1. By Nancy Dagefoerde MSN, FNP-BC
Treating High Cholesterol because Cheeseburgers and Fries Still Exist!!!! By
Nancy Dagefoerde MSN, FNP-BC

2. Objectives
Describe how to interpret the cholesterol guidelines and identify patient populations that qualify for treatment.
Describe the use of statins and non statins in the treatment of elevated cholesterol levels.
Describe common statin intolerance effects and how to address them in practice.

4. Cardiovascular Disease Mortality Trends 1979-2014

5. Cardiovascular Disease Statistics 2018
Cardiovascular disease accounts for 836,546 deaths in the US per year which is 1 of every 3 deaths
2,300 Americans die of CV disease each day: 1 every 38 seconds
About 92.1 million Americans live with some form of CV disease
Coronary Heart Disease remains the leading cause of death (1 in 7 deaths)
Total direct medical costs of CVD are projected to increase to $749 billion in 2035
Hear disease and stroke statistics 2018 update: a report from the American Heart Association. Circulation. DOI:

6. Cholesterol Statistics 2018
About 94.6 million or 39.7% of American adults have a total cholesterol of 200mg/dL or higher
About 28.5 million or 11.9% of American adults have a total cholesterol of 240mg/dL or higher
1 in 3 American adults have high levels of LDL cholesterol
18.7% of American adults have low levels of HDL cholesterol
January 31, Circulation. DOI: /CIR.

7. Screening
Adults should have a lipid panel measured at least every 5 years starting at age 20
Rescreen in 5 years if at goal or if not at goal treat according to the guidelines
Children should have a lipid panel once at age 9-11 and again at age according to the American Academy of Pediatrics
Screen earlier 2 years to 10 years of age if positive family history of dyslipidemia or premature CVD risk factors, medical conditions such as organ transplant, lupus, nephrotic syndrome, or treatment for HIV

8. 2013 ACC/AHA Guidelines for Cholesterol Management to Reduce Cardiovascular Risk
NCEP dates back to 1988 directed by the NHLBI( last update 2004)
Guiding principle is that an elevated cholesterol is the a root cause of ASCVD events based on review of large scale RCT’s
Treatment with past guidelines has led to progressive reduction in ASCVD morbidity and mortality in the last decade.
For all guidelines remember individual decision making for all patients.
Stone.NJ, Robinson J, Lichtenstein AH, et al ACC/AHA guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults. J Am Col Cardiology, 2013.

9. Recommendations Lifestyle modification is the foundation
Mediterranean or DASH nutrition plans
Regular exercise (150 minutes a week, 60 minutes a day is better)
Smoking Cessation: Quit Line
Treat Hypertension
Treat elevated blood sugars
Maintain healthy weight
Statin therapy is the next level of care

10. Recommendations for Pediatric Patients
Lifestyle modifications
Treat greater than 8 years old with apheresis, statin, and Zetia. Refer if LDL > 500
Treatment Goal is to lower LDL to 130mg/dL
www. aafp.org/afp/2010/0901

11. Four Major Statin Benefit Groups
Patients with known ASCVD
Patients with LDL values > 190 mg/dl
Diabetics aged with LDL > 70 mg/dl
Patients without diabetes or ASCVD but with a LDL mg/dl and age with a CV risk estimator score > 7.5%

12. Other Factors that May be Considered
LDL > 160 mg/dl or genetic hyperlipidemia
Family history of premature ASCVD
C- reactive protein > 2 mg/L
Coronary Calcium score > 300 Agatston units
Ankle Brachial Index <.9
Elevated lifetime risk of ASCVD

13. 10 Year ASCVD Risk Calculator
Iphone app: 2013 Pooled Cohort Equations ASCVD
My.americanheart.org
Itunes.apple.com

14. Statin Benefit Groups and Intensity of Statins
Known ASCVD: Age 75 or less high intensity statin
Age > 75 Moderate intensity statin
LDL > 190 mg/dl: High intensity statin
Diabetes age with LDL mg/dl
If ASCVD risk > 7.5% then high intensity statin if not moderate intensity
ASCVD risk >7.5% and age with LDL mg/dl:
Moderate to high intensity statin

