Faculty Disclosure
David G. Carmouche, MD
Director, Center for Cardiovascular Disease Prevention
Baton Rouge Clinic
ASH Specialist in Clinical Hypertension
Diplomate, American Board of Clinical Lipidology
COSEHC CME Committee
Consultant: NovoNordisk, Abbott Labs, Bristol-Myers Squibb
Speaker’s Bureau: Takeda, Abbott, Kowa/Lilly
Objectives
• Describe the practical limitations of individual risk stratification using LDL-C
• Understand the basic pathophysiology of the common dyslipidemia seen in patients with cardiometabolic risk
• Explore the value of apoB or non-HDL-C as important targets of lipid-modifying therapies
• Review important recent clinical trials which focus on the role of combination lipid therapy
• Propose a possible treatment algorithm
• Briefly review new statin label changes
Lipid Levels in 136,905 Patients Hospitalized with CADGet With the Guidelines CAD Program
• LDL-C levels• >130 mg/dL (23.1%)• <100 mg/dL (49.6%)• <70 mg/dL (17.6%)
• Mean LDL-C • 104.9 + 39.8 mg/dL
• About half admits at NCEP ATP III goal
Am Heart J 2009;157:111-7.e2.
Sachdevaet al, Am Heart J 2009;157:111-7.e2.
LDLC Levels in 136,905 Patients Hospitalized With CAD: 2000- 2006
LDLC (mg/dL) 130-159 > 160100-129< 100
A Common Phenotype• Metabolic
syndrome• Type 2 DM• PCOS• NASH• Familial combined
hyperlipidemia• Lipodystrophy
(HIV)
Relationship Between LDL Particles and LDL Cholesterol to Levels of HDL Cholesterol and Triglycerides:
The Framingham Offspring Study
1000
1200
1400
1600
1800
20 40 60 80 100
100
120
140
160
180
0 100 200 300 400
100
120
140
160
180
1000
1200
1400
1600
1800
LD
L P
art
icle
s (n
mo
l/L
)
LD
L C
ho
leste
rol (
mg
/dL
)
HDL Cholesterol (mg/dL) Triglycerides (mg/dL)
LDL Particles
LDL Cholesterol
LDL Particles
LDL Cholesterol
Reprinted from Otvos JD, et al. Am J Cardiol 2002;90:22i-29i, with permission from Elsevier Limited.
HDL = high-density lipoprotein; LDL = low-density lipoprotein
Understanding ApoB/ApoA1 and Non-HDL-C
Walldius G, Jungner I, Eur Heart J 2005;26:210-212
Non-HDL-C.
Non–HDL-C Is Superior to LDL-C in Predicting CHD Risk
• Within non–HDL-C levels, no association was found between LDL-C and the risk for CHD
• In contrast, a strong positive and graded association between non–HDL-C and risk for CHD occurred within every level of LDL-C
• Non–HDL-C is a stronger predictor of CHD risk than LDL-C
Liu J, et al. Am J Cardiol. 2006;98:1363-1368.
Non–HDL-C, mg/dL
Re
lati
ve
CH
D R
isk
<130 130-159 ≥160
≥190160-189
<160
ADA/ACC 2008 Consensus Statement Treatment Goals in Patients with Cardiometabolic Risk and
Lipoprotein Abnormalities
LDL-C Non-HDL-C ApoBHighest Risk Patients <70mg/dL <100 mg/dL <80mg/dL
Known CVD
DM + 1 additional major CV risk factor*
High Risk Patients <100mg/dL <130mg/dL <90mg/dL
No DM or known CVD but > 2 major CV risk factors
DM but no other major CV risk factors
Brunzell JD, et al. Diabetes Care. 2008;31:811-822
*Major CV risk factors beyond dyslipidemia include smoking, hypertension, and family history of premature CHD.
