Montepara Dyslipidemia

Dyslipidemia

Abnormal blood levels of lipids, specifically:

• High total cholesterol

• High LDL

• High TGs

• Low HDL

• Any combination of the above abnormalities

Why is LDL typically not measured in a blood test?

It is expensive, so it is better to calculate using the Friedewald Formula

Friedewald Formula

LDL = TC - HDL - (TG/5)

• Cannot not be used if TG > 400 mg/dL

  • Must measure LDL directly instead (expensive)

ASCVD risk increases with high levels of _____

LDL

Nonpharmacological therapy for dyslipidemia

• Heart healthy diet

• Regular exercise habits

• Maintain healthy weight

• Avoid tobacco products

• Limit alcohol consumption

Pharmacological therapy classes for dyslipidemia

• HMG-CoA Reductase Inhibitors

• Cholesterol absorption inhibitor

• PCSK9 inhibitors

• ATP Citrate Lyase (ACL) inhibitor

• Bile acid sequestrants

• Fibric acid derivatives (Fibrates)

• Niacin

• Omega-3 fatty acids

• Microsomal Triglyceride Transfer Protein (MTP) inhibitor

• Angiopoietin-like protein 3 (ANGPTL3) inhibitor

First line therapy for primary and secondary ASCVD prevention

Statins (HMG-CoA Reductase inhibitors)

• Effects on morbidity and mortality

Primary ASCVD Prevention

Preventing first event

Secondary ASCVD Prevention

Already had an event, preventing future ones

Pleiotropic Effects

Effects other than what the drug was developed for

Pleiotropic effects of statins

• Anti-inflammatory

• Antioxidative

• Help to stabilize atherosclerotic plaques

High-intensity statins

Daily dose lowers LDL by ≥ 50% on average

• Atorvastatin 40-80 mg

• Rosuvastatin 20-40 mg

Moderate-intensity statins

Daily dose lowers LDL by 30%-49% on average

• Atorvastatin 10-20 mg

• Rosuvastatin 5-10 mg

• Simvastatin 20-40 mg

• Pravastatin 40-80 mg

• Lovastatin 40-80 mg

• Fluvastatin XL 80 mg

• Fluvastatin 40 mg BID

• Pitavastatin 1-4 mg

Low intensity statins

Daily dose lowers LDL by < 30% on average

• Simvastatin 10 mg

• Pravastatin 10-20 mg

• Lovastatin 20 mg

• Fluvastatin 20-40 mg

Statin Benefit Group 1

Clinical atherosclerotic cardiovascular disease (already had an event), ≥ 18 years of age

Statin Benefit Group 2

Primary elevations of LDL-C ≥ 190 mg/dL, 20-75 years of age

Statin Benefit Group 3

Diabetes, 40-75 years of age, without ASCVD, and with LDL-C 70-189 mg/dL

Statin Benefit Group 4

Estimated 10-year ASCVD risk ≥ 7.5%, 40-75 years of age, without ASCVD or diabetes, and with LDL-C 70-189 mg/dL

Statin Benefit Group 1 Statin Intensity

Very High Risk ASCVD

• High intensity statin

Not Very High Risk ASCVD

• Age <= 75 = High intensity statin

• Age > 75 = Moderate or High intensity statin

Very High Risk of ASCVD

2 or more major events

OR

1 major event and 2 or more high risk conditions

Statin Benefit Group 2 Statin Intensity

High Intensity Statin

Statin Benefit Group 3 Statin Intensity

Moderate intensity statin

If multiple ASCVD risk factors are present, may consider High intensity statin

Statin Benefit Group 4 Statin Intensity

ASCVD Risk 7.5%-<20%

• Moderate intensity statin

ASCVD Risk >= 20%

• High intensity statin

Statin Contraindications

Active Liver Disease

Pregnancy

Breastfeeding

Concurrent use of strong CYP3A4 inhibitors with Simvastatin and Lovastatin

Concurrent use of cyclosporine with pitavastatin

Statin Adverse Effects

Hepatotoxicity

• Rare, causes jaundice

Myalgia

Myopathy

Rhabdomyolysis

• Very rare

Diarrhea

Increased A1C and fasting blood glucose

Cognitive impairment

• Very low risk

What is the ADA recommendation if a statin increases blood glucose in a patient with diabetes?

