LCHF/Ketogenic Diet effects on cardiovascular disease

1. Low Carbohydrate High Fat
Diet: Is it just a fad?
Jered Cook, MD
Cardiovascular Disease Fellow
University of Toledo
1/24/19

2. Objectives
Epidemiology
Current dietary guidelines
Evidence on different food types
Ketogenic diet basics
Effects of the ketogenic diet on CVD
Research

3. Objectives
Epidemiology
Current dietary guidelines
Evidence on different food types
Ketogenic diet basics
Effects of the ketogenic diet on CVD
Research

4. Obesity in America
 >65 % of adults in the US are overweight or obese
www.cdc.gov

5. Consequences of Obesity
 All-causes of death (mortality)
 Hypertension
 High LDL cholesterol, low HDL cholesterol, or high levels of triglycerides (Dyslipidemia)
 Type 2 diabetes
 Coronary heart disease
 Stroke
 Gallbladder disease
 Osteoarthritis (a breakdown of cartilage and bone within a joint)
 Sleep apnea and breathing problems
 Cancers (endometrial, breast, colon, kidney, gallbladder, and liver)
 NASH cirrhosis
 Low quality of life
 Mental illness such as clinical depression, anxiety, and other mental disorders8
 Body pain and difficulty with physical functioning
www.cdc.gov
OBESITY is a root
cause in the
epidemics of
hypertension,
diabetes, heart
disease, and
cancer

6. Obesity

7. Cost of Obesity: Not just the food
 Medical care costs of obesity in the United States are
high.
 In 2008, these costs were estimated to be $147 Billion
 Annual nationwide productivity cost due to
absenteeism was over $3 Billion
www.cdc.gov

8. Diabetes in 1994

9. Diabetes in 2015

10. Cost of Diabetes in America
 The total direct and indirect estimated cost of diagnosed diabetes
in the United States in 2012 was $245 billion.
 Medical expenditures were approximately 2.3 times higher than
expenditures for people without diabetes
www.cdc.gov

11. How did we get here?
Recommend low
Fat intake
Over the last ~150 years, sugar intake
among human populations has gone
from very rare to ubiquitous.
Roughly 10 fold increase in annual
sugar intake from 1840 to 2000
Dietary guidelines advising limited
total and saturated fat intake have
led to increased sugar and
carbohydrate intakes and high rates
of obesity and diabetes

12. Low Fat foods are often high in sugar
This low fat yogurt has
26 grams of sugar per
serving
That equals ~ 7
teaspoons of sugar!

13. Effects of Low Fat dietary guidelines
https://alivebynature.com/steps-to-lower-your-blood-sugar-levels-and-live-longer/

14. How Are We Combating These Issues?
 What are the dietary guidelines?
 How are they being assessed?

15. Objectives
Epidemiology
Current dietary guidelines
Evidence on different food types
Ketogenic diet basics
Effects of the ketogenic diet on CVD
Research

16. Current Dietary Guidelines
How is it so?

17. Bradford Hill Criteria
 1965 by Sir Austin Bradford Hill
 Widely used in public health research
 Strength – larger the association the more likely
 Consistency (reproducibility) – Consistent through change
 Specificity – More specific the population being studied
 Temporality – Effect must occur after the cause
 Biological gradient – Greater exposure should lead to greater incidence
 Plausibility – Can be limited by current knowledge
 Coherence – Epidemiologic and lab findings should be coherent
 Experiment – Appeal to experimental evidence
 Analogy – Effect of similar factors

18. Current Dietary Guidelines: USDA 2015-2020
 “A healthy dietary pattern is high in vegetables, fruit, whole grains, seafood, legumes, and
nuts; moderate in low- and non-fat dairy products; lower in red and processed meat; and
low in sugar-sweetened foods and beverages and refined grains.”
 3 different advised diets
 Healthy US Eating Pattern
 Mediterranean Style Eating Pattern
 Vegetarian Eating Pattern
 Avoidance of saturated fats, sodium and “added” sugars

19. Current Dietary guidelines:
ACC/AHA/ADA
 “A heart-healthy dietary pattern emphasizes vegetables, fruits, and whole grains; includes
low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oils, and nuts; and
limits intake of sodium, sweets, sugar-sweetened beverages, and red meats.”
 Cochrane review - reducing dietary saturated fat reduced the risk of CV events by 17%,
mortality was not affected and the interventions were all very different.
 This was mostly led by studies substituting saturated fat with polyunsaturated and other subgroups
did not show significant change.
 Meta-analysis with Linoleic Acid(LA) addition in non-CHD patients, showed a CHD risk
reduction, though there is only a dosage of LA, not an actual replacement. Also used
observational studies within the meta-analysis
Cochrane Database Syst Rev. 2015 Jun 10;(6):CD011737. doi: 10.1002/14651858.CD011737
Circulation. 2014;130:1568–1578

