Intermittent Fasting for Obesity Treatment. Disclosures CASE

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1 Intermittent Fasting for Obesity Treatment Victoria A. Catenacci, MD Associate Professor, Division of Endocrinology, Metabolism, and Diabetes University of Colorado Anschutz Medical Campus Disclosures No conflicts of interest to disclose CASE Mrs. D is a 42 yo female who presents to establish care, trying to lose weight PMH: gestational DM Meds: Mirena IUD, mvite Wt 233 lbs, ht 5 4 (BMI = 40), BP 120/75, PE normal Labs: CBC, CMP, Lipids, TSH WNL, A1C 5.6% Enrolled in diabetes prevention program 6 months ago: Daily caloric restriction ( kcal/day) Increased PA (300 min/week moderate intensity) Self-monitoring strategies (calorie counting, food and PA logs) Weekly group based-behavioral support

2 CASE After 3 months: wt 220 lbs (5% weight loss) After 6 months: wt 226 (3% weight loss) Doing well with exercise but reports increasing difficulty adhering to daily calorie goal Open to weight loss medications in the future, but does not want to start yet She has read about fasting for weight loss and is wondering if you would recommend this strategy? Learning Objectives Upon completion of this program, the participant should be able to: Understand common fasting paradigms for weight loss Describe the current evidence base for time restricted feeding (TRF) and intermittent fasting (IMF) as treatments for overweight/obesity. Humans evolved in environment where food was relatively scarce Mammals have organs (liver, adipose tissue) that function as energy depots and enable fasting for various amounts of time depending on the species Metabolic, endocrine, and nervous systems evolved in ways that allow maintenance of high levels of physical and mental performance when in a food-deprived/fasted state Mattson et al. Aging Research Reviews 39 (2017) 46-58

3 Hunting and Gathering in kcals Smart phone app to record all ingestive events over 3 weeks. N = 156 (non-shift workers) Polar plot of aggregate data Most subjects ate frequently and erratically throughout wakeful hours. Only 5 hours (1AM to 6AM) where frequency of eating events declined. Representative scatter plot of ingestive events (n=11) Lack of clustering in breakfast-lunch-dinner temporal pattern. Median daily eating duration was hours

4 Eat Less Often! Fasting paradigms for weight loss are gaining popularity Male model Nicklas Kingo shares the regimen he used to take him from the grey suburbs of Copenhagen to the runways of Louis Vuitton in Paris

5 Cookbooks for Fasting??? Fasting Paradigms for Weight Loss *no clear consensus on terminology Time Restricted Feeding (TRF): food intake is restricted to a window of <8-10 hours/day. Intermittent Fasting (IMF): recurring pattern of short fasting periods (16-48 hours) with little or no energy intake on fast days, with intervening periods of normal food intake. Periodic Fasting (PF): periods of substantial energy restriction lasting 2-21 days, with intervening periods of normal food intake. Mattson et al. Ageing Research Reviews 39 (2017) Fasting Paradigms for Weight Loss *no clear consensus on terminology Time Restricted Feeding (TRF): food intake is restricted to a window of <8-10 hours/day. Intermittent Fasting (IMF): recurring pattern of short fasting periods (16-48 hours) with little or no energy intake on fast days, with intervening periods of normal food intake. Mattson et al. Ageing Research Reviews 39 (2017) 46-58

6 Why Consider Fasting Paradigms For Obesity Treatment? Daily caloric restriction (DCR) most commonly prescribed dietary strategy to induce weight loss 1 Current guidelines recommend DCR (along with comprehensive lifestyle intervention) as cornerstone of obesity treatment 2 Typically results in 5-10% weight loss over 6 months 3,4 However, many find it difficult to adhere to conventional weight loss diets in which food is limited every day 1. Julia et al. PLoS One. 2014;9(5). 2. Jensen et al. Circulation. 2014;129:S Dansinger et al. JAMA. 2005;293(1): Johnston et al. JAMA. 2014;312(9): Self-reported Dietary Adherence Declines Rapidly Within 4 Months: Scores of 4 Diet Groups, According to Study Month Dansinger, M. L. et al. JAMA 2005;293(1): Copyright restrictions may apply. Weight Loss in A Comprehensive Behavioral Weight Loss Intervention a Using DCR b Weight Change (%) 10% 5% 0% -5% -10% -15% -20% -25% -30% -35% -40% Individual Variability in Change in Weight (%) at 12 Months 46% lost <5% 5% -38.2% +7.8% LOCF analysis of N=170 participants in ongoing R01 DK (Catenacci) Optimal Timing of Exercise Initiation in a Group Based Behavioral Weight Loss Program a All participants received group-based behavioral support weekly for weeks 1-20, every other week for weeks and monthly for weeks Participants were randomized to received a 26-week supervised exercise intervention during weeks 1-26 (STANDARD) or (SEQUENTIAL). b DCR, kcals/day for women, kcals/day for men.

