Pathophysiology:

lipid-production

Dyslipidemia Causes:

lipid-causes

Classification of Cholesterol and Triglyceride levels:

classify-lipid

Approach to Treatment:

  • Nonpharmacological interventions
    • Weight reduction if BMI ≥ 25 kg/m2
    • Diet
      • Vegetables, fruits, whole grains, legumes, nuts
      • Consume fish, oily fish at least twice per week
      • At least 50% of grain intake should be whole grains (modest LDL reduction, satiety)
      • Limit intake of saturated fat to <7% of total, trans fat <1% of total, cholesterol
      • Choose lean meat (limit red meat) and vegetable alternatives
      • Select fat-free, 1% fat and low fat dairy products
      • Minimize partially hydrogenated fats
    • Exercise: 40 minutes of aerobic activity 3-4 days per week , moderate-vigorous intensity
    • Alcohol: men ≤ 2 drinks, women ≤ 1 drink per day
      • Increases HDL and TRG
    • Tobacco Cessation
    • Limit/Eliminate added sugars including those from beverages
      • Added sources of sucrose and fructose can significantly impact triglycerides

2013 ACC/AHA Guideline:

acc-aha-pathway

Treatment Peals:

— ACC/AHA —

Risk groups

1. Individuals with ASCVD

  • ASCVD = history of acute coronary syndromes, MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease of atherosclerotic origin
  1. Individuals with LDL > 190
  2. Diabetes aged 40-75 years with LDL 70-189
  3. Individuals aged 40-75 without ASCVD or diabetes with LDL 70-189 and 10 year ASCVD risk >7.5%

2. Additional markers of increased ASCVD risk

  • Apply to patients with risk score 5-7.4% who do not qualify for the 4 ACC/AHA risk groups
    1. Ldl > 160 mg/dl
    2. Family history premature ascvd
    3. CAC score > 300 Agatston units or 75th percentile
    4. Hs-CRP> 2 mg/L
    5. Ankle-brachial index <0.9
    6. High lifetime risk ages 20-59

Primary reason for not being a statin candidate is intolerance (myalgias).

  1. Consider alternative dosing (tiw, weekly)
  2. Switch to a different statin
  3. Check vitamin d level and replace as necessary
  4. Consider coenzyme q 10 trial (100-200 mg daily) for 2-4 weeks and restart statin.

Ldl levels

Goals of Treatment:

  1. Prevent lipid complications
  2. Familial: LDL 50% reduction in both levels
  3. If triglycerides >500 mg/dl (1000 mg/dl), becomes primary goal until
  4. Identify and manage other cardiovascular risk factors (obesity, tobacco use, DM, etc.)
  5. ACC/AHA: reduce LDL by 40-50%

Initiating Statin Therapy in Pt w/o ASCVD:

acc-aha-pathway-ii

Monitoring:

  1. Adverse effects of lipids
  2. Symptoms: HA, chest pain, SOB, nausea
  3. Medication adverse effects (see table above) and nonadherence

lipid-monitoring

4. Lab monitoring

  1. Changes in treatment-12 weeks
  2. Stable-12 months

Statin Intensity:

statin-intensity

Medications:

Lipid-Lowering Drug MOA Effects Adverse Effects Monitoring Comments
Fibric Acid Derivatives

Fenofibrate

Fenofibric acid (the active metabolite) activates perioxisome proliferator activated receptor alpha (PPARalpha). Increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of an inhibitor of lipoprotein lipase activity, apoprotein C-III. LDL: -31 to+45%

HDL +9-23%

TG: -23-54%

Non HDL: -5-19%

*LDL may increase if high TG

·         GI upset

·         Gallstones

·         Myopathy

·         Non-CHD death

·         Lipid panel

·         Liver function test

·         Renal function

·         CBC

·         Contraindication:

-CKD

-Severe hepatic disease

-Drug interactions (Statin)

·         discontinue therapy if LFT levels remain >3 times normal limits.

Gemfibrozil inhibition of peripheral lipolysis; reduced hepatic extraction of free fatty acids, which reduces hepatic triglyceride production; inhibition of synthesis and increased clearance of VLDL carrier, apolipoprotein B, which also reduces VLDL production LDL: -30 to +30%

HDL +10-30%

TG: -20-60%

Total Chol: -2-16%

·         Abdominal pain

·         GI upset

·         Rhabdomyolysis

·         Liver function test ·         Contraindications:

-active liver disease

-gallbladder disease

-pregnancy & lactation

Lipid-Lowering Drug MOA Effects Adverse Effects Monitoring Comments
Bile Acid Sequestrants

Cholestyramine

forms a nonabsorbable complex with bile acids in the intestine, releasing chloride ions in the process; inhibits enterohepatic reuptake of intestinal bile salts and thereby increases the fecal loss of bile salt-bound low density lipoprotein cholesterol LDL: -15-30%

HDL +3-5%

TG: May increase in pts with elevated TG

Non-HDL: -4-16%

·         GI upset

·         Constipation

·         Flatulence

·         N/V

·         Lipid panel ·         Contraindication:

-Dysbeta-lipoproteinemia

-TG >400 (caution if >200)

-complete biliary obstruction

Colesevelam LDL: -15-18%

HDL +3-5%

TG: May increase in pts with elevated TG

Total Chol: -70-10%

Colestipol LDL: -15-30%

HDL +3-5%

TG: May increase in pts with elevated TG

Total Chol: -10-25%

Statins

In order of potency

Rosuvastatin

Atorvastatin

Simvastatin, lovastatin, pravastatin, fluvastatin

Competitive HMG CoA reductase inhibitors (block the rate limiting in cholesterol biosynthesis. LDL: -30-63%