20. Fats Battle Back
 “Epidemiological evidence to date found no significant difference
in CHD mortality and total fat or saturated fat intake and thus does
not support the present dietary fat guidelines. The evidence per se
lacks generalisability for population-wide guidelines.”
Harcombe, Z et al. Br J Sports Med. 2017 Dec;51(24):1743-1749

21. Diabetes / Obesity Epidemic: Carb
Addiction
http://prohealthadvisor.com/diet/h
yperinsulinemic-obesity-and-
carbohydrate-addiction/
Carb intake causes
glucose spikes
Insulin surges
Hunger and craving
follows
Eventually:
-hyperinsulinemia
-obesity
-diabetes

22. Fighting Obesity
America is Losing

23. Weight loss: Different diets
 Low fat diet showed that when compared to diets of similar intensity it was not beneficial
at long-term weight loss over higher fat interventions.
 These studies did not include all low carbohydrate diets
Tobias, DK et al. Lancet Diabetes Endocrinol 2015;3: 968–79

24. Low Carb vs Low Fat Diet
 119 pts randomized followed up at 3,6 and 12 months
 Pts without CVD or DM
 Low Carb diet (<40 grams/day total carbohydrates)
 Low Fat Diet (<30% daily energy intake from fat and <7% calories from saturated fat)
 At 12 month follow up, subjects randomized to Low carb diet had the following compared
with low fat diet:
 Greater average weight loss (3.5kg greater weight loss on average)
 Greater decrease in fat mass: change of 1.5% more
 Greater decrease in Triglycerides: drop by 14 mg/dL more
 Greater increase in HDL cholesterol: By 7mg/dL
Bazzano, L et al. Ann Intern Med. 2014;161(5):309-318.

25. Objectives
Epidemiology
Current dietary guidelines
Evidence on different food types
Ketogenic diet basics
Effects of the ketogenic diet on CVD
Research

26. Food Items
What food items are beneficial?
What foods are harmful?

27. Potatoes
 Potato consumption was directly linked with developing T2 DM. (Worst = French fries)
 Every 3-servings/week increment of potato consumption in 4 years was associated with a
4% (95% CI 0-8%) higher T2D risk.
 Potatoes are associated with an increased risk of developing hypertension.
 Compared to non-starchy vegetables
 A systematic review of these and other studies refuted the argument, though stated that
RCTs would be needed to further delineate the risks of potato consumption.
Muraki, I et al. Diabetes Care. 2016 Mar;39(3):376-84. doi: 10.2337/dc15-0547. Epub 2015 Dec 17.
Borgi, L et al. BMJ 2016;353:i2351
Borch, D et all. Am J Clin Nutr. 2016 Aug;104(2):489-98. doi: 10.3945/ajcn.116.132332. Epub 2016 Jul 13.

28. Tree Nuts
 Tree nut intake lowers total cholesterol, LDL cholesterol,
ApoB, and triglycerides.
 Nut dose more important than type
 Nut intake associated with lower rates of MI and stroke in
the PREDIMED randomized controlled trial
 In PREDIMED, subjects randomized Mediterranean diet
with nuts received 30 g of mixed nuts per day per person
(15 g of walnuts, 7.5 g of hazelnuts, and 7.5 g of
almonds)
 Multiple tree nuts, including walnuts, pecans, almonds,
and pistachios, have been shown to have favorable
cardiovascular effects
Estruch R, Ros E, Salas-Salvadó J, et al. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J
Med 2013;368:1279-1290.

29. Dairy
 Observational data does not support the belief that dairy fat or high-fat dairy contribute
to obesity or cardiometabolic risk.
 Also no link between dairy and MACE or all cause mortality
 Observational data does not support the belief that dairy fat is associated with heart
disease
 Diabetes incidence shows a trend toward reduction with dairy foods (i.e. yogurt),
especially full fat (no added sugar) dairy products
Kratz, M., Baars, T. & Guyenet, S. Eur J Nutr (2013) 52: 1. https://doi.org/10.1007/s00394-012-0418-1
Guo, J et al. Eur J Epidemiol. 201
Gijsbers, L et al. The American Journal of Clinical Nutrition, Volume 103, Issue 4, 1 April 2016, Pages 1111–11247 Apr;32(4):269-287.