Statin benefit worth the risk

• If glucose control worsens, don’t stop statin, adjust diabetes treatment

Statin Monitoring

Liver Function Tests (LFTs) at baseline (before starting statin) and clinically indicated thereafter

Creatine kinase (CK) if clinically indicated (signs/symptoms of muscle damage)

Fasting lipid panel (preferred) at baseline, 4-12 weeks after initiation or dose up-titration, then up to 3-12 months thereafter

General statin interactions

Lovastatin, simvastatin, and atorvastatin (lesser extent) are metabolized by CYP3A4

• CYP3A4 inhibitors increase the serum concentration and may lead to adverse effects → dose reductions are required

Use with fibrates or niacin >= 1 g/day increases the risk of adverse skeletal muscle effects

• Absolutely must avoid gemfibrozil

May increase INR if on warfarin → bleeding

Simvastatin drug interactions

Itraconazole, ketoconazole, posaconazole, erythyromycin, clarithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine, danazol

• Contraindicated

Verapamil, diltiazem, dronedarone

• Do not exceed 10 mg daily

Amiodarone, amlodipine, ranolazine, lomitapide

• Do not exceed 20 mg daily

Ticagrelor

• Do not exceed 40 mg daily

Grapefruit juice

• Avoid large quantities (> 1 quart daily)

Lovastatin drug interactions

Itraconazole, ketoconazole, posaconazole, erythyromycin, clarithromycin, HIV protease inhibitors, nefazodone, gemfibrozil, cyclosporine

• Contraindicated

Verapamil, diltiazem, dronedarone, amlodipine, danazol

• Do not exceed 20 mg daily

Amiodarone, ticagrelor

• Do not exceed 40 mg daily

Grapefruit juice

• Avoid large quantities (> 1 quart daily)

How should therapeutic effectiveness of a statin be assessed?

Anticipated therapeutic response?

• Yes → Reinforce continued adherence, follow up 3-12 months

• No → Intolerance to statin?

  • Yes → Management of statin intolerance

  • No → Reinforce adherence, follow up 4-12 weeks, anticipated therapeutic response?

    • Yes → Reinforce continued adherence, follow up 3-12 months

    • No → Reinforce adherence, increase statin intensity or consider nonstatin therapy addition, follow up 4-12 weeks and thereafter as indicated

What should you do if muscle symptoms develop in a patient taking a statin?

Discontinue statin until symptoms can be evaluated, consider other conditions that might increase risk for muscle symptoms. If symptoms resolve and no contraindication exists, give patient original or lower dose of the same statin to establish a causal relationship. If causal relationship exists, discontinue statin → try lower dose or different statin → increase dose as tolerated

If after 2 months without a statin, muscle symptoms or elevated CK levels do not resolve completely, consider other causes of muscle symptoms. If persistent muscle symptoms are unrelated to statin therapy, or if the predisposing condition has been treated, resume statin therapy at original dose.

No recommendation regarding the initiation or continuation of statin therapy for:

NYHA class II-IV heart failure

Individuals on maintenance hemodialysis

Example of cholesterol absorption inhibitor

Ezetimibe

Ezetimibe Route of Administration

Oral

Ezetimibe Contraindications

Not many for just ezetimibe, depends on contraindications of other LDL lowering therapy combined with ezetimibe

Adverse Effects of Ezetimibe

• Diarrhea

• Fatigue

• URTIs

• Sinusitis

• Arthralgia

• Limb pain

Monitoring for Ezetimibe

LFTs at baseline and clinically thereafter when used with a statin and/or fenofibrate

