Obesity Update 2013: Scientific and Clinical Advances

Dan Bessesen, MD Professor of Medicine

University of Colorado School of Medicine Daniel.bessesen@ucdenver.edu

The Year in Obesity: Game plan

• Is Obesity a problem? • Developments in Basic Science • Developments in Lifestyle Therapy • Developments in Pharmacotherapy • Developments in Bariatric Surgery

Medical Complications of Obesity

Phlebitis venous stasis

Coronary heart disease

Pulmonary disease abnormal function obstructive sleep apnea hypoventilation syndrome

Gall bladder disease

Gout

Diabetes

Osteoarthritis

Nonalcoholic fatty liver disease steatosis steatohepatitis cirrhosis

Hypertension Dyslipidemia

Cataracts

Skin

Pancreatitis

Idiopathic intracranial hypertension

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

Gynecologic abnormalities abnormal menses infertility polycystic ovarian syndrome

Stroke

Relationship Between BMI and Risk of Type 2 Diabetes Mellitus

Chan J et al. Diabetes Care. 1994;17:961. Colditz G et al. Ann Intern Med. 1995;122:481.

Age

-Adj

uste

d R

elat

ive

Ris

k

Body Mass Index (kg/m2)

<23 24-24.9 25-26.9 27-28.9 33-34.9 0

25

50

75

100

1.0 2.9 4.3 5.0

8.1 15.8

27.6

40.3

54.0

93.2

<22 23-23.9 29-30.9 31-32.9 35+

1.0 1.5 2.2

4.4 6.7

11.6

21.3

42.1

1.0

Men Women

0

1

2

3

4

5

6

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

Rel

ativ

e R

isk

Weight Change (kg) Willett et al. N Engl J Med 1999;341:427.

-10 -5 0 5 10 15 20

Men

Women

Age-Adjusted Prevalence of Obesity and Diagnosed Diabetes Among U.S. Adults Aged 18 Years or older

Obesity (BMI ≥30 kg/m2)

Diabetes

1994

1994

2000

2000

No Data <14.0% 14.0-17.9% 18.0-21.9% 22.0-25.9% >26.0%

No Data <4.5% 4.5-5.9% 6.0-7.4% 7.5-8.9% >9.0%

CDC’s Division of Diabetes Translation. National Diabetes Surveillance System available at http://www.cdc.gov/diabetes/statistics

2010

2010

0.0

0.5

1.0

1.5

2.0

2.5

Folsom et al. Arch Intern Med. 2000;160:2117. Body Mass Index Tertile

3 2 1

Rel

ativ

e R

isk

Abdominal Fat Distribution Increases the Risk of Coronary Heart Disease

The Iowa Women’s Health Study

Rel

ativ

e R

isk

of C

VD

M

orta

lity

1 2 3 4 5 6 7 8

Lean Normal Obese

Body Fat Category (% Weight as Fat) <16.7% 16.7%–24.9% ≥25%

Fatness, Fitness, and Cardiovascular Disease Mortality

Lee et al. Am J Clin Nutr 1999;69:373.

Aerobically fit Unfit

Flegal, JAMA Jan 2, 2013, 309: 71-82

Hazard Ratio (risk) of Mortality and Obesity

Mortality is lowest With BMI 25-30 kg/m2

Mortality is not significantly With BMI 30-35 kg/m2

Excess mortality from obesity is likely due to those with BMI >35 kg/m2

The development of weight related illnesses

Diabetes

Coronary Artery Disease

Hypertension

Diet/Physical Activity Overweight Lean

Time

Obese

Arthritis

Cancer

Genes

Environment

So what is the ‘truth’? • Obesity is clearly related to a number of

health problems • Obesity has increased over recent years • People who are obese now “may not have

been obese” 40 years ago. • Mortality may not be increased with

modest increases in weight • Modest weight gain may just increase

disease and disability but not death

Developments in Basic Science

• A New Hormone: Irisin • Genetics • Gut Microbiome: Antibiotics and Weight

Gain • Sleep and Weight Regulation

A New Hormone: Irisin Bostrom, Nature 2012 481: 463-469

• Exercise has a range of metabolic benefits • Overexpression of PGC1-α protects against age

associated weight gain and insulin resistance • Overexpression of PGC1-α in skeletal muscle

resulted in up-regulation of UCP1 in white adipose tissue from these mice (“browning”/ beige fat)

