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Evidence Based Obesity Treatment

Richard D. deShazo, MDLeigh Baldwin Skipworth, BA

University of Mississippi Medical CenterJackson, Mississippi

© Richard deShazo, MD 2014

Major Factors Affecting Mississippi’s Health

Health Literacy

Geography

Poverty

Systems of Care

Race &Culture

Education

Access to Care

Epidemiology 1O Prevalence of obesity among adults aged 2- and

over; US 1997-June 2013

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Hope?

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Epidemiology 2O Prevalence of obesity among adults aged 20 and

over by age group and sex US January – June 2013

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The next 20 years

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Disparities in Mississippi

School Children

overweight or obese

MS Kids Count 2014 Data

O Annie E. Casey Foundation/MS SSRC

America’s Health 

Rankings

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Satiety Cross Talk

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Control of Eating BehaviorsPresent Concepts

Sumithran Clin Science 2013; 124:231

Central and Peripheral Control of Eating Behavior1

CentralO Arcuate nucleus of the hypothalamus

controls food intake and energy balance to maintain homeostasis

O Cortical and subcontrol limbic system inputs can override hypothalamic controls (Hedonic stimuli) 2

PeripheralO Gut, pancreas and fat neurochemical inputs

are important in homeostasis8

O 1. Schwartz. Nature. 2000; 404:661-671; 2. King. Am Psychologist 2013; 68:88-96.The non-homeostatic brain reward circuitry that was acquired during evolution to seek out as many high-dense foods as possible is able to overrule the psychological inhibitory mechanisms that were designed

to limit meal size and weight gain

O After Regulation of Food Intake and Energy Expenditure. Clin Science 2013; 124:231

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HomeostasisHormonal signals from the GI tract and adipocytes stimulate

the arcuate nucleus of the hypothalamus to co-express neuropeptide y and agouti-

related peptide and increase food intake

-OR-To express pro-

opiomelanocortin, and decrease food intake

Hedonic influencesIn response to sight, smell, taste, emotional and

social factors, impulses from the cortex and limbic system under it are sent to the

hypothalamus. These increase the desire for energy dense palatable food and override

homeostatic regulation

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Peptides and hormones involved in appetite regulation

O Sumithran Clin Science 2013; 124:231

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Location Anorexigenic (-) Orexigenic (+)

Central Hypothalamus

POMCNesfatinTRHCRHOxytocinSerotoninHistamineUrocortin

NPYAgRPOrexinsMCHEndocannabinoidsOpioids

Peripheral Gastrointestinal tract

CCKGLP-1PYYOxyntomodulinEnterostatinBombesinUroguanylin

Ghrelin

Pancreas AmylinInsulinPP

Adipocytes Leptin

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Eating

Overeating

Fat accumulation

Metabolic changes

Disease

Activation of hedonicneuronal circuits in

the amygdala, insula, orbito-frontal cortex

Hypothalamic feeding circuits (homeostasis)

Pleasure

Hyperactive reward circuitry to

food stimuli

After King BM. Am Psychologist 2013

Gut and fat hormones

Mechanisms of Eating & Overeating Environment,

human behavior, genetics

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Why Do People Overeat?

O “The non-homeostatic brain reward circuitry that was acquired during evolution to seek out and eat as many nutritionally high-dense foods as possible is able to overrule the physiological inhibitory mechanisms that were designed to limit meal size and weight gain.

O When offered a variety of highly preferred foods, many will eat until feeling ill.”

King. American Psychologist 2013; 68: 88.

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Fat and Inflammation Disease

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O McArdle Front Endo 2013; 4:7 2013

Hypertrophic Adipocytes and M1 Macrophages

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O McArdle. Front Endocrinol. 2013; 4: 52

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What is WAT?

Have Humans Trumped the Hypothalamus with the Cerebral Cortex?

O The biology of obesity appears to be more complex than calories in = calories consumed, stored or excreted

O The hormonal hypothesis of obesity suggests that the kind of food consumed plays a role via appetite and satiety mechanisms. For instance, the types of carbohydrate (refined grains, starches and fructose) seem important

O Since insulin is the primary hormone controlling fat deposition, insulin resistance also seems important.

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Taubes G. Scient Amer 2013; 309.60.

Questions Raised by Seeing Overeating as a Hormonal Not 

a Behavioral Disorder?

O Palliative foods override normal weight control mechanisms

O Obese individuals generally have a paradoxically high level of appetite suppressing hormones, including leptin and insulin

O May obesity seen as a “disease”?O Are obese individuals “victims”?

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Kenney PJ. The Food Addiction. New brain research is revealing why fats and sugars may be driving more and more people toward obesity. Would a rat risk dying just to satisfy its desire for chocolate? Scientific American 2013; 309:44.