Drug Interactions with Ezetimibe

Cyclosporine

• Monitor levels

Gemfibrozil

• Increased risk of myopathy and cholelithiasis (gallstones)

• Avoid use

Bile acid sequestrants

• Take 2 hours before or 4 hours after a BAS

Examples of PCSK9 inhibitors

Alirocumab (mAb)

Evolocumab (mAb)

Inclisiran (siRNA)

PCSK9 Inhibitor Route of Administration

Subcutaneous injection

Adverse Effects of PCSK9 Inhibitors

Alirocumab/Evolocumab

• Injection site reactions, nasopharyngitis, influenza

Inclisiran

• Injection site reactions, arthralgia, bronchitis

Monitoring of PCSK9 inhibitors

Hypersensitivity reactions

Drug Interactions of PCSK9 Inhibitors

None listed in package insert

Example of ATP Citrate Lyase (ACL) Inhibitor

Bempedoic acid

Bempedoic Acid Route of Administration

Oral

Adverse Effects of Bempedoic Acid

Hyperuricemia

• Increased uric acid → gout

Upper respiratory tract infection

Abdominal or back pain

Muscle spasm

Tendon rupture

• (rare)

Monitoring for Bempedoic Acid

Uric acid levels as clinically indicated

Signs/symptoms of tendon rupture

Drug Interactions with Bempedoic Acid

May increase concentrations of:

• Pravastatin (Max 40 mg/day)

• Simvastatin (Max 20 mg/day)

Examples of bile acid sequestrants

Cholestyramine

Colesevelam

Colestipol

Bile Acid Sequestrant Route of Administration

Oral

Contraindications of Bile Acid Sequestrants

Cholestyramine

• Complete biliary obstruction

Colesevelam

• Bowel obstruction, TG > 500 mg/dL, hypertriglyceridemia-induced pancreatitis

Adverse Effects of Bile Acid Sequestrants

Constipation

Abdominal pain

Cramping

Gas

Bloating

Increased triglycerides

Monitoring for Bile Acid Sequestrants

Triglycerides

Drug Interactions witn Bile Acid Sequestrants

Separate administrations of drugs 1-4 hours before or 4-6 hours after taking a BAS

May decrease absorption of warfarin and fat-soluble vitamins

LDL Goal for Statin Benefit Group 1

Very High Risk of ASCVD

• LDL < 55 mg/dL

Not Very High Risk of ASCVD

• LDL < 70 mg/dL

Nonstatin recommendation for Statin Benefit Group 1 not at LDL goal

Very High Risk of ASCVD

1. Ezetimibe and/or PCSK9 mAb

2. Bempedoic acid or inclisiran

Not Very High Risk of ASCVD

1. Ezetimibe

2. Adding or replacing with PCSK9 mAb

3. Bempedoic acid or inclisiran

Important factors when considering ezetimibe vs. PCSK9 mAbs

Ezetimibe

• Oral, less expensive

PCSK9 mAb

• Subcutaneous, much more potent

• If > 25% away from LDL goal, ezetimibe will not be effective enough

LDL Goal for Statin Benefit Group 2

< 100 mg/dL

Nonstatin recommendation for Statin Benefit Group 2 not at LDL goal

1. Ezetimibe and/or PCSK9 mAb

2. Bempedoic acid or inclisiran

3. May consider evinacumab, lomitapide, and/or LDL apheresis for HoFH under care of lipid specialist

LDL Goal for Statin Benefit Groups 3 and 4

Moderate intensity statin therapy

• < 100 mg/dL

  • If not, increase to high intensity statin

High intensity statin therapy

• < 70 mg/dL

• If not, may consider ezetimibe

Hypertriglyceridemia

Triglycerides >= 500 mg/dL

Pharmacological therapeutics for hypertriglyceridemia

Fibric acid derivatives

Niacin

Prescription omega-3 fatty acids

Examples of Fibric Acid Derivatives (Fibrates)

