The Top Myths About Ketosis Debunked by Clinical Trials

1. The Top Myths About Ketosis Debunked by Clinical Trials James McCarter MD PhD Adjunct Professor, School of Medicine, Washington University in St. Louis Former Head of Research, Virta Health Presentation at CrossFit Health, Scotts Valley CA, October 13th, 2019

2. One Goal For This Talk Arm You to Answer Any Objection to Ketogenic and Low Carb Nutrition Approaches.

3. Arm You to Answer Any Objection to Ketogenic and Low Carb Nutrition Approaches. Why? Because the Public is Paying Attention & Defenders of the Status Quo are Nervous. One Goal For This Talk

4. Arm You to Answer Any Objection to Ketogenic and Low Carb Nutrition Approaches. Why? Because the Public is Paying Attention & Defenders of the Status Quo are Nervous. Diets on Google Trends: A Spike Each January From 2004 - 2012 One Goal For This Talk

5. Arm You to Answer Any Objection to Ketogenic and Low Carb Nutrition Approaches. Why? Because the Public is Paying Attention & Defenders of the Status Quo are Nervous. One Goal For This Talk 2/12 3/14

6. Arm You to Answer Any Objection to Ketogenic and Low Carb Nutrition Approaches. Why? Because the Public is Paying Attention & Defenders of the Status Quo are Nervous. One Goal For This Talk “Keto”, short for nutritional ketosis or the ketogenic diet, is the number #1 diet search term of 2018-19.

7. Arm You to Answer Any Objection to Ketogenic and Low Carb Nutrition Approaches. Why? Because the Public is Paying Attention & Defenders of the Status Quo are Nervous. One Goal For This Talk 3/17 3/18 1/19 “Keto”, short for nutritional ketosis or the ketogenic diet, is the number #1 diet search term of 2018-19.

8. One Goal For This Talk By publications, ketogenic research has increased 860% since 2000. (70+ references in this talk)

9. Introduction The Virta-IUH Clinical Trial Top 12 Keto Myths Debunked Another 12 Keto Myths Debunked Even More Keto Myths Debunked Conclusions FOR TODAY

11. Over 10% of U.S. adults have diabetes and one-third have pre-diabetes JAMA 2015. 314:1021-1029 Diabetes costs the U.S. $327 billion annually ADA 2018 estimates

12. Thank you to our Virta team, co-authors, collaborators ... … and our tremendous clinical trial participants. Especially My Co-PIs, Drs. Sarah Hallberg Steve Phinney, and Jeff Volek.

13. Disclosures for Dr. James McCarter I am a shareholder of Virta Health. Founded in 2014 and headquartered in San Francisco, Virta is a nationwide telemedicine provider and full-stack technology company focused on the reversal of type 2 diabetes. I chair the Scientific Advisory Board of Readout. Founded in 2018 and headquartered in St. Louis, Readout is a digital health company that helps customers manage their health through real-time biomarkers.

14. My Personal Journey to Ketosis Began in 2012. McCarter Family, Field Museum, Chicago, 2012

15. Carbs Result in a Glucose & Insulin Roller Coaster (Post-breakfast Munchies, Post-lunch Food Coma)

16. What I Eat During 7 Years in Ketosis … non-starchy vegetables, lots of eggs, oily fish, meat (including liver), dairy, bouillon, olive oil, other high oleic oils, nuts & seeds, nut butters, 85% chocolate, coffee.

17. Quantified Self - Tracking Ketosis With Daily Blood BHB mmol/L Beta-hydroxybutyrate Points – days, Line – 7 day moving average AM fasting 2.0±0.9 PM post-meal 0.9±0.6 < 0.1 mM carb-rich diet > 0.5 mM ketosis

18. Personal Benefits of Ketosis – Sharp Reduction in Blood Pressure Twice Daily Scanadu Scout Blood Pressures Averaging 113/71 BP at Physical Down from High of 136/90 in 2009 to 112/71 in 2014-15 quantifiedself.com/blog/effects-year-ketosis-jim-mccarter

19. Definitions

20. Three Clinically Validated Methods Patients May Choose to “Reverse” Type 2 Diabetes (T2D) ● Bariatric Surgery ● Very Low Calorie Diet (VLCD) ● Low Carbohydrate (including Ketogenic) Nutrition Hallberg et al. Nutrients 2019, 11:766 As a society we can no longer tolerate the continued rising rates of diabetes … some [patients] would surely choose reversal if they understood there was a choice. The choice can only be offered if providers are not only aware that reversal is possible but have the education needed to review these options in a patient-centric discussion. “

21. What is T2D Reversal? ● ADA 2009 Consensus Panel Definition ○ “Remission” - glycemia below diabetic range (HbA1c <6.5%) in the absence of pharmacologic or surgical therapy. ○ Bariatric Surgery 2013 Recommendation - similar. ● Other definitions have made an exception for metformin (biguanide class) ● Virta Health & IUH Trial Research Team 2019 Definition ○ “Reversal” - glycemia below diabetic range (HbA1c <6.5%) in the absence of pharmacologic or surgical therapy with the exception of metformin ○ Per guidelines for metformin use in pre-diabetes we continue to prescribe metformin in 64% of patients de-prescribing only for side effects or at patient request. ○ “Reversal” is NOT cure. Diabetes Care 2009, 32:2133-2135 BMC Surgery 2013, 13:8 Diabetes Care 2018, 41(Suppl 1) Hallberg et al. Nutrients 2019, 11:766 Athinarayanan et al. Frontiers in Endocrinology 2019, 10:348

