Etiology and Diagnosis of Obesity

OBESITY IS A DISEASE 

1

More than Two Thirds of US Adults Are Overweight or Obese

2

since 1962

1.7-foldincrease

in obesity since 1962

NHANES DataU.S. Adults Age ≥20 Years

(Crude Estimate)

BMI, body mass index (in kg/m2); NHANES, National Health and Nutrition Examination Survey (x-axis lists last year of each survey).Flegal KM, et al. Int J Obes Relat Metab Disord. 1998;22:39-47; Flegal KM, et al. JAMA. 2002;288:1723-1727; Flegal KM, et al. JAMA. 2010;303:235-241; Flegal KM, et al. JAMA. 2012;307:491-497. Ogden CL, et al. JAMA. 2014;311:806-814.

BMI ≥30BMI 25-29

The Increase in Diabetes Parallels the Increase in Obesity in the United States

3

*BMI ≥30 kg/m2.CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014.Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283; Ogden CL, et al. JAMA. 2014;311:806-814.

Obesity* Diabetes

96% increase

43% increase

Popu

latio

n (%

)

Women Men

Increased abdominal adiposity is highly correlated with insulin resistance and type 2 diabetes

BMI (kg/m2)<21 22 23 24 25 26 27 28 29 30

6

5

3

2

1

0

4

Rel

ativ

e R

isk

Type 2 diabetes Hypertension Cholelithiasis Coronary heart disease

The Risk of Chronic Conditions Increases With BMI

BMI (kg/m2)

6

5

3

2

1

0

4

<21 22 23 24 25 26 27 28 29 30

BMI, body mass index.Willett WC, et al. N Engl J Med. 1999;341:427‐434. Carey VJ, et al. Am J Epidemiol. 1997;145:614‐619. 4

All‐Cause Mortality Increases with BMI

5

National Institutes of Health AARP Cohort Study, 1996‐2009

(N=109,947 Never‐Smokers)

Mul

tivar

iate

haz

ard

ratio

*

*Regression analyses adjusted for age, race/ethnicity, education, leisure‐time physical activity, and alcohol consumption.

Adams KF, et al. Am J Epidemiol. 2014;179:135‐144.

(Referent)

P<0.0005 for linear trend

Body mass index(kg/m2)

Medical Complications of Obesity 

ObesityObesity

NAFLD

Cardiovascular DiseaseCardiovascular Disease

Dismotility/disabilityGERD

Lung functiondefects

Osteoarthritis

Sleep apnea

Urinaryincontinence

Prediabetic states

HypertensionDyslipidemia

PCOS

DiabetesDiabetes

CardiometabolicCardiometabolicBiomechanicalBiomechanical OtherOther

GERD, gastroesophageal reflux disease; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome. 6

Androgen deficiencyCancer

Gallbladder disease

Psychologicaldisorders

Link Between Obesity, Inflammation, and Poor Outcomes

7

Obesity

Inflammation

Insulin resistance

Type 2 diabetes

Cardiovascular disease

Cancer Alteredimmune function

Mortality

Obesity‐Related Illness Accounts forOne‐Fifth of U.S. Healthcare Costs

8

Total$923.2 billion

Obesity$190.2 billion

20.6% of total costs

1. Cawley J, Meyerhoefer C. J Health Econ. 2012;31:219-230.2. ADA. Diabetes Care. 2013; March 6 epub before print.

Obesity Costs1U.S. Adults Age ≥18 Years

Total$1,333 billion

Diabetes$176 billion

13.0% of total costs

Diabetes Costs2U.S. Residents, All Ages

Obesity Has Multiple Pathophysiologic Origins

9

Genetic

• Monogenic syndromes• Large subsets of at‐risk alleles, which together enhance aggregate obesity risk

• Polygenetic determinants of adiposity on metabolism, insulin resistance, and glucose tolerance

Environmental

• Limited availability of fresh food

• Environmental endocrine disruptors

• Sociocultural attitudes and customs

Behavioral

• Poor health literacy or decision‐making

• Diet preferences• Sedentary lifestyle• Food‐seeking behavior related to psychological conditions (depression, anxiety, etc)

AMA, American Medical Association.Mechanick JI, et al. Endocr Pract. 2012;18:642-648.

