Dyslipidemia



Dyslipidemia | |

Signs and Symptoms

- can get ( TC and LDL and/or ( HDL and/or ( TG

Pathophysiology

- abnormalities in total cholesterol and triglycerides have been shown to contribute to CAD and pancreatitis (THOUGH HIGH TGs CONTRIBUTE TO CAD IN DM AND CRD)

- ETIOLOGY: PRIMARY (GENETIC) OR SECONDARY

Cholesterol

- essential component for formation of bile acids, cell membranes, steroid hormones

- endogenous (liver and intestine) and exogenous (20-40% of serum cholesterol – diet) synthesis

- biosynthesis (modulated by HMG CoA reductase) ( between midnight and 3 a.m.

- target TC < 5.2 mmol/L

Lipoproteins

- cholesterol and triglycerides are water-insoluble; transported through blood in the form of lipoproteins

- 5 classes: chylomicron, VLDL, IDL, LDL, HDL

Low-density lipoprotein (LDL)-cholesterol

- 60 – 70 % of TC (BAD cholesterol)

- transport cholesterol from liver ( peripheral tissues

High-density lipoprotein (HDL)-cholesterol

- 20 – 30 % of TC (GOOD cholesterol)

- transport cholesterol from tissues ( liver for removal

- for every 0.3 mmol/L ( in HDL, risk of CHD ( by 2-3%

- target HDL > 0.9 mmol/L

Triglycerides (VLDL-cholesterol)

- 10 – 15 % of TC

- to avoid post-prandial ( in TG, pts should fast for 12-15 hrs before lipoprotein analysis

- target TG < 2.3 mmol/L

Lipid Triad – highest risk for CHD

1. TG > 2.3

2. TC/HDL ratio > 5

3. LDL/HDL ratio > 5

Pathogenesis of Acute Ischemic Syndromes

1. Plaque rupture and thrombosis

- 10-20% of all coronary artery lesions are unstable plaques (vs. large fibrous plaques), which are responsible for up to 90% of all acute ischemic events

2. Coronary endothelial dysfunction

- significant role in atherosclerosis, coronary vasoconstriction, acute ischemic events

3. Oxidation of LDL within vessel wall

- critical role in progression of atherosclerosis and endothelial dysfunction

Diagnosis

Routine Screening

- fasting lipid profile (TC, HDL, TG, calculated LDL levels)

- men > 40 ; women > 50

- pts with ( 2 RF; clinical CAD or DM or family hx

- symptomatic pts

Physical Examination

- evidence of cholesterol disorders – cutaneous eruptions, tendon xanthomas, arcus cornealis

- evidence of atherosclerosis – abdominal bruits, carotid bruits, diminished peripheral pulses, ankle-brachial index < 0.9

Risk Factors

-FAMILY HX OF DYSLIPIDEMIA OR SECONDARY CAUSES (BELOW)

-HIGH LDL: HYPOTHYROID, OBSTRUCTIVE LIVER DISEASE, NEPHROTIC SYNDROME

-HIGH TG: DM, PREGNANCY, OBESITY

-LOW HDL: OBESITY, MALNUTRITION

Risk Stratification

- Framingham Stratification = directs tx and targets

- pts with clinical CHD or DM are automatically very high risk

- do not apply to pts with extreme or unusual RF (i.e. familial hypercholesterolemia or hypoalphlipoproteinemia)

Diseases Causing Dyslipidemia

1. Endocrine: diabetes, hypothyroid

2. Renal dysfunction: uremia, nephritic syndrome

3. Hepatic dysfunction: 1( biliary cirrhosis, acute hepatitis

4. Immunologic: systemic lupus erythema (SLE)

Drugs Causing Dyslipidemia

-HIGH LDL: PROGESTINS, GLUCOCORTICOIDS, HIGH-DOSE THIAZIDES

-HIGH TG: ESTROGENS, GLUCOCORTICOIDS, PROTEASE INHIBITORS, BARS, EXCESSIVE ETOH

-LOW HDL: PROGESTINS

Target Lipid Values by Level of Risk

| |Target Values |

|Risk Level |LDL (mmol/L) |TC (mmol/L) |TG (mmol/L) |

|Very hightx immediately |< 2.5 |< 4 |< 2.0 |

|(>30%) | | | |

|Hightx immediately |< 3.0 |< 5 |< 2.0 |

|(20-30%) | | | |

|Moderatelifestyle x 3 mos|< 4.0 |< 6 |< 2.0 |

|(10-20%) | | | |

|Lowlifestyle x 6 mos |< 5.0 |< 7 |< 3.0 |

|( PRO IN DECREASING RECURRENT MI)