22. What is Low Carbohydrate Nutrition? ● Very low-carbohydrate, ketogenic ○ ≤ 50 grams/day of total carbohydrate (usually <10% of daily kcals) ○ Can require <30 grams/day to achieve nutritional ketosis (BHB ≥0.5mM) ○ Moderate protein, fat as primary energy source ○ Dietary fat includes saturated, monounsaturated & polyunsaturated ● Low carbohydrate ○ 51 - 100 grams/day or <30% of daily kcals ○ Generally not ketogenic (BHB <0.5mM) unless exercising or fasting ● Anything ≥30% daily kcals is not a low carbohydrate diet Hallberg et al. Diabetes, Obesity and Metabolism 2019, 21:1769

23. • Nutritional ketosis is a metabolic state in which the body is predominantly fueled by dietary fat or body fat • Occurs when dietary carbohydrates are limited to <30 grams/day with moderate protein • Ketone bodies are natural products of liver metabolism • During fasting, ketones provide ~60% of the brain’s energy Benefits of ketosis arise from … • Alternative energy source to glucose especially in individuals with insulin resistance • Lowers insulin levels and restores insulin sensitivity • Hormonal properties - ketones signal for reductions in oxidative stress and inflammation BODY FAT DIETARY FAT KETONES What is Nutritional Ketosis? Newman & Verdin Diabetes RCP 2014. 106:173 (BHB or BOHB)

25. Virta-IUH Clinical Trial • 5-yr, non-randomized prospective controlled study, 2015-2021 • 465 participants recruited in Central Indiana, Aug 2015 - Mar 2016 • Patient self-selected intervention • CCI: continuous care intervention with individualized nutritional ketosis, 262 w/ T2D, 116 w/ pre-diabetes • UC: usual care following 2015-16 ADA guidelines, 87 with T2D Baseline characteristics for T2D CCI • Mean age: 54 yrs • Mean BMI: 40.3 kg/m2 • Mean weight: 257 lbs • Mean time with T2D: 8.4 yrs • 67% female Retention • 83% at 1 yr • 74% at 2 yrs 25

26. The CCI (Virta) Continuous Remote Care Platform including extensive nutrition education & individualization

27. Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56 McKenzie et al. JMIR Diabetes 2017. e5 Significant improvement in T2D at 1 year Significant improvement in cardiovascular risk factors at 1 year Rapid improvement in T2D at 70 days The Virta - Indiana University Health (IUH) T2D Reversal Trial Results Have Been Published in Six Peer-reviewed Publications Papers in progress on 2-year outcomes for - Pre-diabetes - Metabolic syndrome - System Utilization - Depression - Joint Function - Inflammation Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Sustained improvement in T2D at 2 years Vilar-Gomez et al. BMJ Open 2019. 9:e023597 Significant improvement in fatty liver disease at 1 year Siegmann et al. Sleep Medicine 2019. 55:92 Significant improvement in reported sleep at 1 year

28. Virta-IUH Clinical Trial Demonstrates CCI Reversal of Type 2 Diabetes Status at 1 Year Blood Glucose Improvement 1.3% average HbA1c reduction, 70% below 6.5% of completing patients reverse diabetes Glycemic control without use of diabetes-specific medications 60% Medication Reduction 94% of insulin users reduced or eliminated usage Weight Loss 12% average weight loss (30 pounds) CVD Risk Improvement including Dyslipidemia 12% improvement in 10-year ASCVD Risk Score 22 of 26 risk factors show significant improvement Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56

29. HbA1c Reduced While Removing Medications 1.3% 46% $2,044 Continue Care (CCI) Usual Care (UC) Hallberg et al. Diabetes Therapy 2018. 9:583 CCI UC

30. Less-controlled (A1c ≥ 9%) 1 Year HbA1c Reductions are More Dramatic for Patients With Poor Glycemic Control at Baseline Hallberg et al. Diabetes Therapy 2018. 9:583 (Post-hoc analysis) Well-controlled (A1c < 9%) 3.45% CCI UC UCCCI

31. HbA1c Improvement is Sustained at 2 Years in CCI Versus UCHbA1c(%) -0.9 HbA1c Reduction -32% Insulin Resistance (c-peptide derived HOMA-IR) 55% Diabetes Reversal Continue Care (CCI) Usual Care (UC) Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 (Completers analysis)

32. At 2 Years … 67% of all diabetes prescriptions eliminated 100% of sulfonylurea prescriptions eliminated 91% of insulin prescriptions reduced or eliminated 81% mean reduction in insulin doseHallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Improved Glycemia Necessitated Diabetes Medication Reductions Early reduction of sulfonylurea and insulin avoids hypoglycemia during dietary changes.