Energy intake

Ingestion of:

Proteins

Fats

Carbohydrates

Energy expenditure

Physical activity

Diet-induced thermogenesis

Basal metabolic rate

Body Weight

Increase

Energy Homeostasis

10

Decrease

Effect of Diet Changes onMetabolic Rate

11

Each box encloses the data from the second and third quartiles and is bisected by a line at the value for the median. The tips of vertical lines indicate the minimum and maximum values

BMR, basal metabolic rate.

Dulloo AG, et al. Obes Rev. 2012;13(suppl 2):105-121.

Minnesota ExperimentHealthy Men

Week 12(n=32)

Week 24(n=32)

Week 12(n=32)

Week 16(n=12)

Week 20(n=12)

Semi-starvation RefeedingRestricted Ad libitum Post-refeeding

hyperphagia

A

djus

ted

BM

R(%

con

trol

per

iod)

Neural Signaling: Peripheral and Central Regulation of Energy Intake

12

AGRP, agouti‐related peptide; CART, cocaine‐ and amphetamine‐regulated transcript; CCK, cholecystokinin; GLP‐1 glucagon‐like peptide 1; LH, lateral hypothalamus; NPY, neuropeptide Y; POMC, proopiomelanocortin; PVN, paraventricular nucleus;PYY, peptide YY.Morton GJ, Schwartz MW. Physiol Rev. 2011;91:389‐411; Sumithran P, Proietto J. Clin Sci (Lond). 2013;124:231‐241.

Hypothalamus

Ghrelin

CCKPYYGLP‐1

Leptin

Insulin

Amylin

Peripheral Signals

Arcuate nucleus Y1RY5R

MC4R

MSH

AGRP

NPY

PVN, LH

IntakeHigher cortical 

centers Intake

POMC/CART NeuronsAnorexigenic =  food intake• Stimulated by leptin and other 

appetite‐suppressing signals

NPY/AGRP NeuronsOrexigenic =  food intake• Stimulated by ghrelin• Inhibited by leptin

Obesity‐Related Impairments in Hormonal Regulation of Appetite and Energy Balance

Hormone Source Normal function Alteration

Cholecystokinin (CCK)

Duodenum Suppress appetite Levels decrease during dieting and weight loss

Glucose‐dependent insulinotropic polypeptide (GIP)

Duodenum, jejunum

Energy storage Levels increase during dieting and weight loss

Ghrelin Gastric fundus Stimulate appetite, particularly for high‐fat, high‐sugar  foods

Levels increase during dieting and weight loss

Glucagon‐like peptide 1 (GLP‐1)

Ileum Suppress appetite and increase satiety

Decreased functionality

Insulin Pancreas Regulate energy balanceSignal satiety to brain

Insulin resistance in obese personsReduced insulin levels after dieting

Leptin Adipocytes Regulate energy balanceSuppress appetite 

Levels decrease during weight loss

Peptide YY (PYY) Distal small intestine

Suppress appetite Levels decreased in obese persons

13Sumithran P, Proietto J. Clin Sci (Lond). 2013;124:231‐241.

Key Hormone Changes Associated with Weight Gain and Regain

Assessing Obesity in Clinical Practice

Body Mass Index• PQRI measure

– Overweight: ≥25 to <30 kg/m2

– Obese: ≥30 kg/m2

• Calculated by dividing weight by the square of height (kg/m2)– Free BMI calculator available 

from the National Heart, Lung, and Blood Institute

Waist Circumference• Marker of high risk*

– Men >40 inches– Women >35 inches 

• Indirect measure of central adiposity, correlated with visceral fat

• Excess abdominal fat is an independent predictor of risk factors and morbidity

14

*WHO waist circumference cutoff varies by race/ethnicity.

NHLBI, National Heart, Lung, and Blood Institute; PQRI, Physician Quality Reporting Initiative; WHO, World Health Organization.

NHLBI. Obesity guidelines. Obesity Res. 1998;6(suppl2):51S‐209S. NHLBI BMI calculator. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/BMI/bmicalc.htm.

Limitations of BMI

Insensitive to small changes in weight Does not distinguish between high weights due to excess body

fat, large muscle mass or edema Does not reveal differences in fat distribution (visceral vs.

subcutaneous) Does not differentiate between men and women Is not accurate when height is compromised (kyphosis, scoliosis) Clinical judgment needed (frail elderly, etc.)

Clinical Tools:Measuring Waist Circumference

• Locate upper hip bone and top of right iliac crest

• Place measuring tape around abdomen at level of iliac crest, keeping it parallel to the floor

• Ensure tape is snug but not compressing the skin

16NHLBI Obesity Education Initiative. Obesity in adults. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf.

