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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