TREATING PATIENTS WITH OBESITY:

BEYOND DIETINGKyaw Soe win, Asso Prof / Senior Consultant Cardiologist

Vintage Luxury Yachet Hotel, 30 May 2015

Treating Patients with Obesity:Who, Why, How and to What Ends

Guide for Selecting Obesity Treatment

The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084

Treatment 23-26.9 27-29.9 30-34.9 35-39.9 >40

Diet, Exercise, Behavior Tx + + + + +

Pharmaco-therapy

With co-morbidities + + +

Surgery With co-morbidities +

BMI Category (kg/m2)

Take Home Massage

What is overweight , obesity & morbid obesity? Definition : Obesity is a state of excess adipose tissue

mass. (Harrison’s :17th )

Obesity is a disease of caloric imbalance that results from an excess intake of calories above their consumption by the body. (Robbins : 8th)

Obesity can be defined as an excess of body fat accumulation or adiposity, with multiple organ-specific adaptive or maladaptive consequences, and has been considered more prone to develop cardiovascular diseases.

• Calling it a disease would define one-third of Americans as being ill and could lead to more reliance on costly drugs and surgery rather than lifestyle changes

• Some people might be overtreated because their BMI was above a line designating them as having a disease, even though they were healthy

Why Obesity is NOT a Disease• It is a lifestyle choice• No specific symptoms associated with it• It is a risk factor for disease, not a disease

itself*

* What about high cholesterol or hypertension?

Why Obesity IS a Disease• It is associated with impaired body function• Like other diseases, it results from physiological

dysfunction (precipitated by numerous forces in modern society)

• It causes, exacerbates or accelerates more than 65 significant comorbid diseases

• It is associated with a substantial burden of morbidity and premature death

7

Consequences of ObesityHippocrates recognized that :

“sudden death is more common in those who are naturally fat than in lean.”(in BC 400)

Complications of ObesitySeveral of these complications exacerbate the underlying obesity, creating a vicious cycle:

Diabetes Many diabetes drugs cause weight gain

PCOS Insulin resistance promotes lipogenesis

Sleep apnea Disrupted sleepcan cause weight gain

Arthritis Limit exercise capacityBack pain

Inflammatory Steroids often causedisorders weight gain

Depression Eating disorders andPsychological many psychotropic agents cause weight gain

Psychological

Neoplastic

Inflammatory

Structural

Metabolic

Degenerative

Medical Complications of Obesity

Phlebitisvenous stasis

Coronary heart disease

Pulmonary diseaseabnormal functionobstructive sleep apneahypoventilation syndrome

Gallstones

Gout

Diabetes

Osteoarthritis

Fatty liver diseasesteatosissteatohepatitiscirrhosis

HypertensionDyslipidemia

Cataracts

Skin disorders

Pancreatitis

Intracranial hypertensionCognitive dysfunction

Cancerbreast, uterus, cervix, ovary, prostate, kidney, colon, esophaguspancreas, gallbladder, liver

Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome

Stroke

Affects men and women of all ages

Predominates in developed countries.

obesity?

PREVALENCE OF RISK FACTORS FOR NON-COMMUNICABLE DISEASES IN MYANMAR

Risk Factors

Yangon*(2003-2004) (%)

National**(2009) (%)

Male Female Both Sexes Male Female Both Sexes

Current smoking 36.00 11.11 23.20 33.61 6.13 16.68

Current drinking 25.96 1.09 11.96 31.17 1.47 12.87

Physical inactivity 7.32 7.86 7.62 10.44 14.1 12.69

Fruits and vegetable consumption (% Who eat 5servings of fruits and vegetables/day)

98.64 98.73 98.69 89.8 90.6 90.29

Hypertension 27.94 24.11 25.87 30.99 29.34 29.97

Overweight (BMI 25) 20.60 29.96 23.80 17.74 30.27 25.38

Obesity (BMI 30) 4.77 10.35 7.85 4.27 8.37 6.8

Raised Blood cholesterol level (5.2mmol/L)

21.16 35.12 27.42 - - -

Diabetes (diagnosed by OGTT) 11.51 12.64 12.14 - - -

*STEP Survey in Yangon Division (2003-2004)** National STEP Survey (2009) ((Prof. TSLatt et al, JAFES vol 26 no 2, November 2011)

Assessment of Overweight and Obesity

Body Mass Index (BMI)Weight (kg)/height (m2)Weight (lb)/height (in2) x 703

Waist Circumference (WC)High risk: Men >102 cm (40 in.) Women >88 cm (35 in.)

Waist Hip Ratio (WHR) Skin-fold thickness Measurement of Abdominal

Fat by CT

Classification BMI (kg/m2) Risk of co-morbiditiesUnderweight <18.5 Low (but risk of other clinical

problems increased)

Normal range 18.5-24.9 AverageOverweight* ≥25Pre-obese 25.0-29.9 Mildly increased

Obese >30.0Class I 30.0-34.9 ModerateClass II 35.0-39.9 SevereClass III 40.0 Very severe

WHO Classification of adult categories of BMI

Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. NIH Publication # 98-4083, September 1998, National Institutes of Health.

Classification

BMI (kg/m2)

Risk of co-morbidities

Waist circumference< 90 cm (men)< 80 cm (women)

≥ 90 cm (men)≥ 80 cm (women)

Underweight

<18.5 Low (but risk of other clinical problems increased)

Average

Normal range

18.5-22.9

Average Increased

Overweight ≥23At risk 23.0-

24.9Increased Moderate

Obese I 25-29.9 Moderate SevereObese II ≥ 30.0 Severe Very severe

World Health Organization, 1998

WHO classification of BMIs for adults of Asian origin

BMI Values are age independent & same for both

sexes. At similar BMI, fat content in women > men

BMI 30 is threshold for obesity.

BMI 25 - 30 medically significant & requires intervention

• At a given BMI, women, on average, have more body fat.

