Obesity updateObesity update

Internal Medicine Review

Columbia University

August 12, 2010

Judith Korner, MD, PhD

Assistant Professor, Department of Medicine

College of Physicians & Surgeons

Director, Weight Control Center

Columbia University Medical Center

19961991

Obesity Trends* Among U.S. AdultsBRFSS, 1991, 1996, 2004

(*BMI 30, or about 30 lbs overweight for 5’4” person)

No Data <10% 10%–14% 15%–19% 20%–24% ≥25%

2004

Pulmonary diseasePulmonary diseaseabnormal functionabnormal functionobstructive sleep apneaobstructive sleep apneahypoventilation syndromehypoventilation syndrome

Nonalcoholic fatty liver Nonalcoholic fatty liver diseasediseasesteatosissteatosissteatohepatitissteatohepatitiscirrhosiscirrhosis

Coronary heart diseaseCoronary heart disease

DiabetesDiabetes

DyslipidemiaDyslipidemia

HypertensionHypertension

Gynecologic abnormalitiesGynecologic abnormalitiesabnormal mensesabnormal mensesinfertilityinfertilitypolycystic ovarian syndromepolycystic ovarian syndrome

OsteoarthritisOsteoarthritis

SkinSkin

Gall bladder diseaseGall bladder disease

CancerCancerbreast, uterus, cervixbreast, uterus, cervixcolon, esophagus, pancreascolon, esophagus, pancreaskidney, prostatekidney, prostate

PhlebitisPhlebitisvenous stasisvenous stasis

GoutGout

Medical Complications of ObesityIdiopathic intracranial Idiopathic intracranial hypertensionhypertension

StrokeStroke

CataractsCataracts

Severe pancreatitisSevere pancreatitisGERDGERD

0

25

50

75

100

Relationship Between BMI and Risk of Type 2 Relationship Between BMI and Risk of Type 2 DiabetesDiabetes

Chan J et al. Diabetes Care 1994;17:961.Colditz G et al. Ann Intern Med 1995;122:481.

Age

-Adj

uste

d R

elat

ive

Ris

k

Body Mass index (kg/m2)

MenMen

WomenWomen

<22 <23 23-

23.9

24-

24.9

25-

26.9

27-

28.9

29-

30.9

31-

32.9

33-

34.9

35+

1.0

2.91.0

4.31.0

5.01.5

8.12.2

15.8

4.4

27.6

40.3

54.0

93.2

6.711.6

21.3

42.1

Slide Source:www.obesityonline.org

0

1

2

3

4

5

6

Relationship Between Weight Gain in Adulthood and Relationship Between Weight Gain in Adulthood and Risk of Type 2 Diabetes MellitusRisk of Type 2 Diabetes Mellitus

Re

lativ

e R

isk

Weight Change (kg)Willett et al. N Engl J Med 1999;341:427.

-10 -5 0 5 10 15 20

MenMen

WomenWomen

Slide Source:www.obesityonline.org

0.6

1.0

1.4

1.8

2.2

2.6

3.0

Relationship Between BMI and Relationship Between BMI and Cardiovascular Disease MortalityCardiovascular Disease Mortality

Rel

ativ

e R

isk

of D

eath

Body Mass index

<18.5

MenMen

WomenWomen

Calle et al. N Engl J Med 1999;341:1097.

18.5–

20.4

20.5–

21.9

22.0–

23.4

23.5–

24.9

25.0–

26.4

26.5–

27.9

28.0–

29.9

30.0–

31.9

32.0–

34.9

35.0–

39.9

>40.0

Lean Overweight Obese

Slide Source:www.obesityonline.org

Relationship Between BMI and Comorbidities Relationship Between BMI and Comorbidities is Positive, Even in the “Normal” Rangeis Positive, Even in the “Normal” Range

Willett WC, et al. N Engl J Med. 1999;341:427-434.

Body Mass IndexBody Mass Index(kg/m(kg/m22))

Relative Relative RiskRisk

WomenWomen MenMen

4

6

5

3

2

1

0<21 22 23 24 25 26 27 28 29 30

Body Mass IndexBody Mass Index(kg/m(kg/m22))

4

6

5

3

2

1

0<21 22 23 24 25 26 27 28 29 30

Type 2 diabetesType 2 diabetes

CholelithiasisCholelithiasis

HypertensionHypertension

Coronary heart diseaseCoronary heart disease

Physical Exam

•Vitals (use appropriate size BP cuff )

•Height, Weight, Calculate BMI (kg/m2)

wt (lb) x 703 Overweight ≥ 25ht (in2) Obese ≥ 30

•Measure waist circumference

(>35 inches for women; >40 inches for men)

•Skin changes: acanthosis nigricans, pigmented striae

9

How to Measure Waist Circumference

● Place a measuring tape, held parallel to the floor, around the patient’s abdomen at the level of the iliac crest

● The tape should fit snugly around the waist without compressing the skin

● Take the measurement at the end of a normal expiration

A waist circumference of ≥40 inches in men or ≥35 inches in women is diagnostic of abdominal obesity and suggests the presence of other cardiometabolic risk factors.

