1st Obesity, Diabetes and Nutrition Summit

The Challenges of Preventing and

Treating Obesity
Lee M. Kaplan, MD, PhD
Obesity, Metabolism & Nutrition Institute
Massachusetts General Hospital
Harvard Medical School
LMKaplan@partners.org

Womens Health Society, San Juan, Puerto Rico

November 15, 2014

Obesity by the Numbers

Overweight U.S. adults:

68%

U.S. adults with obesity:

36%

U.S. children with obesity: 17%

Annual U.S. health care expenditures for obesity:

> $ 200 billion

U.S. consumer expenditures for weight loss products:

Daily deaths from obesity complications

> 1,000

> $ 50 billion

Disproportionate Increase in Severe Obesity

Today, more than 1.7 million US adults with BMI>50

Sturm R, Pub Health, 2007

Complications of Obesity

Metabolic
Structural
Inflammatory
Degenerative
Neoplastic
Psychological

65

Medical Complications of Obesity

Stroke
Pulmonary disease
abnormal function
obstructive sleep apnea
hypoventilation syndrome

Intracranial hypertension
Cognitive dysfunction
Cataracts
Coronary heart disease

Pancreatitis

Diabetes
Dyslipidemia

Fatty liver disease

steatosis
steatohepatitis
cirrhosis

Hypertension

Gallstones
Cancer
breast, uterus, cervix, ovary,
prostate, kidney, colon, esophagus
pancreas, gallbladder, liver
Skin disorders
Gout

Gynecologic abnormalities
abnormal menses
infertility
polycystic ovarian syndrome
Osteoarthritis
Phlebitis
venous stasis

Obesity is Counterintuitive

Hides in plain sight

Most obesity NOT recognized by physicians or the public

Did NOT start in the past 30 years

NOT a problem of eating too much
NOT a single disorder
Probably several dozen or more clinically meaningful subtypes
This recognition is essential to solving the problem

The problem is NOT slowing down

NOT mainly in America

Obesity is a Worldwide Epidemic

2008

Obesity is a Worldwide Epidemic

2014

28.7%
(self-report)
66+% overweight

Obesity
Historical view
Lifestyle choice
Characterological flaw (willpower, psychology)

Obesity
Historical view
Lifestyle choice
Characterological flaw (willpower, psychology)

Current perspective
Dysfunction of a complex physiological regulatory system
Epidemic from changes in modern environment
Widely recognized as a disease
Huge burden of associated illness
Devastating effect on efficacy and quality of life

Weight and Energy Balance

By the laws of physics

Food
Intake

Energy
Expenditure

Weight and Energy Balance

Adding physiology to physics

Energy
Expenditure

Food
Intake

Brain

The Normal Physiology of Energy Balance

Average adults require approximately 1300 kcal/day
Average adults consume 2000-2500 kcal/day
Average adults therefore consume 1.5-2 times as much food as
required
Excess intake is available for physiological emergencies

Maintaining weight within 20 lbs. between ages 21 and 65

requires matching of intake and expenditure within 0.2%
Corresponds to accuracy of 4-5 kcal/day
Less than one-half potato chip

Maintenance of normal fat stores (and body weight) requires

precise disposal of 40-50% of ingested calories daily
Thus, daily energy balance is likely an evolved physiological
trait largely independent of cultural or behavioral differences.

Feedback Regulation of Energy Metabolism

Sensory Organs
GI Tract

Environmental
sensing

Muscle

Liver
Bone

Irisin
Metabolic
activity and
needs

Energy
stores
Food intake
Nutrient handling
Energy expenditure

Leptin
This process involves
as much as 20% of the
human genome

Adipose
tissue

GI Regulation of Metabolic Function

Central Mechanisms
Appetite, Food Reward
Energy Expenditure
Metabolic Function

Gut
hormones

Efferent
neurons

Immune
Cells

Energy Balance
Metabolic Function

Liver
Pancreas
GI Tract

Nutrients

The Body Maintains a Stable Adipose Tissue Mass

Similar to other regulated tissue mass

Liver
Red blood cells

Weight Loss Curve

Sumithran et al. NEJM 2011; 365:1597-1604.