• Morbidity and mortality increase with BMI similarly for men and women

Limits of using BMI BMI is not an index of regional fat distribution BMI may overestimate body fat in athletes and

individuals with a muscular build BMI DOES NOT

show the difference between excess fat and muscle.

identify whether the fat is laid down in particular sites. eg, abdominal fat has more serious health consequences than fat located elsewhere

BMI may underestimate body fat in older persons and individuals who have lost muscle mass

Measuring Waist Circumference

Waist circumference is calculated by comfortably measuring the waist halfway between the bottom of the rib cage and the top of the pelvis.

Measuring Waist Circumference WC is a good surrogate index of visceral

adiposity. WC is an independent and powerful risk factor for

CAD and MI. WC is related to increased risk of DM,

hypertension, stroke, sleep apnoea and dyslipidaemia.Increased risk Substantially increased

riskMen 94 cm 102 cmWomen 80 cm 88 cm

Country/Ethnic group Waist circumference

Europids MaleFemale

≥ 94 cm≥ 80 cm

South Asians MaleFemale

≥ 90 cm≥ 80 cm

Chinese MaleFemale

≥ 90 cm≥ 80 cm

Japanese MaleFemale

≥ 90 cm≥ 80 cm

Ethnic South and Central Americans

Use South Asian recommendations until more specific data are available

Sub-Saharan Africans Use European data until more specific data are availableEastern Mediterranean and

Middle East (Arab) populations

Country/ethnic specific values for waist circumference

Measuring obesity Measuring Waist Circumference

Large waist circumference (WC) can identify some at increased risk over BMI alone

If BMI and other cardiometabolic risk factors are assessed, currently there is insufficient evidence to: Substitute WC for BMI Measure WC in addition to BMI

Klein, et al. Waist Circumference and Cardiometabolic Risk. Diabetes Care. 2007 0: dc07-9921v1-0.

Other methods Waist hip ratio - >0.9 for women - > 1 for men Anthropometry ( skin fold thickness )

Harpenden skin calliper < 40 mm in males, < 50 mm in females

Densitometry ( under water weighing ) CT Scan, MRI, Electric impedance

Waist-to-hip ratioRatio = WAIST

HIPS

TO FIND RATIOWaist: Measure atnarrowest point withstomach relaxed

Hips: Measure atfullest point

Desired RatioWomen : <0.8Men : < 1.0Risk increases if

waist circumference is >94 cm in men and >80 cm in women

Skin Fold Thickness Harpenders callipers / MRNL callipers It is measured at biceps/triceps/illiac

and interscapular. Total of all four sites is considered

15-45 mm – 8-22 % of total body fat46-75 mm – 23-30 % of total body fat76-150 mm – 31-40 % of total body fat151-170 mm – 41-45 % of total body fat

Upto 22% it is normal (males)Upto 30% it is normal (females)

Measuring Abdominal Fat by CT

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Obesity Phenotypes Peripheral adiposity

Collection of fat on hips and buttocks Women are more likely to have a peripheral

distribution Associated with mechanical problems

Abdominal adiposity or central obesity More likely to have a waist distribution Associated with insulin resistance and heart disease

Mixed central – peripheral adiposity Severely obese women and men ( BMI >40 kg/m2)

Peripheral adiposity central obesity

Measuring Waist Hip Ratio

•Mixed central – peripheral adiposity

“Super obese" male A "super obese" male with a BMI of 47 kg/m2: weight 146 kg (322 lb), height 177 cm (5 ft 10 in)

Adipose tissue

WHY is it HARD to maintain the weight loss for those who lose after dietary restriction?- Constant number of adipocytes- -Higher no. in obese

Fat Cells Adipose cells store majority of the body’s fat. Vary in size and

number. Increase in body fatness is due to:

Fat cell hypertrophy Fat cell hyperplasia

Fat Cell Number Number of fat cells appears to be biggest factor in determining risk

for obesity. Determined mostly in adolescent years Average non-obese person: 25-30 bill. Moderately obese: 60-100 bill. Massively obese: 300 bill. +

Fat cells development (significant ): Last trimester of pregnancy First year of life During adolescent “growth spurt”

..Adipocyte number is established in childhood and adolescence…

Fat Cells and Weight Gain Typically only see an increase in size of existing cells in adults.

(Hypertrophy) If cells begin to reach their maximum size of 1.0 micrograms of lipid per

cell then new cells may develop. (Hyperplasia)

Fat Cells and Weight Loss Cells decrease in size, not number:

Studies have proven, fat cells ONLY decrease in size not number. Individuals with higher number of cells, regained weight more readily. Person’s with smaller, more numerous cells reported more “cravings” for food

Leptin?

Development of Adipose tissuesAs expected, studies have shown that nutritional and exercise

interventions in the growing years, results in a LOWER FAT CELL NUMBER, and a subsequent decrease in relative RISK of obesity!!!

All Fat Cells Are Not Created Equal

•Large Insulin-ResistantAdipocytes

•Adrenergic Receptors

• Insulin-MediatedAntilypolysis

•Catecholamine-Mediated Lipolysis

•Small Insulin-SensitiveAdipocytes

•Adrenergic Receptors

Fatty Acids

Adipose Tissue is an Endocrine Organ!!!

LEPTINADIPONECTININTERLEUKIN-6

Cortisol(11betaHSD)

Angiotensinogen

Angpt4/PGAR/FIAFSAA2

Retinol Binding Protein

Adipokines (adipose hormones) and other key secretory products produced by fat cells.

LEPTINADIPONECTININTERLEUKIN-6

Cortisol(11betaHSD)

Angiotensinogen

Angpt4/PGAR/FIAFSerum Amyloid A

Omentin

Visfatin

Adipokines are also produced by non-adipose cells within adipose tissue.