Adapted from Grundy SM, et al. Circulation. 2005;112:2735-2752.

Laboratory Tests

•Biochemistry Profile

•Thyroid Profile

•Lipid Profile

•Fasting Insulin and Glucose

Consider insulin resistance if insulin > 10U/ml or glucose is >95 mg/dl

•EKG

•If clinical suspicion of Cushing’s - 24 hr UFC

•If clinical suspicion of PCOS - androgen profile

•If clinical suspicion of sleep apnea - sleep study

Initiating a Discussion about Weight

What’s in a Name?Patients’ Preferred Terms for Describing Obesity

• “Imagine you are visiting your doctor for a check up. The nurse has measured your weight and found that you are at least 50 pounds over your recommended weight.”

• “Please indicate how desirable or undesirable you would find each of the following terms if your doctor used it to describe your weight.”

Wadden Obesity Res 11, 2003

Wadden, Obes Res 11:1140

Initiating a Discussion

• “Ms. Jones, could we talk for a moment about your weight?”

• “Tell me your thoughts about your weight at this time. I know how hard you’ve worked in the past to control it. What are your goals now?”

as opposed to

• The “call-it-what-it-is” approach which fails to recognize the offensive, derogatory manner in which the terms fatness and obesity are used by the public.

Wadden Obesity Res 11, 2003

Setting Realistic Goals

Realistic Goals

• Moderate weight loss: 5-10% reduction in body weight over 6-12 months

• Weight loss of this magnitude significantly decreases the severity of obesity-associated risk factors

NIH/NHLBI, Obes Res 1998

Forget about Barbie

• Barbie’s projected human measurements:

39-18-33

• Average white woman:

age 18-25: 38-32-41

age 36-45: 41-34-43

Goal Weight Loss Defined by Subjects

% Reduction

•Dream 38%

•Happy 31%

•Acceptable 25%

•Disappointed 17%

•Average goal weight reduction was 32%

Cornerstone of Weight Loss Treatment

• Behavior Therapy, Diet, Exercise

Behavior Therapy• Self-monitoring includes recording dietary intake (food choices,

amounts, times), exercise and changes in body weight. • Stimulus control - identify and change cues that are associated with

eating too much and exercising too little. For example, limiting exposure to food or separating eating from other activities such as reading or watching television.

• Reinforcement encourages attainment of difficult to achieve goals. Reinforcement may come from a social support network or getting non-food rewards for reaching goals.

• Stress management helps coping with stressful events by developing outlets besides eating for reducing stress. Evaluating setbacks and determining how to do better next time can break the chain of negative thinking and self-punishment when lapses occur.

Diet

• Whatever works, but is healthy. Don’t be afraid to try different approaches.– Low glycemic diets may reduce appetite (Ludwig DS)– Low calorie density foods enhance satiety with fewer calories (Rolls B)– Less palatable foods reduce calorie intake– Structure helps

• Liquid meal replacements• Prepackaged food

VLCD: ≤800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior

Wadden Annals of Int Med 119:688 1993

Long-Term Weight Loss: Non-Pharmacologic Treatment

Weight Loss Treatment

• Behavior Therapy, Diet, Exercise

• Pharmacotherpy:

BMI 30, or 27 and 2 co-morbidities

Adapted from Ryan et al. Adapted from Ryan et al. Obesity Res.Obesity Res. 1995;3(suppl 4):553S-559S. 1995;3(suppl 4):553S-559S.