NHLBI Classification of Weight, Waist Circumference, and Disease Risk

ClassificationBMI

(kg/m2)

Disease Risk*

Men WC ≤40 inWomen WC ≤35 in

Men WC >40 inWomen WC >35 in

Underweight <18.5

Normal 18.5 – 24.9

Overweight 25.0‐29.9 Increased High

Obesity Class I 30.0‐34.9 High Very high

Obesity Class II 35.0‐39.9 Very high Very high

Obesity Class III ≥40 Extremely high Extremely high

*Type 2 diabetes, hypertension, and cardiovascular disease.

17

BMI, body mass index; NHLBI, National Heart, Lung, and Blood Institute; WC, waist circumference.

NHLBI Obesity Education Initiative. Obesity in adults. Available at: http://www.nhlbi.nih.gov/guidelines/obesity/prctgd_c.pdf.

Obesity‐Focused History

18

Life Events and Weight Gain• Recap of patient life events that 

coincided with weight gain, such as smoking cessation, medication initiation, pregnancy or menopause, job loss, change in marital status, etc

Diet and Activity• Extent of daily physical activity• Sleep habits and difficulties• Food preferences and 

frequency/quantity of meals• Psychological assessment

– Mood/anxiety disorders, ADD, PTSD– Eating disorders

A detailed obesity history enables development of tailored treatment 

recommendations to address individual patient needs

Weight Loss Readiness• Motivation and social support• Psychiatric status• Presence of stressful life circumstances• Time constraints• Goals and expectations

Kushner RF. Circulation. 2012;126:2870-2877.

Review of Systems• Checklist of obesity‐related 

complications

Medical History

Elicit risk factors and symptoms of the manifestations of obesity:

• Dysmetabolic syndrome• Type 2 diabetes• Cardiovascular disease (and angina)• Sleep apnea• Gallstones• Potential Pregnancy

Medical Causes of Obesity

• Hypothyroidism (???YH)• Cushing's syndrome• Depression (Beck’s depression inventory)

Beck AT. The Beck Depression Inventory. San Antonio, TX: The Psychological Corporation; 1987.Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Inventory: Twenty-five years of evaluation. Clin Psychol Rev. 1988;8:77-100.

Selected Medications That Can Cause Weight Gain

• Psychotropic medications

– Tricyclic antidepressants

– Monoamine oxidase

inhibitors

– Specific SSRIs

– Atypical antipsychotics

– Lithium

– Specific anticonvulsants• -adrenergic receptor blockers

clozapine (Clozaril) 4.4 kg gain*olanzapine (Zyprexa) 4.2 kg*

risperidone (Resperdal) 2.1 kg*Paxil, Prozac

*Allison DB et al. Am J Psychiatry 1999 Nov;156(11):1686-96

Selected Medications That Can Cause Weight Gain Diabetes medications

– Insulin– Sulfonylureas– Thiazolidinediones

Highly active antiretroviral therapy

Tamoxifen

Steroid hormones– Glucocorticoids– Progestational steroids

Psychiatric History

• Comfort Eating (in response to negative emotions)• Boredom• Sadness and Depression • Anger

• Anorexia• Bulimia• Binge eating • Addictions: Smoking

Exercise History

• Exercise habits• Physical activity patterns• Limitations• Preferences

Family and Social Histories

• Identify support networks and cultural factors – May influence the patient’s ability to participate in a

weight management program• Other household members with obesity

– May impact the ability for the patient to modify his or her lifestyle and diet.

• Dietary changes– Easier to implement if the other members of the family

also adopt healthier nutrition habits.

Checklist of Obesity Related Complications

26

Complication Initial method of identification Secondary testing

Metabolic syndrome Waist circumference, BP, HDL‐C, TG, FPG CVD screen

Prediabetes FPG 2‐h OGTT, CVD screen

Type 2 diabetes FPG2‐h OGTT or A1C, Screen for CVD and microvascular complications

Dyslipidemia Fasting TG and HDL‐C with lipidpanel Lipoprotein subclasses

Hypertension Sitting systolic and diastolic BP Ambulatory BP, screen for hypertension complications

NAFLD Liver exam, liver function tests Imaging, liver biopsy

PCOS Physical exam, ROS Hormone testing

(continued next slide)

BP, blood pressure; CVD, cardiovascular disease; FPG, fasting plasma glucose; HDL-C, high density lipoprotein cholesterol; NAFLD, nonalcoholic fatty liver disease; OGTT, oral glucose tolerance test; PCOS, polycystic ovary syndrome; ROS, review of systems; TG, triglycerides.