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Food Science and the FLAVORConnection

O Kupferschmidt K. Following the Flavor. Science 2013; 340:808-809

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Increasing Scientific Support of Factors Favoring Overeating 

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O (Hyper)Palatable Processed Foods (salt/sugar/fat/calorie dense)

O Super-sizingO Low cost/availabilityO Sedentary life styleO Normative behavior O Habituation/addiction

Honesty by Accident?

Food Science, Taste & FlavorThe oral sensations of food in the mouth are taste,

retronasal-olfaction (smell) and chemosensation (heat).

O Taste is composed of five oral perceptions (sweet, salty, sour, bitter and umami (savory). It is assessed with nose clips

O Flavor = Taste plus retronasal olfaction (Smell) and is assessed without nose clips

O Flavor and heat are chemically modified in processed foods 21

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Food

Teeth

Papillae

Taste

(retronasal oflaction) (scent receptors)

Sensors also in small intestine, bladder (sweet),

spine (savor), testes (bitter), sperm (umami)

Moyer M (Ed) Taste: Making Sense of Flavor. Nature 2012; 486:S1-S43.

Environment (Visual and auditory cues)

Nose

Smell

Flavor

Sweet, sour, salt, bitter,

umami (soy sauce, parmesan)

Chemical Modification of Taste and Flavor in Food Can Modify Eating Behavior

Food Science and Taste Foods with certain mixtures of salt, sugar and fat

are especially pleasurable (palatable) and stimulate pleasure (hedonic) centers in the brain

O Energy dense foods (fat, sugar) are more palatable than low-energy dense foods and promote their ingestion over satiety

O Salt inhibits bitterness from oxidation of fatty acids with cooking of fat and makes it palatable

O Hyper-insulinemia, hyper-leptinemia and leptinresistance also influence taste

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fMRI in Obese Subjects Show

O Satiety centers (caudolateral orbitofrontal cortex) that promote sensory-specific satiety are less active in obese as compared to lean individuals

O There are decreased brain dopamine receptors in obese subjects that could result from O Overeating to compensate for fewer receptors and

under activation of reward circuits orO Down-regulation of dopamine receptors from high

dopamine levels from overeating.

Wang. Brain dopamine and obesity. Lancet 2001; 357:354.

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fMRI are informative in Food Science and Obesity Research Fructose (corn syrup) vs Sucrose (glucose) 

Studies

O Page KA, JAMA. 2013;309(1):63-70.

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O Moss M. The Extraordinary science of addictive junk food. NYT, Feb 20, 2013

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DietsWeight Loss Improves Risk Factors for 

CV Disease in Young People 

O 5-10% weight loss via lifestyle changes reduces CV risk factors, delays onset of type 2 diabetes, and improves other health consequences of obesity. Greater weight loss has greater benefit.1

O Regain of weight can be attenuated but not eliminated by continued lifestyle treatment.2

O Additional approaches are needed.

1. Expert Panel on CV Risk Reduction in Children and Adolescents. Pediatrics 2011; S213.2. Kimm SY et al. National Trends in Management of CV Risk Factor Reduction in Children. Pediatrics 1998; 102:50.

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Why Diets Don’t Work: They Make You Hungry

O Calorie restriction increases fMRI activity in hypothalamic and midbrain areas associated with attention, reward, motivation and taste(1-3)

O On-diet changes in appetite regulating hormonespromote weight gain with decrease in levels of leptin, PY4, CCK, insulin, amylin (all decrease appetite normally), increase ghrelin

O Sympathetic overdrive associated with obesity persists and may cause down-regulation of adrenergic receptors with impairment of fat metabolism, etc. 8

1. Stice et al. Neuroimage 2012; 67: 322-330. 2. Cornier PLOS One 2009; 4:e6310, 3. Kroemer et al. Addiction Biology 2012; 18:855-862. 4. Sumithran, NEJM 2011; 365:1597. 5. Rosenbaum Am J Clin Nutrit 2008; 88:906. 6. Filoaf Obes Res 2000; 8:205. 7. Drewnowski. Phy

Behavior 1986; 35:617. 8. Straznicky. J. Clin Endo Metab 2011; 96:E503. 9. Mitchell. J Clin Invest 2010; 120: 13X5,

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Is “Food Addiction” the Explanation of Obesity?

O DSM5 has no “food addiction” categoryO Most obese individuals do not demonstrate

aberrant patterns of food consumption, or the psychopathology and behavioral disturbances associated with addiction.1

O DSM-5 established binge-eating disorder (BED) as a free-standing entityO Diagnosis of BED requires binge-eating average

once a week for 3 monthsO Animal and human research suggest that drug

and food addiction have a common biology2, 3

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1. Davis. Appetite 2005; 53:1-8, 2. Kenny Neuron 2011; 69: 664-679. 3. Smith Bio Psychiatry 2013; 804-810.