30. Coffee/Tea
 3-5 cups of coffee per day showed an 11% CVD risk reduction
 Heavy coffee consumption did not show adverse CVD risk
 Black tea is not cardioprotective
 Limited data on green tea support a reduction in CAD, though more studies needed
Ding, M et al. Circulation. 2014 Feb 11; 129(6): 643–659.
Butt, M. Crit Rev Food Sci Nutr. 2011 Apr;51(4):363-73.
Coffee has a rich phytochemistry, including caffeine, chlorogenic acid, caffeic acid, hydroxyhydroquinone (HHQ)
Wang, ZM. Am J Clin Nutr. 2011 Mar;93(3):506-15.
Coffee drinkers: drink up!
However, benefits of coffee will be negated by:
1) added sugar
2) “non-dairy creamer”: which is basically hydrogenated oils and very atherogenic

31. Non-dairy creamer
Keep it simple:
-black coffee or coffee with milk or dairy
cream = GOOD
-coffee with sugar and/or non-dairy
creamer = BAD

32. Fiber
 Dietary fiber intake was associated with decreased CVD and CAD, with heterogeneity
between types of fiber.
 Increase in fiber to above recommended minimum, as in the US, trends toward a
decrease in hypertension.
 Dietary fiber may cause a miniscule drop in total and LDL cholesterol. Unlikely to be much
benefit. Approximately 0.13 mmol/L (approximately 5 mg/dL) decrease.
BMJ 2013;347:f6879
Streppel, MT et al. Arch Intern Med. 2005 Jan 24;165(2):150-6.
Brown, L et al. American Journal of Clinical Nutrition 69(1):30-42

33. Macronutrients
 PURE – Prospective Urban Rural Epidemiology Study
 Epidemiologic Cohort Study
 18 countries ages 35-70, median 7.4 years of follow up, >135k people
 High Carbohydrate intake was associated with higher risk of mortality
 Fat intake did not correlate with higher risk, nor did type of fat eaten
 Saturated fat had an inverse relationship with stroke incidence
Dehghan, M et al. Lancet 2017; 390: 2050–62

34. Glycemic index/Glucose Regulation
 High glycemic load and index, as well as high carbohydrate and starch intake, are
associated with an increased risk of cardiovascular disease.
 Low carbohydrate diet vs low glycemic index diet (500 kcal daily deficit), LC showed
better glucose control and less medication needed.
 Very low carbohydrate diet (<50g/day) shows better glucose control with a decrease in
diabetic medications along with a low carbohydrate diet (<130g/day)
Burger, KN et al. PLoS One. 2011;6(10):e25955
Westman, E et al. Nutrition & Metabolism. 2008. 5:36
European Journal of Clinical Nutrition. volume 72, pages311–325 (2018)

36. Objectives
Epidemiology
Current dietary guidelines
Evidence on different food types
Ketogenic diet basics
Effects of the ketogenic diet on CVD
Research

37. Differences in blood glucose and insulin
levels with low carb vs. low fat diets
dietdoctor.com
Low Fat (High
Carb) diet
Low Carb
(High Fat) diet

38. Rationale Behind low carbohydrate diets
for diabetes and obesity
 Low carb high fat (LCHF) (VLCHF, also known as ketogenic) diet attacks the root cause of
diabetes and obesity: hyperglycemia and hyperinsulinemia
 For Obese diabetics, rather than treating with exogenous insulin, why not attack the root
cause of hyperinsulinemia and insulin resistance?
 Observational and RCT evidence with low carb diet consistently demonstrate:
 Weight loss
 Decreased HbA1c
 Decreased need for diabetic medications and insulin

39. Basics of the LCHF/Ketogenic Diet
Low carb, no grains
Helps burn fat more effectively
Benefits in weight loss, health and performance

41. Low Carb Wins!!!
 Low Carb vs Low Fat diet RCTs
 Weight loss
 HDL
 TG
 A1C
 Glucose
 Insulin
 Inflammation
 Waist
 TC/HDL

42. What to eat…
www.dietdoctor.com

43. What NOT to Eat…
www.dietdoctor.com

45. Objectives
Epidemiology
Current dietary guidelines
Evidence on different food types
Ketogenic diet basics
Effects of the ketogenic diet on CVD
Research

46. Benefits of the Ketogenic Diet on CVD
 Weight Loss
 Energy
 Hypercholesterolemia/Dyslipidemia
 Hypertension
 Atherosclerosis/Blood Flow
 Diabetes
 ?Heart Failure

47. Obesity
 As shown prior, weight loss and reversing metabolic syndrome is possible with a low
carbohydrate diet more effectively than low fat diets.

