FCM Lipids

What are some risk factors for development of high cholesterol (helps us determine who may benefit from lipid lowering therapy)?

- Family hx of premature CAD (males <55, females <65)

- Primary hyperlipidemia

- Metabolic syndrome

- Chronic kidney disease

- Chronic inflammatory conditions (psoriasis, RA, HIV/AIDS)

- Hx of preeclampsia or of premature menopause before age 40

- High-risk race/ethnicities (South Asian ancestry)

- Persistently high TGDs

- Elevated high-sensitivity CRP

- Elevated lipoprotein A

- Elevated apolipoprotein B

- ABI < 0.9

What is CT calcium scoring?

Single best test for risk stratification for lipid disorders

Around $100, 15 minutes

If calcium score is 0 with no RFs --> may not benefit from statin, can repeat in 5 years

What are the different dyslipidemias?

- Hyperlipidemia/hypercholesterolemia: elevated overall cholesterol (LDL, HDL, both)

- Hypertriglyceridemia: elevated triglycerides

- Familial hypercholesterolemia: inherited disorder, overproduction or impaired removal (monogenic, autosomal dominant, high LDL from birth, xanthomata)

What are the 4 groups of patients who will benefit from statin therapy?

- Individuals with clinical ASCVD (dx through CT angio, calcium score, prior CVA/MI)

- Individuals with LDL above 190

- Individuals aged 40-75 with diabetes and LDL > or = to 70

- Individuals aged 40-75 without ASCVD or diabetes with LDL 70-189 and 10 year CAD risk of 7.5% or higher

What are major risk factors for ASCVD?

- Advancing age

- Increased total serum cholesterol level

- Elevated non HDL-C

- Elevated LDL-C

- Low HDL-C

- Diabetes mellitus

- HTN

- Stage 3 or 4 chronic kidney disease

- Cigarette smoking

- Family history of ASCVD

When should we screen middle age adults for ASCVD risk?

- In the absence of ASCVD risk factors, every 1-2 years

- If multiple global ASCVD risk factors present, screen more frequently

When should we screen older adults (>65 y/o) for ASCVD risk?

Pts with 0-1 ASCVD risk factors, screen annually

When should we screen young adults for ASCVD risk?

Every 5 years as part of global risk assessment (more frequently if RFs)

When should we screen for family hyperlipidemia?

- Family hx of premature ASCVD

- Elevated cholesterol levels (total, non-HDL, and/or LDL consistent with familial hyperlipidemia --> screen yearly

What are clinical features of heterozygous familial hypercholesterolemia?

- Asymptomatic in childhood and adolescence

- Caught in screening

- Total/LDL-C >95th percentile

- Tendon xanthoma or arcus lipoides

What are clinical features of homozygous familial hypercholesterolemia?

- Rare, occurs in 1st decade

- alpha to LDL-R mutation degree

- Null phenotype (<2% LDL receptor activity) --> intrauterine death

- Skin/ocular lipid deposits

- CVS/CNS/PAD+

- Aortic stenosis/CAD frequent

- Hypothyroid and DM

What is the clinical criteria to diagnose heterozygous familial hypercholesterolemia?

- LDL-C >= 160 mg/dL for children

- LDL-C >= 190 mg/dL for adults

- PLUS one first degree relative similarly affected or with premature CAD or positive genetic testing for an LDL-C raising gene defect

What is the clinical criteria to diagnose homozygous familial hypercholesterolemia?

- LDL-C >= 400 mg/dL

- PLUS one or both parents having clinically diagnosed familial hypercholesterolemia, positive genetic testing for an LDL-C raising gene defect or autosomal recessive FH

How does hypertriglyceridemia (>1000 mg/dL) present clinically?

- Eruptive xanthomas

- Tendinous xanthomas

- Lipemia retinalis

What screening tests should we use to evaluate for dyslipidemias?

- Fasting lipid profile

- LDL-C

- HDL-C

- Non-HDL cholesterol

- Triglycerides

- Apolioproteins (ApoB, apoA1)

What are some uncommon screening tests that can be used to evaluate for dyslipidemias?

- Coronary artery calcification (calcium score)

- High sensitivity CRP

- Lipoprotein-associated phospholipase A (Lp-Pla2)

- Homocysteine

- Carotid intima media thickness

What are some secondary causes of increased total cholesterol and LDL-C?

- Hypothyroidism

- Nephrosis

- Dysgammaglobulinemia (SLE, multiple myeloma)

- Progestin or anabolic steroid tx

- Cholostatic diseases of the liver due to abnormal lipoproteins, as in primary biliary cirrhosis

- Protease inhibitors for tx of HIV infection

What are some secondary causes of increased triglycerides and VLDL-C?