Garvey TW, et al. Endocr Pract. 2014;20:977-989.

Checklist of Obesity Related Complications

27

(continued from previous slide)

ROS, review of systems.

Garvey TW, et al. Endocr Pract. 2014;20:977-989.

Complication Initial method of identification Secondary testing

Obstructive sleep apnea Physical exam, ROS Neck circumference, sleep study

Osteoarthritis Physical exam, ROS Radiographic imaging

Urinary stress incontinence Physical exam, ROS Urine culture, urodynamic testing

Gastroesophageal reflux disease (GERD) Physical exam, ROS Endoscopy, esophageal motility

Disability/immobility Exam, ROS Functional testing

Psychological disorder Exam, ROS Psychological testing

Secondary causes: genetic syndromes, hormonal disease, iatrogenic medications

Exam, ROS, medicalreview, family history Genetic or hormone testing

Small Amounts of Weight Gain or Loss Have Important Effects on CHD Risk

28

*Patients with Low HDL‐C, high cholesterol, high BMI, high systolic BP, high triglyceride, high glucose.**P <0.002 vs baseline.Wilson PW, et al. Arch Intern Med. 1999;159:1104‐1109.

Framingham Offspring Study 16-year Follow-up*Ch

ange in

 Risk Factor Sum

 (%)

****

****

Weight Loss ReducesLifetime Healthcare Costs

29Dall TM, et al. Am J Prev Med. 2011;40:338-344.

Projected Lifetime Healthcare ExpendituresObese Individuals <45 Years of Age

Cost offsets+ $23+ $930 +

$1700

-$357

-$4080

- $8100

5% Weight Lossfor 2 Years

Total Benefit$334

Permanent5% Weight Loss

Total Benefit$3150

Permanent10% Weight Loss

Total Benefit$6400

NIH Guide to Selecting Obesity Treatment

TreatmentBMI Category

25-26.9 27-29.9 30-34.9 35-39.9 >40

Lifestyle Therapy*

WithComorbid.

WithComorbid.

YES YES YES

Pharmacotherapy

With Comorbid.

YES YES YES

Surgery *Lap Band WithComorbid.

YES

*Lifestyle therapy: diet, physical activity, and behavioral therapy.•Consider pharmacotherapy only if a patient has not lost 1 pound per week after 6 months of combined lifestyle therapy.

LIFESTYLE IS THE FOUNDATION OF OBESITY MANAGEMENT

Pharmacologic and Surgical Management of Obesity

Components of Therapeutic Lifestyle Change

• Nutrition– Reduced calorie diet– Healthy eating

• Sufficient physical activity• Avoidance of tobacco products• Limited alcohol consumption• Sufficient sleep• Stress reduction (including behavioral therapy as necessary)

33Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

Nutrition

Topic Recommendation

General eating habits

Regular meals and snacks; avoid fasting to lose weight Plant‐based diet (high in fiber, low calories, low glycemic index, high in 

phytochemicals/antioxidants) Understand Nutrition Facts Label information Incorporate beliefs and culture into discussions Informal clinician‐patient discussions  Use mild cooking techniques instead of high‐heat cooking

Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1‐53.

Reduced Calorie Diet

A negative energy balance is necessary to achieve weight loss

Effect of Low‐Fat and Low‐Carbohydrate Diet on Weight Over 2 Years

Foster GD, et al. Ann Intern Med. 2010;153:147‐157.

Obese Adults(N=307)0

‐8

‐12

‐14

‐10

‐6

0 6 12

Weigh

t (kg)

Months

243

‐4

‐2Low‐fat dietLow‐carbohydrate diet

Adherence Is More Important Than Diet Type for Weight Loss Success

Dansinger M. JAMA. 2005;293:43‐53.

Weight Change byDiet Type

Weight Change byDietary Adherence

AACE Physical Activity Recommendations

Patients• ≥150  minutes per week of 

moderate‐intensity (ie, “conversational”) exercise – Flexibility and strength training– Aerobic exercise (eg, brisk walking)– Cross‐train– Heart rate to 70% maximum

(max HR = 220 – age)• Start slowly and build up 

gradually– Use exercise partners, organized 

activities, or professional trainer to help with motivation

Healthcare Professionals• Exude positive attitude• Evaluate for contraindications 

and/or limitations to increased physical activity before patient begins or intensifies exercise program

• Develop exercise recommendations according to individual goals and limitations– Set realistic goals and 

schedules

37Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

Long‐term Weight Loss Is Difficult to Maintain

38DPP, Diabetes Prevention Program; T2DM, type 2 diabetes mellitus.

