Why Wait?Lose WeightUpdate in Obesity Medicine

John B Cleek MD, ABOM diplomate

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Obesity Trends in the United States• By 2030, 65 million more obese adults– 6-8.5 million more cases of diabetes– 5.7-7.3 million more cases of coronary artery disease– 500,000 more cases of cancer– increase cost of 66 billion Dollars

– 75% overweight or obese by 2020

– Lancet, August 27,2011, Vol 378: 815

Disclosures

• None

Intermittent Fasting (IF)

Sun Mon Tue Wed Thu Fri Sat

Normal EatingAlternate-Day Fasting (ADF)

Alternate-Day Modified Fasting (ADMF)

5:2 DietFasting-Mimicking Diet (FMD)

(Once a month only)

Weekly Intermittent Energy Restriction

(Alternating weekly periods)

Time-Restricted Feeding (TRF)

Normal Eating Fasting Reduced kcalShorter eating window

Intermittent Fasting (IF)

Sun Mon Tue Wed Thu Fri Sat

Normal EatingAlternate-Day Fasting (ADF)Alternate-Day Modified Fasting (ADMF)

5:2 DietFasting-Mimicking Diet (FMD)

(Once a month only)

Weekly Intermittent Energy Restriction

(Alternating weekly periods)

Time-Restricted Feeding (TRF)

Normal Eating Fasting Reduced kcal Shorter eating window

(1) Periodic Fasting: Full-day fast

Intermittent Fasting (IF)

Sun Mon Tue Wed Thu Fri Sat

Normal EatingAlternate-Day Fasting (ADF)

Alternate-Day Modified Fasting (ADMF)

5:2 DietFasting-Mimicking Diet (FMD) (Once a month only)

Weekly Intermittent Energy Restriction

(Alternating weekly periods)

Time-Restricted Feeding (TRF)

Normal Eating Fasting kcalReduced Shorter eating window

(2) Intermittent Energy Restriction

Intermittent Fasting (IF)

Sun Mon Tue Wed Thu Fri Sat

Normal EatingAlternate-Day Fasting (ADF)

Alternate-Day Modified Fasting (ADMF)5:2 DietFasting-Mimicking Diet (FMD) (Once a month only)

Weekly Intermittent Energy Restriction

(Alternating weekly periods)

Time-Restricted Feeding (TRF)

Normal Eating Fasting Reduced kcalShorter eating window

(3) Daily IF

Cardiometabolic Benefits of IF in Animals

• Greater weight loss

• Greater fat mobilization/oxidation

• Improved metabolic flexibility

• Lower glucose and/or insulin levels

• Lower blood pressure

• Improved lipid profile

• Lower inflammation and oxidative stress

• Improved recovery after ischemia/MI/stroke

• Longer lifespan and healthspan

GROWTHREPAIR

Alternate-Day Fasting (ADF)

• 22-day study in 16 people1:

• Induced weight and fat loss

• Mixed results for glucose and insulin by biological sex

• Increased hunger with no signs of lessening ADF may not be sustainable

1 Heilbronn et al., Am J Clin Nutr, 2005. 2Catenacci et al, Obesity, 2016. 3Stekovic et al, Cell Metabol, 2019

ADF Induces Weight Loss

• Two more recent studies compared ADF vs. continuous energy restriction and reported conflicting results for weight loss2,3

Alternate-Day Modified Fasting (ADMF)

• Alternates “fast” days (25% of daily calorie needs) with “feast” days (125% of daily calorie needs)

• Most extensively studied by Dr. Krista Varady

• Multiple studies in rodents and humans1

• Initially found ADMF induces weight loss and improves glucose and insulin levels, blood pressure, lipids, and hs-CRP in humans11 Many studies

First Large ADMF Trial in Humans

• 1 year long

• 100 participants

• Three groups: (1) Control group, (2) Continuous Energy Restriction, and (3) ADMF

ADMF is Not More Effective Than Continuous Energy Restriction

ADMF is No Better Than Conventional Dieting For Weight Loss1

• No differences in glucose, insulin, blood pressure, heart rate, lipids, visceral fat, and hs-CRP1

• Dropout rate was higher (38% vs. 29%)1

• Post-hoc analysis showed benefits for insulin resistance2

1 Trepanowski et al., JAMA Intern Med, 2017. 2 Gabel et al., Obesity, 2019.

5:2 Diet and Cardiometabolic Health• Involves eating a very-low-calorie diet twice a week (e.g., 25-35%

of energy needs on “fast” days)

• Studied most by Drs. Michelle Harvie and Anthony Howell (3 trials1,2,3 and 12 trials by other teams4-15)

• 2013 Trial2:

• 3-month trial in 115 overweight women

• 5:2 diet reduced body fat, insulin levels, and insulin resistance more than continuous energy restriction

