Dyslipidemia Cardiology REM

Lipids

Organic compounds, poorly soluble in water (i.e., lipophilic)

Transported in blood as large complexes of liquids + proteins, known as lipoproteins

Triglycerides Primary Functions

Energy supply, energy storage, insulation, organ protection

Phospholipids Primary Functions

Cell membrane structure, lipid transport, signaling molecule precursors

Cholesterol

Cell membrane integrity, precursor for steroid hormones, bile acids, and vitamin D production

Endogenous generation

Liver is primary site for synthesis, closely tied to glucose/carb metabolism

Cholesterol synthesis regulated by HMG-CoA reductase (rate- limiting enzyme)

Diurnal variation: synthesis rates greater at night

Feedback regulation: high intracellular cholesterol inhibits HMG-CoA reductase

Stored or packaged (into VLDL lipoproteins) for transport

Lipoproteins

Mechanism for transporting lipids in the blood

Includes High density lipoproteins (HDL), low density lipoproteins (LDL), Intermediate density lipoproteins (IDL), very low density lipoproteins (VLDL)

Lipid transportation

The liver synthesizes and secretes VLDL, primarily composed of triglycerides, with smaller amounts of cholesterol and phospholipids

In the bloodstream, VLDL loses triglycerides through enzymatic transformations, converting into IDL and then LDL, which is cholesterol-rich (Hence, you will see LDL often written as LDL-C)

Chylomicrons

Large, triglyceride-rich lipoproteins

Transports lipids from dietary intake

Not present ~12 hours after fasting

VLDL

Lipoprotein that is released by the liver

Similar in structure to chylomicrons, but carries high levels of endogenous TG (followed by cholesterol)

LDL

Major cholesterol transporter (hence, often written LDL-C)

IDL is modified form of LDL

Cleared by uptake by LDL receptors

HDL

Synthesized by a distinct process of the liver

Responsible for removing excess cholesterol and taking it back to the liver for catabolism or to the gut for excretion

Causes of dyslipidemia

Often multifactorial with environmental factors and genetic abnormalities involved

Mostly secondary causes – the “4 Ds” of diet (western diets = strong contributor), disorders, disease, and drugs

Primary or Familial dyslipidemia is fairly rare

Secondary causes or contributors of High Total Cholesterol and LDL

Atypical antipsychotics

Glucocorticoids

Immunosuppressants (e.g., cyclosporine, sirolimus)

Progestins

Isotretinoin

Thiazide diuretics

Beta-blockers

Protease inhibitors

Mirtazapine

Gemfibrozil

Secondary causes or contributors of High TG

Secondary causes or contributors of Low HDL

Clinical presentation

Most patients are asymptomatic

May present with multiple signs of metabolic syndrome

May present with cardiovascular events if have had underlying dyslipidemia for sufficient time period

Eruptive xanthomas can develop in childhood/early adulthood in aggressive forms of dyslipidemia (i.e. familial)

Pancreatitis in patients with TG > 500 mg/dL

Patient evaluation (Required lab for diagnostics)

Fasting lipid profile (FLP) (12-hour fast, preferred) - Includes total cholesterol, LDL, HDL, and TG

Total cholesterol, HDL and TG can be measured directly with assays, whereas LDL cholesterol is calculated

TG > 400 mg/dL → can mislead calculation, so LDL cannot be calculated; A direct-LDL (assay) can be obtained in this case; direct-LDL is also preferred if calculated LDL is < 70 mg/dL (due to limitations of accuracy)

FLP lab recommended in all > 20 years old, at least every 5 years

In nonfasted state, only total cholesterol and HDL will be usable; If total cholesterol > 200 mg/dL or HDL < 40 mg/dL, obtain a follow-up fasting panel

Cholesterol calculations

LDL = Total cholesterol – HDL – (TG ÷ 5); TG ÷ 5 estimates the VLDL

Non-HDL cholesterol = total cholesterol – HDL

Total Cholesterol Values (mg/dl)

<200 = desirable

200-239 = Borderline high

> 240 is high

LDL Values (mg/dl)

< 70-100 = Optimal

100-129 = Near or above optimal

130-159 = Borderline high

160-189 = High

> 190 = Very high

TG Values (mg/dl)

< 150 = Normal

150-174 = Borderline high

175-499 = Moderately high

>500 = High – at risk for acute pancreatitis

HDL Values (mg/dl)

< 50 (female) ; < 40 (male) = Low

> 60 = High – good

> 90-100 (FYI) = Extremely high (FYI)– paradoxically negative effects*

Primary prevention

Assess risk of developing ASCVD

Screen FLP every 5 years starting at age 20 to determine if lipid abnormalities exist