TNF-ALPHA

Interleukin-8

PAI-1

Obesity and Insulin Resistance

Hyperinsulinemia +

HyperglycemiaActivation of the

sympathetic nervous system

Increase of arterial tone

Na+ reabsorption

Hypertension

Overstimulation of pancreatic -

cell functionReduction of

insulin secretion

Type 2 Diabetes

Risk Factor Defining LevelAbdominal obesity Men Women

Waist circumference>102 cm (>40 in)>88 cm (>35 in)

Triglycerides ≥150 mg/dL (1.7 mmol/L)HDL cholesterol Men Women

<40 mg/dL (1.04 mmol/L)<50 mg/dL (1.29 mmol/L)

Blood pressure ≥130/ ≥85 mmHg Fasting glucose ≥100 mg/dL (5.6 mmol/L)

In order to make a diagnosis of the metabolic syndrome a patient must present with three or more of the following five risk factors:

Metabolic syndrome: The NCEP ATP III definition*

*2001, updated 2005

Metabolically Healthy ObesityFeatures of MHO subjects Predominant subcutaneous peripheral adiposity Younger age when compared with complicated obese

subjects Normal fasting glucose and glucose tolerance Normal systolic and diastolic BP (≤120/80 mmHg) Normal lipid profile, including normal levels of TG

(≤150 mg/dl) and HDL cholesterol (≥40 and ≥50 mg/dl in men and women, respectively)

The existence of MHO subjects is a well-defined clinical entity.

when compared with complicated obese subjects Lower prevalence of small LDL particles Better insulin sensitivity Lower inflammatory status

Normal liver enzymes Normal resting electrocardiogram Appropriate echocardiographic left ventricular

mass or no LV hypertrophy Low c-IMT No clinical evidence of coronary artery disease or

heart failure

Metabolically Healthy ObesityFeatures of MHO subjects

MHO subjects show a more prevalent subcutaneous, peripheral obesity phenotype rather than the central, visceral obesity phenotype.

MHO subjects also need clinical management and weight loss strategies similar to morbidly obese subjects.

Their better insulin sensitivity and lower visceral adiposity may contribute to a better response to weight-loss interventions.

Metabolically Healthy ObesityManagement of MHO subjects

Managing the Obesity

48

What causes Obesity? Genetics Nutrient and Energy model of

obesity: Energy output (physical activity) Energy input (dietary intake)

Behavioral and cultural factors

Medications

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Genetic Links Study in Cambridge University has isolated at least

two genes that when manipulated…control weight gain / loss (Leptin)

Genetics account for ~40% of weight differences Genes affect metabolic rate, fuel use, brain chemistry

A child with no obese parents has a 10% chance of becoming obese

A child with 1 obese parent has a 40% chance A child with 2 obese parents has a 80% chance

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Obesity results from a failure of normal weight and energy regulatory mechanisms

Control of appetite

Berthoud HR. Curr Opin Neurobiology 2011;21:888-896

Satiety Regulator

The hypothalamusWhen feeding cells are stimulated, they signal

you to eatWhen satiety cells are stimulated, they signal you

to stop eatingSympathetic nervous system

When activity increases, it signals you to stop eating

When activity decreases, it signals you to eat

Leptin Produced by adipocytes Product of ‘ob’ gene Provides signal for “energy

sufficiency”. Abundant fat Leptin

secretion Regulated by insulin

stimulated glucose metabolism

Stimulates thermogenesis, activity, energy expenditure

Leptin

+ POMC/CART neurons

Anorexic neuropeptides-

(MSH)

Leptin

-NPY/AgRP neurons

Produce orexinergic neuropeptides

Adiponectin Produced mainly by

adipocytes Low levels in obesity Stimulates fatty acid

oxidation “Fat-burning molecule” “Guardian angel against

obesity” ↓ fatty acid influx in liver,

liver glucose production ↓ Protects against

Metabolic syndrome

Adiponectin

AdipoR1, AdipoR2 in skeletal muscle, liver, brain

+ cAMP activated protein kinase

Inactivates acetyl coenzyme A carboxylase (Key enzyme in Fatty acid synthesis)

GI Hormonal influencePeptide Where

synthesizedEffect on feeding

Ghrelin Stomach Orexigenic

CCK Duodenum Anorexigenic

PYY Distal small intestine

Anorexigenic

GLP-1 Small intestine Anorexigenic

Amylin Pancreas Anorexigenic

CCK = cholecystokinin; PYY = polypeptide YY;GLP-1 = glucagon-like peptide 1; [exenatide, liraglutide]; Amylin [pramlintide]

“Age and Obesity”

Greatest fat gain is from 25 – 44 years of age in most people.

Average man will gain 0.2 to 0.8 kg per year. This equates to an average of over a pound a year.

14% of all women will gain over 30 lbs from age 25 to 34.

Medication-induced Weight Gain

Medications account for 5-10% of obesity in the U.S.

In each relevant category, remove or substitute weight gain-promoting

medications with weight neutral or weight loss-promoting alternatives

Selected Medications That Can Cause Weight Gain

Psychotropic medications Tricyclic antidepressants Monoamine oxidase inhibitors Specific SSRIs Atypical antipsychotics Lithium Specific anticonvulsants

-adrenergic receptor blockers

SSRI=selective serotonin reuptake inhibitor

Diabetes medications– Insulin– Sulfonylureas– Thiazolidinediones

Highly active antiretroviral therapy

Tamoxifen Steroid hormones

– Glucocorticoids– Progestational

steroids

Macroenvironmental Influences*

• 24-hour lifestyle• Economic structure• Time pressures• Workload• Loss of downtime• Speed of life• Global stressors

*Amenable only to societal intervention

Microenvironmental Influences*

• Types of nutrients• Eating schedules• Physical activity• Sleep health• Drugs and medications• Local stressors

*Amenable to individual action

The goal of lifestyle-based therapies is tonormalize the patient’s microenvironment

Management of Obesity and GoalsGoal is to reduce or prevent co-morbidities.

