Obesity 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

Obesity Trends* Among U.S. Adults BRFSS, 1991, 1996, 2004 (*BMI



30, or about 30 lbs overweight for 5’4” person) 1991 1996 2004

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

Medical Complications of Obesity

Pulmonary disease

abnormal function obstructive sleep apnea hypoventilation syndrome

Nonalcoholic fatty liver disease

steatosis steatohepatitis cirrhosis

Gall bladder disease Idiopathic intracranial hypertension Stroke Cataracts Coronary heart disease

Diabetes Dyslipidemia Hypertension

GERD Severe pancreatitis Gynecologic abnormalities

abnormal menses infertility polycystic ovarian syndrome

Cancer

breast, uterus, cervix colon, esophagus, pancreas kidney, prostate

Osteoarthritis Skin Gout Phlebitis

venous stasis

Relationship Between BMI and Risk of Type 2 Diabetes

100 75 Men Women 54.0

50 27.6

25 1.0

0 <22 2.9

1.0

<23 4.3

1.0

23 23.9

5.0

1.5

24 24.9

8.1

2.2

25 26.9

15.8

4.4

27 28.9

6.7

29 30.9

Body Mass index (kg/m 2 ) Chan J et al.

Diabetes Care

1994;17:961.

Colditz G et al.

Ann Intern Med

1995;122:481.

40.3

11.6

31 32.9

21.3

33 34.9

93.2

42.1

35+ Slide Source: www.obesityonline.org

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

4 3 2 6 5 Men Women 1 -10 0 -5 0 5 10 Weight Change (kg) Willett et al.

N Engl J Med

1999;341:427.

15 20 Slide Source: www.obesityonline.org

Relationship Between BMI and Cardiovascular Disease Mortality

3.0

2.6

Men Women 2.2

1.8

1.4

1.0

Lean Overweight 0.6

<18.5

18.5

20.4

20.5

21.9

22.0

23.4

23.5

24.9

25.0

26.4

26.5

27.9

Body Mass index 28.0

29.9

Calle et al.

N Engl J Med

1999;341:1097.

30.0

31.9

Obese 32.0

34.9

35.0

39.9

>40.0

Slide Source: www.obesityonline.org

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

Women 3 2 6 5 4 1 0 <21 22 23 24 25 26 27 Body Mass Index (kg/m 2 ) 28 29 Willett WC, et al.

N Engl J Med.

1999;341:427-434.

30 Men Type 2 diabetes Cholelithiasis Hypertension Coronary heart disease 6 5 4 3 2 1 0 <21 22 23 24 25 26 27 28 Body Mass Index (kg/m 2 ) 29 30

Physical Exam •Vitals (use appropriate size BP cuff ) •Height, Weight, Calculate BMI (kg/m 2 ) wt (lb) x 703 ht (in 2 ) •Measure waist circumference Overweight ≥ 25 Obese ≥ 30 (>35 inches for women; >40 inches for men) •Skin changes: acanthosis nigricans, pigmented striae

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.

9

Laboratory Tests •Biochemistry Profile •Thyroid Profile •Lipid Profile •Fasting Insulin and Glucose Consider insulin resistance if insulin > 10  U/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

•Dream •Happy •Acceptable •Disappointed % Reduction 38% 31% 25% 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

watching television.

- 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 •

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

Long-Term Weight Loss: Non-Pharmacologic Treatment VLCD: ≤800 kcal/day BMOD: behavior + 1200kcal/day Combined: VLCD + behavior Wadden Annals of Int Med 119:688 1993

Weight Loss Treatment

• Behavior Therapy, Diet, Exercise • Pharmacotherpy: BMI  30, or  27 and 2 co-morbidities

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

MAO

REUPTAKE Release

Serotonin MAO

REUPTAKE

Norepinephrine

Release

S = sibutramine  = norepinephrine,  = serotonin Adapted from Ryan et al.

Obesity Res.

1995;3(suppl 4):553S-559S.

0

Sibutramine: Efficacy Mean Weight Change in 1 Year Trial

-2

Mean Weight Change (%)

-4 -6 -8

* *

-10 0 1 2 3 4 5 6 7 8 *

P

< 0.01 vs placebo.