DPP Research Group. Lancet. 2009;374:1677-1686.

10 32 54 76 8 109Years

DPP Outcomes Study(N=2766)

PHARMACOTHERAPIESPharmacologic and Surgical Management of Obesity

Lorcaserin

Indications

• Adjunct to diet and exercise in patients with– BMI ≥30 kg/m2

– BMI ≥27 kg/m2 with ≥1 weight‐related comorbidity

• Hypertension• T2DM• Dyslipidemia

• Schedule IV Controlled Substance

Dosing• 10 mg twice daily• Discontinue if 5% weight loss is 

not achieved within 12 weeks

DEA, Drug Enforcement Agency.Belviq prescribing information. Woodcliff Lake, NJ: Eisai Inc.; 2012.

See prescribing information for specific instructions

Mechanism of Action

• Specific 5‐HT2C (serotonin) receptor agonist

40

Lorcaserin: Summary of Warnings and Contraindications

Contraindications• Pregnancy

Warnings• Coadministration with other 

serotonergic or antidopaminergic agents has not been established

• Valvular heart disease• Cognitive impairment• Psychiatric disorders: 

euphoria, dissociation, suicidal thoughts, depression

• Priapism• Increased risk of hypoglycemia 

with antidiabetic medications

Belviq prescribing information. Woodcliff Lake, NJ: Eisai Inc.; 2012.

• Headache• Dizziness• Nausea

Adverse Effects

41

42

Effect of Lorcaserin on Body Weight in Obese Adults Over 2 Years

Smith SR, et al. N Engl J Med. 2010;363:245-256.

BLOOM Study

Effect of Lorcaserin on Progressionto T2DM

43

P=0.003

Patie

nts

with

A1C

≥6.

5% (

%)

Proportion of BLOOM and BLOSSOM PatientsWith Newly Diagnosed Diabetes After 52 Weeks of Treatment

Lorcaserin hydrochloride briefing document for FDA Advisory Committee. Woodcliff Lake, NJ: Eisai Inc.; 2012. Available at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM303200.pdf.

Effect of Lorcaserin on Cardiometabolic Risk Markers

Risk Factors(Mean % Weight Loss)

Lorcaserin 10 mg(5.8%) P value*

Systolic BP, mmHg ‐1.4 0.04

Diastolic BP, mmHg ‐1.1 0.01

Triglycerides, % ‐6.15 <0.001

Total cholesterol, %  ‐0.90 0.001

LDL‐C, % 2.87 0.049

HDL‐C, % 0.05 NS

hsCRP, mg/L ‐1.19 <0.001

Fibrinogen, mg/dL ‐21.5 0.001

*P values represent comparisons to placebo.Intent to treat, last observation carried forward analysis for total study population.Smith SR, et al. N Engl J Med. 2010;363:245-256.

BLOOM Study

44

Lorcaserin Adverse Events

Event occurring in ≥5% of patients and more frequently than with placebo, %

Lorcaserin 10 mg BID(N=3195)

Placebo(N=3185)

Headache 16.8 10.1Upper respiratory tract infection 13.7 12.3

Nasopharyngitis 13.0 12.0

Dizziness 8.5 3.8Nausea 8.3 5.3Fatigue 7.2 3.6Urinary tract infection 6.5 5.4

Diarrhea 6.5 5.6

Back pain 6.3 5.6

Constipation  5.8 3.9Dry mouth 5.3 2.3

Belviq (lorcaserin HCl) prescribing information. Woodcliff Lake, NJ: Eisai Inc.; 2012. 45

Phentermine/Topiramate ER 

Indications• Adjunct to diet and exercise in patients 

with– BMI ≥30 kg/m2

– BMI ≥27 kg/m2 with ≥1 weight‐related comorbidity

• Hypertension• T2DM• Dyslipidemia

Dosing• Once daily in morning

– Starting dose: phentermine 3.75/topiramate ER 23 mg for 14 days

– Usual dose:  7.5/46 mg– Maximum dose: 15/92 mg

• If <3% weight loss after 12 weeks on usual dose, either discontinue medication or advance to maximum dose (transition dose  phentermine 11.25 mg/topiramate ER 69 mg for 2 weeks)

• If <5% weight loss after 12 weeks on maximum dose, then discontinue the medication (to discontinue take every other day for one week)

Qsymia prescribing information. Mountain View, CA: Vivus, Inc.; 2012.

