endocrinology of obesity - amazon s3 · – discuss the challenges associated withaining maint...

Endocrinology of Obesity

Scott D. Isaacs, MD, FACP, FACEInternational Seminar

Houston, TXNovember 10‐12, 2016

© 2016. All Rights Reserved. 1

Disclosure

Scott D. Isaacs, MD, FACP, FACE, practices at Atlanta Endocrine Associates.

Professional Education Services Group staff have no financial interest or relationships to disclose.


DisclosureThis continuing education activity is managed and accredited by Professional Education Services Group. Neither PESG nor any accrediting organization supports or endorses any product or service mentioned in this activity.


Educational Grant Support

This continuing education activity is supported by an educational grant from PCCA.


Learning Objectives• At the conclusion of this activity, the participant will be able to:

– Discuss obesity as a complex and multifactorial disease, not a lifestyle choice.

– Review the science of appetite regulation through the fat cell, gut and pancreas, and effects on the appetite centers in the brain.

– Discuss the challenges associated with maintaining weight loss due to adaptive physiologic process.

– Discuss step therapy for obesity management including lifestyle and nutrition, medications, devices, and surgery.


U.S. Prevalence of Overweight and Obesity

* Ogden, CL. JAMA. 2014;311(8):806‐814.


Prevalence of Obesity Among U.S. Adults, 2011

* http://www.cdc.gov/obesity/data/prevalence‐maps.html


Definition of Obesity• Obesity is defined as the abnormal accumulation of excess fat

that may impair health• Obesity: DYSREGULATION of energy balance• The body mass index (BMI) is a simple index of weight‐for‐height

expressed in kg/m2

• The BMI is a convenient and objective measure of overweight and obesity irrespective of gender, age, ethnicity or body frame* http://www.who.int/mediacentre/factsheets/fs311/en/


Definition of ObesityWeight Category BMI (kg/m2)Underweight < 18.5Healthy weight > 18.5 and < 25Overweight > 25 and < 30Obesity > 30

Obesity class I > 30 and < 35Obesity class II > 35 and < 40Obesity class III > 40

* http://www.who.int/mediacentre/factsheets/fs311/en/


Contributors to the Obesity Epidemic

• Increased calorie intake• Reduced physical activity• Less sleep• Drug induced weight gain• Food marketing practices• Endocrine disruptors• Increase in climate controlled

areas

• Decreased smoking• Viruses• BMI association with increased

reproductive fitness• Older parental age at birth• Demographic / ethnicity status• Epigenetic effects• Microbiome changes


Stigma: Obesity is Not a Disease Because it is Behavior Induced

• Behavior induced diseases:– Alcoholic liver disease– Sexually transmitted disease– Lung cancer– Fractures– Addiction


Why is Obesity a Disease?

• Physical changes (adiposity)

• Metabolic changes (adiposopathy)

• Psychological changes


Obesity is a Disease

* Cleveland Clinic 10th Annual Obesity Summit


Obesity

Sleep Apnea

Cancer

Cardiovascular disease Immobility/Disability

Prediabetes

Hypertension

Gallbladder Disease

Dyslipidemia

Diabetes

Depression

Metabolic Complications

Biomechanical Complications

Other Complications

Stress Incontinence

GERD

Osteoarthritis

NAFLD PCOSAsthma

Medical Complications of Obesity

* Pi‐Sunyer X. The medical risks of obesity. Postgrad Med. 2009 Nov;121(6):21‐33.


Therapeutic Weight Loss


Obesity Results from Energy Imbalance


Obesity is a Complex and Multifactorial Disease


The Hypothalamus Plays a Key Role in Appetite Regulation


Multiple Hormones Influence Hypothalamic Neurons and Appetite Regulation


Leptin and Insulin Play a Key Role in Signaling Total Body Adiposity


Gut Hormones Play a Key Role in Hunger and Satiety


Physiologic and Metabolic Response to Weight Loss Drives Weight Regain


Long‐Term Persistence of Hormonal Adaptations to Weight Loss

* Sumithran. New Engl J Med 2011; 365:1597‐1604


Metabolic Response Defends the Set‐point

• Maintenance of body weight loss is met with a disproportionate decrease in metabolic rate (decreased energy expenditure and increased muscle efficiency)– Following a 10% weight loss:

• 24 hour energy expenditure decreases by > 20%• Non‐resting energy expenditure decreases by > 30%• Skeletal muscle work efficiency increases by > 20%