Short term Goal: Decrease body weight by 10 percent from baseline. If goal is achieved, further weight loss can be

attempted if indicated. Reasonable timeline: 6 months of therapy.

• Interim goal: Maintenance – May need to be continued indefinitely.

• Long-term goal: If unable to lose weight, prevent further weight gain.

How much weight loss is significant?

A 5-10% reduction in weight (within 6 months) and

weight maintenance should be stressed in any weight loss program and contributes significantly to decreased morbidity

Benefits of Modest Intentional Weight Loss Improvement in comorbid diseases Type 2 diabetes Hypertension Dyslipidemia Fatty liver disease Obstructive sleep apnea

Asthma Osteoarthritis Cancer risk

• Improved quality of life• Decreased health care costs• Decreased surgical

complication rates • Orthopedic surgery• Heart surgery• General and thoracic

surgery

• The effect on cardiovascular risk is less clear

Obesity Treatment Pyramid

Surgery

Pharmacotherapy

Lifestyle Modification

Diet Physical Activity

Requires two steps: Assessment

Degree of obesity Determine absolute risk status

Management Weight management

Weight loss Weight maintenance

Control of associated risk factors

Management of Overweight/Obese Patients

Assessment of Overweight and Obesity

Body Mass Index (BMI)Weight (kg)/height (m2)Weight (lb)/height (in2) x 703

Waist Circumference (WC)High risk: Men >102 cm (40 in.) Women >88 cm (35 in.)

Waist Hip Ratio (WHR) Skin-fold thickness Measurement of Abdominal Fat

by CT

Determine Absolute Risk Status

Evaluate: Disease conditions (e.g., CHD, type 2 diabetes,

sleep apnea)(+ = very high risk)

Cardiovascular risk factors: smoking, hypertension, high LDL, low HDL, IGT, family h/o (>3 = high risk

Other obesity-associated diseases (e.g., gynecological abnormalities, osteoarthritis)

Other risk factors: Physical inactivity High serum TG (>200 mg/dL)

Classification Of Obesity (Clinical staging) Stage 0: no apparent obesity-related risk factors

Stage 1: presence of obesity-related sub-clinical risk factors, mild physical symptoms.

Stage 2: presence of established obesity-related chronic disorders

Stage 3: established end-organ damage

Stage 4: severe (end-stage?) disabilities

Treatment AlgorithmPatient Encounter

Hx of 25 BMI?³

• Measure weight, height, and waist circumference

• Calculate BMI

Examination

Brief reinforcement/ educate on weight management

Periodic weight check

Advise to maintain weight/address other risk factors

Clinician and patient devise goals and treatment strategyfor weight loss andrisk factor control

Assess reasons for failure to lose weight

Maintenance counseling: Dietary therapy Behavior therapy Physical activity:

Treatment

Assess risk factors

No

Yes

1

2

14

15 13

12

11 1016

3

4 6

5 7

8

9

Yes

No

Yes

No

Hx BMI 25? ³

No

Yes

Yes

No

Does patient want to lose weight?

Yes

No

Progress being made/goal

achieved?

BMI 25 OR ³ waist circumference

> 88 cm (F) > 102 cm (M)

BMI ³ 30 OR

{[BMI 25 to 29.9 OR waist circumference

>88 cm (F) >102 cm (M)] AND 2 risk ³

factors}

BMImeasured in past

2 years?

No

BMI ³ 30 OR

{[BMI 25 to 29.9 OR waist >88 cm (F)

>102 cm (M)] AND ³ 2 risk

factors}

Treatment Algorithm (Part 1 of 3)Patient Encounter

Hx of ³ 25 BMI?

• Measure weight, height, and waist circumference

• Calculate BMI

Assess risk factors

NoYes

1

2

3

46

5

7

Yes

No

BMI measured in

past 2 years?

BMI ³ 25 ORwaist > 88 cm (F)

> 102 cm (M)

Yes

ExaminationTreatment

Devise goals andtreatment strategy forweight loss and riskfactor control

Assess reasons forfailure to lose weight

Maintenance counseling

12

11 10

8

9

No

Yes

Yes

No Desire tolose weight?

Yes

No

Progress made?

BMI ³ 30 OR

{[BMI 25 to 29.9 OR waist >88 cm (F)

>102 cm (M)]AND ³ 2 risk

factors}

ExaminationTreatment

7

Periodic weightcheck

• Advise to maintain weight• Address other risk factors

13

16

Treatment Algorithm (Part 2 of 3)

• Brief reinforcement • Educate on weight

management

Periodic weight check

• Advise to maintain weight

• Address other risk factors

14

1513

16

5Yes

No

Yes

No

Hx BMI ³ 25?

BMI ³ 25 OR waist > 88 cm (F)

> 102 cm (M)

ExaminationTreatment

Treatment Algorithm (Part 3 of 3)

* This algorithm applies only to the assessment for overweight and obesity and subsequent decisions based on that assessment. It does not include any initial overall assessment for cardiovascular risk factors or diseases that are indicated.

Dietary Therapy (Total Fasting)Not recommendedThere is diuresis, natriuresisAll deficiencies

Re Feeding Syndrome-severe an potentially fatal electrolyte, fluid and metabolic abnormalities when feeding is resumed.

Why Diets Don’t Work Obesity is a chronic disease

Treatment requires long-term lifestyle changes Dieters are misdirected

More concerned about weight loss than healthy lifestyle Unrealistic weight expectations

Body defends itself against weight loss Thyroid hormone concentrations (BMR) drop during weight loss and make

it more difficult to lose weight Activity of lipoprotein lipase increases making it more efficient at taking up fat for storage Weight cycling (yo-yo dieting) Typically weight loss is not maintained Weight lost consists of fat and lean tissue Weight gained after weight loss is primarily adipose tissue Weight gained is usually more than weight lost Associated with upper body fat deposition

Clinical Application “Doctor, I know I need to reduce my calories

and exercise more in order to lose weight. I have done it more times that I would like to admit. But I get hungry and its hard to stay on a calorie reduced diet. What is it about my metabolism that causes me to be so hungry?”