- Chronic renal failure

- T2DM

- Obesity

- Excessive alcohol intake

- Hypothyroidism

- Antihypertensive medications (thiazide diuretics, beta blockers)

- Corticosteroid therapy (or severe stress that increases endogenous corticosteroids)

- Orally administered estrogens, oral contraceptives, pregnancy

- Protease inhibitors for tx of HIV infection

What are the treatment goals for the following lipid measurements:

HDL, non-HDL cholesterol, apolipoproteins, triglycerides

HDL: >40

Non-HDL cholesterol: 30 mg/dL higher than the individual's specific LDL goal, 25 mg/dL higher than specific LDL goal in individuals at extreme risk

Apolipoproteins:

- Optimal apoB goal of <90 mg/dL for those with increased risk of ASCVD or with diabetes

- Individuals with ASCVD or diabetes and another risk factor --> apoB goal <80 mg/dL

- For extreme risk individuals, apoB goal <70 mg/dL

Triglycerides: <150 mg/dL

What are the LDL goals for low risk, moderate risk, high risk, very high risk, and extreme risk patients?

Low risk: <130 mg/dL

Moderate risk: <100 mg/dL

High risk: <100 mg/dL

Very high risk: <70 mg/dL

Extreme risk: <55 mg/dL

What are appropriate LDL levels for children?

- <100 mg/dL is acceptable

- Borderline is 100-129 mg/dL

- High is >130 mg/dL

What are the different levels of triglycerides? What is the goal level?

- Normal: <150 mg/dL

- Borderline high: 150-199 mg/dL

- High: 200-499 mg/dL

- Very high: >= 500 mg/dL

Goal: <150 mg/dL

What are some lifestyle changes we can recommend to patients to treat dyslipidemias?

- Physical activity

- Medical nutrition therapy

- Smoking cessation

What are the different pharmacological therapies we can use for dyslipidemias?

- Statins

- Fibrates

- Omega-3 fish oil

- Niacin

- Bile acid sequestrants

- Cholesterol absorption inhibitors

- PCSK9 inhibitors

- MTP inhibitor

- Antisense apo B oligonucleotide

- Combination therapies

What are some nutritional approaches/diet therapy we can recommend to patients to lower their cholesterol?

Dietary therapy can decrease LDL-C by 5-10%

Can do:

- Dean Ornish diet

- Vegetarian diet

- Mediterranean diet

- Soluble fiber can reduce LDL by 5-10%

What is the primary pharmacologic agent to achieve target LDL-C goals?

Statins

What is the first line medication to treat hypertriglyceridemia?

Fibrates

What is the mechanism of action of statins?

Competitively inhibits rate-limiting step of cholesterol synthesis in the liver --> leads to upregulation of hepatic LDL receptors

- Decreases LDL-C by 21-55%

- Decreases TGDs by 6-30%

- Increases HDL-C by 2-10%

What are some adverse effects of statins?

- Myalgias, muscle weakness, rhabdomyolysis

- New onset-diabetes increased in individuals with statins

What are the indications for high intensity and moderate intensity statins?

- Presence of clinical ASCVD

- Primary elevation of LDL cholesterol >190 mg/dL

- Age 40-75 y/o, presence of DM, LDL > 70

- Age 40-75 y/o, no clinical ASCVD or DM, LDL 70-189 mg/dL, estimated 10 year ASCVD risk > 7.5% or calcium score >0 and >75th percentile

If a patient has clinical ASCVD, what is the treatment recommendation for dyslipidemia?

High-intensity statin or moderate intensity statin if over age 75

If a patient has primary elevation of LDL cholesterol >190 mg/dL, what is the treatment recommendation?

High-intensity statin

If a patient is between 40-75 years old, has diabetes, and an LDL level of >70, what is the treatment recommendation?

Moderate intensity statin or high-intensity statin if 10 year CHD risk is >7.5% or patient has other risk enhancing criteria

What is the mechanism of action of PCSK9 inhibitors?

Fully human monoclonal antibodies that block PCSK9 protein in the blood which allows the body to clear LDL effectively

- Decreases LDL-C by 48-71%

- Decreases non-HDL-C by 49-58%

- Decreases ApoB by 42-55%

**Require subcutaneous self-injection, refrigeration needed

What are some adverse effects of PCSK9 inhibitors?

- Flu-like sx (nasopharyngitis, influenza, bronchitis)

- Myalgias

- Diarrhea

What are examples of PCSK9 inhibitors and what are they approved for?

Alirocumab, evolocumab approved in US for familial hypercholesterolemia or CVD who need additional LDL lowering

What are the current recommendations for use of PCKS9 inhibitors in dyslipidemia treatment?

Add to statins in those at very high risk for CVD (recent ACS, multiple prior MI/CVAs, CAD plus CVA or PVD)

What is the mechanism of action of fibrates?