2009 Canadian Cholesterol GuidelinesTarget lipid levels
Primary targets
Risk level Initiate treatment if: LDL-C Alternate
High•CAD, PVD, atherosclerosis•Most patients with DM•FRS>20%•RRS>20%
Consider treatment in all patients
<2 mmol/L or >50% ↓ LDL-CClass 1, level A
apoB<0.80 g/LClass 1, level A
Moderate•FRS 10-19%
LDL-C>3.5 mmol/LTC:HDL-C>5.0Hs-CRP>2 mg/L
Men>50Women>60
Family Hx and hs-CRP modulates risk (RRS)
<2 mmol/L or >50% ↓ LDL-CClass 2a, level A
apoB<0.80 g/LClass 2a, level A
Low•FRS <10%
LDL-C>5.0 mmol/L >50% ↓ LDL-CClass 2a, level A
Can J Cardiol. Vol 25, No. 10, October 2009
Barriers to Effective Non-HDL-C Treatment
0% 10% 20% 30% 40% 50% 60% 70%
Aware that non-HDL is a secondary target
Knew non-HDL treatment goals
Could calculate non-HDL from lipid panel
Knew that non-HDL could be calculated from a standard lipid panel
Am J Med. 2011 Sep;124(9):876-80.e2
Proportion of CHD patients attaining goals for LDL-C, and in patients with high TG, combined goals for LDL-C and non-HDL-C
ATP III goals*
CHD patients(n=22,817)
n (%)
Overall cohort with LDL-C at goal 18,549 (81%)
Subset of patients with TG >200 mg/dL 3,893 (17%)
Both LDL-C and non-HDL-C at goal 1,997 (51%)
LDL-C at goal 2.901 (75%)
Non-HDL-C at goal 1,998 (51%)
*LDL-C goal <100 mg/dL; in patients with TG >200 mg/dL, non-HDL-C goal <130 mg/dL
Virani SS, et al. Am Heart J. 2011 Jun;161(6):1140-6. Epub 2011 May 11
Factors Associated with Dual Goal Attainment
Significant
• Older age (65-74 yo)
• Diabetes
• Obesity
• Higher number of primary care visits
• Mild increase in illness severity of patients in provider’s panel
• African American (lesslikely to achieve goals)
Not significant
• Receipt of care from MD vs. non-physician
• Specialist vs. primary care
• Number of patients in provider’s panel
• Percentage of patients with hyperlipidemia diagnosis
Virani SS, et al. Am Heart J. 2011 Jun;161(6):1140-6. Epub 2011 May 11
Is Ezetimibe a Reasonable Option?
Arbiter 6 Trial J Am Coll Cardiol 2010; DOI: 10.1016/j.jacc.2010.03.017
• Long acting niacin was superior in effects (positive lipid changes in HDL-C) compared to ezetimibe when combined with simvastatin on Carotid IMT.
Sands Trial J Am Coll Cardiol 2008; 16; 52:2198-2205
• Type 2 DM Native American trial with benefit of LDL < 70 whether ezetimibe given with or without simvastatin on Carotid IMT.
Seas Trial N Engl J Med 2008; DOI: 10.1056/NEJMoa0804602
• No improvement with ezetimibe, and raise question associated cancer risk which was later disproved.
Enhance Trial N Engl J Med 2008; 358:1431-1443
• No improvement (Carotid IMT) with ezetimibe, but disease burden too low
Study of Heart and Renal Protection (SHARP)
• 9270 patients with CKD either on dialysis or with a creatinine of >1.7 in men or >1.5 in women
• Assigned simvastatin/ezetimibe 20/10 mg or placebo
• Primary endpoint: first major atherosclerotic event (nonfatal MI, coronary death, nonhemorrhagic stroke, or any revascularization)
• Active treatment reduced primary endpoint by 17%• 25% reduction in nonhemorrhagic stroke
• 21% reduction in revascularization
• 27% reduction in coronary revascularization
• Trend toward reduction in MI
Lancet 2011; DOI 10.1016/S0140-6736(11)60739-3
ACCORD Trial – Lipid Arm
• Inclusion criteria• T2DM with A1c >7.5
• Age 40-79 if clinical CVD
• Age 55-78 if subclinical CVD or 2+ risk factors
• LDL-C 60-180
• HDL <55 (women, blacks) HDL <50 (all others)
• TG <770 (if on no therapy) TG <400 (on therapy)
• Intervention• Open label simvastatin + placebo or fenofibrate
• Baseline lipids• TC 175 LDL 100 HDL 38 TG 162 (non-HDL 127)
N Engl J Med 2010; 362:1563-1574
ACCORD – Lipid: Primary Outcome – Major Fatal or Non-fatal Major Cardiovascular Events
N Engl J Med 2010; 362:1563-1574
HR (95% CI) 0.92
(0.79 - 1.08)
P=0.32
HR (95% CI) 0.91
(0.75 - 1.10)
P=0.33
AIM-HIGH Trial
• 3414 patients with CHD, low HDL, and raised TG
• All patients received simvastatin with or without ezetimibe to maintain LDL <80 mg/dL
• Randomized to placebo vs. 1500-2000 mg niacin ER• Niacin increased HDL from 35 to 42 mg/dL
• Triglycerides lowered from 164 to 122 mg/dL
• LDL lowered from 74 to 62 mg/dL
• Trial stopped early due to futility and signal of excess ischemic CVA in niacin arm• Final adjudication of stroke data showed non-statistical trend
(P=0.11)
N Engl J Med 2011; DOI: 10.1056/0a1107579
AIM-HIGH Results
N Engl J Med 2011; DOI: 10.1056/0a1107579
End points Niacin(%) Placebo(%) HR(95% CI) P
