Obesity Grand Rounds by Dr. Susan Beland

Susan S. Beland, M.D.

Associate Professor

General Internal Medicine

Obesity Update 2014

35-year-old woman

5’4” tall, weight 190 lbs (BMI = 32.6 kg/m2)

BP 150/100

FBS 240, HbA1C 8.5%

LDL 180

Strong family history of diabetes, HTN, and CHD

Referred to dietician, started on lisinopril, metformin,

and statin; also instructed to begin a walking program.

We can treat these problems, but how successful will we

be on changing her underlying problem of obesity?

The Case

History of Obesity

Term “obesity” does not appear in English language

until the 17th century.

Prior to modern times, corpulence was associated

with power and influence.

Art in Middle Ages and Renaissance portrays

statuesque women (Michelangelo and Rubens).

In literature, the corpulent were portrayed as jolly

and lovable.

Not until the latter half of the 20th century did

obesity become stigmatized.

History of Obesity (Cont.)

Burden of disease was that of pestilence and famine for

early hunter-gatherers in prehistoric times.

Natural selection rewarded the “thrifty” genotypes of

those who could store the greatest amount of fat.

Discovery of agriculture and domestication of animals

gradually reduced the precarious food supply.

Hunger remained and the Bible is filled with food

imagery (promise of a land of milk and honey, etc.).

Obesity in Art and Literature

“Let me have men about me

that are fat, sleek-headed men

and such as sleep a nights.

Yon Cassius has a lean and

hungry look. He thinks too

much.”Julius Caesar, Shakespeare

“Falstaff sweats to

death, and lards the lean

earth as he walks along”

Henry IV, Shakespeare

Obesity in Art and Literature

“But wait a bit,” the Oysters

cried, “before we have our chat.

For some of us are out of breath,

and all of us are fat!”“Through the Looking Glass”, Lewis Carroll

“No woman can

ever be too rich or

too thin.”Duchess of Windsor

NY Times 1894

Definition of Obesity

Body Mass Index (BMI; kg/m2) is the most helpful

measure:

Underweight = <18.5

Normal BMI = 20.0 - 24.9

Overweight = 25.0 - 29.9

Class I = 30.0 - 34.9

Class II = 35.0 - 39.9

Class III = >40.0

Complications of Obesity Hypertension

Hyperlipidemia

Metabolic syndrome

Coronary heart disease

Type II diabetes

Respiratory disease (OSA)

Gastrointestinal disease (NAFLD and NASH)

Cancer

Rheumatologic disease (osteoarthritis, gout)

Psychiatric

Increased risk of mortality

Geographic Distribution of Obesity

Geographic Distribution of Smokers

Demographics of Obesity

Results from 2011-12 National Health and Nutrition

Examination Survey (NHANES).

9100 participants in cross-sectional national surveys.

Last survey completed in 2003-04.

Odgen et al., JAMA 311:806-814 (2014)

Demographics of Obesity

Overweight or obese Obese

White men 72.7% 33.4%

Black men 69.1% 37.0%

Hispanic men 77.9% 40.1%

White women 64.6% 33.7 %

Black women 82.1% 56.7%

Hispanic women 76.2% 43.3%

Overall 33.7% of men and 36.5% of women were obese,

and 6.4% overall had class III obesity.

No significant increase since the last survey in 2003-04.

900,000 participants, primarily from Western Europe

and North America.

Mean age 46.

Analysis adjusted for age, sex and smoking status.

Mortality lowest at BMI of 22.5 - 25.0.

BMI 30 - 35, median survival reduced by 2 - 4 years.

BMI 40 - 45, median survival reduced by 8 - 10 years.

BMI < 22.5, excess mortality mainly due to smoking.

Prospective Studies Collaboration, Lancet 373:1083-1096 (2009)

Body-Mass Index and Cause-Specific

Mortality in 900,000 Adults: Collaborative

Analyses of 57 Prospective Studies



Analyses of 57 Prospective Studies (Cont.)

Overall mortality for each 5 kg/m2 increase was 30%.

40% for mortality due to vascular disease.

60-120% for diabetic, renal and hepatic mortality.

10% for neoplastic mortality.

Obesity is approaching cigarette smoking as a

leading avoidable cause of premature death.


Cause-Specific MortalityHazard ratio

(BMI 25-50)

Ischemic heart disease 1.39

Stroke 1.39

Diabetes 2.16

Kidney disease 1.59

Liver disease 1.82

Respiratory disease 1.20

All causes 1.29



Analyses of 57 Prospective Studies (Cont.)


Obesity and Mortality

In adult life, it may be easier to avoid substantial

weight gain than to lose weight.

By avoiding a further increase from 28 kg/m2 to 32

kg/m2, a typical person in early middle age would

gain ~2 years of life expectancy, and avoiding an

increase from 24 kg/m2 to 32 kg/m2, a young adult

would on average gain ~3 extra years of life.

Childhood Obesity

Childhood Obesity

Weight >85th percentile defines overweight, and

>95th percentile defines obesity in children (based

on standard CDC thresholds).

2011-12 NHANES data:

Overall, 31.8% of children between 2-19 years

old are overweight.