7 Weight Regain After Weight Loss 2001 Meta-Analysis of US Dietary Weight Loss Studies # of Studies with Data Available % of lost weight regained 77% of lost weight regained % of Lost Weight Regained Years after Weight Loss Adapted from Anderson et al. AJCN. 2001;74(5): Why Consider Fasting Paradigms For Obesity Treatment Current dietary approaches only modestly effective Important to consider and rigorously evaluate alternative dietary strategies as part of a range of dietary approaches that can be offered to individuals desiring weight loss. Best approach for a given individual is likely to be the one they can adhere to over time Metabolic and Health Benefits of Fasting Mattson et al. Ageing Research Reviews 39 (2017) 46-58

8 Patients ask about this Fasting Paradigms for Weight Loss *no clear consensus on terminology Time Restricted Feeding (TRF): food intake is restricted to a window of <8-10 hours/day. Mattson et al. Ageing Research Reviews 39 (2017) Animal Studies Suggest Weight Loss Benefit of TRF Lean rodents: restricting feeding to 8 hour window during the active phase prevented adverse metabolic effects of a high fat diet (including weight gain, hyperinsulinemia, and hepatic steatosis) 1 Diet-induced obese rodents: switching from ad libitum high fat diet to a time restricted high fat diet promoted weight loss (or weight stabilization) and improved glucose homeostasis and insulin sensitivity 2 1. Hatori et al. Time-Restricted Feeding without Reducing Caloric Intake Prevents Metabolic Diseases in Mice Fed a High-Fat Diet. Cell Metabolism 2012;15: Chaix et al. Time-Restricted Feeding Is a Preventative and Therapeutic Intervention against Diverse Nutritional Challenges. Cell Metabolism 2014;20:

9 Importance of Meal Timing for Weight Loss N=420 adults enrolled in 20 week weight loss program (Mediterranean diet + cognitive behavioral techniques) Age 42±11 yrs, BMI 31.4± 5.4 kg/m 2, 49.5% female Divided into Early (51%) and Late (49%) Eaters based on lunch time before and after 1500 hours No differences in EI, diet composition, estimated EE, appetite hormones, and sleep duration Garaulet et al. Int J Obes, 2013 Time-Restricted Feeding Elicits Weight Loss n=8 adults (BMI >25, eating window >14 hrs/day) Asked to restrict eating to 10 hrs/d, no other dietary changes Compliance assessed with smart phone app 3.4 kg weight loss at 16 weeks, maintained at 1 year Gill et al. Cell Metab, 2015.

10 Pilot Study of TRF as a Weight Loss Intervention COMIRB , PI Elizabeth Thomas N=30 healthy adults with overweight/obesity randomized to TRF+RCD vs RCD alone TRF = energy intake restricted to 10 hour/day window RCD = standard reduced calorie diet ( kcal/d) 12 week intervention, 6 month follow up Outcomes: body weight, DXA, energy intake/eating patterns (smart phone app),glucose variability (CGM), PA and sedentary behavior, sleep Elizabeth.Thomas@ucdenver.edu Fasting Paradigms for Weight Loss *no clear consensus on terminology Intermittent Fasting (IMF): recurring pattern of short fasting periods (little or no energy intake on fast days), with intervening periods of normal food intake. Alternate-day fasting (ADF) 1-3 fast days/wk 2 consecutive fast days/wk Total (100%) energy restriction on fast day Partial (>75%) energy restriction on fast day Mattson et al. Ageing Research Reviews 39 (2017) Why is IMF Appealing? Dieters do not have to count and restrict calories every day 1 Periodic nature of fasting may mitigate the constant hunger associated with DCR 2 Less complicated: this is the easiest diet I have ever been on, I just need to remember which days I eat and which days I don t! 1 Johnstone A. Int J Obes (Lond). 2015;39(5): Horne BD et al. Am J Clin Nutr. 2015; 102:464-70