• No difference in other fasting cardiometabolic endpoints

1 Harvie et al., Int J Obes, 2011. 2 Harvie et al., Br J Nutr, 2013. 3 Harvie et al., Breast Cancer Res, 2016. 4 Carter et al., Diab Res ClinPrac, 2016. 5 Antoni et al., Br J Nutr, 2018. 6 Conley et al., Nutr Diet, 2018. 7 Schubel et al., Am J Clin Nutr, 2018. 8 Sundfør et al., NutrMetab Cardio Dis, 20189 Carter et al., JAMA Netw Open, 2018. 10 Antoni et al., Eur J Nutr, 2019. 11 Pinto et al., Clin Nutr, 2019. 12 Corley et al., Diabet Med, 2018.13 Fitzgerald et al., Mult Scler Relat Disord, 2018. 14 Headland et al, Int J Environ Res Public Health, 2018. 15 Headland et al, Int J Obes, 2019

5:2 Diet and Weight Loss In Longer-Term Studies

• 4 one-year RCTs with about 50-110 participants per group1-4

• Marginal difference in weight loss at 12 weeks but not 50 weeks1,6

• No change in fasting cardiometabolic risk factors1-3

• But improved postprandial C-peptide and triglyceride levels5

1 Schubel et al., Am J Clin Nutr, 2018. 2 Sundfør et al., NutrMetab Cardiovasc Dis, 2018. 3 Carter et al, JAMA Netw Open, 2018. 4 Headland et al, Int J Obes, 2019. 5 Antoni et al., Br J Nutr, 2018. 6 Antoni et al., Eur J Nutr, 2019.

• Involves fasting for at least 12-14 hours daily

• Can be practiced both with or without cutting calories

Time-Restricted Feeding (TRF)

TRF Improves Multiple Aspects of Health in Animals

• About four to five dozen studies1 in animals report that TRF:

• Reduces body weight and/or food intake

• Prevents and reverses type 2 diabetes

• Improves cardiovascular risk factors, including hyperlipidemia

• Extends lifespan

• Benefits are proportional to the length of the daily fasting period

• Following TRF for 5 out of 7 days per week produces much of the same benefits as following it daily3,4

1 Too many to cite. 2 Chaix et al., Cell Metabol, 2014. 3 Olsen et al., Physiol Behav, 2017.

TRF in Humans• 12 pilot studies in humans with 4-11-hour eating windows1-12

• When food intake is limited to early in the day (“early TRF”1,2) or the middle of the day (“mid-day TRF”3-6), TRF improves

• Appetite and/or food intake1-6,8,10

• Weight and/or fat mass3-6,8,10-12

• Glucose and insulin levels and insulin sensitivity1-3,6-7,10

• Fat oxidation2

• Blood pressure1,4

• Oxidative stress1

1 Sutton et al., Cell Metabol, 2018 2 Ravussin et al., Obesity, 20193 Gill and Panda, Cell Metabol, 20154 Gabel et al., Nutrition and Healthy Aging, 2018 5 Moro et al., Sci Transl Med, 20176 Antoni et al., J Nutr Sci, 20187 Hutchison et al., Obesity, 20198 Anton et al., Nutrients, 20199 Tinsley et al., Am J Clin Nutr, 201910 Arnason et al., World J Diabetes, 201711 Stote et al., Am J Clin Nutr, 200712 Tinsley et al., Eur J Sports Sci, 2017

Summary

Weight Loss

• Periodic fasting and intermittent energy restriction likely produce similar weight loss to continuous energy restriction

• TRF may induce modest weight loss, even when no reduction in energy intake is prescribed

Adherence

• Some types of IF are less feasible than continuous energy restriction for long-term weight loss (e.g., ADMF, 5:2 Diet)

• Adherence appears to wane over time (e.g., 5:2 diet)

What Works ?

1Zachwieja JJ. Endocrinol Metab Clin North Am 1995;25:965-988.

Effect of Physical Activity Without Diet on Body Weight Loss1

Mode Frequency Weight LossEpstein and Wing Walk/run 2 - 5x/wk 0.09 kg/wk

Ballor and Kessey Walk/run/cycle 3 - 4x/wk 0.1 kg/wk

Garrow and Summerbell Walk/run/cycle 3 - 4x/wk 0.1 kg/wk

Hadjiolva, et al Various Daily(10 hrs/day) 1.8 kg/wk

Lee, et al Military Training 5x/wk 0.6 kg/wk

Physical Activity and Weight Loss

• Most studies suggest a reasonable amount of physical activity – does not produce weight loss

• Exercise alone - 0.06 to 0.1 kg/week• Dose response relationship

– does not ssi

• significantly increase initial weight loss over what is obtained by caloric restriction alone

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exercise effect in obesity

PA <150 min·wk−1results in minimal weight loss compared to controls, PA > 150 min·wk−1 results in modest weight loss of ∼2-3 kg, and PA between 225 and 420 min·wk−1 results in 5- to 7.5-kg weight loss.