Often abnormalities are a mixture of elevated LDL, elevated TG and low HDL

Elevated LDL: if >190 mg/dL, more likely to be genetic (HeFH or HoFH) but would require genetic testing to confirm (not often done), often requires combination treatment

Elevated TG: when > 500 mg/dL becomes an acute risk (pancreatitis), often requires TG-targeted drug

If lipid abnormity is identified, gather patient data

1) age, 2) gender, 3) family history, 4) cardiovascular risk factors (e.g., age, smoking, BP, lipids, A1c), 5) medication history, 6) potential secondary causes of lipid abnormalities 7) other pertinent history (e.g., history of pancreatitis)

Physical exam by provider

Secondary prevention: what constitutes very high-risk?

History of multiple major ASCVD events or 1 major ASCVD event + multiple high-risk conditions

Major ASCVD Events

Recent ACS (within past 12 months)

History of MI

History of ischemic stroke

Symptomatic PAD

High-risk conditions

Age > 65 years

Heterozygous familial hypercholesterolemia

History of prior CABG or PCI outside of major ASCVD events

Diabetes

Hypertension

Chronic kidney disease

Heart failure

Persistently elevated LDL (> 100) despite maximally tolerated statin therapy + ezetimibe

“Statin” Benefit Groups

Severe hypercholesterolemia (LDL > 190)

Age 40-75 years, with diabetes, and LDL > 70

Age 40-75 years, without diabetes, LDL > 70 to < 190, and 10-yr ASCVD risk > 7.5%

Clinical ASCVD

Severe hypercholesterolemia (baseline LDL > 190)

Initial therapy: High-intensity statin or maximally tolerated statin

Subsequent therapy: Consider ezetimibe if LDL ≥ 100 mg/dL on maximally tolerated statin; consider PSCK9i if LDL is still ≥ 100 mg/dL (despite statin + ezetimibe) with HeFH diagnosed patients

Age 40-75 years, with diabetes, and LDL > 70

Moderate-intensity statin at least (if pt agreeable); if has multiple risk factors and/or > 50 yrs of age, consider high-intensity statin

Age 40-75 years, without diabetes, LDL > 70, and 10-yr ASCVD risk

> 7.5% = Moderate intensity statin if shared decision favors statin (i.e., risk enhancers present or check CAC)

> 20% = High-intensity statin or maximally tolerated statin

Clinical ASCVD

Initial therapy: High-intensity statin or maximally tolerated statin

For those > 75 years of age and not at very-high risk, a moderate-or high-intensity

Subsequent Therapy: If very high-risk ASCVD + LDL > 70 mg/dL on maximally tolerated statin, there is the highest level of evidence to consider adding non-statins (consider ezetimibe first; if goal not achieved on statin plus ezetimibe, then consider PCSK9 inhibitor)

LDL-C = > 190 mg/dL

Primary severe hypercholesterolemia

LDL-C < 70 mg/dL

Very high risk ASCVD

> 50% reduction in LDL-C from baseline measurement

All others indicated for a high-intensity statin, including: Age 40 – 75 years, without diabetes, LDL-C > 70 mg/dL, and ASCVD risk > 20%

Age 40 – 75 years, with diabetes, LDL-C > 70 mg/dL, and multiple risk factors

30-49% reduction in LDL-C from baseline measurement

Those indicated for a moderate-intensity statin, including: Age 40 – 75 years, without diabetes, LDL-C > 70 mg/dL, and ASCVD risk 7.5 – 19.9%

Age 40 – 75 years, with diabetes and LDL-C > 70 mg/dL

Therapeutic Lifestyle Changes (TLC) diet

Emphasize intake of vegetables, fruits, legumes (lentils, beans, peas, chickpeas, whole grains, nuts, healthy protein sources (fish, well-sourced dairy or poultry)

Limit refined carbohydrates, sweets, sweetened beverages, and processed meats (ex. bacon, deli meat)

Achieve ideal body weight

Modify to meet personal and cultural food preferences and nutritional needs for concomitant diseases

TLC Ideal Diet Goals

Calories from saturated fat: 5-6%; Avoid trans fat

Cholesterol intake < 200 mg/day

Sodium intake < 1500 mg/day to 2400 mg/day

Other diet interventions/supplements

Fiber - Found in vegetables, fruits, legumes, chia seeds, whole grains (whole/rolled oats, oat bran, barley), Soluble fiber especially beneficial (25% or 6g/d of total dietary fiber)