11 But don t people just eat more on non-fast days? Short-term (8-12 week) weight loss studies using selfreported measures of EI suggest individuals do not fully compensate on fed days for the calorie deficits on fast days Partial ADF (10 weeks)àei on fed days 95±6% baseline requirements 1 Partial ADF (12 weeks)àei on fed days 99±10% baseline requirements 2 Total ADF (8 weeks)àei on fed days 103±13% baseline requirements 3 Some studies suggest carry-over effect of IMF à reduction in energy intake of 23-32% on non-fasting days 4,5 1 Klempel et al. Nutr J. 2010;9:35 2 Varady et al. Nutr J :146 3 Catenacci et al. Obesity 2016;24(9): Harvie et al. Int J Obes (2011): 35(5) Harvie et al. Int J Obes (2013) British J Nutr What about Hunger? Total (100% energy restriction) ADF Hunger (daily VAS 10AM, 12PM, 2PM, 4PM) increased from baseline and did not decrease over 3 week study 1 Partial (75% energy restriction) ADF Hunger (daily 1-10 scale q 2h) increased at week 2 but no different from baseline at week 8 of the intervention 2 Hunger (daily evening VAS scale) initially high but decreased by week 2 and remained low over 8 week intervention 3 Hunger (AUC fasting and postprandial VAS response to test meal) unchanged from baseline at week Heilbronn et al. Am J Clin Nutr 2005; 81: Johnson et al. Free radical biology & medicine. 2007;42(5): Klempel et al. Nutr J. 2010;9:35 4 Hoddy et al. Clin Nutr. 2016; 35(6) Is IMF Safe? Pilot Study Design 26 adults (6 men, 20 women), BMI 30 kg/m 2, age18-55 Randomized 1:1 to alternate-day fasting (ADF) or daily caloric restriction (DCR) 8 week intervention period (all food provided) ADF: Total (100%) energy restriction on fast days, ad libitum intake on fed days a DCR: -400 kcal/day b a On fed days, ADF provided diet estimated to meet energy requirements plus 5-7 optional food modules (200 kcals) b Considered standard of care dietary weight loss intervention when study was designed in 2006 Catenacci et al, Obesity (2016) 24,

12 Is Fasting Safe? BMP, CBC, heart rate, blood pressure, ECG, QEWP-R (binge eating behavior) and CES-D (depression) measured at baseline and week 8 No changes in safety parameters, no adverse events over the 8 week study N = 59, age 25-65, BMI Underwent 8 week partial (75% ER) ADF (weight loss 4.2±0.3%) Assessed with Adverse Events Questionnaire Assessed with Multidimensional Assessment of Eating Disorder Symptoms (MAEDS) Current Evidence for IMF as a Weight Loss Strategy Several studies 1-13 suggest various IMF paradigms are safe and tolerable and produce 3-8% weight loss along with improvements in body composition and metabolic parameters in adults with overweight/obesity However, limitations to current evidence base 1 Johnson et al, Free Radic Biol Med (2007);42(5): , 2 Varady et al, Am J Clin Nutr (2009);90: , 3 Varady et al, Lipids Health Dis (2011);10: , 4 Harvie et al, 2011 Int J Obes (2011);35(5): , 5 Harvie et al, 2013 Br J Nutr (2013);110: , 6 Esghinia et al, J Diabetes Metab Disord (2013);12(1):4, 7 Bhutani et al, Obesity (2013);21(7):1370-9, 8 Klempel et al, Metabolism (2013):62: , 9 Varady et al, Nutr J (2013);12(1):146, 10 Hoddy et al, Obesity (2014);22: , 11 Catenacci et al, Obesity (2016) 2;24(9): , 12 Carter et al, Diabetes Res Clin Pract (2016):122: , 13 Trepanowski et al, JAMA Int Med (2017);177(7):

