A discussion of lipid target and statin use from ATP to the 2014 AHA/ACC Guidelines.

1. Lipids: Old vs. New Targets
Henry Tran, MD, MSc
April 24th, 2015

2. Disclosures
• None

3. Goals
• ATP III and CHD Risk Assessment
• Major Trials after ATP III
• Review the 2013 Guidelines for Cholesterol
treatment
• 4 Groups that Benefit from Statin
• ASCVD Risk Assessment
• Future Directions

4. ATP III Guidelines
NCEP. NIH 2002
• Extended ATP II guidelines to lower
LDL goals in patients without CHD
• Risk model included risk factors or
global risk for CHD
• Diabetes as CHD risk equivalent
• LDL-C < 100 mg/dL is “optimal”

5. Clinical Case #1
• Mr. Simon is a 60 yo man with no significant
PMHx. He presents for his annual physical
feeling well. He doesn’t smoke. Jogs 4x/wk.
• BP 122/84 HR 68 BMI 24.3 kg/m2
• Total Chol 180, HDL-C 40, LDL-C 108.
• A1c 5.4%
• He asks if his cholesterol should be treated?

6. Clinical Case #1
No, 10 yr CHD risk <
10%. LDL-C is already
lower than goal

7. Major Trials after ATP III
• 2005 Treating to New Targets (TNT)
• 2008 JUPITER
• 2010 ACCORD-LIPID
• 2011 AIM-HIGH

8. Treating to new Targets (TNT)
• 10,000+ patients with CVD randomized to
Atorvastatin 10 mg vs Atorvastatin 80mg for 5
years
LaRosa et al. NEJM 2005
LDL-C Total Chol Trig HDL-C
10mg 101 178 156 47
80mg 77 150 132 47
Mean Lipid Levels (mg/dL) During the Study

9. Outcomes of TNT
• 1o: Reduced Major CV events driven by reduced
non-fatal MI (HR 0.78, p<.0002)
• No change in CV Death (HR 0.80, p=0.09)
• No difference in overall mortality (insufficient
power)
• Atorvastatin 80mg:
– More adverse events (p<0.001)
– Signal for increased non-CV death
LaRosa et al. NEJM 2005

10. JUPITER Trial
• 17,802 patients without CVD randomized to
rosuvastatin 20mg vs placebo
• Mean age: 66 yo
• Metabolic Syndrome: 41 %
• All patients hs-CRP ≥ 2
• Stopped early after 1.9 years (5 years planned)
Ridker PM et al. NEJM 2008
LDL-C Trig HDL-C
Rosuvastatin 20mg 55 99 50
Placebo 109 108 50
Mean Lipid Levels (mg/dL) During the Study

11. Ridker PM et al. NEJM 2008

12. ACCORD Lipid
ACCORD Study Group. NEJM 2010; 362:1563-74.
• 5518 pts T2DM treated with simvastatin randomized to fenofibrate or
placebo
• The primary outcome was the first occurrence of nonfatal myocardial
infarction, nonfatal stroke, or death from cardiovascular causes.
• Possible benefit in men but harm in women (P=0.01 for interaction)

13. ACCORD Lipid
Primary Outcome: First occurrence of nonfatal MI, nonfatal stroke, or CV death
ACCORD Study Group. NEJM 2010; 362:1563-74.

14. AIM-HIGH Trial
• 3414 patients with CVD randomized to simvastatin
vs simvastatin + niacin
• Goal LDL 40-80 mg/dL, pts could receive ezetimibe
10mg
• 1o: First event of CV death, nonfatal MI, CVA,
hospitalization for ACS, or revascularization Stopped
early due to futility
AIM-HIGH Investigators. NEJM 2011
LDL-C Total Chol Trig HDL-C
Simvastatin 68 141 152 39
Simvastatin + niacin 65 137 120 44
Mean Lipid Levels (mg/dL) at 3 years of the Study

15. AIM-HIGH Primary Outcome
AIM-HIGH Investigators. NEJM 2011

16. Results

17. Fenofibrates
Statins for
Secondary Prevention
Niacin
(HDL Hypothesis)
Statins for
Primary Prevention

18. 2013 ACC/AHA Guideline on the Treatment of
Blood Cholesterol to Reduce Atherosclerotic
Risk in Adults
• 2008 Task Force convened by NHLBI
– Used data from 1995 – 2009, additional data until
July 2013 added
• 2013 writing was transferred to ACC/AHA
• Two clinical questions:
– What is the evidence for LDL–C and non-HDL–C goals for
the secondary prevention of ASCVD?
– What is the evidence for LDL–C and non-HDL–C goals for
the primary prevention of ASCVD?
Stone et al. JACC 2013.