* Sumithran. New Engl J Med 2011; 365:1597‐1604


Biggest Loser Study


Biggest Loser Study• Danny Cahill• 46 years old• Now, 295 pounds• Metabolic rate: now burns

800 fewer calories a day than would be expected for a man his size

430 pounds 191 pounds

* New York Times, May 7, 2016http://www.nytimes.com/2016/05/02/health/biggest‐loser‐weight‐loss.html


Persistent Metabolic Adaptation 6 Years After “The Biggest Loser” Competition

• Daily body weight changes in the individual subjects (thin lines) and the mean linear weight change (thick line) over the 2 weeks before the follow‐up measurements 6 years after “The Biggest Loser” competition.* Obesity. Volume 24, Issue 8, pages 1612‐1619, 2 MAY 2016 DOI: 10.1002/oby.21538.

http://onlinelibrary.wiley.com/doi/10.1002/oby.21538/full#oby21538‐fig‐0002


Persistent Metabolic Adaptation 6 Years After “The Biggest Loser” Competition

* Obesity. Volume 24, Issue 8, pages 1612‐1619, 2 MAY 2016 DOI: 10.1002/oby.21538. http://onlinelibrary.wiley.com/doi/10.1002/oby.21538/full#oby21538‐fig‐0002


Biology Defends the Set Point


Treatment of Obesity


Management of Obesity• Step therapy:

– Energy deficit meal plan– Increased physical activity – Behavioral modification– Anti‐obesity medications & supplements– Devices– Surgery

• Therapeutic lifestyle changes combined with any treatment modality enhances weight loss


Complications of Obesity: Obstacles to Weight Loss

* Gonzalez‐Campoy et al. Int. J. Endocrinology, May, 2014

Fatigue

OBESITY

Osteoarthritis

Insulin Resistance

Hyperinsulinemia

Sleep ApneaDepression

Low Testosterone

Dyslipidemia


Patient Expectations for Weight Loss

• Dream weight ‐37%• Happy weight ‐31%• Acceptable weight ‐24%• Disappointed weight ‐15%

* Foster & Wadden et al. J Consult Clin Psychol. 1997 Feb;65(1):79‐85.


Efficacy of Currently Available Treatments

0% 5% 10% 15% 20% 25% 30% 35%

Lifestyle Meds + Lifestyle Surgery

Dream weight37%

Improvement in comorbidities5‐10%


Risks and EfficacyLower risk

Higher risk

Lower efficacy Higher efficacy

BPD‐DS

Devices*

Pharma

Diets

VLCD

Lapband Sleeve

Roux‐en‐Y bypass

* Endoluminal gastric sleeve, gastric balloon, and vagal stimulator

• VLCD = very low calorie diet* Jensen MD, J Am Coll Cardiol. 2013;pii:S0735‐

1097(13) 06030‐0. http://formularyjournal.modernmedicine.com/print/368664


Therapeutic Lifestyle Change(aka Behavior Modification)

• Set realistic achievable goals• Individualized• 5‐10% of body weight in 4‐6 months• Specific behavior goals (e.g. I will walk at lunch 3 times a week)• Help patients gradually make changes to dietary patterns that are

harmful to their health• Communication should focus on a healthy lifestyle• Encourage “physical activity” over “exercise”


Physical Activity• Physical activity alone is rarely effective for weight loss• Getting to and staying at a healthy weight requires a long term

PA plan• Physical activity is necessary for long term weight loss and

maintenance• >150 minutes / week moderate intensity PA or >75 minutes /

week vigorous intensity PA for weight maintenance (more is better)

• Devices can be helpful (pedometer, FitBit, Apple watch, etc.)


Sitting Less Lowers Mortality


Macronutrient Content Does Not Influence Weight Loss


Healthier “Meal Pattern”

dairy


Medications for Diabetes and Weight

* Only liraglutide 3.0 is FDA‐approved for chronic weight management in patients with BMI 30+ kg/m2 or BMI 27 <30 kg/m2 with one or more comorbidities.* Apovian CM, Aronne LJ, Bessesen DH et al. Pharmacologic Management of obesity: An Endocrine Society clinical practice

guideline. J Clin Endocrinol Metab 2015 doi:10.1210/jc.2014‐3415


Cardiologic Medications and Weight

* Apovian CM, Aronne LJ, Bessesen DH et al. Pharmacologic Management of obesity: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2015 doi:10.1210/jc.2014‐3415


