Cholesterol: The Expanded Lipid

ProfileBen Brown MDDecember 19, 2011Thanks also to Wendy K and Fasih H

Outline What is the expanded lipid panel? Why order it? How to order it? What to do with results? Cases Questions

Cases1. 54 y/o woman with no risk factors and an

LDL of 189. She does not want meds.2. 35 y/o Latino male with new onset DM and a

“perfect” lipid panel.3. 40 y/o male who comes in and tells you that

his Dad and brother both had their first MI at 45y/o. His lipids look more or less normal.

4. Bonus Case from Wendy5. A 72 y/o woman obese, HTN, IGT, depression.

What is my risk of heart disease or stroke?

Why bother with more?1. Not all lipids are the same risk:

impact of LDL size & number HDL subtypes

2. In selected patients: Other Risk Factors missed with typical lipid panel

Lp(a) hsCRP

FHx early CADz and close to normal lipids

Metabolic Syndrome and need more info to change

High Lipids and wants to avoid statins or difficulty tolerating

Question?In addition to the standard lipid profile, What is

included in the expanded lipid panel?

A. LDL subtypes (apoB)

B. HDL subtypes (2 and 3)

C. LPa

D. hsCRP

E. Homocysteine

F. All of the above

G. It depends

What is there and How to Order?

Expanded Lipid Profiles

Quest: expanded lipid panel (or lipid- or homocyt- with homocysteine)

Lipoprotein Particle Analysis (LPP) Spectracell Berkeley HeartLab (BHL) NMR: Liposcience VAP: Atherotec Hunter: Cardiovascular Risk/Metabolic

Syndrome

LDL: particle size and numberBigger is Better

Small LDL is the bad guy why? it goes across the

endothelium more readily absorbed by

macrophages more readily = foam cells…bad

Less is more (better)

ApoB ( one per particle) scientifically accepted measurement for LDL particle number. Can be used to Monitor statin therapy.

Apo B (LDL pattern)Nl <60

Small LDL= pattern B

Case 1

According to ATP 3 Guidelines what would you recommend for our 54 y/o woman with no risk factors and an LDL of 189?

A. Life style with a goal of LDL 160

B. Life style with a goal of LDL 130

C. Start a Statin

D. Start Bile Acid Binder or Niacin

Case 1

According to ATP 3 Guidelines what would you recommend for our 54 y/o woman with no risk factors and an LDL of 189?

A. Life style with a goal of LDL 160

B. Life style with a goal of LDL 130

C. Start a Statin

D. Start Bile Acid Binder or Niacin

ATP 3 Guidelines-surprisingly generous

Google: ATP 3 Guidelines at a glance

ATP3 Guidelines Step 3:risk factors

Her expanded panel results

LDL=189, TG=102, HDL =63 apoB 20 (low) hsCRP 0.5 (normal) HDL2 (normal) HDL3 (normal) Lp(a) low Later an AIC was 5.0

What if her Apo B or hsCRP or AIC was high?

Treatment of small dense LDL Treat LDL cholesterol and think

Metabolic or Inflammation Insulin Resistance (glycocylation)

Check AIC and treat accordingly Note: I start metformin early in someone who does not make LS

changes easily (provider choice).

Inflammation (oxidation) Check hsCRP Think of antioxidants Will cover with hsCRP

HDLHDL 2 (a and b) Again bigger is better Reverse cholesterol

transport Antioxidant effect Increases with exercise,

fish oil, niacin, fibric acid, statin and niacin combo’s, moderate alcohol consumption.

HDL 3 Smaller less protective

(signal of inefficient transport)

Case 2

35 y/o Latino male with new onset DM and a “perfect” lipid panel.

TC 168 HDL 41 TG 115 LDL 104

Expanded Panel Apo B high HDL 2 low/3 normal Hs CRP 1.7 Lp(a) normal

What would you do?

Treatment of Low HDL 2 Exercise Niacin Moderate alcohol consumption (both 2 and 3) Stop smoking ?Fish oil ?statin, Fibric Acids, Bile acid binder might start

for high apoB Mediterranean Diet, fish oils, consider probiotic

for his high CRP

LipoProtein (a)Treatment options:• Lp(a) is an inherited

abnormal protein attached to LDL.

