why wait? lose weight health/health...weight loss to continuous energy restriction • trf may...
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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?