33. Even the 40% of CCI Patients that Did Not Reverse Diabetes at 1 Year Had Very Favorable Outcomes 81% Percentage of insulin-users who reduced or eliminated insulin Insulin Use 45% Rx Elimination 17% Average relative reduction in 10-yr ASCVD risk score 10-yr ASCVD Risk Score 27% Average reduction in triglycerides Triglyceride Reduction 1.2 Average decrease in HbA1c to 7.0% A1c Reduction 23 lbs Average weight loss (9.8%) Weight Reduction Percentage of diabetes prescriptions eliminated Hallberg et al. Diabetes Therapy 2018. 9:583 (Post-hoc analysis)

35. Myth 1. Keto is Unsustainable. - False 1. Nearly all T2D intervention patients achieved nutritional ketosis by daily beta- hydroxybutyrate (BHB) tracking. 2. BHB was still elevated 50% over baseline at 2 years as carbohydrate restriction was individualized. 3. 74% of patients completed 2 years of the clinical trial with extensive tracking demands and most agreed to extend their participation to 5 years. 4. In commercial clinical practice, Virta sees retention of >90% at 1 year and >80% at 2 years. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348

36. BHB Was Still Elevated 50% Over Baseline at 2 Years Daily values Lab values Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348

37. Significant Weight Loss of 12% Sustained at 2 Years Clinically Significant Weight Loss -5% at 2 years -12% 75% of patients lost > 5% 49% of patients lost > 10% Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 (Completers analysis at 2 years)

38. Most Dietary Interventions Display Return of Weight and HbA1c Toward baseline. CCI Outcomes are More Sustainable at 2 Years. CCI Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Tay et al. Diabetes Obes Metab 2018. 20:858 Lean et al. Lancet Diabetes Endo 2019. 7:344 (DIRECT) Look AHEAD. Archives of Internal Medicine 2010. 170:1566

39. Myth 2. Keto Will Cause Diabetic Ketoacidosis (DKA). - False 1. There were no DKA events in the trial. 2. There was no evidence of metabolic acidosis or anion gaps in our patients. 3. DKA has not been an issue in other ketosis clinical trials. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Rosenstock and Ferrannini. Diabetes Care 2015. 38:1638 Clinical management: We usually de-prescribe SGLT-2 inhibitors (canagliflozin, dapagliflozin, empagliflozin) as these medication are associated with increased risk of euglycemic DKA.

40. State Ketones (mmol/L) Moderate-carbohydrate diet (fed state) <0.1 Moderate-carbohydrate diet (fasted state) 0.1 to 0.3 Very low-carbohydrate diet (<50 g/day) 0.5 to 3.0 Very low-carbohydrate diet (post-exercise) 1.0 to 5.0 Keto-acidosis (insulin insufficiency) 10 to 20+ Nutritional Ketosis is Not Diabetic Ketoacidosis. • Nutritional ketosis results in moderate ketone levels (0.5 to 3.0 mM beta-hydroxybutyrate), no insulin insufficiency and no metabolic acidosis • Diabetic ketoacidosis (DKA) results in high ketone levels (10 – 20 mM BHB) due to insulin insufficiency resulting in metabolic acidosis Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348

41. Myth 3. Keto Will Cause Hypoglycemia. - False 1. There were no instances of symptomatic hypoglycemia while patients were in ketosis. 2. Hypoglycemia has not been an issue in other ketosis clinical trials except in cases of continued use of high dose insulin and sulfonylureas (e.g. glyburide, glipizide). Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Clinical management: In the trial, we reported one patient no longer following dietary changes had a hypoglycemic event due to insulin use beyond the prescribed dose.

42. Myth 4. Keto Will Deprive the Brain of Required Glucose. - False 1. Blood glucose levels are not low in ketosis. 2. With reduced dietary carbohydrate, the liver produces glucose by gluconeogenesis. 3. The brain metabolizes ketones in preference to glucose. 4. Patients reported improved daily mood and energy and reduced symptoms of depression. 5. Ketosis is used to treat brain disorders such as epilepsy and migraine and improves cognitive performance. Courchesne-Loyer et al. J Cerebral Blood Flow Metabolism 2016. 37:2485 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Adams et al. Abstract. Society of Behavioral Medicine, 2019 Kossoff et al. Epilepsia Open 2018. 3:175 Di Lorenzo et al. Nutrients 2019. 11:1742 Ketones spare the brain’s need for glucose. 11-C labeled acetoacetate. 18-F labeled fluorodeoxyglucose.

43. Myth 5. Keto Will Impair the Heart & Cause Vascular Damage. - False 1. At one year, the mean 10-yr ASCVD risk score of our patients improved 12%. 2. Significant improvements were observed in 22 of 26 CVD risk factors versus 0 of 26 in the usual care group. 3. Recent studies indicate ketosis may improve congestive heart failure. Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56 Horton et al. JCI Insight 2019. 4:e124079* Nielsen et al. Circulation 2019. 139:2129

44. Myth 5. Keto Will Impair the Heart & Cause Vascular Damage. - False 1. At one year, the mean 10-yr ASCVD risk score of our patients improved 12%. 2. Significant improvements were observed in 22 of 26 CVD risk factors versus 0 of 26 in the usual care group. 3. Recent studies indicate ketosis may improve congestive heart failure. Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56 Horton et al. JCI Insight 2019. 4:e124079* Nielsen et al. Circulation 2019. 139:2129 * Animal models with incorrectly formulated diets are responsible for many keto myths. Correctly formulated ketogenic diets extend lifespan and healthspan in mouse models. Animal model papers are noted with a star*. Roberts et al. Cell Metabolism 2017. 26:539* Newman et al. Cell Metabolism 2017. 26:547*

45. 12% Improvement in 10-year ASCVD Risk Score at 1 Year Intent-to-treat P = 4.9 X 10-5 Continue Care (CCI) Usual Care (UC) Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56 The atherosclerotic cardiovascular disease (ASCVD) risk score was developed by the American College of Cardiology and American Heart Association.