• Hypothesized a protein secreted from muscle induced these changes in adipose tissue

A New Hormone: Irisin Bostrom, Nature 2012 481: 463-469

• Five proteins were identified as PGC1-α target genes in muscle: IL-15, FNDC5, VEGF-b, LRG1 and TIMP4

• FNDC5 is the focus of this paper because it appears to be secreted and – Increases energy expenditure – Improves insulin sensitivity – Reduces weight

• Named after the Greek messenger goddess Iris

Effects of 10 d of Irisin Exposure Bostrom, Nature 2012 481: 463-469

A New Hormone: Irisin Bostrom, Nature 2012 481: 463-469

Genetics of Obesity: Genetic Variability

Nature 2012 490: 267-273 • In general GWAS of weight have

suggested that a moderate number of genes have relatively small effects on determining weight.

• Genes may affect “weight variability” • Greater variability suggests a breakdown

of homeostatic control or a gene x environment interaction=greater range of “acceptable weights”

Genetics: Interaction of Diet and Genes N Engl J Med 2012;367:1387-96.

Those with 10 high risk genetic alleles who consumed >1 SSB/d had a mean BMI 2.4 kg/m2 greater than those who consumed SSB but were at low genetic risk

Gut Microbiome and Weight

• Studies in germ free mice demonstrated that gut microbiome has effects on weight.

• Work has focused on characterizing the differences in the microbiome between lean, obese and reduced obese.

• More recently work has focused on the acquisition of the gut microbiome and potential therapeutic effects.

Antibiotic Use and Weight Nature 2012; 488: 621-626

• In agriculture use of antibiotics is found to increase animal body weight and growth rate.

• The average American child receives 1 course of antibiotics per year.

• Blaser group exposed mice to sub-therapeutic doses of antibiotics and examined body fat, the gut microbiome and metabolic genes.

Antibiotic use and weight Nature 2012; 488: 621-626

Circadian Rhythms and Weight

• Epidemiological data shows that shortened sleep time is associated with obesity

• Shortened sleep time is associated with increased food intake associated with ghrelin

• Unclear if increasing sleep in those with short sleep time increases effectiveness of weight loss treatment.

• Recent data suggests peripheral clock genes are involved as well.

Adipocyte Specific KO of Clock Gene Results in Obesity Paschos GK,Nature Med, 2012

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

A Guide to Selecting Treatment

Treatment BMI category

25-26.9 27-29.9 30-34.9 35-39.9 ≥40

Diet, physical activity, and behavior therapy

Pharmacotherapy

Surgery

With co-morbidity

With co-morbidity

With co-morbidity

+ + + +

+

+

+ +

The Practical Guide. 2000

Behavioral Weight Loss: The Look AHEAD (Action for Health in Diabetes) Trial

• 5,145 subjects with T2 DM recruited from 16 intervention centers across the US.

• Hypothesis: weight loss would reduce cardiovascular events.

• Average weight loss=8% at 6 months, 4% at 4 years.

• Sept 2012 after 11 years of intervention the trial was halted by the NIH as a ‘negative trial’.

Behavioral Weight Loss: The Look AHEAD (Action for Health in Diabetes) Trial

Clin Trials. 2012 Feb;9(1):113-24. • Problem was that the study was powered for an

event rate of 3.125%/year and at the 3 year mark the event rate was 0.7%/year

• This was due to – Secular trends in CVD – Those who enrolled in the trial were

“healthier” than those in epidemiologic cohorts.