48. Atherosclerosis
 A meta-analysis of prospective epidemiologic studies showed that there is no significant
evidence for concluding that dietary saturated fat is associated with an increased risk of
CHD or CVD.
Siri-Tarino, P et al. The American Journal of Clinical Nutrition, Volume 91, Issue 3, 1 March 2010, Pages 535–546

49. Atherosclerosis
 DIRECT-Carotid – RCT
 Low-fat, Mediterranean, or low-carbohydrate diets
 2 years
 5% regression in vessel wall volume (VWV), no difference in diet type
 Reduction in the ratio of apolipoprotein B100 in the low carb arm
 Patients with regression had greater weight loss and lowering of SBP
 Decreased homocysteine levels and increased apolipoprotein A1 in low carb arm
 Multivariate regression models showed - SBP was a significant independent modifiable
predictor of a decrease in VWV and intima thickness
Shai, I et al. Circulation. 2010;121:1200–1208

50. Cholesterol levels
 Link btwn small LDL-c and atherogenesis
 LCHF diet increases the size of LDL-c molecules
 Decrease in Triglycerides (TG) in LCHF diets
 TG being a strong independent risk factor for CVD.
 High insulin represses lipolysis and increases lipogenesis, increasing TG levels.
 Lower glucose and insulin concentrations also reduce ChREBP and SREBP1c expression, which
activate key lipogenic enzymes, thereby reducing hepatic lipogenesis and VLDL production
 High carb diet prolongs circulatory exposure to saturated fatty acids
 Carb restricted diet = less exposure
 Higher rates of lipid oxidation
Volek, J.S., Phinney, S.D., Forsythe, C.E. et al. Lipids (2009) 44: 297.

51. Cholesterol levels
 Carb restriction leads to
 Decreases in malonyl-CoA concentration (so, inc in oxidation of FA)
 Dis-inhibition of the carnitine acyltransferase
 Enhanced mitochondrial shuttle and β-oxidation of fatty acids
 Lower RBP-4, which is found to be increased in insulin-resistant states
 Lower glucose (especially lower fructose)
 Limits glycerol-3-phosphate production for the re-esterification of free fatty
acids.
Volek, J.S., Phinney, S.D., Forsythe, C.E. et al. Lipids (2009) 44: 297.

52. Hypertension
 307 subject Randomized Controlled Trial
 Low Carb diet versus low Fat diet
 Low Carb diet: <20g carbs per day and unlimited fats/proteins
 Low fat diet was 1200 to 1800 kcal/d; ≤ 30% calories from fat
 Systolic Blood Pressure decreased in both with weight loss and a 3 mmHg change
that was statistically significant in the low carb diet at 6 months with a strong trend at
2 years.
Foster, GD et al. Ann Intern Med. 2010 Aug 3;153(3):147-57.

53. Blood Flow
 2008 Australian study in 50 obese patients over 8 weeks
 Low carbohydrate diet effect on endothelial function
 Endothelial markers, E- and P selectin, intracellular and cellular-adhesion molecule-1,
tissue-type plasminogen activator, and plasminogen activator inhibitor-1 decreased
 Adiponectin did not change significantly
 More weight loss and abdominal girth lost in low carbohydrate, high sat fat diet
compared to High carbohydrate, low sat fat diet.
 HCLF diet had a greater decrease in LDL and CRP
Gromsen, LC et al. J Am Heart Assoc. 2017 Mar; 6(3): e005066.

54. Myocardial Blood Flow
 Given 390 minutes of ketone infusion vs 390 minutes of saline infusion, with an endogenous
ketogenesis clamp.
 Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were
recorded on both study days
 MGU was halved by hyperketonemia (Myocardial Glucose Uptake)
 No effect observed on palmitate(FA) uptake oxidation or esterification (Link to CAD)
 Hyperketonemia increased heart rate by ≈25% and myocardial blood flow by 75%.
Gromsen, LC et al. J Am Heart Assoc. 2017 Mar; 6(3): e005066.