Fenofibrate

Fenofibric Acid

Gemfibrozil

Fibrate Route of Administration

Oral

Contraindications of Fibrates

• Severe liver or kidney disease

• Gallbladder disease

Adverse Effects of Fibrates

• Increased LFTs

• Myopathy

• Abdominal pain

• Dyspepsia

Monitoring for Fibrates

• LFTs

• Renal function

Drug Interactions with Fibrates

Statins

Niacin Route of Administration

Oral

Contraindications of Niacin

• Active liver disease

• Active peptic ulcer disease

• Arterial bleeding

Adverse Effects of Niacin

• Flushing

• Itching

• N/V/D

• Dyspepsia

• Hepatotoxicity

• Hyperglycemia

• Hyperuricemia

Monitoring for Niacin

• LFTs

• Glucose (If diabetes)

• Uric acid (If gout)

  • INR (If warfarin)

Drug Interactions with Niacin

• Monitor with other concurrent hepatotoxic drugs

• Take 4-6 hours after bile acid sequestrants

Why is “flush-free” niacin ineffective for hypertriglyceridemia?

Wrong type of niacin for lowering triglycerides

Examples of Omega-3 Fatty Acids

• Lovaza (EPA/DHA)

• Epanova (EPA/DHA)

• Vascepa (EPA)

Omega-3 Fatty Acid Route of Administration

Oral

Omega-3 Fatty Acid Warnings

Hypersensitivity to fish and/or shellfish → Use with caution

Adverse Effects of Omega-3 Fatty Acids

• Burping

• Dyspepsia

• May prolong bleeding time

• May increase LDL-C

Monitoring of Omega-3 Fatty Acids

LFTs in patients with hepatic impairment

Drug Interactions with Omega-3 Fatty Acids

May increase INR if on warfarin

Heterozygous Familial Hypercholesterolemia (HeFH)

LDL >= 160 for children and >= 190 for adults

Incidence = 1 in 250 people

Homozygous Familial Hypercholesterolemia (HoFH)

LDL >= 400

Incidence = 1 in 1 million people

So much LDL it deposits into xanthomas + lipid rings around eyes

Treatment of Familial Hypercholesterolemia

First Line Treatment

• Statins for both HeFH and HoFH

Additional

• HeFH and HoFH

  • Ezetimibe

  • Alirocumab/Evolocumab

  • LDL apheresis

• HeFH only

  • Inclisiran

  • Bempedoic acid

• HoFH only

  • Lomitapide

  • Evinacumab

Example of Microsomal Triglyceride Transfer Protein (MTP) Inhibitor

Lomitapide

Route of Lomitapide

Oral

Contraindications of Lomitapide

• Pregnancy

  • Teratogenic, need pregnancy test to get this med

• Use with moderate or strong CYP3A4 inhibitors

• Moderate or severe hepatic impairment

• Active liver disease

Adverse Effects of Lomitapide

• GI side effects if taken with a meal

  • Take 2 hours after evening meal

• N/V/D

• Dyspepsia

• Abdominal pain

• Flatulence

• Chest and back pain

• Fatigue

• Weight loss

• Hepatotoxicity

  • Black box warning

  • Patient needs regular LFTs

  • Pharmacy can only dispense after normal LFT

Monitoring for Lomitapide

• LFTs

• Pregnancy test in females of reproductive potential

Drug Interactions with Lomitapide

• CYP3A4 inhibitors

• P-glycoprotein substrates

• Simvastatin (Max 20 mg/day) and lovastatin (Dose reduction required)

• Increases INR if on warfarin

Example of Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitor

Evinacumab

Evinacumab Route of Administration

IV Infusion

Adverse Effects of Evinacumab

• Nasopharyngitis

• Flu-like symptoms

• Dizziness

• Rhinorrhea

• Nausea

Monitoring for Evinacumab

Hypersensitivity reactions

Drug Interactions with Evinacumab

None listed in package insert