– GXT excluded people with low exercise tolerance

Effect of Weight Loss on Glycemic Control in Type 2 Diabetes (Look AHEAD)

Wing R, et al. Diabetes Care. 2011;34:1481

Change in HbA1c (%) Change in Fasting Blood

Glucose (mg/dL) (%)

p<0.0001

Gain>2% Gain≤2% Lost≥2% Lost≥5% Lost≥10% Lost≥15% Lost<2% Lost<5% Lost<10% Lost<15%

0

0.2

0.4

0.6

0.8

-1 Gain>2% Gain≤2% Lost≥2% Lost≥5% Lost ≥10%Lost ≥15% Lost<2% Lost<5% Lost<10% Lost<15%

0

-10

-20

-30

-40

--50

p<0.0001

Effect of Weight Loss on Blood Pressure in Type 2 Diabetes (Look AHEAD)

Wing R, et al. Diabetes Care. 2011;34:1481

Gain>2% Gain≤2% Lost≥2% Lost ≥5% Lost ≥10% Lost ≥15% Lost<2% Lost<5% Lost<10% Lost<15%

0

-2

-4

-6

-8

-10

-12

-14

SBP: p<0.0001 DBP: p=0.0001

SBP DBP

mm Hg

1o Drug Treatment of Obesity

• Current medications 5-12% wt loss • Likely will need to use long term. • Typically not paid for by insurance so cost is

a big issue for patients. • Issues of FDA approval, long term safety, and

efficacy. • Older medications: Phentermine and Orlistat

Phentermine/Topiramate (Qsymia, Vivus)

• Combination gives greater efficacy with fewer side effects

• Doses 7.5/46 mg and 15/92 mg phenterming/topiramate

• Cost: $150.00/month • Side effects: dry mouth, paraesthesias,

insomnia, dizziness, anxiety, irritability and disturbance in attention

Phentermine/Topiramate • Only being dispensed by special on line

pharmacies, women need – pregnancy test on starting and monthly while using.

• Reduces blood pressure, glucose, insulin, triglycerides and raises HDL

• Unclear if physicians will prescribe off label using generic phentermine and topiramate.

• Most effective medication available 10-12% weight loss.

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

Topiramate/Phentermine (Qsymia) Effects on Weight

Topiramate/Phentermine (Qsymia) Effects on Weight

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

Topiramate/Phentermine Effects on Lipids

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

Topiramate/Phentermine Effects on Blood Pressure

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

Lorcasarin (Belviq) • Serotonin 2C receptor agonist, activates

POMC neurons which leads to α−MSH activation of MC4R leading to satiety

• Previous serotonin agonists fenfluramine and dexfenfluramine caused cardiac valve disease, removed from market

• 2C receptor only in the brain not in heart • Studies in 1-2,000 people for up to 2

years do not show evidence if valvulopathy with lorcasarin.

Lorcasarin (Belviq) • Weight loss: 4-5% no better than

phentermine or orlistat • Side effects: minimal headache,

dizziness and nausea (rare priapism, monitor for depression)

• Cost: not known at this time • Unclear if physicians will prescribe off

label with phentermine (no safety/efficacy data)

Lorcasarin: Weight Effects

N Engl J Med. 2010 Jul 15;363(3):245-56

Gastric Bypass

Lap Band

Sleeve Gastrectomy

Stampede Trial: Randomized Trial of Bariatric Surgery for T2DM

N Engl J Med 2012;366:1567-76

• Previous studies suggested DM went into remission following bariatric surgery.

• 150 patients randomized to intensive medical therapy, gastric bypass or sleeve gastrectomy for management of type 2 diabetes

• Average baseline A1C was 9.2% • 93% follow up at 12 months

Health Benefits: Stampede Trial: N Engl J Med 2012;366:1567-76

CV Medications Stampede Trial: N Engl J Med 2012;366:1567-76

Swedish Obese Subjects Trial Bariatric Surgery vs Usual Care

• Nonrandomized prospective controlled study

• 2010 pts had surgery compared to 2037 contemporaneously matched controls

• Began 1987 • Median follow up 14.7 years • 2012 papers published on diabetes,

cardiovascular, cancer and health care utilization endpoints

Weight loss in the SOS

JAMA. 2012;307(1):56-65

Cardiovascular Events in the SOS

JAMA. 2012;307(1):56-65

Cancer in the SOS

Lancet Oncol 2009; 10: 653–62

Flum DR, N Engl J Med. 2009 Jul 30;361(5):445-54.

Risks of Bariatric Surgery: the LABS Study

Summary • Obesity is associated with health

problems but the relationship is complicated and may be changing over time.

• Exciting new developments in basic science

• New medications may give hope to some obese patients.

• Weight loss surgery appears to be quite effective but who should have it?