Antidepressant Medications and Weight



Antipsychotic and Anticonvulsant Medications and Weight

• Only phentermine/topiramate ER is FDA‐approved for chronic weight management in patients with BMI 30+ kg/m2 or BMI 27 <30 kg/m2 with one or more comorbidities* Apovian CM, Aronne LJ, Bessesen DH et al. Pharmacologic Management of obesity: An Endocrine Society clinical practice

guideline. J Clin Endocrinol Metab 2015 doi:10.1210/jc.2014‐3415


Gynecologic Medications and Weight



Rationale for Treatment of Obesity With Medications

• Obesity is a chronic disease• Most chronic diseases are treated with medications (ie. diabetes,

HTN, hyperlipidemia)• The biochemistry of people with obesity is different than that of

lean people• When people with obesity lose weight their biochemistry does

not become the same as lean people• Medications change biochemistry


Criteria for Using Anti‐obesity Medications

• BMI > 27 kg/m2 with at least one comorbidity• BMI > 30 kg/m2 with or without comorbidity• Always as an adjunct to an energy‐deficit meal plan, increased physical activity and behavior modification.


Role of Medications in Weight Loss

• They do not work on their own• Medications amplify the effects of behavioral changes to produce consumption of fewer calories

• Addition of a medication to a comprehensive weight loss program produces an additive effect


Should Pharmacotherapy be Used as an Adjunct to Lifestyle Intervention?

• Yes, if patients have a history of struggling to achieve and sustain weight loss.

• Yes, if patients meet indications• Yes, always with lifestyle

intervention, because the medications don’t work on their own


The Meds Don’t Work on Their OwnIt is important to use medication as an adjunct to lifestyle counseling:

here’s why

* Wadden TA, et al. N Engl J Med 2005;353:2111–2120.


Medication Follow Up

• Use a team approach for follow up appointments• Understand risks, cautions, and monitoring essentials

• Reinforce behavior modification, nutrition, and physical activity

• Assess medication efficacy and / or adverse effects and make changes as appropriate


Medication Follow Up• Best weight loss outcomes come with frequent face to face visits• Monthly x 3 months or at month 1 & 3, then every 3 months• Continue beyond 3 months if > 5% weight loss• If only modestly effective, may be augmented by addition of

second agent• Weight plateau and return to increased hunger is expected

(medication is still working if no substantial weight regain)


Medications Approved for Chronic Weight Management and How They Work

* http://www.accessdata.fda.gov/scripts/cder/drugsatfda/http://www.accessdata.fda.gov/scripts/cder/drugsatfda/

* ER: extended release / SR: sustained release / 5HT: serotonin / GABA: Gamma aminobutyric acid / GLP‐1: Glucagon‐like peptide 1


Medications Approved for Chronic Weight Management ‐ Dosing and Response Evaluation

* All data from product label


Placebo‐subtracted Weight Loss in Patients With and Without T2DM

* Values are placebo‐subtracted and approximated from kg weight reductions where applicable

* 1. Torgerson et al. Diabetes Care 2004;27:155–61; 2. Berne et al. Diabet Med 2005;22:612–8; 3. Smith et al. N Engl J Med 2010;363:245–56; 4. O’Neil et al. Obesity 2012;20:1426–36; 5. Apovian et al. Obesity (Silver Spring) 2013;21:935–43; 6. Hollander et al. Diabetes Care2013;36:4022–9; 7. Pi‐Sunyer et al. Diabetologia 2014;57:73‐OR; 8. Davies et al. Diabetologia2014;57:39‐OR; 9. Gadde et al. Lancet 2011;377:1341–52; 10. Garvey et al. Diabetes Care online September, 2014

‐3.2‐3.5

‐3.9

‐3.2

‐4.9

‐4.0‐3.6

‐5.4 ‐5.2

‐6.6

‐9

‐6

‐3

0

T2D Non‐T2DPercent w

eight loss a

t one

year

Orlistat1,2120 mg TID 52 weeks

Lorcaserin5,610 mg BID52 weeks

PHEN/TPM9,10

7.5/46 mg ER QD 56 weeks

Liraglutide7,83.0 mg QD56 weeks

Naltrexone/bupropion3,4

32/360 mg ER QD56 weeks


Other Medications for Obesity• Naltrexone (25‐50 mg QD)• Diethylpropion 12.5‐25 mg