19. New Areas in the Guidelines
• 4 Groups with statin benefits
• A new perspective on lipid goals
– No RCT evidence to support continued use of targets
– Non-statin therapies
• Global risk assessment for ASCVD
– Pooled Cohort Equation
– Abandoned Framingham 10 years CHD Risk
• Safety Recommendations
• Monitoring therapy

20. Clinical Question
• Mr. Jones is a 73 yo man with ischemic
cardiomyopathy. He had an MI 6 years ago s/p
stent to LAD . At that time LVEF 35%. He
complains of mild ankle edema and dyspnea
after 1/4 mile walking.
• LDL-C 137 HDL-C 48
• He has been taking aspirin 81 mg.
• Would you add a statin to his regiment?

21. Statin Benefit Groups
Excluding patients with heart failure symptoms or
hemodialysis-dependent
LDL > 190 mg/dL
10-year ASCVD
Risk > 7.5%
Diabetic Patients
(40-75 yo)
Established
Atherosclerosis
Stone et al. JACC 2013.

22. CORONA Trial
• 5011 pts NYHA II-IV
randomized to
rosuvastatin 10mg vs
placebo for ~3 years
• 60% hx of MI
• LVEF 31%
• Baseline
– LDL-C 138 mg/dl
– HDL-C 48 mg/dl
Kjekshus et al. NEJM 2007

23. CORONA Trial
• Rosuvastatin did not reduce the primary outcome or the
number of deaths from any cause in older patients with
systolic heart failure, although the drug did reduce the
number of cardiovascular hospitalizations.
Kjekshus et al. NEJM 2007

24. Established ASCVD
<75 yo > 75 yo
First Choice High-intensity
- Atorvastatin 80mg or
- Rosuvastatin 20mg
Moderate-
intensity
Second Choice Moderate-Intensity Individualize
therapy
Stone et al. JACC 2013.

25. Statin Therapy Intensity
High-Intensity Moderate-Intensity Low-Intensity
LDL-C reduction >50% LDL-C 30%-<50% LDL-C Reduction <30%
Atorvastatin (40)-80 mg
Rosuvastatin 20 (40) mg
Atorvastatin 10 (20) mg
Rosuvastatin (5) 10mg
Simvastatin 20-40 mg
Pravastatin 40 (80) mg
Lovastatin 40 mg
Fluvastatin XL 80mg
Fluvastatin 40mg BID
Pitavastatin 2-4mg
Simvastatin 10mg
Pravastatin 10-20 mg
Lovastatin 20mg
Fluvastatin 20-40 mg
Pitavastatin 1 mg
Stone et al. JACC 2013.

26. Hyperlipidemia (LDL-C > 190)
Secondary Cause Elevated LDL-C Elevated Triglycerides
Diet Saturated or trans fats,
weight gain, anorexia
Weight gain, very low-fat diets, high intake
of refined carbohydrates, excessive
alcohol intake
Drugs Diuretics, cyclosporine,
glucocorticoids,
amiodarone
Oral estrogens, glucocorticoids, bile acid
sequestrants, protease inhibitors, retinoic
acid, anabolic steroids, sirolimus,
raloxifene, tamoxifen, beta blockers (not
carvedilol), thiazides
Disease Biliary obstruction,
nephrotic syndrome
Nephrotic syndrome, chronic renal failure,
lipodystrophies
Disorders and
altered states of
metabolism
Hypothyroidism, obesity,
pregnancy*
Diabetes (poorly controlled),
hypothyroidism, obesity; pregnancy*
*Cholesterol and triglycerides rise progressively throughout pregnancy ; treatment with statins, niacin, and ezetimibe are
contraindicated during pregnancy and lactation.
Stone et al. JACC 2013.

27. Hyperlipidemia
• Evaluate family for familial
hypercholesterolemia (FH)
• Reasonable to start high-intensity statin (goal <
50% reduction of LDL-C)
• Non-statin medications are often needed to
lower to “acceptable levels”
Stone et al. JACC 2013.