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High Intensity Interval Training

• 30 minutes of moderate intensity exercise most days of the week does not result in loss of fat mass—brings increased cardiorespiratory fitness and maintenance of lean mass

• Brief periods of anaerobic exercise followed by longer period of low intensity exercise (aerobic)

HIIT

• Tremblay et al—20 week study of intermittent HIIT versus moderate intensity exercise for 20 weeks. Fat loss was greater with HIIT.

HIIT

• Improves insulin sensitivity• Improves blood glucose control• Improves oxidative capacity in muscle

Medications Approved for Obesity

Medication Mechanism of Action Potential Side Effects

Orlistat(Xenical™) Lipase Inhibitor Steatorrhea, incontinence

Phentermine - CIV

(Adipex™, Ionamin™) Adrenergic Tachycardia, hypertension

Diethylpropion - CIV

(Tenuate™) Adrenergic Tachycardia, HTN, anxiety

Benzphetamine - CIII

(Didrex™) Adrenergic Tachycardia, HTN, anxiety

Phendimetrazine - CIII

(Bontril™, Prelu-2™) Adrenergic Tachycardia, HTN, anxiety

Phentermine/topiramate CR-CIV

(Qsymia)Adrenergic/? Tachycardia, HTN, Anxiety,

Confusion, Paresthesias

Lorcaserin(Belviq) 5-HT2c agonist Headache, Nausea, Dizziness

Medications Approved for Obesity

Medication Mechanism of Action Potential Side Effects

Bupropion/Naltrexone ER Dopamine agonist/Opioid antagonist

Nausea, headache, anxiety

Liraglutide GLP-1 Agonist Nausea, Diarrhea, Pancreatitis, Medullary thyroid cancer

Vyvanse Amphetamine Tachycardia, Blood pressure elevation, anxiety

Medication Weight Loss beyond diet and exercise

Study Length

Phentermine 7.9 pounds 2-24 weeks

Diethylpropion 6.6 pounds 6-52 weeks

Orlistat 6.5-7.5 pounds, 2.9-

3,4%

1 year

Phentermine/Topiramate ER 7.5mg

Phentermine/topiramate ER 15mg

14.5 pounds, 6.6%

18.9 pounds, 8.6%

1 year

1 year

Lorcaserin 7.9 pounds, 3.6% 1 year

Bupropion/Naltrexone ER

4.8% 1 year

Liraglutide 12.8 pounds, 4.5% 1 year

Medication StoppageMedication Stoppage Rule

Phentermine (IV), Diethylpropion (IV),

Phendimetrazine (III)

Phentermine – longer half life than Diethylpropion

Phendimetrazine – available 35 mg short acting or

105 mg ER

Phentermine / Topiramate ER (IV) If < 3% at 3 months – either titrate from

recommended dose (7.5/46) to full dose (15/92) or

d/c. If < 5% at 6 months, d/c

Lorcaserin f < 5% at 3 months, d/c

Naltrexone / Bupropion SR If < 5% after 3 months at full dose, d/c (note – full

dose is not achieved until 4th week of dosing

titration)

Liraglutide If < 4% at 16 weeks, d/c

Medication Contraindications and Warnings

Phentermine, Diethylpropion, Phendimetrazine Pregnancy & breast feeding (BF), Heart disease, uncontrolled HTN Anxiety d/o, sz, mao inhibitors,hyperthyroidism, glaucoma, h/o drug abuse

Orlistat Pregnancy & BF, Cyclosporine (take 2h before or after), chronic malabsorption, pregnancy, BF, cholestasis, levothyroxine, warfarin, antiepileptic drugs

Phentermine / Topiramate ER Pregnancy & BF (teratogenic), see Phentermine

Lorcaserin Pregnancy & BF, caution: SSRI, SNRI, MAO, St John’s wort, Triptans,

Naltrexone / Bupropion SR Pregnancy & BF, uncontrolled HTN, seizure d/o,

anorexia, bulimia, drug/

alcohol withdrawal, MAO‐I, narcotic use

Liraglutide Pregnancy & BF, Medullary Thyroid Carcinoma (MTC), Multiple Endocrine

Current Anti-Obesity Medications

Bupropion

Topiramate

Naltrexone/Bupropion

Zonisamide

Semaglutide/Exenatide

Liraglutide

Pramlintide

Phentermine

Phentermine/Topiramate

Lorcaserin

Metformin

Orlistat

Off label Use FDA Approved

for seizures, migraines

for diabetes

for depression

Canagliflozin (Dapa-,Empa-)

Phendimetrazine

Diethylpropion

Naltrexone for addiction

Benzphetamine

Schedule IV

Schedule IV

Schedule III

Lorcaserin

• Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients – Thrombolysis in Myocardial Infarction 61 (CAMELLIA-TIMI 61)

• 4.5 year world wide study—median follow up 3.25 years• One additional cancer per 470 patient years• 7.7 % cancer development versus 7.1% in the placebo group

primarily lung, colorectal, and pancreatic cancer imbalance• Longer on drug, higher the risk

lorcaserin

• Voluntarily removed from the market

Questions?