TID (before meals) or 75 mg ER qAM

• Metformin 500‐2000 mg daily

• Zonisamide 25‐100 mg QD or BID

• Mirabegron 25‐50 mg QD• GLP‐1 agonists• SGLT‐2 inhibitors• Pramlintide• Bupropion


Compounded Medications for Obesity

• Oxytocin troche (20‐80 IU QD or BID)• Naltrexone SR (3‐25 mg QD)• Phentermine (3‐30 mg)• Topical Metformin 500‐1000 mg BID• hCG NOT RECOMMENDED (weight loss identical to placebo)

• Thyroid medications NOT RECOMMENDED


Supplement Use for Weight Loss• 15% of Americans

– 20.6% of females– 9.7% of males

• 34% of those who have made a serious weight loss attempt• One of the top reasons for supplement use• $26.9 billion in 2009

* J AM Diet Assoc 2007; 107: 441‐447. Obesity 2008; 16:790‐796. JAMA Int Med 2013; 173: 355‐361


Supplements for Weight Loss• Very little placebo‐controlled data• Widely held belief that supplements are natural and therefore safe

• Belief that supplements are a substitute for diet and exercise

• May contain added ingredients (laxatives, diuretics, prescription appetite suppressants, thyroid hormones, drugs to mask side effects, i.e. beta blockers)


Common Supplements for Weight Loss• Bitter orange• Caffeine• Calcium• Capsaicin• Chitosan• Chromium• Garcinia cambogia• Glucomannan• Conjugated linoleic acid

• Dimethylamylamine• Green coffee bean extract• Green tea• hCG• Irvingia gabonensis• Phaseolus vulgaris• Probiotics• Red raspberry ketones


hCG• First used in 1950s • Simeon method‐500 cal/d• Proposed mechanism relates to caloric utilization for fetal

support• Claim: redistributes fat from hips, thighs, stomach without

hunger or irritability• Injections, drops, lozenges, pellets

* Ann Pharmacother 2013;47:e23. Int J Obesity 2012;36:385‐386


hCG• FTC has ordered weight loss clinics to discontinue claim that hCG

programs are safe and effective per FDA• Facilitates stromal cell decidualization (leiomyoma,

endometriosis exacerbation)• Prostatic hyperplasia, testicular tumors, male breast tumors• Possible thromboembolism secondary to hormonal surge,

release of vasoactive substances• Weight loss identical to placebo in most studies

* Ann Pharmacother 2013;47:e23. Int J Obesity 2012;36:385‐386


hCG

• “hCG, like lozenges and sprays, sold over the Internet and in some health food stores are fraudulent and illegal if they claim weight‐loss powers.”* http://www.nytimes.com/2011/03/08/nyregion/08hcg.html


hCG


Caffeine for Weight Loss• Increases thermogenesis• Adenosine receptor antagonist• Studies have shown improved exercise endurance• Stimulates fat utilization in muscle during exerciseSide effects: increased heart rate, anxiety, irritabilityLarge doses: nausea, vomiting, seizures, cerebral edemaDrug interactions: ephedra, bitter orange, beta agonists, cimetidine

* Int J Sport Nutr Exer Metab 2004; 14: 626‐646


Caffeine for Weight Loss• Used in various forms with varying amounts of caffeine (yerba mate,

guarana, kola nut, etc.)• Combined with other herbals (damiana, ethereal oils, resins, tannins,

ephedra)• FDA: <400 mg/day not associated with dangerous effects (8 oz. cup of

brewed coffee has ~85 mg of caffeine)• May have serious adverse effects with 15 mg/kg, fatalities with > 150

mg/kg• Higher content in energy drinks (5‐hour energy 207 mg, Rockstar 250

mg)* Int J Sport Nutr Exer Metab 2004; 14: 626‐646


Camellia Sinensis (Catechins & Caffeine)

• Catechins (Epigallocatechin gallate [EGCG]; caffeine)• 1 cup brewed tea: 240‐320 mg catechins, 45 mg caffeine (act

synergistically)• Hot tea (not iced) preferred form• Increases calorie and fat metabolism• Decreases lipogenesis and fat absorption• Inhibits catechol‐O‐methyltransferase (increases NE)• Appetite suppression

* J Nutr 2009; 139:264‐70. J Med Food 2012; 16:120‐127.