When assessing Nutrition Facts, ideally there should be > 1 gm of fiber for ever 10 gm of carb

10-15 g/d of psyllium seed reduced total and LDL cholesterol by 5-20%

MOA: binds cholesterol in the gut and reduces hepatic production and clearance

Other diet interventions/supplements 2

Plant sterols (whole foods have enough) & stanols (isolated/added to fortified food)

Sterols are available in high enough levels of whole foods (nuts, seeds, whole grains); whereas stanols are isolated from soybean and tall pine-tree oils to then be added to fortified foods

2-3 g/day reduced LDL by 6-15%

MOA: resemble cholesterol → compete for gut absorption; may also have anti-inflammatory effects

Atorvastatin

Lipitor

Dosage Range: 10-80 mg daily

Fluvastatin

Lescol

Dosage Range: 20-80 mg in evening or bedtime

Lovastatin

Mevacor

20-80 mg in evening or bedtime

Pitavastatin

Livalo

1-4 mg daily

Pravastatin

Pravachol

10-40 mg in evening or bedtime

Rosuvastatin

Crestor

5-40 mg daily

Simvastatin

Zocor

5-40 mg in evening or bedtime (80 mg should no longer be used)

High intensity statin

Daily dose lowers LDL by > 50%

Atorvastatin (Lipitor) 40-80mg

Rosuvastatin (Crestor) 20-40mg - Has greatest lowering potential (up to 63%)

Moderate intensity statin

Atorvastatin 10-20mg

Rosuvastatin 5-10mg

Simvastatin (Zocor) 20-40mg

Pravastatin (Pravachol) 40-80mg

Lovastatin (Mevacor) 40-80 mg

Fluvastin XL (Lescol XL) 80mg

Fluvastatin (Lescol) 40 mg BID

Pitavastatin (Livalo) 1-4mg

Low intensity statin

Daily dose lowers LDL < 30%

Simvastatin 10 mg

Pravastatin 10-20mg

Lovastatin 20mg

Fluvastatin 20-40mg

Statins Tolerability

ADE – overall one of the best tolerated lipid agents

Myalgias (1-10%): muscle pain without elevated CK (benign), Subjective pain/aches are more likely to be drug-related if bilateral, involves proximal muscles, onset weeks to months after initiation, resolves after discontinuation

Myositis: muscle pain plus increased CK

Rhabdomyolysis (<0.6%): muscle breakdown/severe pain, CK > 10x ULN, increased SCr, brown urine

Pravastatin (followed by rosuvastatin): least likely to cause myopathies, less muscle penetration (more lipophilic)

Elevations in LFTs > 3x ULN: Statin hepatotoxicity is rare (< 0.1%), Rule out other causes (e.g., fatty liver disease, hepatitis, heavy alcohol use)

Small increases in glucose level, but not a reason to stop therapy

Statins Drug Interactions

CYP 3A4 substrate– simvastatin, lovastatin, atorvastatin - Contraindicated to give simvastatin or lovastatin with azole antifungals, macrolides, HIV protease inhibitors, cyclosporine, grapefruit juice (> 1 qt/day)

Do not exceed 10 mg of simvastatin when taking: verapamil, diltiazem, dronedarone

Do not exceed 20 mg of simvastatin when taking: amlodipine, amiodarone, ranolazine

CYP 2C9 substrate – fluvastatin, rosuvastatin

None – pravastatin

Avoid gemfibrozil with ALL statin drugs

Statins Monitoring

Efficacy: follow-up lipid panel 4 – 12 weeks after initiation of therapy, then 3-12 months thereafter

Safety: LFTs: likely done at baseline; no need for routine checks; repeat if develop s/sx of liver disease

Creatinine kinase (CK): only checked if develops symptoms of myopathy

Statins Contraindications

Acute liver disease/decompensated cirrhosis or unexplained elevated LFTs

Statins Precautions

Pregnancy

Prior myopathy with statin use - Appropriate to use statins, when indicated, as long as monitoring LFTs

Chronic liver disease

Renal insufficiency - Recommended to continue statins in CKD/if progresses to dialysis, but do NOT first initiate a statin after dialysis

Statins Primary Prevention

Always 1st line therapy

Moderate intensity Statins in Primary Prevention

DM age 40 – 75 y

Age 40 – 75 y and LDL-C 70 – 189 and ASCVD borderline risk + risk enhancers OR intermediate risk (higher/stronger evidence)