16.9% are obese, with Hispanic (22.4%) and

black (20.2%) at greater risk.Odgen et al., JAMA 311:806-814 (2014)

Childhood Obesity

Data from the Early Childhood Longitudinal Study,

Kindergarten Class 1998-99.

>700 participants followed through 8th grade.

At entry (mean age 5.6 yrs) 12.4% were obese and

14.9% were overweight.

By 8th grade (mean age 14.1 yrs) 20.8% were obese

and 17.0% were overweight.

Overweight 5-year-olds were 4x as likely as normal

weight children to become obese.

Cunningham et al., NEJM 370:403-411 (2014)

Economic Costs of Obesity

Data from US Medical Expenditure Panel Survey

Impact on annual medical costs estimated to

be $3,613 for women and $1,152 for men.

Estimate of costs of obesity-related illness is

$209.7 billion (in 2008 dollars).

20.6% of US national health expenditures are

spent in treating obesity-related illness.

Cawley & Meyerhoefer, J Health Econ 31:219-230 (2012)

Control of body weight is complex, involving hormones

and neurotransmitters.

Leptin and the OB gene were discovered in 1994.

Secreted by adipocytes - signals brain to reduce food

intake.

Mouse model.

Not found to be of use clinically, as obese people have

increased leptin levels but are resistant to its effects.

Leptin

FTC Cracks Down on Fad Weight-Loss Products

There is No Magic Pill

FDA-Approved Diet Pills

Phentermine: Amphetamine-like action.

Xenical (Orlistat).

Contrave (Bupropion/Naltrexone).

Qsymia (Phentermine/Topiramate).

Belviq (Lorcacerin): 5HT receptor agonist.

Concern over cardiovascular events with Qsymia and

Belviq. Post-marketing trials are not to be completed

until 2017.

Meridia (Sibutramine) was one of the most popular pills

but was taken off the market due to cardiovascular risks.

Fenfluramine/Phentermine (Fen-Phen) also banned due to

risk of pulmonary HTN and valvular heart disease.

FDA Approved Diet Pills (Cont.)

None is approved for long-term use.

Weight loss benefits modest at best.

FDA approval only for BMI >30 (or BMI >27,

with a weight-related illness).

Many diet fads have come and gone over the years.

General agreement that if dieting is going to work

long-term, weight loss must be accomplished slowly

and consistently.

Diets only work if people adhere to them.

“Miracle diets” that cause acute weight loss

invariably fail.

Long-term success rates are low for many reasons:

Set-point theory of weight control.

Failure to make behavioral modifications.

Adherence to restrictive regimens diminishes

with time.

Diets and Weight Loss

415 obese patients with at least one cardiovascular

risk factor recruited from primary care practices.

Two behavioral interventions:

Remote support through telephone, web site,

and email.

In-person support with group and individual

sessions + the three remote means.

Control group weight loss was self-directed.

PCP’s had a supportive role and received regular

progress reports. Appel et al., NEJM 365:1959-1968 (2011)

Comparative Effectiveness of Weight-

Loss Interventions in Clinical Practice

Comparative Effectiveness of Weight-

Loss Interventions in Clinical Practice

(Cont.)

Appel et al., NEJM 365:1959-1968 (2011)

147 adults with BMI 30 - 45.

73 randomized to low fat diet (< 30% of intake).

75 randomized to low carbohydrate diet (< 40

g/day).

Total caloric intake was similar in each group.

At 12 months, low carb group had significantly

greater weight loss (5.3 kg vs. 1.8 kg), increase

in HDL, and decrease in Framingham 10-year

CHD risk score.

Bazzano et al., Ann Intern Med 161:309-318 (2014)

Effects of Low-Carbohydrate and Low-

Fat Diets: A Randomized Trial

Maintaining significant weight loss over the long

term is problematic.

Hypothesis is that weight loss leads to decline in

energy expenditure and an increase in hunger,

resulting in weight gain.

Examined effects of 3 diets on energy expenditure

after weight loss.

21 young adults with BMI >27.

Run-in diets achieved 10-15% weight loss.

Ebbeling et al., JAMA 307:2627-2634 (2012)

Effects of Dietary Composition on

Energy Expenditure During Weight-Loss

Maintenance

3 diets:

Isocaloric low-fat (60% carbs, 20% fat, & 20% protein).

Low-glycemic index (40% carbs, 40% fat, & 20%

protein).

Very low carbohydrate (10% carbs, 60% fat, & 30%

protein).

All participants were fed each diet in random order for 4

weeks each.

Resting energy expenditure (REE) measured by indirect

calorimetry.

Ebbeling et al., JAMA 307:2627-2634 (2012)



Maintenance (Cont.)

Decrease from baseline REE was greatest in the low-fat

diet (-205 kcal/d).

Low glycemic index diet decrease was -166 kcal/d.

Very low carbohydrate decrease was -138 kcal/d.

Total energy expenditure showed a similar pattern.

Authors maintain that this study challenges the notion

that a calorie is a calorie from a metabolic perspective.