Camellia Sinensis (Catechins & Caffeine) (cont’d)

Side effects: • Headache, dizziness• Hepatotoxic? (ethanolic extracts)• Increased blood pressure• GI discomfortDrug interactions:• Warfarin• Antihypertensives?

* J Nutr 2009; 139:264‐70. J Med Food 2012; 16:120‐127.


Microbiome Changes in Obesity

• Increased Firmicutes• Decreased Bacteroidetes • Decreased Akkermansia mucimiphila

Firmicutes

Bacteroidetes


Prebiotics and Probiotics

• Gut microbiota: trillions of gut microorganisms• Obesity, antibiotic use, and unhealthy diets are associated with gut dysbiosis(increased levels of “bad” bacteria)

• Microbes allow calorie extraction from indigestible polysaccharides

• Prebiotics: stimulate growth of beneficial bacteria* Am J Health‐Syst Pharm 2010;14:626‐646. Nutr Res 2015;35:566‐575


Prebiotics and Probiotics (cont’d)

• Probiotics: compete with pathogenic microbes for intestinal epithelial receptors

• Side effects: gas, diarrhea, constipation

• No definitive evidence of benefit* Am J Health‐Syst Pharm 2010;14:626‐646. Nutr Res 2015;35:566‐575


Garcinia Cambogia• Hydroxycitric acid• 500‐1000 mg TID• Decreases fatty acid

synthesis (inhibits ATP citrate lyase)• Enhances satiety (increases glucagon)• Enhances well‐being (increases serotonin)• Side effects: headache, cough, GI, hepatotoxic?• Drug interactions: diabetes meds, statins?, SSRIs?• Long term studies not available (benefit, safety?)

* JAMA 1998; 280:1596‐1600. Physiol Behav 2000;71:87‐94


Red Raspberry Ketones• Rubris idaeus• Similar structure to capsaicin, synephrine• May increase metabolism by increasing NE induced lipolysis and

thermogenesis• May increase adiponectin • Side effects: palpitations (cardiotoxicity), stimulant‐like

properties, hypoglycemia• Drug interaction: decreased INR with warfarin

* Life Sciences 2005;77:194‐204. Reg Toxicol Pharmacol 2015;73:196‐200


Questionable Ingredients

• Usnic acid (hepatotoxic)• “M” synephrine (vs. “P” synephrine)• Phenolpthalein (carcinogenic laxative)• Dimethylamylamine (DMAA)• Dimethylbutamine (DMBA)• Dinitrophenol (DNT)


Questionable Ingredients (cont’d)

• Aegeline (hepatoxic)• High dose caffeine• Red raspberry ketones (cardiotoxic)• Astrolochia (renal toxin, carcinogen)• Bee pollen (cardiotoxic, seizures, psychiatric)


Supplements for Weight Loss Conclusions

• Myth: products are natural and don’t have side effects

• No standardized formulations

• Limited studies• No long term studies

• No long term outcomes• Safety concerns• No standardized outcomes

• Use at your own risk!


Devices for Weight Loss

• Gastric band• AspireAssist• Gastric balloons• Vagal stimulator


Intragastric Balloons

• Endoscopic outpatient procedure• Relatively easy to perform• Removed after 6 months• Modest weight loss (~10%)

Orbera®

Reshape


Vagal Blockade (VBLOC)

• “Pacemaker” for the stomach• Difficult surgery, need expertise• Neuroregulator implanted

subcutaneously• Modest weight loss


Bariatric Surgery Procedures

(Indication BMI >40 or BMI >35 with comorbidity)


Nutritional Deficiencies Prior to Bariatric Surgery

• Vitamin A 12%• Vitamin B12 13%• Folate 6%• Vitamin D 40%• Zinc 30%• Iron 16%• Selenium 58%

* Madan et al. Obes Surg. 2006 May;16(5):603‐6.

• Obesity may mask malnutrition– Decreased consumption of

vegetables and fruits– Increased intake of high

calorie, nutritionally poor foods

– Irreversible sequestration of fat soluble vitamins


Management of Obesity• Obesity is a chronic disease• Step therapy includes:

– Nutritional changes – Physical activity – Behavioral changes – Anti‐obesity medications and supplements– Devices– Surgery

• Therapeutic lifestyle changes combined with any treatment modality enhances weight loss


Questions

Scott D. Isaacs, MD, FACP, [email protected]


Obtaining CE

If you would like to receive continuing education credit for this activity, please visit:http://pcca.cds.pesgce.com


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