S = sibutramineS = sibutramine

= norepinephrine,= norepinephrine, = serotonin= serotonin

Mechanisms of Action: Sibutramine and Active Metabolites Block Serotonin, Norepinephrine, and

Dopamine Reuptake

Norepinephrine

Serotonin

MAOMAO

Catabolism

Catabolism

ReleaseRelease

MAOMAO

Catabolism

Catabolism

SSSS

SSSS

SSSS

SSSS

ReleaseRelease

REUPTAKEREUPTAKE

REUPTAKEREUPTAKE

Sibutramine: EfficacyMean Weight Change in 1 Year Trial

**PP < 0.01 vs placebo. < 0.01 vs placebo.Bray et al, Obes Res 1996;4:263-270Bray et al, Obes Res 1996;4:263-270

Treatment MonthTreatment Month

00

MeanMeanWeightWeightChangeChange

(%)(%)

-8-8

10 mg qd (n = 79)10 mg qd (n = 79)

15 mg qd (n = 93)15 mg qd (n = 93)

-10-10

-6-6

-4-4

-2-2

00

11 22 33 44 55 66 77 88 99 1010 1111 1212

Placebo (n = 76)Placebo (n = 76)

**

**

Mean (±SE) Weight Loss in the Four Groups, as Determined by an Intention-to-Treat Analysis (Panel A) and a Last-Observation-Carried-Forward Analysis (Panel B)

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

Proportion of patients who maintained 5% and 10% weight loss from baseline on sibutramine

67%

90%

57%

82%

44%

69%

56%59%

36%

56%

26%

52%

21%

46%

0

10

20

30

40

50

60

70

80

90

100

Placebo Sibutramine

5% Responders 10% Responders

6 12 18 24 MONTH 6 12 18 24James PT et al. Effect of sibutramine on weight maintenance after weight loss: arandomised trial. Lancet 2000; 356: 2119–25

Sibutramine: Safety– Adverse events:

Headaches, constipation, fatigue, dry mouth most common

– Vital signs:

Potentially clinically significant blood pressure increases (1/12)

– Contraindicated in patients with uncontrolled hypertension, coronary heart disease, other vascular disease or co-administration with SSRIs or MAOIs.

– Pulmonary hypertension and valvular heart disease, associated with fenfluramines, not reuptake inhibitors

OrlistatMechanism of Action

30% of fat not absorbed

Weight Change Over 104 Weeks

**PP < 0.05 (vs placebo). < 0.05 (vs placebo).Sjöström L, et al. Sjöström L, et al. LancetLancet. 1998;352:167. 1998;352:167172.172.

1313

1010

WeekWeek

8.1%8.1%**

00 1515 3030 4545 6060 7575 9090 104104

00

EucaloricEucaloricHypocaloric Hypocaloric

DietDiet

4.5%4.5%55

Weight Loss (%)Weight Loss (%)

PlaceboPlacebo

OrlistatOrlistat

Orlistat Safety

• The most common side effects include abdominal discomfort, oily spotting, flatuence with discharge, fecal urgency and incontinence.

• Absorption of fat-soluble vitamins and some medications (eg. cycolsporine) may be affected.

Noradrenergic Agents• Schedule IV drugs have a low potential for abuse

• Phentermine (Adipex-P, Fastin): 18.75-37.5 mg/day

• Phentermine resin (Ionamin): 15-30 mg/day

• Diethylpropion (Tenuate, Tenuate Dospan):25 mg 3x/day or sustained release 75 mg/day

• Phenylpropanolamine (Dexatrim, Acutrim): withdrawn from market due to association with hemorrhagic stroke

Yanovski NEJM 346:591 2002

Noradrenergic Agents (cont’d)

• Approved by the FDA for short-term use:

~ 3 months• Studies show between 2-10 kg weight loss over

placebo• Side effects: insomnia, dry mouth, constipation,

euphoria, palpitations, hypertension

R. Steinbrook, NEJM 350, 2004

Other Options for Weight Loss

• Metformin

• Review patient’s medications and consider alternatives

Does lifestyle intervention or administration of metformin prevent or delay the development of diabetes?

Eligibility Criteria•3234 nondiabetic persons•Elevated fasting glucose (95-125 mg/dl) and•Elevated glucose 2h after 75g glucose load (140-199 mg/dl)•BMI ≥ 24 (≥ 22 in Asians)

NEJM 346:393 2002

Diabetes Prevention Program Research Group

Average Wt LossPlacebo: 0.1 kg

Metformin: 2.1 kg

Lifestyle: 5.6 kg50% ≥7% at 24 wk38% ≥ 7% at most recent visit

Decrease in dailyenergy intakePlacebo: 249 kcalMetformin: 296 kcalLifestyle: 450 kcal

Cum

ulat

ive

Inci

denc

eof

Dia

bete

s (%

)

Year

Placebo

Metformin

Lifestyle

Diabetes Prevention Program Research Group

Reduction in Incidence Compared with PlaceboMetformin: 31%LifeStyle: 58%

Number needed to treat for 3 y to prevent 1 case of DMMetformin: 13.9Lifestyle: 6.9 NEJM 346: 393 2002

