Transcript Judith Korner
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