See prescribing information for specific titration and discontinuation instructions

Mechanism of Action• Central noradrenergic effects

– Phentermine: immediate‐release sympathomimetic—affects appetite

– Topiramate ER: delayed‐release gabanergic—affects satiety

46

Phentermine/Topiramate ER: Summary of Warnings and Contraindications

Contraindications• Pregnancy• Glaucoma• Hyperthyroidism• Treatment with monoamine 

oxidase inhibitors (MAOIs)

Warnings• Fetal toxicity• Increased heart rate• Suicide and mood and sleep 

disorders• Acute myopia and glaucoma• Metabolic acidosis• Creatinine elevations• Hypoglycemia with concomitant 

antidiabetic therapy

Qsymia prescribing information. Mountain View, CA: Vivus, Inc.; 2012.

• Dry mouth• Tingling• Constipation• Altered taste sensation• Upper respiratory infection

Adverse Effects

47

SEQUEL ExtensionSEQUEL ExtensionCONQUER TrialCONQUER Trial

Effect of Phentermine/Topiramate ER on Weight Loss in Obese Adults Over 2 Years

Data are shown with mean (95% CI).Phen/TPM ER, phentermine/topiramate extended release.Garvey WT, et al. Am J Clin Nutr. 2012;95(2):297-308.

SEQUEL Study(Completer Analysis)

Placebo Phen/TPM ER 7.5/46 Phen/TPM ER 15/92

LS m

ean

wei

ght l

oss

(%)

-2-4-6-8

-10-12-14-16

0 12 20 92

0

Weeks28 36 44 52 60 68 76 84 100 108 LOCF

Placebo n: 227 227 227 208 197 227Phen/TPM 7.5/46 n: 153 152 153 137 129 153Phen/TPM 15/92 n: 295 295 295 268 248 295

48

Effects of Phentermine/Topiramate ER on Glucose, Insulin, and Progression to T2DM

Glucose and Insulin

*P≤0.005 vs placebo.NS, not significant; Phen/TPM ER, phentermine/topiramate extended release; T2DM, type 2 diabetes mellitus.Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.

**

* *

*

Placebo Phen/TPM ER 7.5/46 mg Phen/TPM ER 15/92 mg

SEQUEL StudyAnnualized Incidence of T2DM

P=0.008

76%

P=NS

54%

49

Effect of Phentermine/Topiramate ER on Cardiometabolic Risk Markers

Risk Factors(Mean % Weight Loss)

Phentermine/ Topiramate ER7.5/46 mg(8.4%) P value*

Phentermine/Topiramate ER

15/92 mg(10.4%) P value*

Systolic BP, mmHg ‐4.7 0.0008 ‐5.6 <0.0001

Diastolic BP, mmHg ‐3.4 NS ‐3.8 0.0031

Triglycerides, % ‐8.6 <0.0001 ‐10.6 <0.0001

Total cholesterol, % ‐4.9 0.0345 ‐6.3 <0.0001

LDL‐C, % ‐3.7 NS ‐6.9 0.0069

HDL‐C, % 5.2 <0.0001 6.8 <0.0001

hsCRP, mg/L ‐2.49 <0.0001 ‐2.49 <0.0001

Adiponectin, g/mL 1.40 <0.0001 2.08 <0.0001

*P values represent comparisons to placebo.Intent to treat, last observation carried forward analysis for total study population.Gadde KM, et al. Lancet. 2011;377:1341-1352.

CONQUER Study

50

Selected Phentermine/Topiramate ER Adverse Events

Event occurring in ≥5% of patientsand more frequently than with placebo, %

Phentermine/Topiramate

Placebo(N=1561)

3.75 mg/23 mg(N=240)

7.5 mg/46 mg(N=498) 

15 mg/92 mg(N=1580) 

Paresthesia  4.2  13.7  19.9  1.9 Dry mouth  6.7  13.5  19.1  2.8 Constipation  7.9  15.1  16.1  6.1 Upper respiratory tract infection  15.8  12.2  13.5  12.8 Headache  10.4  7.0  10.6  9.3 Nasopharyngitis  12.5  10.6  9.4  8.0 