Nutrients Influence

Presence of energy yielding nutrient registers satiety in the brain

Apolipoprotein A-IV on the chylomicrons signals satiety in the brain

Absence of these nutrients will signal hunger

Behavior Therapy: Important Concepts

Techniques to conquer eating triggers

eating regular meals eating at the same time and

place use smaller plates keeping accessible food out of

sight eating only when hungry avoiding activities that

encourage eating

• slowing pace of eating

• reducing portion sizes

• measuring food intake

• leaving food on plate• improving food

choices• eliminating second

servings •

Physical Activity, Exercise, and Physical Fitness

Physical activity: Any bodily movement produced by skeletal muscles that results in energy expenditure.

Exercise: A subset of physical activity That is planed, structured, and repetitive and is done to improve or maintain physical fitness.

Physical fitness: A set of attributes that are either health or skill related Health- endurance, strength, flexibility, Skill- balance, agility, power, reaction time, speed and coordination

Regular Physical Activity

Fat use is enhanced with regular physical activity

Increases energy expenditure Duration and regularity are important Make it a part of a daily routine

Physical Activity Activity blunts the weight gain seen with aging. Studies in active adults

No statistical relationship between caloric consumption and body fat percentage

Linear relationship between activity level and body fat%.

Reduced physical activity is the MAIN cause of adult obesity!

Increasing energy expenditure:

exercise is very effective in preventing long term weight regain.

At least, doing aerobic exercise 3-5 times /week for 45 minute

Include 5-10 minute warm up and cool down

Pharmacological Therapies

Drug Treatment of Obesity: Indicated when

BMI is greater than 30BMI is higher than 27 and there are other cardiovascular complications

After several attempts diet alone is not enough

Anti-Obesity Medication – General Principles

Should not be first-line in treatment of obesity

Should only be used in conjunction with a healthy eating and good exercise programme.

Should not be prescribed to children in General Practice – if all other advice on behavioural changes, exercise and diet is failing – refer to secondary care.

Pharmacotherapy: sibutramine

Sibutramine is a centrally acting inhibitor of serotonin and noradrenaline reuptake. A starting dose of 10 mg once daily is recommended; after 4 weeks this can be titrated to 15 mg once daily.

Sibutramine induces ≥10% loss of initial body weight in almost 50% of overweight/obese patients.

Treatment Options 2012

Phentermine Short term medication

Orlistat Fat blocker with limited efficacy and well known

side effectsMetformin

Pharmacotherapy: Orlistat Orlistat is a reversible lipase inhibitor for

obesity management that acts by inhibiting the absorption of dietary fats.

Orlistat may induce ≥10% loss of initial body weight in almost 30% of obese patients.

Orlistat produces beneficial effects on cardiometabolic profile in overweight/obese individuals.

Orlistat - Mechanism of Action

FA

MG

GI lipase + orlistat

TGIntestinal lumen Mucosal cell Lymphatics

MicelleBile acidsMG

30% not absorbed

FFA

Orlistat inhibits absorption of approximately 30% of dietary fat

30

25

20

15

10

5

0

Mean faecal fat (g/day)

-5 -4 -3 -2 -1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15Study days

Guerciolini, Int J Obesity 1997; 21 (Suppl. 3): S12-23

Orlistat 120 mg tid

Orlistat (Xenical) License – BMI 30+ or BMI 27+ with

associated risk factors. Continue after 3mths only if patient has lost

at least 5% of body wt since starting.

Continue for longer than 12mths only after discussing benefits / limitations with pt.

Vitamin supplementation (esp D) may be considered if concern about absorption of fat soluble vitamins.

Contra-indications – chronic malabsorption syndrome, cholestasis, breast-feeding

Cautions – pregnancy Side Effects – GI – flatulence, faecal urgency

and incontinence, oily stools, abdo pain and distension. Tooth and gingival disorders, fatigue, headache, anxiety.

Dose – 120mg during or up to an 1hr after a meal up to TDS. If a meal is missed or contains no fat – omit the dose of orlistat.

Orlistat (Xenical)

Meta-analysis of RCTs Evaluating Effect of Orlistat Therapy on Weight Loss at 1-Year

Study or Sub-category

WMD (random)95% CI

Hollander 1998*Sjostrom 1998Davidson 1999Finer 2000Heuptman 2000Lindgarde 2000Rossner 2000Bakris 2002Broom 2002Kelley 2002*Miles 2002* Total (95% CI)

Padwal et al. Int J Obes 2003;27:1437

*All subjects had type 2 diabetesWMD=weighted mean difference Favours

TreatmentFavoursControl

-10 -5 0 105

-12

-9

-6

-3

0

Effect of Long-term Orlistat Therapy on Body Weight

0Weeks

52

Torgenson et al. Diabetes Care 2004;27:155

Cha

nge

in W

eigh

t (kg

)

104 156 208

P<0.001 vs placebo

-4.1 kg

-6.9 kg

Placebo

Orlistat

Gastrointestinal Side Effects of Orlistat Therapy

Year 1 Year 2Placeb

o Orlistat Placebo

Orlistat

Fatty/oily stool 5 31 1 8Increased defecation 7 20 2 2Liquid stools 10 13 5 8Fecal urgency 3 10 2 3Flatulence 3 7 2 3Flatus with discharge 0 7 0 1Fecal incontinence 0 7 0 2Oily evacuation 1 6 0 5Low plasma vitamin conc: Vitamin A 0.6 0.3 0.8 0 Vitamin D 0.6 5.1 0.8 3.1 Vitamin E 0.9 4.6 0 1.6Sjostrom et al. Lancet 1998;352:167.

Values are percentage of subjects.

Pharmacotherapy: Metformin Metformin is an oral anti-diabetic drug that improves

glucose tolerance and insulin sensitivity.