13 IMF Weight Loss Studies* Reference N Duration BMI (kg/m 2 ) Intervention Groups Weight Loss Johnson et al, weeks >30 ADF (80% ER on fast day) 8.0±1.5% Varady et al, weeks ADF (75% ER on fast day) 5.8±1.1% Varady et al, weeks ADF (75% ER on fast day) D Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 5.2±1.1% 5.0±1.4% 5.1±0.9% -0.2±0.4% 7.8±5.9% 6.6±5% Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 6.2±4.6% (12 weeks weight loss, IER ( kcal/d, 2 consecutive days/wk) + PF 5.7±3.9% 4 weeks maintenance) 4.3±4.6% Esghinia et al, weeks 25 IMF (70-75% ER on fast day, 3days/wk) 7.1±1.4% Bhutani et al, weeks ADF (75% ER on fast day) ADF + EX Klempel et al, weeks ADF (75% ER on fast day), 45% FAT ADF (75% ER on fast day), 25% FAT Varady et al, weeks ADF (75% ER on fast day) Hoddy et al, weeks ADF (75% ER on fast day), LUNCH ADF (75% ER on fast day) DINNER ADF (75% ER on fast day) SMALL MEALS Catenacci et al, weeks 30 ADF (100% ER on fast day) DCR (-400 kcal/d) 3±1% 1±0% 7±2% 0±0% 4.8±1.1% 4.2±0.8% 6.8±1.0% 0.3±1% 3.5±0.4% 4.2±0.5% 4.6±0.6% 8.8±0.9% 6.2±0.9% Carter et al, weeks 27 (T2DM) IER (70-85% ER, 2 consecutive days/wk) + EX (2000 steps) CR (35-45% ER daily) + EX (2000 steps) 6.2±3.0% 5.6±4.4% Trepanowski et al, weeks (26 weeks weight loss, 26 weeks maintenance) ADF (75% ER on fast day) D 6.8%, 6.0% 6.8%, 5.3% (relative to control) *Weight loss studies 8 weeks duration in individuals with overweight/obesity involving Alternate Day Fasting (ADF), Intermittent Fasting (IMF, 1-3 fast days/wk), or Intermittent Energy Restriction (IER, 2 consecutive fast days/wk) with 70% energy restriction (ER) on fast days. IMF Weight Loss Studies* Reference N Duration BMI (kg/m 2 ) Intervention Groups Weight Loss Johnson et al, weeks >30 ADF (80% ER on fast day) 8.0±1.5% Varady et al, weeks ADF (75% ER on fast day) 5.8±1.1% Varady et al, weeks ADF (75% ER on fast day) D Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 5.2±1.1% 5.0±1.4% 5.1±0.9% -0.2±0.4% 7.8±5.9% 6.6±5% Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 6.2±4.6% (12 weeks weight loss, IER ( kcal/d, 2 consecutive days/wk) + PF 5.7±3.9% 4 weeks maintenance) 4.3±4.6% Esghinia et al, weeks 25 IMF (70-75% ER on fast day, 3days/wk) 7.1±1.4% Bhutani et al, weeks ADF (75% ER on fast day) ADF + EX Klempel et al, weeks ADF (75% ER on fast day), 45% FAT ADF (75% ER on fast day), 25% FAT Varady et al, weeks ADF (75% ER on fast day) Hoddy et al, weeks ADF (75% ER on fast day), LUNCH ADF (75% ER on fast day) DINNER ADF (75% ER on fast day) SMALL MEALS Catenacci et al, weeks 30 ADF (100% ER on fast day) DCR (-400 kcal/d) 3±1% 1±0% 7±2% 0±0% 4.8±1.1% 4.2±0.8% 6.8±1.0% 0.3±1% 3.5±0.4% 4.2±0.5% 4.6±0.6% 8.8±0.9% 6.2±0.9% Carter et al, weeks 27 (T2DM) IER (70-85% ER, 2 consecutive days/wk) + EX (2000 steps) CR (35-45% ER daily) + EX (2000 steps) 6.2±3.0% 5.6±4.4% Trepanowski et al, weeks (26 weeks weight loss, 26 weeks maintenance) ADF (75% ER on fast day) D 6.8%, 6.0% 6.8%, 5.3% (relative to control) *Weight loss studies 8 weeks duration in individuals with overweight/obesity involving Alternate Day Fasting (ADF), Intermittent Fasting (IMF, 1-3 fast days/wk), or Intermittent Energy Restriction (IER, 2 consecutive fast days/wk) with 70% energy restriction (ER) on fast days. IMF Weight Loss Studies*: > 12 Weeks Reference N Duration BMI (kg/m 2 ) Intervention Groups Weight Loss Johnson et al, weeks >30 ADF (80% ER on fast day) 8.0±1.5% Varady et al, weeks ADF (75% ER on fast day) 5.8±1.1% Varady et al, weeks ADF (75% ER on fast day) D Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 5.2±1.1% 5.0±1.4% 5.1±0.9% -0.2±0.4% 7.8±5.9% 6.6±5% Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 6.2±4.6% (12 weeks weight loss, IER ( kcal/d, 2 consecutive days/wk) + PF 5.7±3.9% 4 weeks maintenance) 4.3±4.6% Esghinia et al, weeks 25 IMF (70-75% ER on fast day, 3days/wk) 7.1±1.4% Bhutani et al, weeks ADF (75% ER on fast day) ADF + EX Klempel et al, weeks ADF (75% ER on fast day), 45% FAT ADF (75% ER on fast day), 25% FAT Varady et al, weeks ADF (75% ER on fast day) Hoddy et al, weeks ADF (75% ER on fast day), LUNCH ADF (75% ER on fast day) DINNER ADF (75% ER on fast day) SMALL MEALS Catenacci et al, weeks 30 ADF (100% ER on fast day) DCR (-400 kcal/d) 3±1% 1±0% 7±2% 0±0% 4.8±1.1% 4.2±0.8% 6.8±1.0% 0.3±1% 3.5±0.4% 4.2±0.5% 4.6±0.6% 8.8±0.9% 6.2±0.9% Carter et al, weeks 27 (T2DM) IER (70-85% ER, 2 consecutive days/wk) + EX (2000 steps) CR (35-45% ER daily) + EX (2000 steps) 6.2±3.0% 5.6±4.4% Trepanowski et al, weeks (26 weeks weight loss, 26 weeks maintenance) ADF (75% ER on fast day) D 6.8%, 6.0% 6.8%, 5.3% (relative to control) *Weight loss studies 8 weeks duration in individuals with overweight/obesity involving Alternate Day Fasting (ADF), Intermittent Fasting (IMF, 1-3 fast days/wk), or Intermittent Energy Restriction (IER, 2 consecutive fast days/wk) with 70% energy restriction (ER) on fast days.