HDL: +5% (rosuvastatin has largest HDL raising abilities)

TG: -20-40%

Non-hdl: -15-51%

·         Hepatic dysfunction – increased liver enzymes

·         Arthralgia and myalgia

·         UTI

·         Diarrhea

·         Nasopharyngitis

·         Extreme pain

·         Rhabdomyolysis

·         Tendon rupture

·         Baseline serum creatine kinase, aminotransferase levels, AST/ALT,

·         Lipid panel annually if indicated, 3 months after starting

In patients with decreased RF monitor serum creatine kinase more closely

·         Active liver disease

·         Unexplained persistent serum transaminase elevation (3x upper limit of normal) dc

·         Pregnant women and nursing mothers (category X, also want them to stop prior to conception)

·         Drug interactions most to least (A, L, S, F, R, P)

·         Lipophilic: A, L, S, F

·         Hydrophilic: R, P

Lipid-Lowering Drug MOA Effects Adverse Effects Monitoring Comments
Niacin B-complex vitamin, exact MOA unknown. May reduce esterification of hepatic TG’s, decrease release of free fatty acids LDL : -8-9%

HDL: +20%

TG : -23%

Non-HDL: -8-23%

·         Flushing (can be minimized by taking ASA or ibuprofen 1 hour prior)

·         N/V

·         Hepatotoxicity

·         Rhabdomyolysis

·         Lipid panel periodically

·         Baseline liver function, then every 6-12 wks for 1st year, then q6months

·         Blood glucose (esp if diabetic)

·         Phosphorus levels (in those at risk of hypophosphatemia)

·         PT time in pt’s with hx of jaundice

·         Muscle pain

·         Serum creatine phosphokinase and K+

·         Active liver disease or elevated hepatic transaminases

·         Active peptic ulcer

·         Arterial bleeding

Cholesterol Absorption Inhibitors

Ezetimibe

Ezetimibe localizes and appears to act at the brush border of the SI and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. LDL: -18%

HDL +1-2%

TG: -7-9%

Non HDL: -14-19%

·         Diarrhea

·         Increased AST/ALT

·         Lipid panel

·         Serum creatinine kinase

·         No dosage adjustment is necessary with renal or mild hepatic insufficiency

·         Contraindication: -hypersensitivity to drug

·         reduction of hepatic cholesterol stores and an increase in the clearance of cholesterol from the bloodà complementary to that of the HMG-CoA reductase inhibitors

Omega 3 fatty acids unknown LDL : -6%- +25%

HDL: -5%- +14%

TG : -19-44%

Non-HDL: -5- 14%

·         Fishy taste

·         Bleeding

·         Tolerability

·         Signs of bleeding

·         Consider freezer storage for tolerability
Mipomersen Injectable inhibitor of apolipoprotein b synthesis LDL: additional 25% with max lipid lowering therapies ·         Erythema

·         Injection site edema

·         Nausea

·         Hepatic steatosis

·         LFT elevation

·         Scr

·         LFTs

·         Lipid panel

·         Homozygous familial hypercholesterolemia

·         Uncontrolled hypercholesterolemia on other therapies

·         Injectable

·         Contraindicated in severe renal/hepatic impairment

Lomitapide Oral inhibitor of microsomal triglyceride transfer protein LDL: additional 50% with max lipid lowering therapies and apheresis ·         Diarrhea

·         Vomiting

·         Abdominal pain

·         Hepatic steatosis

·         Fatigue

·         Chest pain

·         Scr

·         LFTs

·         Lipid panel

·         Avoid grapefruit

·         Max 1 alcoholic drink per day

·         Homozygous familial hypercholesterolemia

·         Give with vitamin e, ala, pea, dhea supplement

·         Adjust dose in renal/hepatic impairment

·         Adjust dose/avoid use with CYP3a4 inhibitors

Alirocumab monoclonal antibody that inhibits the binding of Proprotein Convertase Subtilisin Kexin Type 9 (PCSK9) to low-density lipoprotein receptors (LDLRs) on hepatocytes, thus reducing degradation of the LDLR. Increased LDLRs are then available to clear LDL-C from circulation and lower LDL-C levels 36-56% LDL reduction ·         Hypersensitivity reactions

·         Injection site reaction

·         Influenza

·         Nasopharyngitis

·         LDL levels

·         Injection site

·         ASCVD, adjunct to statin therapy

·         Familial hypercholesterolemia

·         No adjustments for renal/hepatic function

Evolocumab Evolocumab binds to and prevents circulating Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) from binding to the LDL receptor (LDLR) on liver cells, thereby preventing PCSK9-mediated degradation. Reductions in serum LDL-C are associated with increased liver LDLR levels Approximately 61% LDL reduction ·         Hypersensitivity reactions

·         Arthralgia

·         URI

·         Nasopharyngitis

·         Injection site reactions

·         LDL levels

·         Injection site

·         Familial hypercholesterolemia

·         Mixed hyperlipidemia, adjunct to statin therapy

·         No adjustments for renal/hepatic function

·         Caution in latex allergy

Trials/Guidelines:

Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 Pt B):2889–2934. *Reference

Goff DC Jr., Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;63(25 PtB):2935–2959. *Reference

Guideline Links

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