15. High, Moderate, and Low Intensity Statin Therapy
High Intensity
Moderate Intensity
Low Intensity
Lowers LDL >50%
Lowers LDL 30%-50%
Lowers LDL <30%
Atorvastatin 40-80mg
Atorvastatin 10-20mg
Simvastatin 10mg
Rosuvastatin 20-40mg
Rosuvastatin 5-10mg
Pravastatin 10-20mg
Simvastatin 20-40mg
Lovastatin 20mg
Pravastatin 40-80mg
Fluvastatin 20-40mg
Fluvastatin 40-80mg
Pitavastatin 1mg
Lovastatin 40mg
Pitavastatin 2-4mg

16. Testing Needed Prior to Statin Initiation
Fasting Lipid Panel
ALT
CK (if indicated)
Hemoglobin A1c (optional)
TSH

17. Case Study #1 74 year old female
Dyslipidemia, HTN
Elevated LFT’s on Niacin, did not want to take statins
ASCVD risk score 13.8%
Plavix 75mg, Amlodipine 10mg and Lipitor 10mg twice a week
April September 2018
TC: 257mg/dL mg/dL
Trig: 173mg/dL mg/dL
HDL: 44mg/dL mg/dL
LDL: 178mg/dL mg/dL
Ratio:
Non-HDL: 213mg/dL mg/dL

18. How Statins Affect Lipoprotein Metabolism
LDL-C
Non- HDL-C
HDL-C
Triglycerides
Decrease 18-55% Decrease 15-51% Increase 5-15% Decrease 7-30%

19. Medications that May Elevate LDL-C
Some Progestins
Anabolic steroids
Danazol
Amiodarone
Cyclosporine
Thiazide diuretics
Glucocorticoids
Thiazolidinediones
Fibrates and Omega-3 Fatty Acids ( in severe hypertriglyeridemia)

20. Dietary Factors that May Elevate LDL-C
Positive Energy Balance
High Saturated Fat
High trans fat
Weight Gain
Anorexia Nervosa

21. Diseases and Disorders that May Elevate LDL-C
Chronic Kidney Disease
Nephrotic Syndrome
Obstructive Liver Disease
HIV infection
Autoimmune disorders
Hypothyroidism
Pregnancy
Polycystic ovary syndrome
Menopause with declining estrogen levels

22. Case Study #2 45 year old male
Hyperlipidemia, HTN, Family Hx of premature CAD, obesity, elevate blood sugar,
Positive stress test that lead to CABG x2, elevated Lpa, 23 year old son with elevated cholesterol
Zetia 10mg, Crestor 40mg,Aspirin 81mg, Bystolic 10mg
March 2018: August 2018:
Total Choleseterol: mg/dL mg/dL
Triglycderides: mg/dL mg/dL
HDL-C mg/dL mg/dL
LDL-C mg/dL mg/dL
Ratio:
Non-HDL-C mg/dL mg/dL

23. Non- Statin Recommendtions
Fibric Acid( fibrates): to lower Triglycerides
Reduces the production of VLDL (triglyceride carrying particles the circulate in the blood) and by speeding up the removal of triglycerides from the blood
Bile Acid Sequestrants: to lower LDL cholesterol
Bind bile acids in the intestines which increases loss, the liver increases the conversion of cholesterol to bile acids
Cholesterol Absorption Inhibitors: to lower LDL
Decreases cholesterol absorption in the small intestine, with less available the liver absorbs more from circulation
Omega- 3 fatty Acids: lower triglycerides
Reduces the rate of VLDL production in the liver which are the primary triglyceride bearing lipoproteins

24. How Lipoproteins are Affected by Non- Statins
Fibric acids: Lipofen, Trilipix, Tricor Lofibra
Bile Acid Sequestrants: Welchol, Questran, Colestid, Cholestyramine
LDL -C Decrease 5% Non- HDL Decrease 5-19% HDL-C Increase 10-20% TG Decrease 20-50% LDL-C Decrease 15-30% Non- HDL Decrease 4-16% HDL-C Increase 3-5% TG Increase 0-10%

25. Cholesterol Absorption Inhibitors: Zetia
Omega-3 fatty acids: Lovaza or Vascepa
LDL-C Decreases 13-20% Non- HDL Decreases 14-19% HDL-C Increases 3-5% TG Decreases 5-11% LDL-C Decreases 6% Non-HDL Decreases 5-14% HDL-C Decreases 5% TG Decreases 19-44%

