327 Exam 1 Dyslipidemia

Roadmap for Dyslipidemia

ASCVD, Lipoproteins, Cholesterol Synthesis and Metabolism, Dyslipidemias, Assessing ASCVD risk, Medication for Dyslipidemia, Treatment Pathways, Monitoring and Follow-up

ASCVD

is the buildup of plaque within arteries, limiting blood flow to organs

Primary prevention

No history of ASCVD or events

Secondary Prevention

Any history of diagnosis of ASCVD also known as an event

Progression of ASCVD

Normal artery, fatty streak develops (increases risk factors), complicated lesions (plaque and thrombosis), occlusion and decreased oxygen supply, ASCVD event

Risk factors for CVD

Hypertension, genetics, obesity, stress, aging, smoking, diabetes, hyperlipidemia

All lead to endothelial dysfunction and eventually atherogenesis (plaque formation)

Oxidized LDL-C

Increased plasminogen inhibitor levels, leads to increased coagulation. Induces local vasoconstriction. Leads to a decrease in nitric oxide release which can cause vasodilation and platelet inhibition. Other lipids form and accumulate. Cholesterol containing macrophages become foam cells, early cells in the arterial fatty streaks

Triglycerides

Store and transport energy

Fatty Acids

are metabolized for energy

Cholesterol

larger molecules that can be broken down into hormones, bile acids, and help metabolize fats

Lipoproteins

vary into multiple categories based upon their size ratio of lipids to proteins and specific apolipoproteins. Lipo (fatty acids, triglycerides, cholesterol + apoproteins = lipoprotein). They are used to carry cholesterol throughout the body because fatty acids are lipophilic and cannot transport through blood

4 kinds of lipoproteins

Chylomicrons, VLDL, LDL, HDL. The combo of all 4 makes up total cholesterol. As particles increase in size, they are less dense (more triglycerides less protein)

Chylomicrons

Are the largest and least dense molecules. They contain the fatty acids. HDL is the smallest, most dense, and contain the least fatty acids.

HDL

Smallest, most dense, and contain the least fatty acids. “Good cholesterol”

Exogenous Pathway of Cholesterol

Fatty acids are digested by bile in the GI tract and are encapsulated into micelles to be carried through the lumen. Triglycerides are incorporated into Chylomicrons which are rare without food. Conversion through lipoprotein lipase (LPL) transports the triglycerides to tissue throughout the body and remnants arrive to the liver and bind to the LDL receptor

Endogenous Pathway of Cholesterol

Production of lipoproteins inside the body. In the liver fatty acid remnants from chylomicrons combine with glucose to be converted into cholesterol. 

Glucose —→ pyruvate —→ acetyl coA —→ metabolized by HMG-CoA reductase —→ cholesterol

The cholesterol is packed with other triglycerides, proteins, into VLDL in the liver. HGL is also created with minimum triglycerides.

The VLDL is released from the liver and LPL continues to drop off triglycerides for energy storage which results in increased adipose tissue 

LDL provides tissue with cholesterol for hormones and cell membranes. Excess cholesterol is placed in the arteries resulting in plaque formation 

LDL is returned to the liver through the LDL-receptor and repackage into VLDL or excreted through bile 

HDL picks up excess cholesterol to be transported back to the liver

Reverse cholesterol transport

HDL from the liver and Apo A from the gut transport cholesterol back to the liver Cholesterol this not needed in the periphery is brought to the surface and harvested.

The HDL gives cholesterol back to ApoB containing molecules which will turn to LDL once back int the liver

HDL subtypes are then further recycled and processed

Cholesterol Risk factors

A high fat diet leads to more triglycerides transported to the liver from chylomicrons and subsequently more cholesterol which can then be deposited by LDL on the arterial walls leading to anthogenesis

Plaque Formation

LDL undergoes oxidation and is taken up by macrophages without order leading to endothelial dysfunction. A decrease in nitric oxide produces vasoconstriction. Foam cells are formed, and a fatty streak develops. Eventually plaques will form. Over year macrophages will destabilize the plaque by deregulating the collagen matrix making it unstable which could lead to a thrombus.