28. Patients with Diabetes
• Since 2012, ADA Standard of Care recommend
statin therapy to all diabetics regardless of
baseline LDL-C
• High-intensity statin to diabetics with 10 year
ASCVD risk > 7.5%
ADA. VI. Prevention, Management of Complications. Diabetes Care
2013

29. 10 yr ASCVD Risk > 7.5%
• Unclear where cutoff was derived
• >7.5%: moderate to high-intensity statin
(~45% RR)
• 5-7.5%: moderate-intensity statin (~30 RR)
• Engage in discussion:
– ASCVD risk reduction benefits
– Adverse events ( Diabetes)
– Drug-Drug Interactions
– Patient Preferences
Stone et al. JACC 2013.

30. New Risk Calculator
• Pooled Cohort Equations for 10yr risk of CVD
(risk of hard CV events: first MI, CV death,
CVA) age 40-80
– Sex specific
– Race specific
• Other covariates similar to prior – age, BP,
HTN, lipids, smoking, DM
• Reassess every 4-6 years
Stone et al. JACC 2013.

31. Other Risk Factors (if calculator
insufficient)
• Class IIb recommendations
– Family history
– CRP
– Calcium score
– ABI
• Class III recommendation – Routine carotid
intima media thickness
• Unknown – ApoB, CKD

32. Clinical Case #1
• Mr. Simon is a 60 yo man with no significant
PMHx. He presents for his annual physical
feeling well. He doesn’t smoke. Jogs 4x/wk.
• BP 122/84 HR 68 BMI 24.3 kg/m2
• Total Chol 180, HDL-C 40, LDL-C 108
• A1c 5.4%
• He asks if his cholesterol should be treated?

33. 10 Year ASCVD Risk
10 year risk of ASCVD: 8.2%
10 year with optimal risk factors 5.7%

34. Cholesterol Goals
• Panel removed treat-to-goal paradigm
– Unclear what target should be
– RCT evidence shows maximum tolerated statin
dose is most effective
• No routine role for non-statin therapies to get
to a goal
• Check lipids only to assess effect (high dose
statin 50% reduction, mod dose 30-50%)
Stone et al. JACC 2013.

35. Follow-up
• Repeat lipid testing 4-12 weeks after to
monitor adherence and biologic response.
• Repeat lipids every 3-12 months thereafter
• CK and ALT monitoring are NOT recommended
• Reinforce adherence of lifestyle changes

36. Statin Benefit Groups
Excluding patients with heart failure symptoms or
hemodialysis-dependent
LDL > 190 mg/dL
10-year ASCVD
Risk > 7.5%
Diabetic Patients
(40-75 yo)
Established
Atherosclerosis
Stone et al. JACC 2013.

37. Fibrates
• Gemfibrozil should not be initiated in statin
users (Class III: Harm)
• Fenofibrate should not be used in patients
with GFR < 30 mL/min (Class III: Harm)
• Fenofibrate may be considered for use in low-
or moderate-intensity statin users if Trig >500
or ASCVD reduction deemed beneficial (Class
IIB).
Stone et al. JACC 2013.

38. Future Directions
• Evidence gaps:
– RCT data for patients > 75 yo on statins
– Outcomes of treat to lipid or apolipoprotein
targets
– Clinical outcomes of new-onset DM associated
with statin therapy
– RCT of new lipid-modifying treatments
Stone et al. JACC 2013.

39. Potential Future Therapies
• PCSK9 inhibitors reduce the degradation of
hepatic LDL receptors
Zhang et al. Int j Biol Sci 2012

40. OSLER
• OSLER-1 and -2 4,465
patients randomized
open-label treatment
with evolocumab (140
mg sq every 2 weeks or
420 mg monthly) vs
standard therapy
• CV events nearly
reduced by 50%
Sabitine MS, et al. NEJM 2015

41. ODYSSEY Long-Term
• 2,300 patients
raondomized to 150
mg of alirocumab or
placebo as a 1-mL
subcutaneous injection
every 2 weeks for 78
weeks.
• MACE reduced to 1.7%
in the alirocumab
group vs 3.3% in the
placebo group (p=0.02)

42. Thank You

43. SEARCH Trial
• Lower is Better Hypothesis:
– Examined high vs low dose simvastatin
• Homocysteine

44. IDEAL Trial
• Atorvastatin 80mg vs Simvastatin 20mg
• No significant difference in vascular events
• No difference in mortality or CV death