- ATOR, SIM, PRA BEST STUDIED

MOA

- inhibit enzyme responsible for cholesterol synthesis in liver

- ( cholesterol synthesis/intracellular stores

- ( LDL receptors

- ( removal of LDL from plasma

Onset = max effect ~ 2 – 3 weeks after starting tx

Pharmacokinetics

- lovastatin, simvastatin – prodrugs, require liver hydrolysis

- atorvastatin, lovastatin, simvastatin – lipophilic (BBB)

- pravastatin – least protein bound; metabolized by multiple pathways (not all 3A4) (( DI)

Dosing

ALL QD (ATOR, ROSU ANYTIME; OTHERS QPM)

- fluvastatin, lovastatin BID at ( doses

Side Effects (ALL RARE)

- Hepatic (( LFT’s) (< 1 %)

- Myalgia (INCREASED CK) (< 1 %)

- GI interolerance (cramps, nausea, heartburn)

Contraindications

- pregnancy, breastfeeding

- active liver disease

Drug Interactions

-ATOR AND SIM METABOLIZED BY 3A4 (AVOID GRAPEFRUIT); ROSU BY 2C9 (LIKE WARFARIN); PRA BEST TO AVOID DIs (ESP IF ON PROTEASE INHIBITORS OR CYCLOSPORINE)

Monitor

- LFT’s (baseline and 3 THEN 6 THEN 12 MONTHS; THEN QYR)

- muscle function (CK at first site of pain)

- INR, digoxin levels (if warfarin/digoxin used)

Fibrates

Efficacy

- BEST FOR HIGH TG; ALSO FOR LOW HDL

MOA

- unclear mechanism

- ( lipoprotein lipase activity ( ( TG

- ( cholesterol synthesis and ( LDL catabolism

Pharmacokinetics

- well-absorbed

- metabolized by 3A4; excreted renally (( in renal failure)

Dosing

- adjust dose if renal impairment

- BID

Side Effects (RARE): INCREASED LFTs/SrCr; MYALGIA

Contraindications

- children, pregnant/lactating women

- severe renal failure

Drug Interactions

- warfarin, oral hypoglycemics (sulfonylureas) – protein binding displacement

- statins (( myalgia)

- 3A4 inhibitors

Resins

Efficacy

- ADD-ON TO STATIN FOR HIGH LDL

MOA

- form insoluble complex with bile in intestine preventing resorption of bile acids

- ( fecal excretion of bile acids

- ( LDL receptors and catabolism

Dosing

- O-TID

- take 30-60 mins before meals mixed with liquid or soft food

Side Effects

- GI S/E’s (constipation, flatulence, bloating, dyspepsia)

- vit A, D, E, K deficiency

- possibly ( TG

- no systemic absorption

Drug Interactions

- ( absorption of meds, vitamins

- take meds 1 hr before or 4 hrs after

EZETIMIBE: ROLE AS ABOVE; CHOL ABSORPTION INHIBITOR; ON OWN DECREASES LDL BY 20 %; WELL-TOLERATED; NO SIGNIFICANT DIs; TAKE QD ANYTIME

Niacin

MOA

-DECREASES LDL AND TG; INCREASES HDL

Dosing

- start with small doses; gradually titrate up to 1.5-2g/d in divided doses

- 125mg BID ( 250 mg BID ( 500 mg BID ( 1g BID ( 1.5g BID ( weekly

Side Effects

- PG-mediated effects (flushing, rash, pruritus)

• pretreat with ASA to avoid these S/E

- HMG S/E (hepatic S/E mostly in SR formulations)

- orthostatic hypotension

- glucose intolerance

- hyperuricemia

Drug Interactions

- drugs causing myositis (fibrates, statins)

- insulin, oral hypoglycemics (( effect)

OMEGA-3 FAs: DECREASE TGs; RISK FOR BLEEDING WITH MEDS WHICH DECREASE CLOTTING

Cost/Convenience

Statins – OD; $$$

Fibrates – OD-BID; $$

Resins – BID-QID; $$

Niacin – titrate dose to prevent S/E; %

*** all covered by ODB

Comparative Efficacy: Lipoprotein Analysis

| |Cholesterol |LDL |HDL |TG |

|Statins |( |(( |( |( |

| |(30%) |(40%) |(15%) |(20%) |

|Fibrates |( |(( |(( |((( |

| |(20%) | |(15%) |(45%) |

|Resins |( |( |( |( |

| |(20%) |(20%) | |(5%) |

|Niacin |( |( |(( |(( |

| |(20%) |(20%) |(20%) |(40%) |

** atorvastatin good for ((( TG in diabetics

*** older generation fibrates (gemfibrozil) can ( LDL

**** resins are 2nd line

Drugs of Choice for Different Lipid Abnormalities

|Lipid Profile |Drug of Choice |

|( LDL |

|alone |Statin ( Resin |

|with ( TG |Statin |

|with ( HDL |Combination (Statin + Fibrate or Statin + Niacin) |

|Normal LDL |

|with ( TG |Niacin or fibrate or combination |

|with ( HDL |Niacin or fibrate or combination |

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