What Causes Dyslipidemia

Primary or familial: significant elevations in cholesterol leading to premature ASCVD caused by abnormalities in certain genes.

Secondary or acquired: abnormalities due to environmental factors like diet, drugs, and diseases

Normally dyslipidemias occur due to a mix of both

Diet

Excessive alcohol intake, lack of physical activity, fat-dense diet, high carb/sugar intake, malnutrition

Medical Conditions

Obesity, uncontrolled diabetes, hypothyroidism, pregnancy, CKD > stage 3, nephrotic syndrome, chronic inflammatory conditions 

Drug use

Progestins, anabolic steroids, oral estrogen, protease inhibitors, glucocorticoids, interferons, beta blocks, thiazide diuretics

Hypercholesterolemia

elevated cholesterol above goal based on ASCVD risk

Hypertriglycerdiemia

> 150 mg/dL

Hypocholesterolemia

low cholesterol 

Low HDL

Common, often accompanying other metabolic conditions

Other risk factors of ASCVD

Obesity, atherogenic dyslipidemia, increased blood pressure, insulin resistance or glucose intolerance, proinflammatory state

Metabolic syndrom

When pts. have 3 or more risk factors for ASCVDS

Signs of Dyslipidemia

Only apparent in very high levels but can include abdominal pain, pancreatitis, xanthomas, peripheral polyneuropathy

Clinical Presentation of ASCVD

Coronary heart disease, MI, ischemic stroke, peripheral artery disease, death. General symptoms: Chest pain, palpitations, sweating, anxiety, shortness of breath, loss of consciousness, difficulty with speech or movement, abdominal pain, severe leg pain or cramping

Secondary causes of ASCVD

Hypothyroidism, diabetes, chronic kidney disease obesity, Lipodystrophy (abnormal adipose tissue distribution), hepatitis, pregnancy

What drugs cause hypercholesterolemia

Thiazide diuretics, progestins, glucocorticoids, beta blockers, isotretinoin

What drugs cause Hypertriglyceridemia

Alcohol, estrogen, isotretinoin, beta blockers, thiazides, snsbolic steroids

Social determinants of health

Environment (access to healthy foods), Economic (afford treatment and time off work), education (navigate healthcare), Social and community (support, cultural norms), Healthcare access (different treatment based upon bias, access, etc)

Lipid Panel components

TC: total cholesterol 

HDL, LDL, TG

Non HDL (TC-HDL)

Purpose of lipid panel

used to screen and guide treatment.

The Friedwald Equation

LDL = TC - HDL - (TG/5)

Not accurate in TG >400 mg/dL, underestimate LDL < 25 mg/dL

The martin equation

LDL = TC - HDL - (TG/factor)

Adjustable factor accounts for VLDL, recommended when LDL<70

Target Cholesterol

TC: <200, 200-239 is borderline, >240 is high

LDL: <100 is optimal, above optimal 100-129, >160 is high, >190 is very high

HDL: <40 in men is low, <50 in women is low

TG: <150 is normal, 150-199 is borderline, 200-249 is high, >500 is very high

Coronary artery Calcium

Non-invasive methods to assess risk. Oxidized lipids lead to a pro-calcification state in the vasculature leading to increased collection of fatty streaks. 0= no plaque, over 400 is high to very high risk. 

Pooled Cohort Equation

Assess 10-year risk score in individual 40-79 years old. Also assesses lifetime risk 20-59 years old.

Components: Age, sex, systolic BP, total cholesterol, HDL cholesterol, diabetes, smoking, hypertension medications

Prevent Calculator

Ages 30-79, predicts the risk of CVD, ASCVD, and heart familiar. Potentially minimizes number of people indicated for statin therapy. Screens for CVKM syndrome by assessing lifestyle and health. Low Risk is less than 5, high risk is greater than 20

Limitation of PCE

Severity of other conditions is not accounted for, race, age-limitations, only for primary prevention, lots of conditions known to increase ASCVD risk are not included

HMG CoA Reductase Inhibitors

Inhibits the enzyme HMG CoA reductase which inhibits the production of cholesterol. Decreases TGs, Non HDL, LDL, and TC. It increases HCL.