14 IMF Weight Loss Studies*: > 16 per arm Reference N Duration BMI (kg/m 2 ) Intervention Groups Weight Loss Johnson et al, weeks >30 ADF (80% ER on fast day) 8.0±1.5% Varady et al, weeks ADF (75% ER on fast day) 5.8±1.1% Varady et al, weeks ADF (75% ER on fast day) D Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 5.2±1.1% 5.0±1.4% 5.1±0.9% -0.2±0.4% 7.8±5.9% 6.6±5% Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 6.2±4.6% (12 weeks weight loss, IER ( kcal/d, 2 consecutive days/wk) + PF 5.7±3.9% 4 weeks maintenance) 4.3±4.6% Esghinia et al, weeks 25 IMF (70-75% ER on fast day, 3days/wk) 7.1±1.4% Bhutani et al, weeks ADF (75% ER on fast day) ADF + EX Klempel et al, weeks ADF (75% ER on fast day), 45% FAT ADF (75% ER on fast day), 25% FAT Varady et al, weeks ADF (75% ER on fast day) Hoddy et al, weeks ADF (75% ER on fast day), LUNCH ADF (75% ER on fast day) DINNER ADF (75% ER on fast day) SMALL MEALS Catenacci et al, weeks 30 ADF (100% ER on fast day) DCR (-400 kcal/d) 3±1% 1±0% 7±2% 0±0% 4.8±1.1% 4.2±0.8% 6.8±1.0% 0.3±1% 3.5±0.4% 4.2±0.5% 4.6±0.6% 8.8±0.9% 6.2±0.9% Carter et al, weeks 27 (T2DM) IER (70-85% ER, 2 consecutive days/wk) + EX (2000 steps) CR (35-45% ER daily) + EX (2000 steps) 6.2±3.0% 5.6±4.4% Trepanowski et al, weeks (26 weeks weight loss, 26 weeks maintenance) ADF (75% ER on fast day) D 6.8%, 6.0% 6.8%, 5.3% (relative to control) *Weight loss studies 8 weeks duration in individuals with overweight/obesity involving Alternate Day Fasting (ADF), Intermittent Fasting (IMF, 1-3 fast days/wk), or Intermittent Energy Restriction (IER, 2 consecutive fast days/wk) with 70% energy restriction (ER) on fast days. IMF Weight Loss Studies*: Food Provided Reference N Duration BMI (kg/m 2 ) Intervention Groups Weight Loss Johnson et al, weeks >30 ADF (80% ER on fast day) 8.0±1.5% Varady et al, weeks ADF (75% ER on fast day) 5.8±1.1% Varady et al, weeks ADF (75% ER on fast day) D Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 5.2±1.1% 5.0±1.4% 5.1±0.9% -0.2±0.4% 7.8±5.9% 6.6±5% Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 6.2±4.6% (12 weeks weight loss, IER ( kcal/d, 2 consecutive days/wk) + PF 5.7±3.9% 4 weeks maintenance) 4.3±4.6% Esghinia et al, weeks 25 IMF (70-75% ER on fast day, 3days/wk) 7.1±1.4% Bhutani et al, weeks ADF (75% ER on fast day) ADF + EX Klempel et al, weeks ADF (75% ER on fast day), 45% FAT ADF (75% ER on fast day), 25% FAT Varady et al, weeks ADF (75% ER on fast day) Hoddy et al, weeks ADF (75% ER on fast day), LUNCH ADF (75% ER on fast day) DINNER ADF (75% ER on fast day) SMALL MEALS Catenacci et al, weeks 30 ADF (100% ER on fast day) DCR (-400 kcal/d) 3±1% 1±0% 7±2% 0±0% 4.8±1.1% 4.2±0.8% 6.8±1.0% 0.3±1% 3.5±0.4% 4.2±0.5% 4.6±0.6% 8.8±0.9% 6.2±0.9% Carter et al, weeks 27 (T2DM) IER (70-85% ER, 2 consecutive days/wk) + EX (2000 steps) CR (35-45% ER daily) + EX (2000 steps) 6.2±3.0% 5.6±4.4% Trepanowski et al, weeks (26 weeks weight loss, 26 weeks maintenance) ADF (75% ER on fast day) D 6.8%, 6.0% 6.8%, 5.3% (relative to control) *Weight loss studies 8 weeks duration in individuals with overweight/obesity involving Alternate Day Fasting (ADF), Intermittent Fasting (IMF, 1-3 fast days/wk), or Intermittent Energy Restriction (IER, 2 consecutive fast days/wk) with 70% energy restriction (ER) on fast days. IMF Weight Loss Studies*: Comparison to DCR Reference N Duration BMI (kg/m 2 ) Intervention Groups Weight Loss Johnson et al, weeks >30 ADF (80% ER on fast day) 8.0±1.5% Varady et al, weeks ADF (75% ER on fast day) 5.8±1.1% Varady et al, weeks ADF (75% ER on fast day) D Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 5.2±1.1% 5.0±1.4% 5.1±0.9% -0.2±0.4% 7.8±5.9% 6.6±5% Harvie et al, weeks IER ( kcal/d, 2 consecutive days/wk) 6.2±4.6% (12 weeks weight loss, IER ( kcal/d, 2 consecutive days/wk) + PF 5.7±3.9% 4 weeks maintenance) 4.3±4.6% Esghinia et al, weeks 25 IMF (70-75% ER on fast day, 3days/wk) 7.1±1.4% Bhutani et al, weeks ADF (75% ER on fast day) ADF + EX Klempel et al, weeks ADF (75% ER on fast day), 45% FAT ADF (75% ER on fast day), 25% FAT Varady et al, weeks ADF (75% ER on fast day) Hoddy et al, weeks ADF (75% ER on fast day), LUNCH ADF (75% ER on fast day) DINNER ADF (75% ER on fast day) SMALL MEALS Catenacci et al, weeks 30 ADF (100% ER on fast day) DCR (-400 kcal/d) 3±1% 1±0% 7±2% 0±0% 4.8±1.1% 4.2±0.8% 6.8±1.0% 0.3±1% 3.5±0.4% 4.2±0.5% 4.6±0.6% 8.8±0.9% 6.2±0.9% Carter et al, weeks 27 (T2DM) IER (70-85% ER, 2 consecutive days/wk) + EX (2000 steps) CR (35-45% ER daily) + EX (2000 steps) 6.2±3.0% 5.6±4.4% Trepanowski et al, weeks (26 weeks weight loss, 26 weeks maintenance) ADF (75% ER on fast day) D 6.8%, 6.0% 6.8%, 5.3% (relative to control) *Weight loss studies 8 weeks duration in individuals with overweight/obesity involving Alternate Day Fasting (ADF), Intermittent Fasting (IMF, 1-3 fast days/wk), or Intermittent Energy Restriction (IER, 2 consecutive fast days/wk) with 70% energy restriction (ER) on fast days.