46. At 1 year, Examining All Available Cardiovascular Risk Biomarkers, 22 of 26 in CCI Treatment Show Statistically Significant Improvement Versus 0 of 26 for Usual Care including markers of • hypertension • atherogenic dyslipidemia • chronic inflammation • fatty liver Intent-to-treat for 22 significant changes P < 0.0019 Continue Care (CCI) Usual Care (UC) Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56

47. Ketosis May Improve Congestive Heart Failure Horton et al. JCI Insight 2019. 4:e124079* Nielsen et al. Circulation 2019. 139:2129

48. Myth 6. Keto Will Worsen the Blood Lipid Profile. - False 1. Patients showed improvement in triglycerides and HDL cholesterol. 2. While calculated LDL rose, there was no change in mean LDL particle number as measured by both apolipoprotein B (Apo B) and NMR lipoprofile (LDL-p). 3. There was a favorable shift of LDL subtype from small dense LDL to large buoyant LDL. 4. Other clinical trials of low carbohydrate and ketogenic diets have observed no mean increase in LDL by Apo B. Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56 Hays et al. Mayo Clinic Proceedings 2003. 78:1331 Noakes M et al. Nutrition & Metabolism 2006. 3:7 Wood et al. Journal of Nutrition 2006. 136:384 Tay et al. Journal of the American College of Cardiology 2008. 51:59 Brinkworth et al. AJCN 2009. 90:23

49. LDL Profile: While we observe a rise in mean LDL-C (+9.6%, P=4.9x10-5), overall LDL particle number is unchanged as measured by both Apo B (-1.9%, P=0.37) and LDL-P (-4.9%, P=0.02). Atherogenic Dyslipidemia: All measures improve including mean fasting triglyceride reduced 24.4% (P<10-16) and triglyceride/HDL-C ratio, reduced 29.1% (P<10-16) Continue Care (CCI) Usual Care (UC)Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56

50. Mean LDL-P is Unchanged While Small LDL and VLDL are Reduced Continue Care (CCI) Usual Care (UC) LDL Profile: Particle number shows distribution of response in both CCI & UC CCI: LDL-P (-4.9%, P=0.02). Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56

51. Myth 7. Keto Will Cause Inflammation. - False 1. Chronic inflammation was sharply reduced including a 39% reduction in high sensitivity C-reactive protein (hsCRP) and a 9% reduction in white blood cell (WBC) count at 1 year. 2. In surveys, patients reported improvement in joint function with reduced pain. 3. Other clinical trials of ketogenic diets have also seen reduction in inflammatory markers. 4. BHB is known to inhibit the NLRP3 inflammasome. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Forsythe et al. Lipids 2008. 43:65 Youm et al. Nature Medicine 2015. 21:263* Goldberg et al. Cell Reports 2017. 18:2077* Shimazu et al. Science 2013. 339:211* Newman & Verdin Diabetes RCP 2014. 106:173*

52. Inflammation: High sensitivity C-reactive protein (hsCRP) was reduced 39.3% (P<10-16) and white blood cell count (WBC) was reduced 9.1% (P<3.2x10-11) indicating a substantial reduction in inflammation. Testing of additional inflammatory markers is in progress. Continue Care (CCI) Usual Care (UC) Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56

53. The picture can't be displayed. In Clinical Studies, Ketogenic Diets Reduce Inflammation as Measured by Multiple Biomarkers Forsythe et al. Lipids 2008. 43:65

54. β-Hydroxybutyrate Inhibits Inflammation and Oxidative Stress Shimazu et al. Science 2013. 339:211* Newman & Verdin Diabetes RCP 2014. 106:173* Youm et al. Nature Medicine 2015. 21:263* Goldberg et al. Cell Reports 2017. 18:2077*

55. Myth 8. Keto Will Cause Hypothyrodism. - False 1. Mean thyroid hormone (T4) was unchanged in our patients. 2. Thyroid stimulating hormone (TSH) showed a numeric decrease rather than an increase that would be expected with an under-active thyroid. 3. There were no new cases of symptomatic hypothyroidism. 4. Hypothyroid has not been an issue in other low carbohydrate clinical trials. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 blog.virtahealth.com/does-your-thyroid-need-dietary-carbohydrates