Ghrelin

PYY

Amylin

CCK

Gut Hormone Changes Persistently Oppose

Diet-induced Weight Loss

Sumithran et al. NEJM 2011; 365:1597-1604.

Natural Variation and Zones of Opportunity

BMI
20

22

Excellent

24

26

28

Poor

Degree of Control

30

33

36

39

42

46

50

55

60

Obesity results from a failure of normal weight

and energy regulatory mechanisms

Obesity: A Failure of Weight Regulation

Cortex

Genetics
Development
Environment

HT
GI Tract

Leptin

Food intake
Energy expenditure
Nutrient handling

Adipose tissue

In most obesity, fat mass regulation is not broken

it just regulates to an abnormally high target

Environmental Influences on Metabolism

Direct Influences
on Brain
CNS

Enterokines

Myokines

GI Tract
Adipokines

Muscle

Influences
Through Gut

Fat

Influences
Through Muscle

Environmental Drivers to Obesity

(3) Stress and distress

(4) Drugs
direct impact on relevant areas of the brain)
(accounts for up to 10%)

(2) Decreased
physical activity
(effects on muscle
more than calories)

(1) Altered
food supply
(signaling more
than calories)

Cortex

HT
GI Tract
Muscle

Leptin

Adipose tissue

Food intake
Energy expenditure
Nutrient handling

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

Obesity Treatment

Overall Treatment Strategy

Typical Algorithm
(progress through algorithm as clinically required)
Self-directed Lifestyle Change
Professionally-directed Lifestyle Change
Add Medications
Weight Loss Surgery
Post-surgical Combination Therapies

Goal of Lifestyle Therapy

Normalize the Microenvironment

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

Lifestyle Treatment of the Patient with Obesity

Goal:
To reverse the elevated fat mass set point, which is the cause
of obesity in the first place
Healthy diet to change nutrient environment by changing chemistry

Improves nutrient signaling to the brain

Emphasize unprocessed foods
Encourage complexity
Number of calories is MUCH less important

Regular exercise
To improve muscle health, not to burn calories acutely
Long-term exercise more important than type or intensity
Stress reduction
Reduce both perceived and invisible stresses
Restore sleep
Regularize circadian rhythms

Composition of Popular Diets

Macronutrient Distribution Has Minimal Effect

Fat:
Carbohydrate:
Protein:

Conclusion:
Sacks et al., NEJM 2009; 360:859

Low (20%) vs. high (40%)

Low (35%) to high (65%)
Average (15%) vs. high (25%)

No difference in outcome among

diets of different composition

Variable Weight Loss After Diet Therapy

Zone Diet

Weight Change

Weight Change

LEARN Program

Ornish Diet

Weight Change

Weight Change

No. of Subjects

No. of Subjects

Atkins Diet

Adapted from Gardner et al, JAMA 2007

Physical Activity Extends Weight Loss

Look AHEAD Trial

26

85

149

287

min/wk

min/wk

min/wk

min/wk

Look AHEAD Research Group. Obesity 2009; 17:713

Effects of Chronic Exercise

Decreased food intake

Altered food preferences
Toward healthy foods

Increased brown fat development

Enhanced energy expenditure
Re-regulation of energy set point

Lifestyle Strategy
Keep the goal in mind: significant and durable weight loss
Assess patients current lifestyle and habits
Identify greatest opportunities for lifestyle change
Focus on changes that influence the obesogenic environment, not the
cardiovascular or other risk

Pursue sequential application of limited lifestyle changes

Determine effectiveness of each individual change
Include non-diet, non-exercise interventions (sleep, stress, circadian)
Use classic strategies of habit change (opportunity, cue, reinforcement)
Anticipate need for the additive effects of multiple lifestyle changes