Is “Food Addiction” the Explanation of Obesity?

Consensus View O The most likely psychological factors associated

with being overweight or obese are: O Decreased self-control required for restraint when

exposed to the obesogenic foods and food-like palatable substances1

O Increased sensitivity to reward stimuli of palatable food2

O “Self-medication” of mood disorders or pain using palatable foods3

O Co-existing psychiatric disturbances with compulsive features4

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O 1. Davis. Appetite 2010; 54: 208-213; 2. Moreno Lopez. PLoS ONE; 2012: e49185; 3. Gibson. Behavioral Pharmacology. 2012; 23: 442-460.; 4. Stunkard. Psychiatric Clinics of North America 2011; 34: 765-771.

A Range of Diets with Various Fat, Protein, & Carbohydrate Compositions are Effective in Weight Loss 

& Have Similar Effects at 2 Years

NEJM 2009; 360: 859

Mean Change in Body Weight and Waist Circumference from Baseline to 2 Years According to Dietary macronutrient Content.Solid bars represent high‐protein, high‐fat, or highest carbohydrate diets. Open bars represent average‐protein, low‐fat, or lowest‐carbohydrate diets. T bars indicate standard errors. Panels A and C show the change in body weight and the change in waist circumference, respectively, for all participants who were randomly assigned to a diet (a total of 811); missing data were imputed. A total of 403 participants were assigned to a high‐protein diet and 408 to an average‐protein diet, 405 were assigned to a high‐fat diet and 406 to a low‐fat diet, and 206 were assigned to the highest‐carbohydrate diet and 201 to the lowest‐carbohydrate diet. Panel B shows the change in body weight for the 645 participants who provided measurements at 2 years. Of these participants 325 were assigned to a high‐protein diet and 320 to an average‐protein diet, 319 were assigned to a high‐fat diet and 326 to a low‐fat diet, and 169 were assigned to the highest‐carbohydrate diet and 168 to the lowest‐carbohydrate diet

Panel D shows the change in waist circumference for the 599 participants who provided measurements at 2 years. Of these participants, 303 were assigned to a high-protein diet and 298 to an average-protein diet, 292 were assigned to a high-fat diet and 307 to a low-fat diet, and 159 were assigned to the highest-carbohydrate diet and 155 to the lowest carbohydrate diet.

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Ann Int Med 2014

How Best to Lose Weight?

O Diets?O Which One?

O 15 studies of behavior, diet and lifestyle modification in obese

individuals showed a weight loss of 3.43 pounds at 1 year (NS)

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Dombrowski BMJ 2014; 348:g2646doi.

PreferredProcedures

O Mechanisms of bariatric surgery: restriction and malabsorption

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Present Preferred Bariatric Surgical Operations for Severe Obesity

O Acute post-op complications (<10%)

O Chronic post-op complications: leak, infection, PE, stricture, obstruction, fistula, band slippage, nausea, bone loss, nutritional deficiency1, 2

O Outcomes: weight loss at 1 year – bypass 158.4 lb, sleeve 152.68 lbs, band 73.5 lbs2 ~50% of excess weight loss over IBW at 15 years1

O Sleeve gastrectomy = gastric bypass in weight loss over banding with fewer complications 40

1. NEJM 2014; 370:21 2. Chang JAMA Surg. 2014 Mar;149(3):275-87.

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Sjostrom JAMA 2014; 311:2297.

Gastropexy or Gastric Bypass

O 227 gastropexy and 55 gastric bypass vs 260 medically managed controls followed for ~ 18 years in a retrospective evaluation at 25 surgery sites in Sweden. Men and women with BMI >34 or 38 and diabetes. 42

Sjostrom JAMA 2014; 311:2297.

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Drug Treatment of Obesity. The No Silver Bullet 

PrincipleIn contrast to drugs whose effects are exerted directly at the level of the brain reward dopamine pathway, food affects multiple peripheral and central mechanisms that directly and indirectly convey information to the brain’s DA reward pathway. The hypothalamus plays a particularly prominent role in this regard although it is also strongly implicated in drug reward. 43

Two Important Reports on Drug Treatment for Obesity

O Drug Treatment for Obesity. A Systematic and Clinical Review. Yanoski SZ, Yanoski JA. JAMA 2014; 3: 74-86. Long-term Drug Treatment for Obesity.

O Coleman E et al. The FDA’s assessment of two drugs for chronic weight management NEJM 2012; 367:1577.