High intensity Statins in Primary Prevention

Severe hypercholesterolemia (LDL-C > 190 mg/dl)

DM and age 40 – 75 y with higher risk assessment

Age 40 -75 y and LDL-C 70 – 189 and ASCVD high risk

Borderline Risk

5% - <7.5%

Intermediate Risk

>7.5 - <20%

High Risk

>20%

Statins: Clinical ASCVD

Always 1st line therapy

Moderate or high intensity indicated in: Not very high-risk ASCVD > 75 y old

High intensity indicated in: Not very high-risk ASCVD < 75 y old, Very high risk ASCVD regardless of age

Addressing statin intolerance concerns

Rule out other causes (e.g., injury, exercise-induced soreness, rheum disorders)

Check for drug interactions that may be 1) increasing statin levels or 2) having additive effects

Consider adjustment strategies: Choose alternate statin (less lipophilic if possible), reduce the dose or frequency, hold statin and re-challenge in 2-4 weeks

Provide detailed patient education

Optimize diet + consider non-statin if completely intolerant to statin or unwilling to use

Notably, there is insufficient evidence that Co-enzyme Q-10 supplementation helps

Ezetimibe

Decreases LDL 15-20%

Decreases TG 5-10%

Increases HDL 0-5%

IMPROVE-IT trial was shown to additionally reduce ASCVD risk when added to a statin in post ACS patients

Ezetimibe ADEs

Generally well tolerated

GI upset, fatigue, myalgias/arthralgias

No major drug interactions

No major contraindications

Monitor similar LFT and CK readings as with statins

Ezetimibe in Clinical ASCVD

Typically, 2nd line add-on therapy

For use in patients meeting the following criteria:

1. Clinical ASCVD on maximally tolerated statin with LDL-C still > 70 mg/dL

2. Very high risk ASCVD (regardless of age) or Not very high-risk ASCVD < 75 y old

OR

Severe hypercholesterolemia on maximally tolerated statin with LDL-C still > 100 mg/dL

PCSK9 Inhibitors

Decreased LDL 50-70%

Decreased TG 10%

Increased HDL 5-10%

FOURIER and ODYSSEY OUTCOMES trial - when added to statin therapy, PCSK9 inhibitors reduced risk of ASVCD in high-risk patients

Requires patient education for self-administered injection

Significant cost reduction in 2018-19, however still relatively high cost

PCSK9 Inhibitors ADEs

Injection site pain

Nasopharyngitis

Allergic reactions (non-anaphylactic): rash, eczema, erythema, urticarial

Myalgia

Excess LDL reduction (?)

No drug interactions

Precautions for hypersensitivity reactions

PCSK9 Inhibitors in Clinical ASCVD

Typically, 3rd line add-on therapy

For use in patients meeting the following criteria:

• Very high risk ASCVD

• On maximal LDL-C lowering therapy

• LDL-C still > 70 mg/dL

OR

• Severe hypercholesterolemia, diagnosed with HeFH

• On maximal LDL-C lowering therapy

• LDL-C > 100 mg/dLc

Bile acid sequestrants (BAS)

Available in tablets and powders (can be refrigerated or mixed with drinks to help with taste/texture)

Often multiple daily doses and cannot be administered at same time as many common medications

Take with meals since mechanism is to bind intestinal bile acids

LRC-CPPT trial showed reduced CV events as monotherapy; but have not shown to reduce CV-events when alongside statins

40% discontinue in first year due to complex administration and ADEs

Not systemically absorbed so advantageous with pregnancy, renal, or hepatic disease

Bile acid sequestrants (BAS) ADEs

Common: constipation, obstruction, bloating, nausea, and flatulence, Minimize by increased fluid intake and increase fiber

Other: impaired ADEK absorption possible

Bile acid sequestrants Drug interactions and Safety

Binds many co-administered drugs in gut

Reduced bioavailability of acidic drugs (e.g., ezetimibe, niacin, warfarin, thyroxine, acetaminophen, hydrocortisone, HCTZ, loperamide, iron)

In general, avoid administering other oral drugs at least 1 hour before or 4 hours after

Contraindication in complete biliary obstruction

Precaution - Avoid if TG > 300 mg/dL. Constipation

Niacin (nicotinic acid, vitamin B3)

not shown to reduce CV-events (when alongside statins); some trials have suggested harm, Latest guidelines do NOT recommend use

Niacin ADEs

Cutaneous flushing and itching (prostaglandin mediated): expected ADE with regular release formulations

Manage by taking aspirin 325 mg 30 minutes before medication, taking medication with meals, slowing dose titrating, use of sustained release formulation