Dysgeusia  1.3  7.4  9.4  1.1 Insomnia  5.0  5.8  9.4  4.7 Dizziness  2.9  7.2  8.6  3.4 Sinusitis  7.5  6.8  7.8  6.3 Nausea  5.8  3.6  7.2  4.4 Back pain 5.4 5.6 6.6 5.1Fatigue  5.0  4.4  5.9  4.3 Diarrhea  5.0  6.4  5.6  4.9 Bronchitis  6.7  4.4  5.4  4.2 Vision blurred  6.3  4.0  5.4  3.5 Urinary tract infection  3.3  5.2  5.2  3.6 Influenza  7.5  4.6  4.4  4.4 

51Qsymia prescribing information. Mountain View, CA: Vivus, Inc.; 2012.

Bupropion/Naltrexone(Contrave)

• Bupropion stimulates hypothalamic pro‐opiomelanocortin neurons

• Naltrexone simultaneously blocks opiod‐mediated pro‐opiomelanocortin autoinhibition

• Both drugs may also have an additional mechanism of action by modulation of mesolimbic reward pathways. 

Greenway FL, Fujioka K, Plodkowski RA et al. Lancet. 2010; 376: 595-605

Bupropion/Naltrexone(Contrave)

• 56‐wk, randomized, double‐blind, placebo‐controlled study 

• 1742 patients 18‐65 years old• BMI 30‐45 or 27 and 29.9 with co‐mobidity• Top 3 adverse events:

– Dry Mouth– Paraesthesia– Dry mouth

Greenway FL, Fujioka K, Plodkowski RA et al. Lancet. 2010; 376: 595-605

Bupropion/Naltrexone(Contrave) Demographics at Baseline and Results

360/32mg Contrave Placebo

Age (years) 44.4 43.7

Sex (%female) 85 85

Weight (kg) 99.7 99.5

Waist (cm) 108.8 110

BMI (kg/m2) 36.1 36.2

RESULTS

Weight loss (%) 8.1 1.8

5% weight loss (LOCF) 48 16

10% weight loss (LOCF) 25 7

Greenway FL, Fujioka K, Plodkowski RA et al. Lancet. 2010; 376: 595-605

Bupropion/Naltrexone(Contrave)Percent Weight Loss 

Greenway FL, Fujioka K, Plodkowski RA et al. Lancet. 2010; 376: 595-605

Bupropion/Naltrexone(Contrave)5%, 10%, and 15% weight loss

Greenway FL, Fujioka K, Plodkowski RA et al. Lancet. 2010; 376: 595-605

Liraglutide (Saxenda) 

• Liraglutide is an acylated human glucagon‐like peptide‐1 (GLP‐1) receptor agonist with 97% amino acid sequence homology to endogenous human GLP‐1.

• GLP‐1 is secreted from Intestinal endocrine L cells located mainly in the distal ileum and colon. 

• GLP‐1 binds to the GLP‐1R expressed in the brain.

Fujioka K et al. Diabetologia. 2014; 57 (Suppl 1): Abstract 904-P

Liraglutide (Saxenda)                     Demographics at Baseline and Results

Liraglutide 3mg (Saxenda) Placebo

Age (years)                         45

Sex (%female)                   79

Weight (kg) 106.2 106.2

Waist (cm) 115.0 114.5

BMI (kg/m2)                   38.3

RESULTS

Weight loss (%) 3.0 9.2

5% weight loss 62.3 34.4

10% weight loss 33.9 15.4

Fujioka K et al. Diabetologia. 2014; 57 (Suppl 1): Abstract 904-P

Liraglutide (Saxenda) Percent Weight Loss

Fujioka K et al. Diabetologia. 2014; 57 (Suppl 1): Abstract 904-P

Liraglutide (Saxenda)5% and 10% weight loss

Fujioka K et al. Diabetologia. 2014; 57 (Suppl 1): Abstract 904-P

Combined Lifestyle Intervention and Pharmacotherapy

61Wadden TA, et al. N Engl J Med. 2005;353:2111-2120.

