level Hazard ratio Stage 3 11.7 (5.69-24.2)
Stage 2 6.10 (3.14-11.9)
Stage 1 2.38 (1.26-4.50) Model 2 Metabolically Healthy Adjustment for BMI 1[Reference]
0 5 10 15 20 25 30
Guo F, Moellering DR, Garvey WT. Obesity, In Press, 2013 Hazard ratio
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Improvements in Sleep Apnea (Apnea/Hypopnea Index) with Phentermine/Topiramate ER Therapy
Change in Apnea/Hypopnea Index Change in Body Weight
Winslow DH et al, Sleep, 35:1529, 2012
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