56. Myth 9. Keto Will Harm the Liver and Increase Liver Fat. - False 1. Patient liver function was greatly improved as measured by markers of non-alcoholic fatty liver disease at one year and two years. 2. The liver fat score (N-LFS) improved. 3. The liver fibrosis score (NFS) improved. 4. Other clinical trials of ketogenic diets have also seen improvement in liver markers. Vilar-Gomez et al. BMJ Open 2019. 9:e023597 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Mardinoglu et al. Cell Metabolism 2018. 27:1 Gepner et al. J Hepatol 2019. 71:379 Cotter et al. J. Clin. Investigation 2014. 124:5175*

57. Markers of Non-Alcoholic Fatty Liver Disease (NAFLD) Improve Significantly Following 1-yr of the Intervention CCI Treatment, n=262 Usual care, n=87 Vilar-Gomez et al. BMJ Open 2019. 9:e023597 ALT = alanine aminotransferase

58. Myth 10. Keto Will Harm the Kidneys. - False 1. Mean estimated glomerular filtration rate (eGFR) improved. 2. There were no cases of worsening kidney function. 3. Other clinical trials of low carbohydrate diets have also seen improvement in eGFR. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Tirosh et al. Diabetes Care 2013. 36:2225 Poplawski et al. PLOS One 2011. 6:e18604*

59. Myth 11. Keto Will Cause Muscle Loss. - False 1. Average weight loss in trial completers at 2 years was 12% (about 30 lbs). 2. Dual energy absorptiometry (DEXA) scan demonstrated that most of the weight loss was due to loss of body fat including abdominal fat. 3. In another trial that examined this issue in detail, 87% of the weight loss was fat mass. Much of the non-fat weight loss was water. There was no change in muscle strength. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Gomez-Arbelaez et al. J Clin Endo Metab 2016. 102:488

60. Myth 12. Keto Will Cause Loss of Bone Mineral Density. - False 1. DEXA scan demonstrated no change in spine bone mineral density at both 1 and 2 years. 2. In another trial that examined this issue in detail, there was no change in bone mineral density. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers in Endocrinology 2019. 10:348 Gomez-Arbelaez et al. J Clin Endo Metab 2016. 102:488

62. Myth 13. Keto is Just a Fad. - False 1. Fasting and low carbohydrate diets resulting in ketosis are ancient. Documentation in the diabetes medical literature dates to the 1800’s. 2. More diabetes trials have examined carbohydrate restriction than any other diet. Myth 14. Keto is Not the Standard of Care. - False 1. The 2019 ADA Standards of Care and Nutrition Consensus Statement incorporate very low-carbohydrate nutrition as an established eating pattern for treatment of T2D. 2. Low carbohydrate patterns were included in the 2018 ADA – EASD Joint Consensus Statement and 2017 Veterans Administration / Dept. of Defense Clinical Practice Guidelines. Fan et al. Int J Clin Med 2016. 9:11166 Meng et al. Diabetes Research Clin Prac 2017. 131:124 Huntriss et al. Euro J Clin Nutrition 2018. 72:311 Hallberg et al. Diabetes, Obesity and Metabolism 2019. 21:1769 Evert et al. Diabetes Care 2019. 42:731-754 Diabetes Care 2019. 42:S46–S60 Davies et al. Diabetes Care 2018. 41: 2669-2701 www.healthquality.va.gov/guidelines/CD/diabetes

63. The Origins of Carbohydrate Restriction for Diabetes - Low carb ancestral eating patterns (e.g. Native Americans of Great Plains and Pacific Northwest, Inuit, Masai, Mongol Nomads, etc.) - Fasting ketosis – religious practice and ancient treatment for disease Medical Practice & Scientific Publications for Diabetes: - Rollo, Latham - England, 1811 - Brunton - England (BMJ), 1874 - Cantani - Italy, 1875 - Ebstein - Germany, 1892 - Naunyn - Germany, 1898 - Allen - US (Rockefeller), 1913 - Joslin - US (Boston), 1919 - Newburgh & Marsh - US (Michigan), 1920 - Wilder - US (Mayo), 1924 - epilepsy - Newburgh & Conn, 1942 T2D “reversal” Fell out of favor with availability of insulin & diet-heart hypothesis. Henderson, Journal of Diabetes and Metabolism 2016. 7:8 Bernhard Naunyn 1839-1935 Germany Frederick Allen 1879–1964 United States

64. More Diabetes Trials Have Examined Carbohydrate Restriction Than Any Other Dietary Pattern > 30 RCTs & meta-analysis 10 other trials Almost all observed HbA1c reduction and/or medication reduction following carbohydrate restriction for diabetes treatment. Fan et al. Int J Clin Med 2016. 9:11166 Meng et al. Diabetes Research Clin Prac 2017. 131:124 Huntriss et al. Euro J Clin Nutrition 2018. 72:311 Hallberg et al. Diabetes, Obesity and Metabolism 2019. 21:1769

65. The 2019 American Diabetes Association (ADA) Standards of Care and Nutrition Consensus Statement Incorporate Very Low-Carbohydrate Nutrition as an Established Eating Pattern for Treatment of T2D ” “Low-carbohydrate eating patterns, especially very low- carbohydrate (VLC) eating patterns, have been shown to reduce HbA1c and the need for antihyperglycemic medications. These eating patterns are among the most studied eating patterns for type 2 diabetes … this eating pattern does not appear to increase overall cardiovascular risk, but long-term studies with clinical event outcomes are needed. Evert et al. Diabetes Care 2019. 42:731-754 (ADA Nutrition Consensus) Diabetes Care 2019. 42:S46–S60 (ADA Standards of Care) Davies et al. Diabetes Care 2018. 41: 2669-2701 (ADA – EASD Joint Consensus)