Examples of Statins

Atorvastatin, Fluvastatin, Lovastatin, Rosuvastatin, Pitavastatin, Pravastatin, Simvastatin

Intensity Dosing of Atorvastatin

High (Dec. LDL by >50%): 40-80mg

Moderate (Dec. LDL by 30-49%): 10-20mg

Low (Dec LDL by 30%): none

Intensity dosing for Rosuvastatin

High (Dec. LDL by >50%): 20-40mg

Moderate (Dec. LDL by 30-49%): 5-10mg

Low (Dec LDL by 30%): none

Intensity dosing of Lovastatin

High (Dec. LDL by >50%): none

Moderate (Dec. LDL by 30-49%): 40mg

Low (Dec LDL by 30%): 20mg

Intensity dosing of Pravastatin

High (Dec. LDL by >50%): none

Moderate (Dec. LDL by 30-49%): 40-80mg

Low (Dec LDL by 30%): 20mg

Intensity dosing for Simvastatin

High (Dec. LDL by >50%): none

Moderate (Dec. LDL by 30-49%): 20-40mg

Low (Dec LDL by 30%): 10mg

Intensity dosing for fluvastatin

High (Dec. LDL by >50%): none

Moderate (Dec. LDL by 30-49%): 40mg

Low (Dec LDL by 30%): 20-40mg

Statin Drug interaction

Simvastatin, lovastatin, atorvastatin: Interact with drugs metabolized by CYP3A4 like CCBs, antifungals, HIV therapy, Paxlovid 

Fluvastatin, Rosuvastatin: CYP2C9

Rosuvastatin: 2C19

Pitavastatin: UGT

Pravastatin: None

Lipophilic Statin

Lovastatin, Simvastatin, Fluvastatin, Atorvastatin, Pitavastatin

Hydrophilic statins

Rosuvastatin, Pravastatin

Active metabolites

When metabolized they continue to have pharmacological action throughout the body

Half life of atorvastatin

7-14 hours

Half life of Rosuvastatin

13-20 hours

Half life of Pitavastatin

12 hours

Half life of Lovastatin, simvastatin, pravastatin, fluvastatin

1-3 hours

Adverse effects of statin

Myalgias/myopathy, new onset diabetes, transient mild elevations in LFTs, SAMS, rhabdomyolysis, severe hepatotoxicity (large increase in LFTs)

Contraindications of statins

Breast feeding, pregnancy (should avoid unless necessary), severe liver disease - cirrhosis or acute liver failure

Nocebo effect

90% of people do not experience a side effect vs 10% of people do experience a side effect 

Which statins should be taken at night

Short acting ones like simvastatin, lovastatin, and fluvastatin because that is when cholesterol synthesis peaks

What statins are affected by grapegruit

Simvastatin, lovastatin, and atorvastatin. GF inhibits CYP34A in the gut and liver

LFTs

Recheck 6-12 weeks after starting statin. Check Creatinine phosphokinase is pt. complains of muscle symptoms. 

Muscle symptoms with statins

Statins inhibit an intermediate important for the production of CoQ10. They decrease circulating levels by 25% before correcting LDL.

Should patients with statin musclesymptomstakeCo10dietary
supplements?

Not recommended because evidence is insufficient but small studies have shown modest improvement

Statins with greatest risk of SAMS

More lipophilic, more common drug interactions, higher doses, longer half life, active metabolites. 

Contributing factors to SAMS

Low vitamin D, CKD, hypothyroidism, older age, female, low body weight, Asian ancestry

SAMS classification

Myalgia, myopathy, rhabdomyolysis

Myalgia

Aches and pains

Myopathy

muscle weakness,

Rhabdomyolysis

Muscle breakdown

Clinical Management of SAMS

Hold statin and reevaluate symptoms, collect LFT and CPK, start alternative statin if labs are fine, consider intermittent dosing, consider non-statin

Dietary supplements for Dyslipidemia

Fiber, phytosterols, garlic, red yeast rice

Fiber

Unknown effect on CVD morbidity and mortality. Can reduce LDL and TC.