• Normal level < 30 mg/dL

• Lp(a) increases coagulation and triples CVD risk.

Niacin NAC 600 mg

twice daily

Case 3

40 y/o male who comes in and tells you that his Dad and brother both had their first MI at 45y/o. His lipids look more or less normal.

Expanded panel results

Lp(a) high (104) Others normal

What would you do?

Lp(a)

Bonus case: Wendy’s patient 58 yo woman, slender, healthy eater with h/o ischemic

stroke age 58. Year later, ischemic bowel.

InflammationHs-CRP

Inflammatory marker

Better then ESR and leucocytes for predicting vascular events

Low Risk level < 1.0 mg/L

Lp-PLA2 Slightly more

specific for vascular inflammation

Low risk <200 mg/ml

hsCRP

Treatment of increased hsCRP Look for cause: inflammation, infection,

trauma. Consider checking Lp-PLA2 (endothelial

inflammation) Anti-inflammatory regimen

Diet (Mediterranean anti-inflammatory or mod elim)

Exercise (any is better) Fish oils (dose by EPA/DHA 2-6g a day) Probiotics (10 billion org a day) Vit D (check level and treat to 50) Decrease Stress and support good sleep (cortisol)

4th Patient • 72 y/o woman obese, HTN,

IGT, depression. • “What is my risk of heart

disease or stroke?” • How do you answer this

question?• Very Concrete thinker• Can you do it in a way that

furthers the patients motivation to change and is affordable?

Thoughts after test

Routine lipid panel• At Goal

– HDL = 65– VLDL = 18– Chol/HDL ratio =3.2– TG’s = 90

• moderate risk– TC = 211– LDL = 128– Non-HDL chol = 146

Advanced Risk Markers• High Risk

– hsCRP = 4.88 [<1] – sd-LDL = 36.2 [20]

• Moderate Risk– Apo B 113 [<60]– Homocysteine 11.2 (<10)At Goal– Lp-PLA2 185.4 (<200)

How to treat• NCEP –ATC diet with goal

of dropping 5-10% weight

• Lower carbohydrate, higher fiber diet

• Omega 3 fats; substitute olive oil

• Screen for DM, hypothyroidism

• Lower LDL*

ECW tricks: 3 other tests you may want…

Summary High apoB = Small dense LDL ~ metabolic syndrome

check AIC, treat LDL earlier, LS changes, consider earlier metformin, check hsCRP

Low HDL (especially low High HDL 2) Exercise, Niacin, moderate ETOH

High Lp(a) bad Niacin, NAC

High hsCRP (cardio CRP) > 1.0 r/o infection, inflammation, trauma. Repeat test/ck lp-PLA2 Anti-inflam regimen (diet, ex, stress, fish oil, probiotic,

antioxidants)

Homocysteine: a definite risk factor, interventions lower it, ?if that makes a difference unless they have the condition hyperhomocysteinuria (rare).

Homocysteine

Methylation (if high also check B12/folate/methylmalonic acid) Functions primarily to protect DNA

How to help For most Mediterranean Diet adequate, if still a

problem may need supplementation B6 25 micrograms/d B12 1000micrograms/d Folate 800micrograms/d (may need as methyl THF)

Progression of Drug Therapy in Primary Prevention

If LDL goal not achieved, intensifyLDL-lowering therapy

If LDL goal not achieved, intensify drug therapy or refer to a lipid specialist

Monitor response and adherence to therapy

• Start statin or bile acid sequestrant or nicotinic acid

• Consider higher dose of statin or add a bile acid sequestrant or nicotinic acid

6 wks

6 wks

Q 4-6 mo

• If LDL goal achieved, treat other lipid risk factors

Initiate LDL-lowering drug therapy

Lipids Background

Cholesterol Functions

1. Plasma Membranes

2. Myelinated structures in the CNS

3. Inner Mitochondrial Membranes

4. Bile Acids

5. Steroid Hormones and Sex Hormones

6. Ergosterol (UV skin) Vit D3

Lipids Background

Lipids in Atherosclerosis Dys-Function

1. Endothelium and damage

2. LDL and Macrophages

3. Oxidized LDL and Foam Cells Also glycosylated and acetylated LDL

4. Plaque and rupture

5. HDL as scavenger

Cholesterol General

Total Cholesterol/HDL ratio (TC/HDL)Best Lipid predictor of CHD in Framingham Study