66. Myth 15. Keto Benefit is Just Weight Loss. - False In a recent clinical trial, even when weight is held constant, ketosis reversed metabolic syndrome in the majority of participants. Myth 16. Keto Weight Loss is Just Water. - False While natriuresis causes water loss early in ketosis, a clinical trial tracking sources of 20 kg average weight loss over four months found it was approximately 87% fat mass, 8% water mass and 5% lean mass. Hyde et al. JCI Insight 2019. 4:e128308 Gomez-Arbelaez et al. J Clin Endo Metab 2016. 102:488

67. Even Without Weight Loss, a Low Carbohydrate Diet Improves Metabolic Syndrome More than High or Moderate Carbohydrate Diets Hyde et al. JCI Insight 2019. 4:e128308 In a randomized order study holding weight constant, significantly more participants reversed metabolic syndrome following a low carbohydrate diet for just 4 weeks. Baseline High carb Moderate carb Low carb

68. Myth 17. Keto Will Cause “Keto Flu”. - False Electrolyte (salt) management can avoid most if not all of the symptoms associated with the transition to ketosis including fatigue, headache, and weakness. Myth 18. Keto Will Cause Constipation. - False Electrolyte (salt) management can avoid most if not all of the symptoms associated with the transition to ketosis including constipation. blog.virtahealth.com/potassium-sodium-ketogenic-diet/ DeFronzo et al. J Clinical Investigation 1975. 55:845 Spark et al. NEJM 1975. 292:1335

69. Electrolyte Management Requires Extra Attention to Avoid Unnecessary Side Effects During Keto-Adaptation Sodium - 5 grams per day necessary for most patients (salt, broth, bouillon, tablets) - In high carbohydrate diets, high insulin levels signal sodium retention by the kidneys. - In ketosis, low insulin levels result in sodium excretion by the kidneys (natriuresis). - Sodium depletion can lead to hypovolemia, headache, fatigue and constipation. Potassium – 4 grams per day dietary or supplementation to avoid muscle cramps, etc. Magnesium – 400 mg per day dietary or supplementation to avoid muscle cramps, etc. blog.virtahealth.com/potassium-sodium-ketogenic-diet/ DeFronzo et al. J Clinical Investigation 1975. 55:845 Spark et al. NEJM 1975. 292:1335

70. Myth 19. Keto Will Require Too Much Sodium- False While U.S. dietary guidelines recommend low sodium (2.3g), multiple studies tracking Na+ excretion associate low salt consumption with increased mortality risk. Therefore, higher Na+ intake (5 g) is advisable. Myth 20. Keto Sodium Will Cause Hypertension. - False Blood pressure is reduced with low carbohydrate and ketogenic diets as is the need for antihypertensive medication. Clinical management: “One of the biggest challenges we encounter in managing people following a ketogenic diet is to get them to pay adequate attention to their sodium and potassium intakes. Part of this stems from the past 50 years of salt demonization, in which we were all taught that the less sodium intake, the better.” O’Donnell et al. NEJM 2014. 371:610 Mente et al. Lancet 2018. 392:496 Hallberg et al. Diabetes Therapy 2018. 9:583 Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56 Unwin et al. Int J Env Research and Public Health. 16:2680.

71. Studies Tracking Na+ and K+ Excretion Associate Low Salt Consumption with Increased Mortality Risk PURE Study of 102,000 People in 17 Countries O’Donnell et al. NEJM 2014. 371:610 Mente et al. Lancet 2018. 392:496

72. Blood Pressure is Reduced with Low Carbohydrate Diets as is the Use of Antihypertensive Medication Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56 Unwin et al. Int J Env Research and Public Health. 16:2680. Continue Care (CCI) Usual Care (UC) Mean systolic BP decreased 4.8% from 132 to 126 (P=1.3x10-8) while mean diastolic BP decreased 4.3% from 83 to 79 (P=7.2x10-8) simultaneous with reduced use of antihypertensives (-17.0%) and diuretics (-24.8%). Mean systolic BP decreased 7.7% from 143 to 132 (P<0.0001) while mean diastolic BP decreased 7.1% from 84 to 78 (P<0.0001) simultaneous with reduced use of antihypertensives (-20%).

73. Myth 21. Keto Will Cause Adrenal Fatigue. - False There is no evidence that ketosis inhibits adrenal function. However, sodium restriction during ketosis will trigger adrenal activity through the renin - angiotensin - aldosterone system so it is advisable not to overly restrict sodium when in ketosis. Myth 22. Keto Will Cause Gall Stones & Requires a Gall Bladder. - False 1. Gall stone formation is associated with very low-calorie liquid diets (VLCD) lacking in fat where gallbladder emptying is not stimulated. 2. Many patients who have had gall bladder removal perform well on a ketogenic diet. Clinical management: Reduced circulating sodium can trigger the adrenal gland to increase production of aldosterone and also increase adrenal production of the stress hormone cortisol and the fight-or-flight hormone adrenaline. blog.virtahealth.com/sodium-nutritional-ketosis-keto-flu-adrenal-function/ blog.virtahealth.com/ketogenic-diet-no-gallbladder/ Clinical management: “If dietary fat tolerance is reduced, consume dietary fats as emulsions (e.g., high oleic mayo, cream, sour cream, yogurt), and spread fat intake throughout the day rather than large amounts with any one meal.