55. Diabetes
 Reduction in HbA1C
Saslow, L et al. Nutrition & Diabetesvolume 7, Article number: 304 (2017)

56. Reduction in HbA1C
 Reducing carbohydrates to <26% of daily caloric intake, show decreases in HbA1C at 3
and 6 months. This was likely due to increased weight loss in carbohydrate restricted diets.
Sainsbury, E et al. Diabetes Res Clin Pract. 2018 May;139:239-252.

57. Diabetes Management
 We conclude that carbohydrate
restriction (E% below 45%) has a
greater effect on glycemic control in
type 2 diabetes than an HCD in the
short term.
 The magnitude of the effect was
correlated to the carbohydrate
intake, the greater the restriction, the
greater glucose lowering
Snorgaard, O et al. BMJ Open Diabetes Research and Care 2017;5
Greater carb restriction = greater drop in HbA1c

58. Virta Health Corp
 Founded in 2014 to combat T2 DM by ironman athlete Sami Inkinen (Prediabetic)
 Drs. Stephen Phinney and Jeff Volek – leaders in carb restriction diets
 2015 start a clinical trial in West Lafayette, IN
 Virta Provides
 Medical Specialists
 Personal Health Coach
 Individualized Treatment Plan – BG, Ketones, weight and more
 Mobile and Desktop App
 Online Resources
 Community
www.virtahealth.com

59. Diabetes Therapy
 Virta Health Corp
 349 patients in an open-label, non-randomized, controlled trial
 HbA1C declined by 1.3% (7.6 to 6.3%) on low carb high fat (LCHF) diet
 Prescription diabetes medications declined from 56.9 ± 3.1% to 29.7 ± 3.0%
 Sulfonylureas eliminated from intervention group
 Insulin was decreased or eliminated in 94% of patients using prior
 No changes in medications seen in the control, usual care arm
Hallberg, SJ et al. Diabetes Ther. 2018.

60. Virta Study Labs
 Insulin resistance was decreased 55% in the LCHF group – measured by gold standard
HOMA-IR
 hsCRP down 39%
 Triglycerides down 24%
 HDL up 18%
 Overall LDL up 10%
 Serum creatinine and liver enzymes declined
 Apolipoprotein B unchanged
 No changes seen in the control arm
Hallberg, SJ et al. Diabetes Ther. 2018.

61. What About Heart Failure…
 How can LCHF help CHF patients?

62. Heart Failure
 Myocardial concentration of acetyl-CoA was significantly increased in end-stage heart
failure.
 In contrast, there was an increased abundance of ketogenic β-hydroxybutyryl-CoA, in
association with increased myocardial utilization of β-hydroxybutyrate.
 Expression of β-hydroxybutyrate dehydrogenase 1, a key enzyme in the ketone oxidation
pathway, was increased in the heart failure samples
 These findings indicate increased ketone utilization in the severely failing human heart
Bedi, KC et al. Circulation. 2016 Feb 23;133(8):706-16. doi: 10.1161/CIRCULATIONAHA.115.017545. Epub 2016 Jan 27.
Aubert, G et al. Circulation. 2016 Feb 23;133(8):698-705. doi: 10.1161/CIRCULATIONAHA.115.017355. Epub 2016 Jan 27.

63. Heart Failure
Increased
ketone
metabolism
and
upregulation of
the ketone
oxidation
pathway
Decreased FA
oxidation and
reduced
enzymes of B-
oxidation

64. Objectives
Epidemiology
Current dietary guidelines
Evidence on different food types
Ketogenic diet basics
Effects of the ketogenic diet on CVD
Research

65. LCHF diet in obese diabetic subjects with CAD
 There are very limited data on obese, diabetic subjects with CAD
 The effects of LCHF diet on lipid levels on statin-treated subjects are not well studied
 The effect of LCHF diet on cardiovascular events is not well documented
 There is a strong need for high quality, randomized controlled trial evidence to guide
dietary recommendations in this patient population.

66. Where do we go?
 Who should we put on the low carb high fat diet?
 How much should we restrict carbohydrates?
 How do we approach patients?
 How do we deal with insulin and diabetic medications?

67. Survey
 I feel Low Carb High Fat diet is safe and effective for obese diabetic patient?
 I am uncertain if low carb high fat diet is safe and effective for obese diabetic patients?
 I feel low carb high fat diet is not safe and of unproven effectiveness in obese diabetic
patients?

68. Thank you!
Questions and/or comments?