O Conclusions: “FDA medications approved for weight loss plus lifestyle modification lead to (a) greater weight loss and (b) greater maintenance of weight loss than placebo. There is little prospect for weight loss in those who do not lose at least 5% of body weight by 12 weeks of treatment.” 44

O Yanoski. JAMA 2014; 3:74

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FDA Approved Weight Loss Drugs (1)

O Centrally Acting Noradrenergic Agents Approved for only 12 weeksa

O Phentermineb, diethylproprionc, phendimetrazined, benzphentaminee (BMI >30)

O Activate adrenergic and dopaminergic receptorsO No long term trials for efficacy or side effects that meet

present FDA trial requirementsO Phentermine is the most popular (15-30 mg/day)

O Many short term studies done before present FDA requirements for efficacy.

O No long term trials meeting existing guidelines.

a. Approved for use for BMI>30 or BMI>27 plus 1 or more comorbid condition. b. adipex; c. tenuate; d. bontril. e. didrex

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FDA Weight Loss Drugs (2)Approved for Long Term Use

O Decreased Lipid AbsorptionO Orlistat (Xenical), approved in 1999, (60mg OTC,

120mg RX) TID inhibits fat absorption by 30%O EffectiveO Because of GI side effects. Less than 10% take

for 1 year and less than 2% take for 2 years

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FDA Weight Loss Drugs Approved for Long Term Use(2)

O Serotonin Receptor Activator (Belviq)O Lorcaserin (Belviq) (10mg BID) approved in

2012, is a selective 2C(5HT2c) receptor antagonist substitute for fenfluramine

O Bloom, Blossum and Bloom DM trials show around 3.4% weight loss at one year. “22% greater weight loss than controls” on calorie control and exercise.

O FDA required long term trials for assessment of CV efforts.

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Ther Adv Chron Dis 2014; 5:135.

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FDA Weight Loss Drugs Approved for Long Term Use(3)

O Combination Therapy (Qsymia)O Phentermine plus toprimate ER 3.75/23

Qsymia (startup 7.5/46, 11.2/69, 15/92 QD doses) approved 2012 with post-marketing requirement for CV toxicity.

O For patients with BMI over 30 or 27 with risk factors

O Trials show benefit in weight 8.6% - 9.4% loss and risk factor improvement with 50% more weight loss than controls

O Every month pregnancy test for toprimateteratogenicity required.

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Ther Adv Chron Dis 2014; 5:135.

Present NIDDK Recommendations on Weight 

Loss Drugs1O Drugs that will probably result in a 5% or greater

weight loss at 1 year:O OrlistatO LorcaserinO Phentermine+topimate SR

O Long term side effects not assessed2

O PipelineO Contrave (buproprion and naltrexone) (FDA did

NOT approve, but granted a 3 month extension for more time to review)

O Liraglutide (5% wt loss at 1 yr) not approved

1. Yanoski SZ. Long term treatment for obesity. A systematic and clinical review. JAMA 2014; 3:74-86.2. Lauer MS Lemons for obesity. Ann Int Med 2012. Ther Adv Chron Dis 2014; 5:135.

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Frequent Side Effects Reported with Recommended Drugs in 

Clinical Trials

O Phentermine/Topiramate – HA, constipation, insomnia, paresthesia, dysgeusia, dry mouth

O Lorcaserin – dry mouth, fatigue, dizziness, HA

Neuropharm 1996; 14:233, Expert Opin Drug Saf 2004; 3:1, Neuropharm 2012; 37:1177

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ConclusionsWhat’s Good and What’s Bad?

Bad Good

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O Obesity plusO Diabetes O CV deathO Cancer

O OsteoarthritisO 7 years life

lost

O Normal weightO Diets and exercise

for a fewO Drugs for a fewO Bariatric surgery,

exercise and diets for many

BestO AVOID processed

foods!

2014 Bibliography 1O Troke RC. The future of gut hormones in the treatment of obesity. Ther Adv Chronic Dis. 2014;

5:4.O Schauer PR, et al. Bariatric surgery vs intensive medical therapy for diabetes. 3 year outcomes.

NEJM 2014; 370:21.O Am College of Obstetrics and Gynecology Committee Opinion No 600: ethical issues in the care

of obese women. Obst Gyn 2014; 123:1388.O Selvin E. et al. Trends in prevalence and control of diabetes in the US 1988-1994 and 1999-

2010. Ann Int Med 2014; 160:577.O Kids Count 2014 Fact Book. http://kidscount.ssrc.msstate.edu/O Ogden C et al. Prevalence of childhood and adult obesity in the US 2011-2012. JAMA 2014;

311:806.O Cunningham SA, et al. Incidence of childhood obesity in the US. NEJM 2014; 370:403.O Moss MM. The extraordinary science of addictive junk food. NYT, Feb 20, 2013O Levin DI. Corpulence and correspondence: President William Howard Taft and the medical

management of obesity. Ann Int Med. 2013; 159.O Davis D. From passive overeating to “food addiction”: a spectrum of compulsion and severity

ISRN Obesity 2013; Article ID 435 027.O Page KA, et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions

involved in appetite and reward pathways. JAMA 2013;309:63. 53

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