TC/HDL ratio 1 unit = CHD risk by 60%

Eg TC/HDL ratio of <4 is normal6 = 120% increased risk3 = 60% decreased risk

JAMA: 200968 Studies: 300,000 patients

Mean fu 6 years

Risk for coronary disease was associated with higher

values of •non–HDL-C and LDL-C,

•higher ratios of non–HDL-C/HDL-C

•apo B/A1•lower values of HDL-C. •not associated with triglyceride levels

•No difference in risk prediction was observed

between fasting and nonfasting measurements.

Di Angelantonio E et al. for the Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009 Nov 11; 302:1993.

Risk for coronary disease was associated with higher values of •non–HDL-C and LDL-C,•higher ratios of non–HDL-C/HDL-C•apo B/A1 (LDL/HDL)•lower values of HDL-C. •not associated with triglyceride levels•No difference in risk prediction was observed between fasting and non-fasting measurements.

IM4U Treatment PyramidEnvironment ResourcesRelationships

IM4U Treatment Pyramid (expanded)

Environment ResourcesRelationships

Drug Therapy1) HMG CoA Reductase Inhibitors (Statins)

Reduce LDL-C 18–55% & TG 7–30% Raise HDL-C 5–15% Major side effects

Myopathy Increased liver enzymes

Contraindications Absolute: liver disease Relative: use with certain drugs

HMG CoA Reductase Inhibitors (Statins) (continued)

Demonstrated Therapeutic Benefits

Reduce major coronary events Reduce CHD mortality Reduce coronary procedures (PTCA/CABG) Reduce stroke Reduce total mortality

Statins: Drug-Nutrient Side Effects

Nutrients Depleted

Coenzyme Q10: Statins inhibit the enzyme HMG CoA reductase that is required to make cholesterol and Coenzyme Q10.

Could explain myalgia, exercise intolerance, myoglobuinuria

Also, Selenium, Zinc, CopperLower serum PUFA’s and alter the relative % of omega 6:3 fats

Arch Neurol 2004;61(6):889Nutr Metab Cardiovasc Dis 2005; 15(1): 36

Drug Therapy2) Bile Acid Sequestrants

Ex: cholestyramine, colestipol, colesevelam

Major actions Reduce LDL-C 15–30% Raise HDL-C 3–5% May increase TG

Contraindications Dysbetalipoproteinemia Raised TG (especially >400 mg/dL)

Bile Acid Sequestrants (continued)

Demonstrated Therapeutic Benefits Reduce major coronary events Reduce CHD mortality

Side effects GI distress/constipation Decreased absorption of other drugs Decreases beta-carotene, calcium, folate, Fe,

Mg, Vit B12, D, E, K & zinc (cholestyramine)

Drug Therapy3) Nicotinic Acid

Major actions Lowers LDL-C 5–25% Lowers TG 20–50% Raises HDL-C 15–35%

Side effects: flushing, hyperglycemia, hyperuricemia, upper GI distress, hepatotoxicity

Contraindications: liver disease, severe gout, peptic ulcer

Nicotinic AcidDrug Form Dose Range

Immediate release 1.5–3 g(crystalline)

Extended release 1–2 g

Sustained release 1–2 g

Nicotinic Acid (continued)

Demonstrated Therapeutic Benefits

Reduces major coronary events Possible reduction in total mortality

Drug Therapy4) Fibric Acids

Example: gemfibrozil, fenofibrate, clofibrate

Major actions Lower LDL-C 5–20% (with normal TG) May raise LDL-C (with high TG) Lower TG 20–50% Raise HDL-C 10–20%

Contraindications: Severe renal or hepatic disease

Fibric Acids (continued)

Demonstrated Therapeutic Benefits Reduce progression of coronary

lesions Reduce major coronary events

Side effects: dyspepsia, gallstones, myopathy

Drug-nutrient interactions: Decrease CoQ10 also, Vitamin E, (fenofibrate incr’s homocysteine)