15 Attrition and Adherence Drop out rates 0-40% Studies which report adherence suggest reasonable compliance with fast days (but rely on self-report ) 80-98% of potential fast days achieved with partial ADF % of potential fast days achieved with 2 consecutive fast days/wk 6-7 Only 1 study using objective measure of EI 8 Partial ADF vs DCR, targeted weekly energy restriction 25% in both groups Actual energy restriction at 6 months: ADF 21±15%, DCR 24±16%, p = Varady et al Am J Clin Nutr (2009): 90: Klempel et al. Metabolism (2013) 63: Varady et al. Nutr J. (2013) 12:146 4 Bhutani et al. Obesity (2013) 21: Hoddy et al. Obesity (2014) Harvie et al. Int J Obes (2011): 35 (5) Harvie et al. British J Nutr (2013)110: Trepanowski et al. JAMA Intern Med 2017;177(7): Comparison of Weight Loss Induced by IMF vs. DCR in Individuals with Obesity: A 1-Year Randomized Trial R01 DK A1 (Catenacci) 9/15/17-6/30/22 Co-Investigators Dan Bessesen, MD Paul Maclean, PhD Ed Melanson, PhD Zhaoxing Pan, PhD R01 DK Overview Pragmatic 1-year randomized trial designed to compare weight loss generated by IMF vs. DCR 150 healthy adults with obesity (18-55 yrs, BMI kg/m 2 ) Randomized 1:1 to IMF or DCR Equivalent targeted weekly energy deficit (30%) Both groups receive behavioral support to compare IMF to current standard of care (DCR) in a robust fashion Objective measure of EI/EE (DLW intake-balance method)