Aim for clinically significant weight loss

Be in sync with the patient

Pharmacological Therapies

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

Weight Loss from Other Medications

Strategy: Aim for Double Benefits when Possible
Medication

Indicated Uses

Comments

Bupropion

Depression

Avoid in bipolar disease

Topiramate

Seizures
Migraines
Mood disorders

May produce neurological side

effects

Zonisamide

Seizures
Mood disorders

Few studies

Metformin

Type 2 diabetes
PCOS

Rare liver toxicity

Liraglutide. Exenatide

Type 2 diabetes

Injectable

Pramlintide

Type 2 diabetes

Injectable; nausea common

Canagliflozin

Type 2 diabetes

Medications Approved for Obesity

Medication
Phentermine
(Adipex, Ionamin)

Phentermine /
Topiramate

Average
Weight Loss*

Mechanism of
Action

Potential Side Effects

~ 5%

Adrenergic

Tachycardia, hypertension

10%

Adrenergic, CNS

Tachycardia, hypertension,
cognitive dysfunction,
neuropathy, teratogenicity

4.5%

CNS; opioid
antagonism

Seizures, confusion, anxiety,

opiate withdrawal

3.5%

Serotonergic
(5HT2C)

Headache

3%

Lipase inhibitor

Steatorrhea, incontinence

(Qsymia)

Bupropion /
Naltrexone
(Contrave)

Lorcaserin
(Belviq)

Orlistat
(Xenical)

* Beyond placebo

Optimal Pharmacological Strategy

Optimize the patients current medical regimen

Avoid weight gain-promoting medications
Substitute a more weight-friendly alternative

Personalize the care: find the best treatment for each patient
Pursue sequential trials of different medications
Minimum threshold for long-term use: 5% weight loss
Build to 2-3 drug combinations as needed

Aim for substantial (not minimally important) weight loss

Use in conjunction with ongoing lifestyle-based therapy
Anticipate life-long use of successful regimens

Weight Loss Varies Widely Among Patients

Sibutramine-induced Weight Loss

Responder Tail

Adapted from Hansen DL et al., IJO 2001; 25:496

56

The Obesities A Plethora of Discrete Disorders

Leptin deficiency
LepR deficiency
MC4R deficiency
MSH deficiency
Sim-1 deficiency
PC-1 deficiency
KSR2 deficiency
MRAP2 deficiency
SH2B1 deficiency
BDNF deficiency
trkB deficiency
Carpenter syndrome
Cohen syndrome
Ayazi syndrome
MOMO syndrome
Rubenstein-Taybi syndrome
Fragile X syndrome
BFL syndrome
Albright osteodystrophy

Prader- Willi syndrome

Bardet-Biedl syndrome
Alstrm syndrome
Hypothalamic
Hyperphagic
Thermogenesis deficient
Circadian-disrupted
Stress-induced
Central
Peripheral
Diffuse
Neonatal
Early childhood
Peripubertal
Gestational
Menopausal
Healthy
Metabolic
Inflammatory

Diet-dependent
Exercise-sensitive
Sleep-sensitive
Insulin-induced
Steroid-induced
Progesterone-induced
Psychotropic-induced
Antibiotic-induced
Endocrine disruptor
Phentermine-responsive
Lorcaserin-responsive
Topiramate-responsive
Metformin-responsive
Bupropion-responsive
GLP-1 responsive
Bypass-responsive
Bypass-resistant
Gastric band-responsive

Multiple Subtypes = Variation in Treatment Response

What Differs Among Different Obesity Subtypes

Timing of obesity onset
Fat location and distribution
Metabolic consequences
Phenotypic differences
Hunger
Satiety
Reward-based eating
Energy expenditure
Response to environmental causes
Eating
Exercise
Stress
Sleep deprivation
Circadian disruption
Response to therapies

Number of Subjects

Heterogeneity of Response

Highly
responsive
subgroup

Weight Loss

Algorithm Example 1 Off-Label Use

Inadequate Weight Loss

Minimum Adequate Weight Loss

Phentermine
15-30 mg/d to clinical effect

Topiramate

Add:

Topiramate
(25-200 mg/d to clinical effect)

(25-200 mg/d to clinical effect)

Metformin

Add:

Phentermine

(1000-3000 mg/d to clinical effect)

Zonisamide
Bupropion
Naltrexone
Liraglutide

Add:

Second agent

Algorithm Example 2 Approved Use

Inadequate Weight Loss

Minimum Adequate Weight Loss

Phentermine
15-30 mg/d to clinical effect

Qsymia
(topiramate/phentermine)
(escalate to clinical effect)

Lorcaserin
(escalate to clinical effect)

Orlistat

Add:

Phentermine

Surgical Therapies

Weight Loss Surgery

Gastric
Adjustable
Gastric Banding

Combination
Vertical Sleeve
Gastrectomy

Roux-en-Y
Gastric Bypass

Metabolic Surgery
Weight-independent
Metabolic Benefits
Adjustable
Gastric Banding

Vertical Sleeve
Gastrectomy

Roux-en-Y
Gastric Bypass

Average Effectiveness of Obesity Treatments

Swedish Obesity Subjects
Diabetes Prevention Program

Surgery Decreases Long-term Mortality

Utah Study
15850 gastric bypass patients and matched controls
7.1 year mean follow-up
Gastric bypass group exhibited overall 40% reduction
in mortality
Specific-cause mortality after gastric bypass
56% reduction from CAD
92% reduction from type 2 diabetes
60% reduction from cancer

Adams et al., NEJM 2007

Weight Loss Surgery Improves T2DM

Glycated Hemoglobin

Change from Baseline

Change from Baseline (%)

Body Mass Index

Month

Schauer PR et al., NEJM 2014

Month

Weight Loss Surgery Improves T2DM

Month

Schauer PR et al., NEJM 2014

Use of DM Medications

Average Number

Change from Baseline (%)

Glycated Hemoglobin Adjusted by BMI

Month

Mechanisms of Diabetes Improvement

Gastric Banding

Gastric Bypass

Gradual effects

Weight Loss

Control of Diabetes
Immediate effect

Why is bariatric surgery so effective?

Mechanisms of Bariatric Surgery

Classical model:
Mechanical

Current model:
Physiological

Restricted food intake

Altered GI signals to brain

Malabsorption

Endocrine
Neuronal
Altered GI signals to other
tissues (pancreas, liver)

Bariatric Surgery
Evidence for Physiological Mechanisms
1.

Dramatic effects on hunger and satiety

2.

Few patients become underweight after surgery

3.

Transient weight gain during pregnancy

4.

Little or no weight loss in thin patients or animals

5.

Changes in GI endocrine markers ghrelin, PYY, GLP-1, amylin

6.

Increased energy expenditure (bypass procedures)

7.

Ability to reverse effects of surgery with drugs and genetic

manipulation (MC4R; FXR)

The effects of bariatric surgery are fundamentally

and broadly different from the effects of other
types of weight loss

GI Endocrine Responses to RYGB

GLP-1

Ghrelin

Shin et al., 2010

PYY

Amylin

Ghrelin

PYY

Amylin

CCK

Gut Hormone Changes Persistently Oppose Dietinduced Weight Loss

Sumithran et al. NEJM 2011; 365:1597-1604.

RYGB is the Opposite of Restrictive Dieting

Diet

RYGB

Energy expenditure

Appetite

Hunger

Satiety

Reward-based eating

Ghrelin

GLP-1, PYY, CCK, amylin

Stress response
Gut peptides

RYGB is the Opposite of Restrictive Dieting

Diet

RYGB

Energy expenditure

Appetite

Hunger

Satiety

Reward-based eating

Ghrelin

GLP-1, PYY, CCK, amylin

Stress response
Gut peptides

GI Regulation of Metabolic Function

Central Mechanisms
Appetite
Energy balance
Glucose metabolism

Gut
hormones

Efferent
neurons

Body
Weight
Weight
Loss
Improved
Metabolic Diabetes
Function

Liver
Pancreas
Gastric
GI Tract
bypass

Nutrients

Case Study A.G.