Metformin can be used alone or in combination with sibutramine, orlistat or rimonabant for weight-loss management in overweight and obese patients with and without diabetes.

Metformin significantly improves the cardiometabolic profile in overweight and obese subjects with and without diabetes.

Medications approved in 2013● Lorcaserin● Phentermine/Topiramate ER

Medications going to the FDA for possible approval● Liraglutide ● Bupropion SR/ Naltrexone SR

Treatment Options 2014

Indications and Dose• Approved by FDA,

July 2012, schedule IV

• Indication Weight loss in pts with BMI ≥30 kg/m2

or BMI ≥27 kg/m2 with weight-related co-morbid condition(s)

• Treatment Dose Dailyphentermine 7.5 mgtopiramate ER 46 mg

• Max Dose Dailyphentermine 15 mg topiramate ER 92 mg

Phentermine/Topiramate ER

Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.

Mechanism of ActionPhentermine• Sympathomimetic

amine, NE release• Blunts appetite

Topiramate• Increases GABA

activity, antagonize AMPA/ kainate glutamate receptor, carbonic anhydrase inhibitor

• Prolongs satiety

Contraindications and WarningsContraindications 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

meds

2012

Lancet. 2011 Apr 16;377(9774):1341-52

Topiramate/Phentermine (Qsymia) Effects on Weight

Phentermine/Topiramate ER Improves Risk Factors and Manifestations of Cardiometabolic Disease CONQUER Study

Variable

Phentermine 7.5mg/

Topiramate 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

Gadde KM, et al. Lancet. 2011;377(9774):1341-1352.

Phentermine/Topiramate ER: EQUIP and CONQUERMost Commonly Reported Treatment Emergent Adverse Events

Adverse Event (%)(N=3749) Placebo PHEN/TPM ER

3.75/23PHEN/TPM ER

7.5/46PHEN/TPM ER

15/92Paresthesia 1.9 4.2 13.7 19.9Dry mouth 2.8 6.7 13.5 19.1Constipation 6.1 7.9 15.1 16.1Upper respiratory tract infection 12.8 15.8 12.2 13.5

Headache 9.3 10.4 7.0 10.6Dysgeusia 1.1 1.3 7.4 9.4Nasopharyngitis 8.0 12.5 10.6 9.4Insomnia 4.7 5.0 5.8 9.4Dizziness 3.4 2.9 7.2 8.6Sinusitis 6.3 7.5 6.8 7.8Nausea 4.4 5.8 3.6 7.2Back pain 5.1 5.4 5.6 6.6Fatigue 4.3 5.0 4.4 5.9Blurred vision 3.5 6.3 4.0 5.4Diarrhea 4.9 5.0 6.4 5.6

Phentermine and topiramate extended-release [package insert]. Mountain View, CA: Vivus; 2012.

Phentermine and Topiramate Neuropsychiatric Safety No serious AEs related to depression, anxiety or

cognition No increase in the risk of suicidality

(C-SSRS*, PHQ-9**, and AE reporting) in a population where 20% had a prior historyof depression

Can be prescribed in patients with stable depression and patients on SSRIs

*Columbia Suicide Severity Rating Scale** Patient Health Questionnaire 9-item depression scale

Phentermine and topiramate extended-release [package insert]. Mountain View, CA : Vivus; 2012.

Phentermine/Topiramate Combination gives greater effectiveness with fewer

side effects Cost: $150.00/month Side effects: dry mouth, numbness, tingling,

insomnia, dizziness, anxiety, irritability and disturbance in attention

Lorcaserin

Lorcaserin hydrochloride [package insert]. Woodcliff Lake, NJ: Eisai Inc.; 2012.

Mechanism of Action• Selective 5-HT2C

receptor agonist• Stimulates α-MSH

production from POMC neurons resulting in activation of MC4R

• Increases satiety

Indications and Dose• Approved by FDA

June 2012• Indication: Weight

loss in patients with BMI ≥30 kg/m2 or BMI ≥27 kg/m2 with weight-related co-morbid condition(s)

• 10 mg po bid• Schedule IV• Discontinue if 5%

weight loss is not achieved in 12 wks

Contraindications and WarningsContraindications • PregnancyWarnings• Co-administration with

other serotonergic or anti-dopaminergic agents

• Valvular heart disease• Cognitive impairment• Psychiatric disorders

(euphoria, suicidal thoughts, depression)

• Priapism• Risk of hypoglycemia with

diabetes meds

2012

Increase in serotonin bioavailability (due to food intake or pharmacological compounds such as sibutramine and fenfluramine) or direct agonism of 5HT2CRs and 5HT1BRs modulates firing of POMC/CART and AgRP NPY neurones within the arcuate nucleus of the ARC

Anorectic POMC neurones expressing 5HT2CR depolarize on receptor activation and release α-melanocyte-stimulating hormone (α-MSH), which in turn activates second-order melanocortin 4 receptor (MC4R) expressing neurones, principally within the paraventricular nucleus of the hypothalamus (PVH; Balthasar et al. 2005)

Concomitant activation of 5HT1BRs expressed on orexigenic AgRP/NPY neurones within the ARC causes membrane hyperpolarization and subsequent inhibition of neuropeptide release

Inhibitory 5HT1BR activation also attenuates inhibitory postsynaptic currents onto POMC/CART neurones further potentiating anorexigenesis

Subsequent downstream neuroendocrine signalling promotes satiety and the cessation of food intake

Garfield A S , and Heisler L K. J Physiol. 2009;587:49-60.