Wei

ght l

oss

(kg)

2

4

6

8

10

12

14

160 3 6 10 18 40 52

0

Weeks

Drug aloneExtensive lifestyle modification aloneDrug + brief lifestyle counselingDrug + extensive lifestyle modification

BARIATRIC SURGERY

62

Pharmacologic and Surgical Management of Obesity

AACE/TOS/ASMBS Selection Criteriafor Bariatric Surgery

Factor Criteria

Weight (adults)BMI ≥40 kg/m2 with no comorbiditiesBMI ≥35 kg/m2 with ≥1 severe obesity‐associated comorbidityBMI 30‐34.9 kg/m2 with diabetes or metabolic syndrome

Weight loss history Failure of previous nonsurgical attempts at weight reduction, including nonprofessionalprograms (eg, Weight Watchers)

Commitment

Expectation that patient will adhere to postoperative care• Follow‐up visits with healthcare team• Recommended medical management, including use of dietary supplements• Instructions regarding any recommended procedures or tests

Exclusion

• BMI <30 kg/m2; there is insufficient evidence to recommend bariatric surgery for control of glucose, lipids, or CV risk reduction independent of BMI

• Reversible endocrine or other disorders that can cause obesity• Current drug or alcohol abuse• Uncontrolled, severe psychiatric illness• Lack of comprehension of risks, benefits, expected outcomes, alternatives, and 

required lifestyle changes

63

ASMBS, American Society for Metabolic & Bariatric Surgery; BMI, body mass index; CV, cardiovascular; TOS, The Obesity Society.

Mechanick JI, et al. Endocr Pract. 2008;14(suppl 1):1-83. Mechanick JI, et al. Endocr Pract. 2013;19:337-372.

Surgical Options

64

Laparoscopic SleeveGastrectomy (LSG)

Gastric Plication

Roux-en-Y Gastric Bypass (RYGB)

Biliopancreatic Diversion

Gastric Restriction Procedures

Metabolic Procedures

Laparoscopic AdjustableGastric Band (LABG)

Mechanick JI, et al. Endocr Pract. 2013;19:337-372.

Weight Loss with Different Bariatric Surgeries in Severely Obese Patients

65BMI entry criteria: ≥34 kg/m2 men, ≥38 kg/m2 women.

Sjostrom L, et al. JAMA. 2012;307:56-65.

Swedish Obese Subjects Study(N=4047)

2015108643210-35

-30

-25

-20

-15-10

-5

0

5

Years

M

ean

Wei

ght (

%)

ControlBandingVertical banded gastroplastyGastric bypass

No. patientsControl 2037 1490 1242 1267 556 176Banding 376 333 284 284 150 50Gastroplasty 1369 1086 987 1007 489 82Bypass 265 209 184 180 37 13

Effect of Different Bariatric Surgeries on Weight‐Related Comorbities at 1 Year

66

*Small numbers of patients with 1 year of follow-up for all comorbidities (n≤38).†P<0.05 vs LAGB; ‡P<0.05 vs LRYGB.

ACS, American College of Surgeons; BMI, body mass index; GERD, gastroesophageal reflux disease; LAGB, laparoscopic adjustablegastric band; LSG, laparoscopic sleeve gastrectomy; LRYGB, laparoscopic Roux-en-Y gastric bypass.

Hutter MM, et al. Ann Surg. 2011;254:410-420.

ACS Bariatric Surgery Center Network Prospective Observational Study

(N=28,616)

Patie

nts

with

reso

lutio

n or

im

prov

emen

t of c

ondi

tion

(%)

‡†

‡

†‡

Summary

• Rates of obesity have risen dramatically in the United States over the past 4 decades– Obesity dramatically increases the risk of diabetes, hypertension, and 

dyslipidemia– Obesity contributes to increased costs of healthcare

• Obesity is a disease– The pathophysiology involves neuroendocrine factors involved in 

regulating both appetite and energy balance– Impairments in physical and physiologic functioning contribute to high 

rates of morbidity and mortality• Obesity can be diagnosed using anthropometric criteria (BMI and 

waist circumference)• Obesity is treatable, and weight loss improves patient outcomes 

and healthcare costs

67

Summary

• Treatment of obesity should be designed according to severity of comorbidities and complications as well as body mass

• Lifestyle change is the foundation of obesity management and should be maintained even if more intensive approaches are used– Weight loss agents are more effective when combined with lifestyle 

change• Pharmacologic therapies

– May be considered for patients with  ≥1 mild to moderate complications that can be treated effectively with moderate weight loss

– Should be used for patients with ≥1 severe complications that require more aggressive weight loss therapy

• Bariatric surgery should be considered for patients with ≥1 severe complications that require more aggressive weight loss therapy

68

AACE Obesity ResourceObesity Resource Center website:

http://obesity.aace.com/• Guidelines• Slide Library• Resource Toolkit• Treatment Algorithm