Primary end point 16.4 16.2 1.02(0.87-1.21) 0.80
CHD death/nonfatal MI/ischemic CVA/
high-risk ACS9.3 10.0 1.08(0.87-1.34) 0.49
CHD death/nonfatal MI/ischemic CVA
8.1 9.1 1.13(0.90-1.42) 0.30
Understanding AIM-HIGH
• Baseline lipids
• TC 141
• LDL 71
• HDL 35
• TG 161
• Non-HDL 106
• apoB~80
• Background therapy
• Previously on a statin (94%); statin > 1 year (76%)
• ACE/ARB (75%)
• Beta blocker (80%)
• ASA (98%)
Eicosapentaenoic acid (EPA) (1.8 g/d) reduced the
incidence of major adverse coronary events in the Japan EPA Lipid Intervention Study (JELIS)
• Prava 10 or simva 5 mg for all
• Randomized to PBO or EPA
• Average baseline LDL-C 183 mg/dL
• LDL-C reduced 25% in both arms
RR ↓ 19%
Lancet. 2007;369(9567):1090-1098
Proposed Patient Treatment Algorithm - LIPIDS
STATIN
<50 % LDL reduction needed to get to goal• Simvastatin 40• Pravastatin 40-80• Lovastatin 40-80• Fluvastatin XL 80• Pitavastatin 2-4
>50 % LDL reduction neede to get to goal• Atorvastatin 40-80• Rosuvastatin 20-40• Simvastatin/ezetimibe
10/20-10/40
TIPS
Statin-intolerant Patients• Check TSH, 25-OH Vit D and
correct deficiency• Fluvastatin XL 80 least likely to
cause myalgia• Rosuva 2.5 mg 2-3 days/week• CoQ10 200 mg/dayOptimal dosing• Bedtime: Prava, fluva• Supper: Simva, lova• Anytime: Atorva, rosuva,
pitava
• F/U 4-6 weeks
• Lab: lipids
LDL-C not at goal
• Change to atorva, rosuva, simva/eze at max tolerated dose
• If on max tolerated dose of potent statin – add ezetimibe 10, or
• Colesevelam 3.75 gram packet or three 625 mg tabs bid (especially if Hgb A1c > 6.5%)
TIPSColesevelam• Lowers glucose• Raises TG when baseline TG >
500• Can bind other meds – take 1
hour after or 4 hours before other meds
Ezetimibe• Avg LDL reduction 20-25% on
top of statin• Greater than expected
response suggests low fat diet particularly helpful
• F/U 4-6 weeks
• Lab: lipids
LDL-C at goal
• non-HDL-C not at goal
• apoB not at goal• LDL-P not at goal
• Fenofibrate (variety of dosages depending on product used) or fenobric acid 45-135 mg
• Niacin ER 500-2000 mg
• Omega-3 FA 1800-3400 mg EPA+DHA
Primary Rx Intensification Rx Intensification Rx
TIPS
apoB available through most
national reference labs and through Atherotech (VAP test)
LDL-P available through
Liposcience as part of Lipoprofile
Figure 2
Proposed Patient Treatment Algorithm - LIPIDS
LDL-C at goal
But…
• non-HDL-C not at goal
• apoB not at goal• LDL-P not at goal
Fibrate: Event reduction in patients with TG > 200, HDL < 35; microvascularprotection (retinopathy, proteinuria)
Cautions: creatininecan increase; myopathy risk; gallstones; potentiates warfarin; pancreatitis; thromboembolic events
Labs every 4-6 months: l ipid panel, AST. ALT, CPK, creatinine
Niacin ER: Decrease in recurrent non-fatal MI, plaque regression. lowers l ipoprotein(a), potent effect on Lp-PLA2
Cautions: cutaneous flushing; increase uric acid (gout); hyperglycemia; dyspepsia; can worsen atrial arrhythmias
Labs every 4-6 months: l ipid panel, AST, ALT, glucose, Hgb A1c, uric acid
Omega-3 FA: Event reduction in one study of CHD pts on statin; important to dose based on EPA+DHA content: 10% TG lowering per 850 mg EPA+DHA
Cautions: dyspepsia; diarrhea; fishy odor or after-taste; mercury content
Labs every 4-6 months: l ipid panel
Agent Precautions Lab F/U
Flushing management: ASA 325 mg 30 min. prior to dose; take at bedtime; low-fat snack; encourage compliance as flushing recurs when drug restarted; benadryl 25 mg + ibuprofen gel cap as “bail -out” therapy
Lovaza is prescription O-3-FA; capsules can be frozen to decrease GI side effects; no effects on bleeding as previously thought
If gemfibrozil has to be used for formulary issues – only statin with which it can be used safely is fluvastatin
Proposed Patient Treatment Algorithm - LIPIDS
Patient’s Initial TG > 500 mg/dL
Exclude common offending agents:
Oral estrogens (patch, shot OK)
Alcohol
Corticosteroids
Thiazide diuretics
First and second generation beta-blockers (atenolol, propranolol, bisoprolol, pindolol,metoprolol)
Carvedilol and nebivololmay be OK
Exclude undiagnosed or under-treated diabetes:
Check fasting glucose, Hgb A1c, 2 hr glucose after 75 g glucose (2 regular Cokes)–diabetes if > 200 mg/dL
Avoid all alcohol
Weight loss
Minimize saturated fat, simple sugars/carbs
Treat diabetes aggressively
Start fibrate or high-dose Omega-3-FA (1700-3400 mg DHA+EPA)
Once TG < 500, treat per LDL-C goal
To prevent acute pancreatitis…
Re-evaluate labs q 2-4 weeks until at goal