Proposed Model of a Serotonergic Pathway Modulating Food Intake

Lorcaserin Phase 3 Trials• n=3,182 • 2 years tx• Dosage 10 mg QD1

1. Smith SR, et al. N Engl J Med 2010;363:245-56.2. Fidler MC, et al. J Clin Endocrinol Metab, October 2011, 96(10):3067–3077.3. O’Neil PM, et al. Obesity (16 March 2012) | doi:10.1038/oby.2012.66Arena Pharmaceuticals

• n=4,008 • 1 year tx• Dosage 10 mg QD2

• n=604 obese/ overweight with type 2 DM

• 1 year+ tx• Dosage 10 mg BID or 10 mg QD3

128

Endpoint Lorcaserin Placebo P valueWaist 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 LDL HDL

−0.902.870.05

0.574.03

−0.21

0.0010.0490.72

Triglycerides (%) −6.15 −0.14 <0.001Safety HR (beats/min) Beck depression II

−2.0−1.1

−1.6−0.9

0.0490.26

Lorcaserin ─ BLOOM Study:Key Secondary Endpoints

Intention-to-Treat Analysis with LOCF ImputationSmith SR, et al. NEJM. 2010;363:245-256.

Lorcaserin: Adverse Events Reported by >5% in Any Group

N (%) Lorcaserin(N = 3195)

Placebo(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)

Smith SR, et al. NEJM. 2010;363:245-256.

Intention-to-Treat Analysis with LOCF Imputation

Naltrexone SR/Bupropion

Target of

2014

2011

Naltrexone/Bupropion• Mechanism of Action

– Naltrexone ─ Opioid receptor antagonist– Bupropion ─ Dopamine/noradrenaline reuptake inhibitor

• Approved by FDA committee but FDA did not approve until a CVD outcome study is performed due to concerns about blood pressure and pulse in some patients

• The Light Study (CVD outcomes) is under way; estimated completion: July 2017

Apovian C, et al. Obesity. 2013.Clinicaltrials.gov. Cardiovascular Outcomes Study of Naltrexone SR/Bupropion SR in Overweight and Obese Subjects With Cardiovascular Risk Factors (The Light Study). 2012. http://clinicaltrials.gov/show/NCT01601704

Mean Weight Loss

Greenway FL, et al. Lancet 2010 Aug 21; 376:595. DOI:10.1016/S0140-6736(10)60888-4.

Naltrexone/ Bupropion

56 Weeks – Completer PopulationCOR-I Phase 3

Side EffectsMost frequent events:

– Nausea• N=171 (29.8%) naltrexone 32 mg plus bupropion• N=155 (27.2%) naltrexone 16 mg plus bupropion• N=30 (5.3%) placebo

– Headache, constipation, dizziness, vomiting, and dry mouth were also more frequent in the naltrexone plus bupropion groups vs. placebo

– Transient increase of ~1·5 mm Hg in mean systolic and diastolic blood pressure was followed by a reduction of around 1 mm Hg below baseline in the naltrexone plus bupropion groups

– Combination treatment was not associated with increased depression or suicides vs. placebo

Naltrexone/Bupropion

Greenway FL, et al. Lancet. 2010 Aug 21;376(9741):595-605.PMID: 20673995.

Liraglutide

2010for Type 2 DM

for anti-obesity

Liraglutide Glucagon-Like Peptide 1 (GLP-1) receptor agonist approved

in 2010 for treatment of type 2 diabetes (1.8 mg/day) Appetite effect mediated by both the activation of GLP-1

receptors expressed on vagal afferents and hypothalamus Affects visceral fat adiposity, appetite, food preference, and

cardiovascular biomarkers in patients with type 2 diabetes Suppresses appetite, and delays gastric emptying Phase III trials assessing effects of doses as high as 3.0

mg/day submitted to FDA

Effects of Liraglutide and Orlistat on Body Weight in Nondiabetic Obese Adults

Data are mean (95% CI) for the ITT populationAstrup A, et al. Lancet. 2009 Nov 7;374(9701):1606-16.

• Generally well tolerated and improved quality of life• Adverse events mostly mild or moderate• Gastrointestinal events (particularly nausea and vomiting),

consistent with the known physiological effects of GLP-1, were more frequent than with placebo

• At year 1, nausea and/or vomiting was associated with greater weight loss with liraglutide 3.0 mg, but even those who did not experience these events lost more weight than those on placebo or orlistat

• Injection regimen did not impair adherence or cause significant withdrawal during treatment or run-in

Liraglutide: Adverse Events

Astrup A, et al. Int J Obes (Lond). Jun 2012; 36(6): 843–854.

Obesity Drugs in the PipelineBeloranib

Phase 2 Trial

Anti-obesity Medications in Development

Kim GW, et al. Clin Pharmacol Ther. 2013 Oct 8. doi: 10.1038/clpt.2013.204. [Epub ahead of print]

Medications Approved for Obesity

Medication Average Weight Loss* Mechanism of Action Potential Side Effects

Phentermine (short-term treatment) ~ 5% Adrenergic Tachycardia, hypertension

Phentermine / Topiramate 10% Adrenergic, CNSTachycardia, hypertension,

cognitive dysfunction, neuropathy, teratogenicity

Lorcaserin 3.5% Serotonergic (5HT2C) Headache

Orlistat 3% Lipase inhibitor Steatorrhea, incontinence

* Beyond placebo

Weight Loss from Other Medications

Medication Indicated Uses Comments

Bupropion Depression Avoid in bipolar disease

TopiramateSeizuresMigraines

Mood disordersMay produce neurological side effects

Zonisamide SeizuresMood disorders Few studies

Metformin Type 2 diabetesPCOS

Rare liver toxicity

Liraglutide. Exenatide Type 2 diabetes Injectable

Pramlintide Type 2 diabetes Injectable

Pramlintide Type 2 diabetes Injectable

Strategy: Aim for Double Benefits when Possible

Pharmacological Treatment of Obesity

Current medications 5-12% wt loss Benefits only last as long as patient takes the medication.

Chronic treatment likely needed. Drugs probably not paid for by insurance so cost is a big issue

for patients. Issues of FDA approval, long term safety, and efficacy. Are medications an appropriate treatment modality for obesity?