26. Medications that May Elevate Triglycerides
Oral estrogens
Tamoxifen
Raloxifene
Retinoids
Immunosuppressive drugs
Interferon
Beta Blockers
Protease Inhibitors
Thiazide Diuretics
Glucocorticoids
Rosiglitazone
Bile Acid sequestrants

27. Dietary Characteristics that May Elevate Triglycerides
Positive energy balance
High glycemic load
Excess alcohol
Weight gain

28. Disorders that May Elevate Triglycerides
Chronic kidney disease
Nephrotic Syndrome
Diabetes mellitus
Metabolic Syndrome
HIV infection
Autoimmune disorders
Hypothyroidism
Pregnancy
Polycystic ovary syndrome
Menopause

29. Case Study #3 41 year old male
Dyslipidemia, Diabetes, and smoking
Insulin, Metformin, Albuteral, Lipitor 80mg, Zetia 10mg, Fenofibrate 160mg, Lovaza , Repatha 140mg every other week
April August 2018
Total Cholesterol: mg/dL mg/dL
Triglycerides: mg/dL mg/dL
HDL-C: 15 mg/dL mg/dL
LDL-C: unable mg/dL
Ratio:
Non-HDL-C: mg/dL mg/dL
HgbA1c:

30. Proprotein Convertase Subtilisin Kexin Type 9 Inhibitors PCSK9 Inhibitors ( human monoclonal antibodies)
Indication for Alirocumab (Praluent) 75mg or 150mg:
Adjunct to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease requiring additional lowering of LDL-C.
Indication for Evolocumab (Repatha) 140mg:
Adjunct to diet, alone or in combination with other lipid lowering therapies (statins, apheresis, zetia) for treatment of adults with hyperlipidemia including homozygous familial hypercholesterolemia and heterozygous familial hypercholesterolemia to reduce LDL-C.
To reduce the risk of myocardial infarction, stroke, and coronary revascularization in adults with established cardiovascular disease.

31. Familial Hypercholesterolemia
Group of inherited mutations with elevations in total cholesterol and LDL-C
80-95% due to lack of LDL receptors
Leads to premature coronary artery disease and significant morbidity and mortality
Diagnosis:
LDL> 190mg/dL in adults, >130mg/dL in children
Family history: premature CAD, Dutch Lipid Clinic criteria and Simone Broome
Physical findings; Corneal arcus, Xanthalasmas, Achilles Tendon Xanthomas
HEFH: 1 in 300 people worldwide, Average LDL is 220 mg/dL, 50% of LDLR available
HOFH: 1 in 1,000,000 people worldwide, Death by 2nd or 3rd decade of life, 2-25% LDLR are available
Goldberg et al., J Clin Lipidology 2011;5:51-58.

32. PCSK9 Inhibitors Lipoprotein Effects
LDL-C is reduced about 50-60%
Patients with HeFH and nonFH respond the same
HoFH patients respond about half as well with mean reductions of LDL-C of 31%
Other blood lipids : Decreases in Lp(a) (21-36%), Apo B (51-59%), Non- HDL-C( 58-65%), triglycerides (12-23%). Increase in HDL-C (4-10%).

33. PCSK9 Inhibitors Cardiovascular Outcomes Trials
Alirocumab ( Praluent)
Evolocumab ( Repatha)
Sponsor
Sanofi/Regeneron
Amgen
Trial
ODYSSEY Outcomes
FOURIER
Sample Size
18,000
28,000
Patients
4-16 weeks post ACS
MI, stroke or PAD
Statin
Evidence based Rx
Atorvastatin >20mg or equivalent
LDL-C
>70 mg/dL
Dosing
Every two weeks
Every 2 or 4 weeks
Endpoint
CHD death, MI, ischemic stroke, or hospitalization
Primary: CV death, MI, stroke, hospitalization, or coronary revasularization
Secondary: CV death, MI or stroke

35. PCSK9 Summary Mechanism of action: Increased hepatic LDLR levels
Increased LDL-C clearance rates
Reduced plasma LDL-C levels
Adverse Reactions: nasopharyngitis, upper respiratory tract infection, influenza, back pain, and injection site reactions