16 Specific Aims Aim 1. Compare changes in body weight (1⁰ outcome), body composition, and metabolic parameters (lipids, BP, HOMA-IR) induced by IMF and DCR. Hypothesis: IMF will generate greater weight loss and improvements in body composition and metabolic parameters at 1 year compared to DCR. Aim 2. Evaluate the impact of IMF vs DCR on energy intake and dietary adherence. Hypothesis: IMF will demonstrate greater degree of energy restriction and better adherence to diet at 1 year. Aim 3. Evaluate the impact of IMF vs DCR on components of energy expenditure and patterns of PA. Hypothesis: REE will decrease less in IMF, changes in PAEE, MVPA, and sedentary time will be similar at 1 year. Aim 4 (Exploratory). Investigate predictors of weight loss within both groups. Outcome Measures Outcomes by Study Week Body Weight (kg) xx xxx xxx xxx xx Fat Mass (kg), Lean Mass (kg): DXA x x? x Metabolic Parameters: Lipid Panel, HOMA-IR, BP x x? x EI and TDEE: Doubly Labeled Water x x? x 7 Day Diet Records x x x x Dietary Adherence, Effort, and Self-Efficacy: Monthly Likert Scale xx xxx xxx xxx xx Hormones Related to Appetite: Leptin, Ghrelin, PYY, BDNF x x? x REE: Indirect calorimetry x x? x MVPA and Sedentary Time: ActivPAL x x x x QOL Measures, Mood State, Binge Eating Behaviors, Sleep x x x x Dietary Interventions IMF: Partial fast, 3 non-consecutive days/week Fast days: calorie goal à75% deficit from baseline requirements Fed days: ad libitum, but encouraged to make healthy food choices DCR: Moderate daily caloric restriction Every day: calorie goal à30% deficit from baseline requirements Additional details Same targeted weekly energy deficit (30%) and dietary macronutrient content (55% carbohydrate, 15% protein, 30% fat) Dietary paradigms maintained for duration of 1 year study Food NOT provided Both groups receive comprehensive, high intensity group-based behavioral support (weekly during weeks 0-13, every two weeks during weeks 14-52)