Very low carbohydrate diets are likely not to work in

practice due to adherence issues.

Moderate carbohydrate restriction seems to be of benefit.



Maintenance (Cont.)

Caloric restriction results in reduction of

circulating leptin as well as other neuropeptides

that control appetite.

One year after initial weight reduction, levels of

these mediators of appetite that encourage

weight regain do not revert to the levels

recorded before weight loss.

Sumithran et al., NEJM 365:1597-1604 (2011)

Long-Term Persistence of Hormonal

Adaptations to Weight Loss

Exercise and Weight Loss

Exercise alone does not result in significant

weight loss.

Increased activity should, however, be a part of

any weight loss strategy.

NHANES data show that about 50% of all

Americans do not have any significant physical

activity.

Even in the overweight and obese, exercise can

lower risks, especially for CHD.

The Sugar Connection

O

OH

O

OHHO

OH

OH

OH

OH

O

HO

Glucose + Fructose

Sucrose

Sugar Intake and Obesity

Lustig et al., Nature 482:27-29 (2012)

Sugar Intake and Obesity (Cont.)

Sugar consumption has tripled worldwide over the

past 50 years, primarily due to added sugars

Sugar is added to nearly all processed foods, often in

the form of high fructose corn syrup.

High fructose corn syrup is composed of 55%

fructose, which is not vastly different from sucrose.

There is growing evidence that fructose intake is

linked to several chronic diseases:

Metabolic syndrome

Obesity

Hypertension

Dyslipidemia

Hepatic dysfunction (NASH)

Metabolism of Glucose and Fructose

Glucose

Insulin

Liver

Glucose-6-phosphate

Glycogen

80% Brain and muscle

2% Pyruvate Acetyl CoA

FFA’s

VLDL

Glucokinase

Metabolism of Glucose and Fructose

(Cont.)

Fructose (Nearly all ingested

fructose goes to the

liver)

Liver

(Only a small amount of

fructose is converted to

glycogen under normal

circumstances)

Fructose-1-phosphate

Pyruvate Acetyl CoAde novo

lipogenesis

Fructokinase

Ethanol enters the liver through osmosis, and is

metabolized to acetaldehyde

This can generate reactive oxygen species

Large doses of ethanol result in metabolism to

acetyl CoA and the generation of FFA’s

“The dose determines the “poison”of either

ethanol or fructose, since both uniquely drive de

novo lipogenesis, leading to fatty liver,

inflammation, and insulin resistance.”

Lustig, Adv Nutr 4:226-235 (2013)

Fructose: It’s “Alcohol Without the Buzz”

The Toxic Truth About Sugar

Sugar consumption is linked to a rise in non-

communicable disease.

Sugar’s effects on the body can be similar to

those of alcohol.

Regulation could include tax, limiting sales

during school hours, and/or placing age limit

on purchases.

Lustig et al., Nature 482:27-29 (2012)

Nation’s First Soda Tax Is Passed

Berkeley, Calif., became the first U.S. city to pass a

law taxing sugary drinks including sodas.

More than three-quarters of the votes cast were in

favor of Measure D, according to the Alameda

County Registrar of Voters. The measure will place a

1-cent-an-ounce tax on soft drinks.

In nearby San Francisco, city voters rejected a

similar measure to tax sugary drinks.

USA Today 5 Nov 14

In overweight humans, diet high in fructose (25%

of total caloric intake) promotes development of

the metabolic syndrome.

Mice lacking the enzyme fructokinase are

incapable of processing fructose.

Wild type mice fed a Western diet (high in fat and

sucrose) developed severe non-alcoholic

steatohepatitis, while the mice lacking

fructokinase did not.

Lyssiotis & Cantley, Nature 502:181-183 (2013)

F Stands for Fructose and Fat

12-ounce serving of Coke

contains 38 grams of sugar

and 140 calories

1 g ≈ 4 cal

1 teaspoon ≈ 4 g = 16 cal

Owens, Nature 507:150 (2014)

Storm Brewing Over WHO Sugar

ProposalIndustry Backlash Expected Over Suggested Cut

in Intake

WHO Sugar Proposal (Cont.)

In 2003, proposed guideline that no more than 10%

of daily calories should come from sugar.

Current proposal cuts this in half to 5%, citing the

need to fight obesity.

Sugar in the average person should only account

for 100 cal/day which translates to ~26 grams or 6

teaspoons

Opposed by the food industry – “If people follow

this advice, that would be very bad for business”.

Owens, Nature 507:150 (2014)

WHO Sugar Proposal (Cont.)

Owens, Nature 507:150 (2014)

Summary

One-third of Americans are obese.

Obesity has a significant impact on morbidity and

mortality, approaching that of cigarette smoking.

Diets work only if adhered to and lifestyle is

modified.

Long-term maintenance of weight loss remains

problematic.

Obesity in children is increasing and fat children

tend to become fat adults.

Sugar consumption is a major factor in obesity and

related diseases due to increased caloric intake and

the effects of fructose metabolism.

There is no magic bullet - “We are what we eat.”

Comments or questions?

Obesity Grand Rounds by Dr. Susan Beland

Health & Medicine