74. Myth 23. Keto Increases Mortality in Nutritional Epidemiology Studies. - False Nutritional epidemiology has not studied ketogenic diets. While some studies based on food surveys have extrapolated higher mortality with higher fat diets, other studies have reached the opposite conclusion. In clinical trials, replacing saturated fat with polyunsaturated fat or carbohydrates has not improved mortality. Myth 24. Keto Requires Meat Consumption. - False Ketogenic diets have been formulated for vegetarians. While more challenging, even vegan ketogenic diets are possible. Dehghan et al. Lancet 2017. 390:2050 Siri-Tarino et al. Am J Clin Nutr 2010. 91:535 Ramsden et al. BMJ 2016. 353:11246 Nutritional epidemiology is a field in need of radical reform (Ioannidis, 2018). Epidemiological studies are not designed to prove causation and even associations are usually wrong because of over-interpretation of small changes in hazard ratios, residual confounding, data dredging, selective publication and investigator bias. One analysis found that of 52 claimed health benefits or harms based on associations from nutritional epidemiology, none were validated when tested in randomized clinical trials (Young and Karr, 2011). Ioannidis. JAMA 2018. 320:969 Young and Karr Significance 2011. 8:116 blog.virtahealth.com/vegan-vegetarian-low-carb-keto/

76. Myth 25. Keto Will Increase Cancer Risk. - False 1. There is no evidence that ketogenic diets increase cancer risk. 2. In fact, several dozen clinical trials are currently examining ketogenic diets as an adjuvant treatment to chemotherapy (e.g. with PI3K inhibitors to counter insulin rise). Myth 26. Keto Increases Circulating Saturated Fat. - False In a randomized order study holding body weight constant, plasma saturated fat levels were lowest during the low carbohydrate diet despite higher saturated fat consumption. Hopkins et al. Nature 2018. 560:499* Tan-Shalaby et al. Federal Practitioner 2017. 34:37S Hyde et al. JCI Insight 2019. 4:e128308

77. Myth 27. Keto Provides Inadequate Dietary Fiber. - False There is no evidence that ketogenic diets provide inadequate dietary fiber. Fiber is not an essential nutrient and there is no RDA. A well formulated ketogenic diet provides ~12 grams of fiber per day (from vegetables, nuts, seeds, etc.) versus the AHA guideline 25 g per day. 1. While the gut microbiome varies with diet, there is no evidence that ketogenic diets result in an inferior microbiome. 2. A key role of the gut microbiome on a high fiber diet is butyrate production, a metabolic role fulfilled on a ketogenic diet by BHB production. David et al. Nature 2014. 505:559 blog.virtahealth.com/fiber-colon-health-ketogenic-diet/ Myth 28. Keto Interferes with the Gut Microbiome. - False

78. Example of Daily Fiber on a Well Formulated Ketogenic Diet Serving of vegetables ½ cup cooked or 1 cup raw Breakfast ½ cup cooked spinach (3.5 g) 2.4 g fiber Lunch 2 cups Romaine (3 g) 2 g fiber 1/2 cup peppers (4.5) 1.5 g fiber Dinner ½ c mushrooms (2.5 g) 1.7 fiber ½ c cauliflower (2.5 g) 1.2 fiber 24 g carb; 12.8 g fiber Snacks 1 oz macadamias (4 g) 2.4 g fiber 1 c celery (4 g) 1.6 g fiber

79. Myth 29. Keto is Environmentally Unsustainable. - False In the plant versus animal agriculture debate, the advantages of plant-based diets are often overstated. According to a recent study, removing all animal agriculture would reduce U.S. greenhouse gas emissions by only 2.6% while resulting in nutrient-deficient food. (Ketogenic diets can be animal or plant-based.) Myth 30. Keto Foods are Too Expensive. - False 1. Among the 3 macronutrients, protein is the most expensive per kcal (e.g. lean cuts of meat). Ketogenic diets replace carbs with fat and are moderate in protein (15-20%). 2. There is no requirement for expensive processed foods, premium ingredients or keto supplements. White and Hall. PNAS 2017. 114:E10301 Fat: The New Health Paradigm. Credit Suisse Report. 2015. Zinn et al. Nutrition & Dietetics 2019. DOI: 10.1111/1747-0080.12534

80. Carbohydrate restriction to achieve nutritional ketosis (initially <30 grams) Highly personalized - budget, culture, religion, omnivore vs. vegetarian, etc. Education & problem solving, not meal delivery/replacement Eat delicious, whole foods until satisfied, no calorie counting Not zero carb - 5 daily servings of vegetables, plus nuts, berries, etc. Nutritional Ketosis Through Individualized Dietary Guidance