17 Why a Partial Fast? Match targeted weekly energy deficit 30% energy restriction is standard of care for DCR Options to achieve 30% weekly energy restriction with IMF Total (100%) energy restriction 2 days/wk Partial (75%) energy restriction 3 days/wk 64/82 (78%) of individuals with obesity preferred partial fast Concerns about compliance/retention over 1 year Decreases in subjective hunger in partial but not total fast Acute effect of total vs partial ER 1 Short-term study suggests less compensation on post-fast day w/ partial vs complete fast resulting in similar 3 day energy defecit Review of lay literature Partial fast by far most commonly endorsed paradigm thus most clinically relevant to study in large, pragmatic trial 1. Antoni et al, British Journal of Nutrition, (2016) 115, Why NOT Provide Food? Limits translatability of results Most individuals do not have access to weight loss programs in which food is provided May bias results in favor of DCR Food provision may increase ease of adherence to DCR but does not reflect challenges faced in free-living conditions (accurately counting calories, choosing appropriate portion sizes) Food provision may model portion size and calorie control for DCR in a way that is not clinically replicable Why maintain the same dietary paradigms for 1 year? Weight loss with DCR typically plateaus at 6 months Many behavioral weight loss programs shift focus to weight loss maintenance at ~6 month mark. However Obtaining adherence and weight loss data over 1 year will help us understand when we should shift focus to weight loss maintenance with IMF.

18 Timeline: 6 cohorts of 25 (Cohort 1 : 5/8/18) 9/2017 9/2018 9/2019 9/2020 9/2021 Study Timeline Year 1 Year 2 Year 3 Year 4 Year 5 Planning and Final IRB approvals Data Collection (n=~25 per cohort) Cohort 1 (randomized 1:1 to IMF or DCR) Cohort 2 (randomized 1:1 to IMF or DCR) Cohort 3 (randomized 1:1 to IMF or DCR) Cohort 4 (randomized 1:1 to IMF or DCR) Cohort 5 (randomized 1:1 to IMF or DCR) Cohort 6 (randomized 1:1 to IMF or DCR) Data Analysis, Manuscripts For more information or to see if you qualify DRIFT2@ucdenver.edu Outstanding Questions Does TRF enhance weight loss with a RCD? Is IMF a durable weight loss strategy? Does IMF or TRF have greater body composition or metabolic benefits? Do adherence patterns differ between IMF and DCR? Does IMF impact resting energy expenditure? Ability to exercise? Can we predict who may respond more favorably to IMF? What is the optimal frequency of fasting for weight loss? For weight loss maintenance? What is the optimal energy restriction and macronutrient content on fast days? Will individuals who self-select IMF do better than individuals who are randomly assigned? CASE Mrs. D is a 42 yo female with BMI 40 trying to lose weight Lost 13 lbs over 3 months with daily calorie restriction and increasing PA regained 6 lbs over next 3 months. Difficulty adhering to the reduced calorie diet. She has read about fasting for weight loss and is wondering if you would recommend this strategy?

19 CASE Short-term studies suggest that TRF and IMF are safe and effective weight loss strategies, however well-designed long term studies have not been completed. Best diet for a given person is one they feel they can stick to over time TRF: limit eating to 10 hour window, recommend starting window within 1-2 hours of waking (+RCD) IMF: 500 kcal/day (women), 600 kcal/day (men) on fast days (or no intake on fast days) 2-3 nonconsecutive days/wk (consume as dinner meal) Active Learning Question 1 Time Restricted Feeding (TRF) is best defined as: A. Short fasting periods (16-48 hours) with little or no energy intake on fast days with intervening periods of normal food intake. B. Periods of substantial energy restriction lasting 2-21 days, with intervening periods of normal food intake. C. Restricting food intake to a window of <8-10 hours/day. Mattson et al. Ageing Research Reviews 39 (2017) Active Learning Question 2 Compared to standard daily caloric restriction, current evidence suggests that Intermittent Fasting (IMF): A. Produces similar short-term weight loss and improvements in metabolic parameters in adults with overweight/obesity B. Produces superior short-term weight loss and improvements in metabolic parameters in adults with overweight/obesity C. Produces inferior short-term weight loss and improvements in metabolic parameters in adults with overweight/obesity Trepanowski et al, JAMA Intern Med (2017);177(7): Catenacci et al, Obesity (2016) 24,

20 Acknowledgements Collaborators/Mentors Edward Melanson, PhD William T. Donahoo, MD James O. Hill, PhD Holly R. Wyatt, MD Zhaoxing Pan, PhD Paul MacLean, PhD Daniel Bessesen, MD Research Staff Kristen Bing, RD Liza Weyland, MS Danielle Ostendorf, MS Elizabeth Kealey, RD Jared Scorsone Grant Support UL1 TR (University of Colorado Clinical and Translational Science Institute) P30 DK (Colorado Nutrition and Obesity Research Center) NIH R21 AT (Donahoo) NIH F32 DK (Catenacci) NIH K23 DK (Catenacci) NIH R01 DK (Catenacci) NIH R01 DK (Catenacci) Discussion