Targeting LipidsStrategies for Patients with Cardiometabolic Risk

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

INTERHEART Study

Lancet. 2004 Sep 11-17;364(9438):937-52.

Pop

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Focus on Lipoproteins

Dyslipidemia

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

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140

160

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0 100 200 300 400

100

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1200

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LD

L P

art

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LD

L C

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mg

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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

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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

Relating LDL-C to non-HDL-C and apoB

Mayo Clinic Proceedings May 2010 vol. 85 no. 5 440-445

Effect of Statin Therapy

Mayo Clinic Proceedings May 2010 vol. 85 no. 5 440-445

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

Ezetimibe + Statin?

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

Fibrate + Statin?

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

Niacin + Statin?

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%)

JUPITER: HDL-C, apoA1

Ridker P, et al. Lancet 2010.(376)333-339.

Omega-3 + Statin?

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

QUESTIONS??