Lab abnormalities: Elevated LFTs (hepatotoxicity), Hyperuricemia, Hyperglycemia

GI upset

Myalgias

Niacin Safety and Drug interactions

Statins: increase risk of myopathy, close monitoring is important

Bile acid sequestrants: bind niacin, must separate administration

Contraindications: Active (acute or chronic?) liver disease, Active peptic ulcer disease, Active bleeding, Uncontrolled diabetes and gout

Safety monitoring: LFTs, uric acid, and glucose at baseline and repeated in 6-12 weeks if on 1000 mg/day or more

CK at baseline and if clinically indicated based on signs and symptoms

Bempidoic Acid

Nexletol

Adjunct to maximally tolerated statin therapy for the treatment of adults with primary or secondary ASCVD prevention or heterozygous FH if requiring additional lowering of LDL-C

Inclisiran

Leqvio

Adjunct to maximally tolerated statin therapy for the treatment of adults with established ASCVD, heterozygous FH, or homozygous FH if requiring additional lowering of LDL-C

Evinacumab

Evkeeza

monoclonal antibody

As an adjunct to other LDL-C lowering therapies for the treatment of adult and pediatric patients, aged 12 years and older, with homozygous FH

Omega-3 fatty acids

Ingestion of large amounts of cold water, oily fish is associated with reduction in CHD risk

Studies of omega-3 dietary supplements have showed inconsistent results

The REDUCE-IT trial led to Vasepa FDA approval for CV risk reduction – it showed a reduction in ASCVD events for statin-treated patients with TG > 135 mg/dL

Primary treatment of hypertriglyceridemia (TG > 500)

Vascepa (specifically): patients with established CV disease or diabetes who have TG > 150

Omega-3 fatty acids ADE

Dyspepsia, belching, fishy after-taste (can freeze OTC omega 3s to reduce this, not recommend for Rx versions)

Thrombocytopenia and increased bleeding risk (especially in high doses)

Contraindication in allergy to fish or shellfish

Omega-3 fatty acids Drug Interactions

Caution with agents that can increase bleeding risk due to additive bleeding (e.g., anticoagulants, antiplatelets, SSRIs)

Fibrates (fibric acid derivatives)

Primary treatment of hypertriglyceridemia (TG > 500)

Fenofibrate

Gemfibrozil (Lopid) - not commonly seen due to drug interaction concerns

Fibrates ADEs and Drug interactions

Not shown to reduce CV-events when alongside statins

GI upsets, gallstones, increases in SCr, more severe (but rare) elevation of LFTs, myopathies

Monitor closely if combined with statins; gemfibrozil (specifically) is CI with statins

Moderate inhibitor of CYP2C9: warfarin (↑ INR)

Fibrates Contraindications and Safety

Active (acute or chronic?) liver disease

Severe renal disease (CrCl < 30 ml/min)

Gallbladder disease

Safety monitoring: Renal function at baseline and periodically – dose adjustments when CrCl < 80 ml/min; CrCl >30 to 80 mL/minute: use lowest available strength (if a formulation is not available in a strength that is ≤67 mg, then an alternate formulation should be used)

Similar LFT and CK monitoring as with statins

Moderate hypertriglyceridemia management

(175-499 mg/dL) – ensure FLP was obtained fasting

Address and treat lifestyle factors, secondary factors (e.g., diabetes), and medications that increase TG

Quite responsive to therapeutic lifestyle changes

Remember, endogenous lipid synthesis is closely tied to glucose metabolism; those with uncontrolled blood glucose may also present with hypertriglyceridemia

If 40-75 years of age + ASCVD risk > 7.5%, consider persistently elevated TG as a factor favoring statin initiation/intensifying of statin

Severe hypertriglyceridemia management

(> 500 mg/dL) – ensure FLP was obtained fasting

Must prioritize treatment of TGs due to added risk of pancreatitis in addition to CV risk

Identify and address secondary causes (e.g., uncontrolled diabetes, alcohol use)

Diet change (reduced cholesterol/saturated fat, avoid refined carbs and sugar, abstain from alcohol, increase consumption of fatty fish)

Consider initiation either: Fenofibrate, An RX omega-3 fatty acids

Low HDL

No specified goal for raising HDL – has not been the focus of research

Often associated with insulin resistance, diabetes, physical inactivity, high carbohydrate intake, and cigarette smoking

Quite responsive to therapeutic lifestyle changes

Drug therapy not usually prescribed – no RCTs have shown reduction in ASCVD