Presentation to the North American Spine Society Annual Meeting. Interdisciplinary Spine Forum: Obesity and Diabetes: Impact on the Spine and Evidence-Based Management Strategies. Organized by Dr. Carrie Diulus Diabetes and obesity have reached epidemic proportion. It is imperative that spine providers take these factors into consideration. We also have the opportunity to be powerful motivators to our patients with some straight forward evidence-based strategies. Upon completion of this session, participants should gain strategies to:  Understand impact of metabolic syndrome on spine conditions/degeneration and treatment outcomes  Learn dietary strategies to have a positive impact on these conditions and the most current science behind these recommendations  Understanding the impact of strategies on heart disease and lipids  How to implement recommendations in a busy clinical setting

1. What Spine Providers Need to Know About
Dietary Strategies for Heart Disease & Diabetes –
Learnings from a Nutritional Ketosis Intervention
James McCarter MD PhD
Adjunct Professor of Genetics, Washington University School of Medicine
Former Head of Research, Virta Health
September 27th, 2019

2. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

3. 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 treatment of type 2 diabetes and metabolic disease.
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.

4. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

5. 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.

6. T2D Reversal with Very Low Carbohydrate Nutrition
e.g. nutritional ketosis
Athinarayanan et al. Frontiers in Endocrinology 2019, 10:348
CCI (ketosis) usual care
Complete Remission requires A1c < 5.7%

7. The 2019 ADA Standards of Care and Nutrition Consensus
Statement Incorporates 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)

8. What is Low Carbohydrate Nutrition?
● Very low-carbohydrate, ketogenic
○ ≤ 50 grams/day of total carbohydrate (usually <10% of daily kcals)
○ Can require <30 g/d 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 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

9. 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 Guidance

10. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

11. The Origins of Carbohydrate Restriction for Diabetes
- High fat 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

12. Shift from high carbohydrate to high fat
stops the glucose insulin rollercoaster.
Why is Carbohydrate Restriction
Effective in the Treatment of T2D?
“Total amount of carbohydrate eaten is the
primary predictor of glycemic response.”
- ADA 2014 Standards of Care
Diabetes Care Jan 2014, 37:S120

13. • 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 g/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 and Why is it Beneficial?
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

14. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

15. 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.
Hallberg et al. Diabetes, Obesity and Metabolism 2019, 21:1769

16. Boden et al. Ann Intern Med 2005, 142:403
• 10 patients with T2 diabetes & obesity
• Hospitalized for 3 weeks with observed meals
• Days 1-7 Usual diet
• Days 8-21 Low-carbohydrate Diet (21 g/day) with ad
libitum fat and protein
• Fasting glucose decreased from 135 to 113 mg/dL
• Medication reduced in 4 patients & discontinued in 1.
• Insulin sensitivity increased 75% by euglycemic
hyperinsulinemic clamp
Effect of a Low-carbohydrate Diet on Appetite,
Blood Glucose Levels, and Insulin Resistance in
Obese Patients with Type 2 Diabetes

17. 12 Month Randomized Trial of a
Moderate Carbohydrate Versus
Very Low Carbohydrate Diet in
Overweight Adults with Type 2
Diabetes or Prediabetes
Saslow et al. Plos One 2014, 9:e91027 (3 month outcomes)
Saslow et al. Nutrition & Diabetes 2017, 7:304 (6 month and 1 year)
RCT with 34 Patients. Very low carbohydrate
diet patients had significantly greater
reductions in HbA1c, lost more weight &
reduced more medications than those following
a moderate carbohydrate calorie restricted diet.
A1c 6.9 to 6.7%
Weight loss of 2.3 kg
A1c 6.6 to 6.1%
Weight loss of 7.9 kg

18. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

19. 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

20. 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 20

21. 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

22. 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

23. 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

24. 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 at 2 years)

25. 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)

26. 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

27. 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
• 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

28. Other Measures of Glycemic
Control: fasting glucose
decreased 22% (P<1.0x10-16),
fasting insulin decrease of 43%
(P=6.7x10-16), HOMA-IR decrease
of 55% (P=73.2x10-5).
Continue Care (CCI)
Usual Care (UC)
Hypertension: 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). BP reductions occurred
simultaneous with reduced use of
antihypertensives (-17.0%) and especially
diuretics (-24.8%).
Hallberg et al. Diabetes Therapy 2018. 9:583
Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56