36. Statins and Muscle Symptoms
Frequency of statin-associated muscle symptoms:
1-5% in randomized controlled trials
11-29% in observational cohorts
Spectrum of statin-associated muscle adverse events:
Myopathy: muscle weakness (not attributed to pain or elevated CK)
Myalgia: unexplained muscle discomfort often described as “flu-like” symptoms with a normal CK level.
Myositis: muscle inflammation ( symptoms with CK elevation)
Myonecrosis with myoglobinuria: increase in serum creatinine > 0.5mg/dL (clinical rhabodmyolysis)( CK >10x ULN and renal involvement)

37. Options for Patients Intolerant to Multiple Statins
Lower the statin dose
Switch to another statin
Reduce the frequency to not daily
Add on a non statin to the highest tolerable statin dose
Measure and supplement with Vitamin D
Adding Co enzyme Q 10

38. Statin Safety: ACC/AHA Guidelines
Use a moderate intensity statin if the following applies:
Renal or Hepatic impairment
Previous statin intolerance of muscle disorder
Unexplained ALT levels
Using other medications that affects statin metabolism
> 75 years old
Asian ancestry
CK not routinely done although it would be important for persons with a risk for adverse muscle events.
Stone NJ et al. Circulation 2013, DOI: /01

39. ACC/AHA Statin Safety Recommendations
Mild to moderate muscle symptoms develop:
Discontinue statin to evaluate symptoms
Evaluate other conditions: hypothyroidism, reduced renal or hepatic function, rheumatologic disorders, steroid myopathy, vitamin D deficiency, primary muscle diseases
If symptoms resolve give the statin at a lower dose to assess causal relationship of muscle symptoms
If symptoms return at the lower dose, use a different statin at a lower dose

40. Monitoring Statin Therapy
Baseline lipid panel should be obtained with a second lipid panel in 4-12 weeks after initiation of statin therapy
Then assessments should be every 3-12 months as clinically indicated.
Dose and frequency can be increased as tolerated.

41. Cognitive Impairment and Statin Use
Statins have been associated with spontaneous reports of adverse cognitive effects such as amnesia, concentration difficulties, and confusion
Two large RCT’s (PROSPER and HPS) show no difference in cognition after many months being on a statin (42 months and 6 months)
At least 12 small RCT’s showed similar results
If a patient reports adverse cognitive effects:
Assess for other causes of change in cognitive function
Consider a trial of discontinuing the statin

42. Statin Use and Liver and Kidney Dysfunction
Liver Function changes:
1-3% through RCT’s show liver function elevations
Liver function elevations may be due to other etiologies (fatty liver or hepatitis )
2012 FDA statin label change recommends liver function testing at baseline and then clinically as indicated.
Renal Function changes:
Possible proteinuria and or hematuria
Consider age, gender, size, frailty, other diseases, family history, excessive exercise, surgery, ETOH, obstructive liver disease, transplants, renal failure
Treatment that is related: high dose statins or interaction with other medications

43. Drug to Drug Interactions affecting Renal Function
Fibrates
Macrolide Antibiotics
Cyclosporines
Protease Inhibitors
Calcium Channel Blockers
Nefazadone
Amiodarone
Alcohol
Niacin
Colchicine
Digoxin
Coumadin
Azole Antifungal

44. Statin Diabetes Safety
Statin use is associated with a modest but statistically significant increase risk for new-onset type 2 diabetes mellitus 10% vs placebo
High Intensity increases risk more than Moderate Intensity statins
Risk is clearly more evident for those with major risk factors for diabetes
Cardiovascular benefits of statin therapy far outweigh the risk of diabetes
Recommendations:
Statin therapy should continue to decrease ASCVD event risk
Lifestyle modification should be emphasized
Patients with diabetes risk factors should be screened with fasting blood sugars or HGA1c prior to starting statin therapy and yearly thereafter

45. Case Study #4 55 year old male
HTN, dyslipidemia, CAD ( 2002, 2005, 2009, 2010, 2011)
Lipitor 80mg, Zetia 10mg, Norvasc 5 mg, Atenolol 25mg, Plavix 75mg, Lisinopril 10mg, ASA 81mg and Repatha 140mg injection every other week.
October January August 2018
Total Cholesterol: 247 mg/dL 81 mg/dL 125 mg/dL
Triglycerides: 148 mg/dL 75 mg/dL 127 mg/dL
HDL-C: 29 mg/dL 32 mg/dL 37 mg/dL
LDL-C: mg/dL 34 mg/dL 52 mg/dL
Ratio:
Non-HDL-C: 218 mg/dL 49 mg/dL 95 mg/dL

46. Thank You!