Dyslipidemia (Part 2)

Secondary Causes of Hyperlipidemia

Diseases:

• hypothyroidism

• nephrotic syndrome

• obstructive liver disease

• diabetes mellitus

Drugs

• alcohol

• progestins

• beta blockers

• thiazide diuretics

• glucocorticoids

• cyclosporine

Lifestyle Factors to reduce ASCVD risk

• adhering to a heart healthy diet

  • DASH diet and low in saturated and trans fats

• regular exercise habits

• avoid tobacco products

• maintenance of a healthy weight

• limit alcohol use

*similar to HTN control

LDL-lowering drugs

• statins (first-line)

• ezetimibe (2nd-line)

• PCSK9 inhibitors (3rd-line)

• bempedoic acid (statin-intolerant)

• evinacumab

Triglyceride-lowering drugs

• fibrates

• icosapent ethyl

• niacine

• olezarsen

Cautions/Contraindications of Statins

absolutely avoid: liver disease, pregnancy and lactation

relative caution:

• renal disease

• hx of liver disease

• niacin

• gemfibrozil (fibrate)

• cyclosporine

• erythromycin

Ezetemibe LDL-C % lowering

20-27% (with statin)

15-20% by itself

Bempedoic Acid LDL-C % Lowering

20%

PCSK9 inhibitor LDL-C % Lowering

50-55%

injection

Inclisiran LDL-C % lowering

50%

siRNA interfering molecule

LDL-C goal for high risk, ASCVD (secondary prevention)

< 55mg/dL

> 50% reduction

LDL-C goal for not high risk, ASCVD (secondary prevention)

< 70 mg/dL

> 50% reduction

LDL-C goal for No ASCVD, no diabetes

Prevent score < 10 = <100 mg/dL

• low (0-3) = lifestyle mods

• borderline (3-5) = lifestyle + potential moderate-intensity statin

  • 30% reduction

• intermediate (5-<10) = lifestyle + moderate to high-intensity statin

  • 30-50% reduction

Prevent Score > 10 = < 70 mg/dL

• high (>10) = lifestyle + high-intensity statin

  • 50% reduction

LDL-C goal for NO ASCVD + diabetes

With ASCVD risk-factors: high-intensity statin, < 70 mg/dL

• 50% reduction

WITHOUT ASCVD risk-factors: moderate-intensity statin, < 100 mg/dL

• 30% reduction

LDL-C goal for NO ASCVD, LDL-C > 190 mg/dL

• high-intensity statin (trx like ASCVD)

• < 100 mg/dl

  • 50% reduction

Familial Hypercholesterolemia (FH)

• marked by elevated levels of LDL-C

• suspect in pts with elevated total serum cholesterol > 300 mg/dL or LDL >/= 190 mg/dL

• avoid using PREVENT 10 yr risk scores in pts with FH (risk is already dramatically increased)

• promote genetic testing, variants in: LDLR, ApoB, PCSK9

High Intensity Statins (>/= 50% reduction of LDL-C)

Atorvastatin 40-80mg

Rosuvastatin 20-40 mg

Moderate Intensity Statins (30-49% risk reduction)

Lower atorvastatin dosage (10-20mg)

Lower rosuvastatin dosage (5-10 mg)

simvastatin 20-40mg

pravastatin 40mg

lovastatin 40 mg

Low-intensity statin

simvastatin 10 mg

pravastatin 10-20 mg

lovastatin 20mg

Statin Drug Interactions

• Warfarin: increased INR

• Bile acid resins: decreases absorption

• Cyclosporine: increased risk of rhabdo

• erythromycin: increased risk of rhabdo (also CYP3A4 inhibitor)

• gemfibrozil: increased risk with rhabdo

• nacin: increased risk of myopathy or rhabdo

• CYP3A4 inhibitors: increased risk of myopathy and rhabdomyolysis

  • -azole antifungals

  • macrolide antibiotics

  • verapamil, diltiazem

• FOOD: red yeast rice and monascus yeast (inhibits HMG coA reductase)