Impact of Anti-Diabetic Therapies on Weight

GAIN NEUTRAL LOSS

Sulfonylurea

Glinide

Metformin GLP-1 agonist

TZDs Alpha-Glucosidase Inhibitor

Pramlintide

Insulin DPP4-Inhibitor

Nathan et al Diabetes Care 31:1-11, 2008

Drugs that MayDrugs that MayPromote Weight GainPromote Weight Gain

Drugs that Cause Little or No Weight Drugs that Cause Little or No Weight Gain or Weight LossGain or Weight Loss

AntidepressantsAntidepressants– ParoxetineParoxetine– MirtazapineMirtazapine– MAOIs, TCAsMAOIs, TCAs

Antiepileptic drugsAntiepileptic drugs– ValproateValproate– GabapentinGabapentin

AntipsychoticsAntipsychotics– Clozapine, olanzapine, Clozapine, olanzapine,

risperidone, quetiapinerisperidone, quetiapine LithiumLithium

AntidepressantsAntidepressants– Bupropion Bupropion – VenlafaxineVenlafaxine

Antiepileptic drugsAntiepileptic drugs– TopiramateTopiramate– LamotrigineLamotrigine– ZonisamideZonisamide

AntipsychoticsAntipsychotics– ZiprasidoneZiprasidone– AripiprazoleAripiprazole

CNS Drug-Induced Weight GainCNS Drug-Induced Weight Gain

MAOIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants.

Different Long-Term Effects of SSRIs on Different Long-Term Effects of SSRIs on Body WeightBody Weight

-1

0

1

2

3

4

0

5

10

15

20

25

30

Me

an

% C

han

ge

inB

od

y W

eig

ht

% In

cid

en

ce o

f >

7%

W

eig

ht

Ga

in

Paroxetine (n = 47)Sertraline (n = 48)Fluoxetine (n = 44)

†P = .015

†P < .001†P < .003

†P < .016

*

*P < .001 compared to baseline, †P-values for comparison to paroxetine

Fava M, et al. J Clin Psychiatry. 2000;61:863-7.

Analysis is for treatment responders

Bray et al, Obesity Research, (2003) 11:722

Efficacy of topiramate for weight loss in obese individuals: randomized double-blind placebo-

controlled multicenter trial

Adverse Events with Topiramate

• Events were dose related and reversible after treatment was stopped

• Paresthesia• Psychomotor slowing• Difficulty concentrating• Fatigue• Somnolence

A look into the future…

Sibutramine: EfficacyMean Weight Change in 1 Year Trial

**PP < 0.01 vs placebo. < 0.01 vs placebo.Data on file, Knoll Pharmaceutical Company.Data on file, Knoll Pharmaceutical Company.

Treatment MonthTreatment Month

00

MeanMeanWeightWeightChangeChange

(%)(%)

-8-8

10 mg qd (n = 79)10 mg qd (n = 79)

15 mg qd (n = 93)15 mg qd (n = 93)

-10-10

-6-6

-4-4

-2-2

00

11 22 33 44 55 66 77 88 99 1010 1111 1212

Placebo (n = 76)Placebo (n = 76)

**

**Why not ?

Vagus Nerve

Food IntakeGut and Liver

Pancreas

AutonomicNervousSystem

Hypothalamus

Energy Expenditure

Adipose Tissue

Aronne LJ. Adapted from Campfield LA, et al. Science. 1998;280: 1383-1387; and Porte D, et al. Diabetologia. 1998;41:863-881.

Adrenal Cortex

Energy Balance

and Adipose Stores

Meal Size

Adrenal Steroids

Leptin

Insulin

External Factorsfood availability,

palatability

Model of a weight-regulating feedback systemModel of a weight-regulating feedback system

Combination Therapies

Topiramate + Phentermine

Zonisamide + Buproprion

Bupropion + Naltrexone

Leptin + Pramlintide

Behavioral Mechanisms: Behavioral Mechanisms: Is Extreme Ravenousness Required?Is Extreme Ravenousness Required?

2 oz chocolate bar = 260 kcal

20 oz cola = 252 kcal

Total = 512 kcal

Forbes GB, et al. Br J Nutr. 1986;56:1-9.Allison DB, et al. Am J Psychiatry. 1999;156:1686-96.

Weight gain: 1 lb/weekWeight gain: 1 lb/week

Disparagement of obese individuals is “the last socially acceptable form of prejudice.”

Stunkard and Sobal, 1995