Ezetimibe (Zetia)

10mg tabs. May be used as an additional agent in pts who do not meet cholesterol treatment goals with dietary modification and maximally tolerated stating. Or as an alternative in patients intolerant of statins. Generally well tolerated. It may increase LFTs, arthralgias, sinusitis, URTI

Ezetimibe MOA

Lowers cholesterol absorption in the small intestine

Ezetimibe indication

Lower cholesterol in pts. with primary hyperlipidemia either alone or with statins. Lower cholesterol in patient with combination fenofibrate. Lower cholesterol in patients with HoFH in combination with atorvastatin or simvastatin

Ezetimibe efficacy

Lower LDL by 18% alone and by 25% with statin. Improves CV outcomes

PCSK-9 inhibitors examples

Alirocumab and Evolocumab

PCK9-Inhibitors

Efficacy: 45-64% decrease in LDL. Minimal DDI. Expensive. Alirocumab prevent ASCVD events in people who have already had them. Evolucumab prevent ASCVD events in everyone

PCK9-Inhibitors Adverse Effects

HA in children more than adults, Nasopharyngitis, Hypertension, Skin rash, GI discomfort, Influenza infection

Indications for PCK9-Inhibitors

↓MACE in adults with ASCVD

+/- LDL-C lowering agents in adults with primary hyperlipidemia, including HeFH to ↓LDL-C

+/- LDL-C lowering agents in adult patients with HoFH to ↓ LDL-C

Evolocumab can be used in pediatric patients >10

Inclisiran Indications

Decrease LDL in adults with ASCVD or HeFH as adjunct to diet and maximally tolerated statin therapy. May need to go to an infusion center. It is generally well tolerated. 

Inclisirian Adverse effects

Antibody development, local injection reaction, arthralgia, bronchitis

Bempedoic Acid

Primary or secondary prevention as an adjunctive agent. Available in 180mg or mixed with ezetimibe 180mg/10mg called Nexlizet

Bempedoic Acid Indication

Lower LDL as an adjunct to diet and maximally tolerated statin therapy for adults with HeFH. Decrease the risk of CVD among statin intolerant patients. Initial concerns for increased uric acid and Achilles tendon rupture

Bempedoic Acid Averse Effects

Hyperuricemia, thrombocytosis, kidney impairment (decreased GFR), cholithiasis, anemia, leukopenia, increased LFTs, gout, tendon rupture

Fibrates examples

Fenofibrate (tricor), Gemfibrozil

Fibrates

Used to decrease TG only. Interacts with statins, increases SAMS. Generally for TG >500 mg/dl. Go through all the lifestyle changes and try statins first to lower LDLs for 4-12 weeks before starting. 

Fish Oils

No benefit in reducing ASCVD but they may decrease TG. Includes EPA and DPA. You need a lot to get to the risk reduction level of EPA. Brand for TG (no CVD risk) is Epanova Omega-3 Carboxylic acids and Lovaza Omega 3 ethyl esters. Side effect is increased bleeding and fishy belches. It is only for pt. with elevated triglycerides. CV reduction

Evkeeza

Angiopoietin like 3 inhibitors. HoFH greater than 5 for lowering LDL. IV infusion.

Lomitapide

Suppresses microsomal triglyceride transfer protein inside ER. HoFH for LDL lowering. can lead to severe GI upset

Bile Acid Sequestrants

Cholestyramine, Colestipol, Colesevelam

Lifestyle therapy

Mediterranean diet (high omega 3, low saturated fats, high fiber), increased exercise, Supplements

Clinical ASCVD

All pts. 18-75. LDL treatment threshold: High risk is 1 event with 2+ high risk conditions <100mg/dl. Very high risk is 2+ ASCVD events or 1 event and 2 high risk conditions <70mg/dL. Start with high intensity statin, add ezetimibe if above threshold, add PCK9-I if still above

If LDL is >190

Age all pts, 18-75 without ASCVD. High intensity statin, add ezetimibe if above threshold, add PCK9-I if still above

When RCEs present

Long duration, CKD, Retinopathy, Neuropathy, family history, primary hypercholesterolemia, inflammatory conditions, metabolic syndrome, elevated TG, CKD, Increased biomarkers