29. 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

30. 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

31. Mean Apo B is Unchanged While Apo B/Apo A1 Ratio Improves
Continue Care (CCI)
Usual Care (UC)
LDL Profile: Particle number shows distribution of
response in both CCI & UC
CCI: Apo B (-1.9%, P=0.37)
Bhanpuri et al. Cardiovascular Diabetology 2018. 17:56

32. 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

33. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

34. Hays et al. Mayo Clinic Proceedings 2003. 78:1331
Effect of a High Saturated Fat and No-
Starch Diet on Serum Lipid Subfractions in
Patients With Documented Atherosclerotic
Cardiovascular Disease
(Patients who are taking statins)
LDL-C
No significant change

35. Comparison of isocaloric very low carbohydrate/high saturated fat and high carbohydrate/low
saturated fat diets on body composition and cardiovascular risk
Noakes M et al. Nutrition & Metabolism 2006. 3:7
ApoB
No change

36. Wood et al. Journal of Nutrition 2006. 136:384
ApoB
Significant Decrease
Carbohydrate Restriction
Alters Lipoprotein Metabolism
by Modifying VLDL, LDL, and
HDL Subfraction Distribution
and Size in Overweight Men
Body weight, trunk fat, and plasma
lipid and lipoprotein concentrations in
men who consumed a CRD for 12 wk1

37. Metabolic Effects of Weight Loss on a Very-Low-
Carbohydrate Diet Compared With an Isocaloric
High-Carbohydrate Diet in Abdominally Obese
Subjects
Tay et al. Journal of the American College of Cardiology 2008. 51:59.
ApoB
No change

38. Brinkworth et al. AJCN 2009. 90:23
ApoB
No change
Long-term effects of a very-low-carbohydrate
weight loss diet compared with an isocaloric
low-fat diet after 12 months

39. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

40. Managing Individual Cardiovascular Risk Factor Response
- While most cardiovascular risk factors improve, LDL response to ketosis is variable.
- Increases are observed in some patients (Creighton, 2018).
- Because of discordance of LDL-C & particle #, measuring ApoB or LDL-P can be valuable.
Creighton et al. BMJ Open Sport Exerc Med 2018. 4:e000429
Otvos et al. J Clin Lipid 2011. 5:105
Sierra-Johnson et al. European Heart J 2009. 30:710
~20% of patients misclassified by LDL-C
Risk stratification by ApoB quartile with typical US population.
Risk of higher ApoB with ketosis is unknown. Caution would suggest
managing to a lower particle number by diet or medication.

41. Managing Individual Cardiovascular Risk Factor Response
- Coronary Artery Calcium (CAC) Scan is a direct measure of cardiovascular disease.
- CAC provides a better prediction of CVD outcomes than risk factors.
Polonsky et al. JAMA 2010. 303:1610
Miedema et al. JAMA Network Open 2019. 2:e197440
Use of CAC before dietary intervention could be used to
establish a baseline with follow-up testing based on risk.

42. Diabetes Reversal & Updated ADA Guidelines
Origins & Mechanisms of Ketosis
Prior Clinical Evidence – Glycemic Control
Virta - IUH Trial Diabetes & CVD Outcomes
Prior Clinical Evidence – CVD Outcomes
Managing Cardiovascular Risk
Conclusions
AGENDA

43. Conclusions
• Carbohydrate restriction is a viable patient choice for type 2 diabetes (T2D) reversal.
• Nutritional ketosis supports diabetes reversal by reducing insulin resistance while
providing an alternative fuel to glucose with favorable signaling properties.
• 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 American Diabetes Association (ADA) and other organizations have updated their
guidelines to include low carbohydrate eating patterns for T2D treatment.
• Most cardiovascular risk factors improve with a ketogenic diet but LDL response varies.
Direct measure of particle number and coronary artery calcium may better predict risk.

44. Thank you to our co-authors, collaborators ...
… and especially our clinical trial participants.

45. Thank you!
jamespmccarter@gmail.com
Twitter and Medium: @jpmccarter
LinkedIn: jamesmccarter