- Primarily decrease TGDs by 20-35%

- Increase HDL-C by 6-18%

- Fenofibrate can also lower LDL-C by 20-25%

- Gemfibrozil may increase LDL-C by 10-15%

Examples of meds: fenofibrate (preferred), gemfibrozil, fenofibric acid

What are some adverse effects of fibrates?

- GI symptoms

- Cholelithiasis (possible)

- Gemfibrozil may increase LDL-C by 10-15%

- May potentiate effects of orally administered anticoagulants

- May cause muscle disorders, myopathy/rhabdomyolysis

- Increased serum creatinine levels (monitor with CMPs)

What is the mechanism of action of bile acid sequestrants?

Bind bile acids in the intestine, reduction in enterohepatic circulation causes liver to increase production of bile acids using hepatic cholesterol

- Decrease LDL-C by 15-25%

What are some adverse effects of bile acid sequestrants?

- May increase serum triglycerides

- Frequent constipation and/or bloating

- Many potential drug interactions

- May reduce absorption of folic acid and fat-soluble vitamins (A, D, and K)

What are examples of bile acid sequestrants?

- Cholestyramine

- Colestipol

- Colesevelam

What is the mechanism of action of cholesterol absorption inhibitors (ezetimibe)?

Inhibit intestinal absorption of cholesterol and decrease its delivery to the liver, leading to upregulation of hepatic LDL receptors

- Decrease LDL-C by 10-18%

- Decrease ApoB by 11-16%

- In combo with statins, additional 25% decrease in LDL-C

What are some adverse effects of ezetimibe?

Myopathy/rhabdomyolysis

What is the benefit of adding ezetimibe to a statin?

- Adds 5-10% relative risk reduction in detrimental CV outcomes

- IMPROVE-IT trial showed combo had a 2% reduction in CV events compared to pts taking a stain alone

What is the mechanism of action of omega-3 fatty acids?

Prominent feature of Mediterranean diet!

- Decrease TGDs by 27-45%

- Decrease VLDL-C by 20-42%

- Decrease apoB by 4%

**Omega-3 acid ethyl esters can increase LDL-C levels (monitor)

What are some adverse effects of omega-3 fatty acids?

- May prolong bleeding time (monitor coagulation status)

- Elevated liver enzymes (monitor AST and ALT levels)

- Caution in pts with known hypersensitivity or allergy to fish/shellfish

- Arthralgia

- Eructation

- Dyspepsia

- Taste perversion

What is the mechanism of action of niacin (nicotinic acid)?

Decreases hepatic synthesis of LDL-C and VLDL-C

- Decreases LDL-C by 10-25%

- Decreases TGDs by 20-30%

- Increases HDL-C by 10-35%

What are some adverse effects of niacin?

- Frequent skin flushing

- Pruritus

- Abdominal discomfort

- Hepatotoxicity

- Nausea

- Peptic ulcer, Afib

What is the mechanism of action of bempedoic acid?

Targets cholesterol synthesis in the liver, results in upregulation of expression of the LDL receptor

Lowers LDL-C by 17-20%

Usually marketed in combo with ezetimibe

What are some adverse effects of bempedoic acid?

- Gout, hyperuricemia

- Risk of tendon rupture

What is the mechanism of action of MTP inhibitors and what is the indication for use?

Decreases LDL-C up to 40%, TGD 45%

Indicated for familial hyperlipidemia

What are some adverse effects of MTP inhibitors?

- Increases in transaminases (ALT, AST)

- Increases in hepatic fat (steatosis)

What is the mechanism of action of mipomersen and what is it indicated for?

MOA: Decreases LDL-C by 21%, apoB by 24%, non-HDL-C by 22%

Indicated for familial hyperlipidemia

What are some adverse effects of mipomersen?

- Increases in transaminases (hepatotoxicity)

- Increases in hepatic fat (steatosis)

How should we monitor dyslipidemia treatment?

- Reassess lipid status 6 weeks after therapy initiation, and again at 6 week intervals until tx goal is achieved

- While on stable lipid therapy, individuals should be tested at 6-12 month intervals

What labs should we check prior to initiating niacin or fibric acid treatment?

Liver transaminases (should also be checked after 3 months of tx)

What should we do if a patient on statins reports clinically significant myalgias or muscle weakness?

- Assess creatine kinase levels

- Discontinue statin

In which patients is combination therapy for dyslipidemia indicated?

- Pts with familial hyperlipidemia on tx and LDL cholesterol is >100

- Pts with existing CVD on tx and LDL cholesterol is >70

- High risk pts with TGD > 150 or non-HDL cholesterol >100

Patients with high triglycerides are at risk for:

Pancreatitis

When do we treat hypertriglyceridemia?

If fasting levels > 500 mg/dL (use statin, omega-3, and fibric acid)

When do we treat hypertriglyceridemia in patients with CVD?

If triglycerides are >150 mg/dL