Bray et al, Obes Res 1996;4:263-270

Treatment Month

9 10 11 12

Placebo (n = 76) 10 mg qd (n = 79) 15 mg qd (n = 93)

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 5% Responders 10% Responders

6 12 18 24 MONTH 6 12 18 24

James PT et al. Effect of sibutramine on weight maintenance after weight loss: a randomised 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

Orlistat

Mechanism of Action

30% of fat not absorbed

Weight Change Over 104 Weeks

Weight Loss (%)

0

Diet Hypocaloric Eucaloric Placebo Orlistat

5 -

4.5%

10 13 0 15 30 *

P

< 0.05 (vs placebo).

Sjöström L, et al.

Lancet

. 1998;352:167 172.

45

Week

60 75 90 104 -

8.1% *

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

Diabetes Prevention Program Research Group 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) •Elevated glucose 2h after 75g glucose load (140-199 mg/dl) •BMI ≥ 24 (≥ 22 in Asians) and NEJM 346:393 2002

Average Wt Loss Placebo: 0.1 kg Metformin: 2.1 kg Lifestyle: 5.6 kg 50% ≥7% at 24 wk 38% ≥ 7% at most recent visit Decrease in daily energy intake Placebo: 249 kcal Metformin: 296 kcal Lifestyle: 450 kcal

Diabetes Prevention Program Research Group Placebo Metformin Lifestyle Year Reduction in Incidence Compared with Placebo Metformin: 31% LifeStyle: 58% Number needed to treat for 3 y to prevent 1 case of DM Metformin: Lifestyle: 13.9

6.9

NEJM 346: 393 2002

Impact of Anti-Diabetic Therapies on Weight

GAIN NEUTRAL LOSS

Sulfonylurea Glinide TZDs Insulin Metformin GLP-1 agonist Alpha-Glucosidase Inhibitor Pramlintide DPP4-Inhibitor Nathan et al Diabetes Care 31:1-11, 2008

CNS Drug-Induced Weight Gain

Drugs that May Promote Weight Gain



Antidepressants

–

Paroxetine

– –

Mirtazapine MAOIs, TCAs



Antiepileptic drugs

– –

Valproate Gabapentin



Antipsychotics

–

Clozapine, olanzapine, risperidone, quetiapine



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



Antidepressants

–

Bupropion

–

Venlafaxine



Antiepileptic drugs

– – –

Topiramate Lamotrigine Zonisamide



Antipsychotics

–

Ziprasidone

–

Aripiprazole MAOIs = monoamine oxidase inhibitors; TCAs = tricyclic antidepressants.

Different Long-Term Effects of SSRIs on Body Weight 4 3 * 30 25 20 Paroxetine (n = 47) Sertraline (n = 48) Fluoxetine (n = 44) 2 1 † P = .015

15 10 0 † P < .001

† P < .003

† P < .016

5 -1 Analysis is for treatment responders 0 *P < .001 compared to baseline, † P-values for comparison to paroxetine Fava M, et al. J Clin Psychiatry. 2000;61:863-7.

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

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

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…

0

Sibutramine: Efficacy Mean Weight Change in 1 Year Trial

-2

Placebo (n = 76) Mean Weight Change (%)

-4 -6 -8 Why not ?

-10 0 1 2 3 4 5 6 7 8 *

P

< 0.01 vs placebo.

Treatment Month

Data on file, Knoll Pharmaceutical Company.

* 10 mg qd (n = 79) *

9 10 11 12

15 mg qd (n = 93)

Model of a weight-regulating feedback system

Hypothalamus Vagus Nerve External Factors food availability, palatability Autonomic Nervous System Gut and Liver Meal Size Food Intake Insulin Leptin Pancreas Adipose Tissue Energy Balance and Adipose Stores Energy Expenditure Adrenal Steroids Adrenal Cortex Aronne LJ. Adapted from Campfield LA, et al.

Science.

1998;280: 1383-1387; and Porte D, et al.

Diabetologia.

1998;41:863-881.

Combination Therapies

Topiramate + Phentermine Zonisamide + Buproprion Bupropion + Naltrexone Leptin + Pramlintide

Behavioral Mechanisms: Is Extreme Ravenousness Required?

2 oz chocolate bar 20 oz cola Total = = = 260 kcal 252 kcal 512 kcal

Weight gain: 1 lb/week

Forbes GB, et al. Br J Nutr. 1986;56:1-9.

Allison DB, et al. Am J Psychiatry. 1999;156:1686-96.

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

Stunkard and Sobal, 1995