81. Myth 31. Keto Will Interfere with Exercise. - False 1. In elite athletes following ketoadaptation, performance can exceed high carbohydrate results (e.g. ultra-endurance world record holder Zach Bitter). Full ketoadaptation likely requires at least 12 weeks. (Performance may vary by sport & energetic needs.) 2. A study of elite athletes found peak fat oxidation was 230% higher in the ketoadapted athletes versus high carbohydrate consuming athletes. Myth 32. Keto Will Deplete Muscle Glycogen. - False The study of elite athletes found no differences in muscle glycogen pre and post-workout in the high carbohydrate and ketogenic adapted groups. High fat oxidation is glycogen-sparing. Phinney et al. Metabolism 1983. 32:757 Volek et al. Metabolism, 2016. 65:100

82. Studies of Keto-Adapted Athletes Demonstrates that Nutritional Ketosis Can Sharply Increase Fat Oxidation. Volek et al. Metabolism, 2016. 65:100 • Comparing 20 male ultra- runners consuming either a low carb (<20%) or high carb (>55%) diet for at least 6 months • Peak fat oxidation was 230% higher in the low carb group • Mean fat oxidation was 59% higher in the low carb group • Muscle glycogen levels did not differ between the groups.

83. Myth 33. Keto Will Raise Long-Term Risk of Gout.- False 1. While uric acid can show a transient increase during ketoadaptation, uric acid levels were unchanged at 1 and 2 years. No new cases of gout were observed. 2. Other clinical trials of ketogenic diets have seen similar changes in uric acid levels. 3. Mechanism studies suggest ketosis may prevent gouty flares by inhibition of IL-1β. Myth 34. Keto Will Raise Long-Term Risk of Kidney Stones. - False 1. Kidney stones have been described in ketogenic diets for pediatric epilepsy. 2. We observed one case of a kidney stone in the second year of the trial. 3. There are no trials documenting a higher rates of kidney stones in adults in ketosis. Hallberg et al. Diabetes Therapy 2018. 9:583 Athinarayanan et al. Frontiers Endo 2019. 10:348 Hussain et al. Nutrition 2012. 28:1016 Goldberg Cell Reports 2017. 18:2077* Sampath et al. J Child Neurology 2007. 22:375 Clinical management: “And after a month or two, the kidneys adapt to maintaining normal uric acid excretion. At Virta, we devote considerable attention to hydration, adequate but not excessive dietary sodium and calcium, and plenty of green vegetables, nuts, and seeds (dietary sources of magnesium). We also supplement magnesium when there are early clinical signs of depletion.”

84. Myth 35. Keto Will Cause “Keto Crotch”. - False It does not exist. The term appears to have been promoted by a public relations (PR) firm in February of 2019 as a paid media campaign to counter the keto trend. Myth 36. Keto Will Cause “Keto Bloat”. - False It does not exist. There is no evidence that ketosis causes bloating. Gibson and Shepherd. J Gastroenterology & Hepatology 2010. 25:252 Lomer. Aliment Pharmacol Ther 2015. 41:262 Clinical management: Instruct patients to be aware of irritable bowel syndrome (IBS) that can occur upon introduction of new foods following any dietary change (not just ketogenic diets) including FODMAP containing foods (Fermentable Oligosaccharides, Disaccharides, Monosaccharides, and Polyols) especially sugar alcohols used as artificial sweeteners in sugar-free processed foods.

85. Myth 37. Keto Will Confuse the Public. - False This is an excuse. In other words, if “experts” embrace the benefits of a high fat diet, the last 40 years of nutrition guidelines and advice is in doubt. Yes, there is good reason for doubt! Myth 38. Keto Will Undermine Science. - False This is another excuse. Ketogenic diets are based on rigorous and increasing scientific study. Johnston et al. Annals of Internal Medicine 2019. 10.7326/M19-1621 www.hsph.harvard.edu/nutritionsource/2019/09/30/flawed-guidelines-red-processed-meat

86. Myth 39. Keto Will Cause Diabetes. - False There is no evidence that ketosis causes diabetes. This myth derives from poorly designed animal studies with improperly formulated “high fat” diets (e.g. high fat, high sugar). Myth 40. It’s Better Just to Stay with Usual Care. - False Usual care does not reverse type 2 diabetes. In a Kaiser Permanente study of 122,781 adults, “The 7-year cumulative incidence of partial, complete, or prolonged remission was 1.47%, 0.14%, and 0.007%.” (Even allowing for metformin use, rates of diabetes reversal are very low with usual care.) Karter et al. Diabetes Care 2014, 37:3188

88. Conclusions – Overcoming Keto Myths. • Nutritional ketosis is a viable patient choice for type 2 diabetes (T2D) reversal. • Low carbohydrate nutrition patterns including ketosis have extensive clinical trial evidence for T2D improvement including the Virta-IUH trial 1 and 2-year outcomes. • The ADA and other organizations have updated their guidelines to include low carbohydrate eating patterns for T2D treatment. • Focus on electrolyte management. 8 of the 40 myths are basically about salt! • Be informed. Talk with your patients. Debunk myths meant to cause fear. • Let patients know they have a CHOICE to reverse diabetes. The decision is THEIRS.

89. Thank you! Twitter and Medium: @jpmccarter LinkedIn: jamesmccarter