51-year-old woman with BMI 43.3
Weight 252 lbs., height 54
Well-controlled hypertension, hypothyroidism, Barretts
esophagus, osteoarthritis (s/p knee replacement), colonic
polyps, and depression
Uncomplicated type 2 diabetes on pioglitazone, glimepiride and
insulin (long- and short-acting to total of 65 units/day)
Sleep apnea well-controlled on CPAP
Other medications include losartan, hydrochlorthiazide,
omeprazole, levothyroxine, aspirin and sertraline

Case Study A.G.

Examination
Central obesity with waist circumference 41 in.
Benign, protuberant abdomen; no signs of chronic liver
disease
No signs of peripheral neuropathy

Laboratory studies
Fasting glucose 111
HbA1c 7.1%
AST 43, ALT 51, alkaline phosphatase 120
BUN 32; creatinine 1.2
TSH 5.64

Case Study A.G.

Weight and lifestyle history
Normal weight as a child; overweight in college and
graduate school (weight 150-175; BMI 26-30)
Progressive weight gain in adult life; insatiable appetite
with frequent cravings and large portions
Numerous unsupervised, supervised and structured diets
with variable weight loss (up to 30 lbs.); none maintained
Average weight stable over the past few years; currently
at highest lifetime weight
Married with grown children; works as financial planner
Cooks regularly and well, and entertains often
Exercises three times a week with a physical trainer

Case Study A.G.

Stop sulfonylurea
Start metformin

45

36
32
27
23

BMI (kg/m2)

40

Case Study A.G.

Stop sulfonylurea
Start metformin
Phentermine
+ Topiramate

45

-17 lbs.

36
32
27
23

BMI (kg/m2)

40

Case Study A.G.

Stop sulfonylurea
Start metformin
Phentermine
+ Topiramate
Zonisamide

45

-6 lbs.

36
32
27
23

BMI (kg/m2)

40

Case Study A.G.

Stop sulfonylurea
Start metformin

Gastric
bypass

Phentermine
+ Topiramate
Zonisamide

45

+3 lbs.

36
32
27
23

BMI (kg/m2)

40

Case Study A.G.

Stop sulfonylurea
Start metformin

Gastric
bypass

Phentermine
+ Topiramate
Zonisamide

45
40
36
32
-51 lbs.

27
23

BMI (kg/m2)

Add
Phentermine

Case Study A.G.

Stop sulfonylurea
Start metformin

Phentermine
+ Topiramate
-6
Zonisamide

-51

Total Weight Loss = 93 lbs.

BMI fell from 43 to 27 kg/m2
Over nearly 3 years

+3

45
Add
Phentermine
-22

40
36
32

-22 lbs.

27
23

BMI (kg/m2)

-17

Gastric
bypass

Take-home Messages

Evaluation of the Patient with Obesity

Characterize the obesity
Measure and follow weight and BMI
Use waist circumference to assess body fat distribution in
patients with BMI between 25 and 35 kg/m2

Identify and treat comorbidities

Aim to reduce disparities in care; respect the patient
Develop a long-term strategy for treating the obesity itself

73

Practical Guidance

Embrace Modest Weight Loss

Current non-surgical weight loss therapies are generally
an adjuvant treatment for obesity comorbidities
Focus on what is achievable and sustainable
Understand that there are biological limits to each therapy
Be clear about what treatment can and cannot do

Understand that one size does not fit all

76

Practical Guidance

Go Slow and Try Different Approaches

Test therapies sequentially
Pursue combination therapies including combinations of specific
lifestyle changes with more classical medical approaches
Be supportive
Be persistent
Be there for the patient

Aim for cure, but always provide care.

Parting Thought Obesity Prevention

The lessons from the development of effective

obesity therapies will be the best guide for more
effective obesity prevention strategies, including:
Recognition of multiple, differing causes of obesity
Expectation that different approaches will benefit different
subpopulations
The same need for multiple, varied and combinatorial
approaches as for obesity treatment

1st Obesity, Diabetes and Nutrition Summit

The Challenges of Preventing and

Treating Obesity
Lee M. Kaplan, MD, PhD
Obesity, Metabolism & Nutrition Institute
Massachusetts General Hospital
Harvard Medical School
LMKaplan@partners.org

Womens Health Society, San Juan, Puerto Rico

November 15, 2014