CYP3A4 Subtrate Statins

Simvastatin

Atorvastatin

Lovastatin

What medications should you use instead of CYP3A4 substrate statins

• rosuvastatin

• pravastatin

• fluvastatin

hydrophilic statins

• rosuvastatin

• pravastatin

less muscle pain with hydrophilic statins

Best statins to lower TGs TOO

1. rosuvastin (best): 21-43% TG reduction

2. atorvastatin: 25% TG reduction

3. simvastatin/pravastatin: 10-15% TG reduction

4. fluvastatin/lovastatin (POOR): minimal %

How to manage statin intolerance

• d/c statin

• d/c then rechallenge at lower dose/ diff statin

  • discontinue, then rechallenge after a 2-week washout

• switch therapy to hydrophilic statin or non-CYP3A4 substrate

  • hydrophillic: rosuvastatin, pravastatin

  • CYP3A4: simvastatin, atorvastatin, lovastatin

• alternate day statin dosing

SLCO1B1

• gene that encodes for OATP1B1 (transporter) in liver cells

• OATP1B1 transports statins into liver → need to enter heaptocytes to inhibit HMG-CoA reductase

• dysfunctional SLCO1B1/OATP1B1 = less statin can be taken up, more systemic exposure = increased statin-associated muscle sx (statin toxicity!)

Statins most affected by an SLCO1B1 variant

SPAR40

• simvastatin

• pitavastatin

• atorvastatin

• rosuvastatin (40 mg - high doses)

PCSK9 inhibitor drugs

Repatha = evolocumab

Praluent = alirocumab

Inclisiran

small interfering RNA (siRNA) that inhibits proprotein convertase, specifically inhibiting translation of the protein PCSK9

same indications as PCSK9 inhibitors

Bempedoic Acid

• ATP citrate lysase inhibitor in the cholesterol-synthesis pathway

• prodrug → converted to an active drug in the liver (not muscles) so no s/e of muscle pain

• decreased cholesterol synthesis and lowers LDL-C via upregulation of LDL receptors

• not as powerful as statin

ANGPTL3 Inhibitor

Evinacumab

• prevents inhibition of LPL and endothelial lipase

• results in creased lipid metabolism

• used for FH

• injection med: nasopharyngitis, GI effects, flu-like sx, injection rxn

Microsomal TG Transfer protein Inhibitor

Lopitapide

• reduces concentrations of all apoB-containing lipoproteins (including VLDL, LDL, chylomicrons)

• used ONLY for FH

• large LDL-C reduction (>50%)

• used as add-on for max statin, ezetimibe, PCSK9 inhibitor

• CYP3A4 inhibitor

• follow low-fat diet to reduce steatorrhea

• must regularly monitor LFTs

Bile Acid Resins

• binds bile salts in GI tract

• up-regulation of LDL receptors

When do you avoid bile acid resins

TG > 500 (absolute)

TG > 200 (relative)

causes constipation

avoid in pregnancy and lactation

Dietary fiber

insoluble: lignins, cellulose

soluble: oats, psyllium, pectin, guar gum

*small reduction of LDL, causes GI distress

Insoluble fiber

moves bulk thru the intestines

• promotes regular bowl movement

• removes toxic wastes

controls and balances the pH (acidity) in the intestines

soluble fiber

binds with fatty acids

prolongs stomach emptying time

• regulates blood sugar for people with diabetes

lowers total and LDL cholesterol

Medications for Hypertriglyceridemia

• olezarsen = for TG levels > 1000 mg/dL

• icosapent ethyl = for TG levels > 150-499 mg/dL

• fibrates = for TG 500-999 or > 1000 mg/dL

Olezarsen

reduces serum apoC-III protein, increasing clearance of triglycerides and very low-density lipoproteins

• common to see antibody development

Fibrates for TG lowering

• AVOID gemfibrozil

• fenofibrates

  • decreased hepatic VLDL production

  • increased lipoprotein lipase activity

  • increased biliary cholesterol excretion

Statin + fibrate

no benefits! avoid due to increased risk for abnormal transaminase levels, myositis, and rhabdomyolysis

Niacin

no benefit to niacin + statin

s/e = flushing, insulin resistance, hepatotoxicity