Practical Use of Weight Loss Medications

Understand risks, cautions and monitoring essentials Start when weight is stable (within 3% over 3 months)

Aim for weight stability with lifestyle management Assess effects at 1 and 3 months Continue medication beyond 3 months if ≥ 5% total weight

loss Some use “4x3” rule - ≥ 4 lbs. weight loss/month x 3

months Weight plateau with increased hunger is expected

Medication still working if substantial weight regain absent

Proper Use of Obesity Medications

Recognizing non-respondersAn obese patient is started on a weight loss medication and is not losing adequate amounts of weight

● STOP the medication Lorcaserin patient should lose 5% or more of their weight by 3

months, otherwise stop Phentermine/topiramate patient should lose 3% by 3 months or 5%

by 6 months

The super-obese (BMI 40 + ) Incidence in U.S. population: 2.1% (4.4

million). Increased risk of OA, cardiopulmonary

failure, OSA, all consequences of metabolic syndrome (DM, NASH, HTN, hyperlipidaemia).

Medical treatment essentially hopeless, though met syndrome improves with 5-10% weight loss.

>2x mortality with BMI>40 kg/m2 due to cardiopulmonary failure, sleep apnea, diabetes

Gastric BypassLap Band

EffectivenessRisk

Low High

C. Biliopancreatic diversion with duodenal switch.

D. Biliopancreatic diversion.

Comparison of Operations

Lap band: 20% weight loss, very low mortality, 1% serious or 2.4% any complication

Sleeve gastrectomy: 25% weight loss, 0.1% mortality, 2.4% serious or 6.3% any complication

Gastric bypass: 30% weight loss, 0.2% mortality, 2.5% serious or 10% any complication

Ann Surg 2013;257: 791–797; Flum DR, N Engl J Med. 2009 Jul 30;361(5):445-54

Who is a Good Candidate? BMI>35 with co-morbidities or >40 without Age 20-60 Co-morbidities: Diabetes, sleep apnea, reflux > Hypertension, DJD Failed other forms of therapy

No serious, active cardiac, pulmonary, or psychiatric disease Must be psychologically stable and wiling to follow

postoperative diet instruction No endocrine cause for obesity Surgical intervention work by decreasing energy intake

Surgical Treatment Morbidity and mortality Mortality ranges from 0.1% for gastric banding and 0.5%

for Roux-en-Y gastric bypass to 1% for biliopancreatic bypass and duodenal switch.

Laparoscopic gastric banding provides a better post-operative safety profile and therefore represents the least invasive of the frequently performed bariatric procedures.

Laparoscopic adjustable gastric banding and roux-en-Y gastric bypass are the most common bariatric surgical procedures.

Effect of bariatric surgery on body fatness parameters

Changes After 2 years After 10 years

Body weight 22% decrease 16% decrease

Waist circumference 16% decrease 12% decrease

BMI 22% decrease 16% decrease

Bariatric Surgery is Associated with aReduced Mortality: the SOS Study

Sjostrom L NEJM 2007: 357-741-752

30% lower riskOf dying

MI: 25 in controlGroup 13 in theSurgery group

Cancer: 47 inThe control group29 in the surgerygroup

Stampede Trial: Benefits of Surgery for Type 2 DM

Parameter Medical Therapy (n=41)

Bypass(n=50)

Sleeve(n=49)

P Value

HbA1c<6 12% 42% 37% 0.008

HbA1C<6 without DM med

0% 42% 27% 0.003

% change in Tg -14% -44% -42% 0.08

% change in HDL 11% 28% 28% 0.001

N Engl J Med 2012;366:1567-76

Guide for Selecting Obesity Treatment

The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. October 2000, NIH Pub. No.00-4084

Treatment 23-26.9 27-29.9 30-34.9 35-39.9 >40

Diet, Exercise, Behavior Tx + + + + +

Pharmaco-therapy

With co-morbidities + + +

Surgery With co-morbidities +

BMI Category (kg/m2)

A Call to Action Obesity IS a disease, regardless of its designation Counsel patients with obesity on the risks of excess weight

and the benefits of weight loss Identify the medical comorbidities of obesity in each

patient Pursue a step-wise strategy for weight loss – lifestyle,

medications and surgery as needed Help patients maintain weight loss by optimizing the

patients lifestyle – healthy diet, regular exercise, adequate sleep, stress reduction

156

Take-home MessagesObesity Treatment

• Lifestyle adjustment is the mainstay of therapy• Medications can be effective

• In selected patients• Medications work differently in different patients –

requires ‘trial and error’ approach• Combination therapies look particularly promising• Go Slow and Try Different Approaches

Currently Available Options

Accept weight where it is Diet/Exercise: 3-10% weight loss Drugs: 5-12% weight loss Medically Supervised/Combination of Diet + Drug: 10-15% weight loss Surgery: 15-30% weight loss

Low

High

Effectiveness

Currently Available Options

Accept weight where it is Diet/Exercise: 3-10% weight loss Drugs: 5-12% weight loss Medically Supervised/Combination of Diet + Drug: 10-15% weight loss Surgery: 15-30% weight loss

Low

High

Risks/Time/Money

KEY FACTS In 2008, 1.5 billion adults, 20 and older, were

overweight 65% of the world's population live in countries

where overweight and obesity kills more people than underweight.

Nearly 43 million children under the age of five were overweight in 2010.

Obesity is preventable.

Prevention of ObesityEat lessEat lessEat less …………………….Use legs

THE REAL NIGHTMARE

Than

k You

Health benefitsWhether or not liposuction provides the health benefits commonly associated with achieving weight loss through other means is a matter of debate in scientific circles. Mainstream doctors agree that liposuction does not help to combat obesity related metabolic disorders like insulin resistance. "Liposuction does not achieve metabolic benefits of weight loss". BMJ 328 (7454): 1457–1450. doi:10.1136/bmj.328.7454.1457-a. PMC 428545.

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