Relationship between LDL-C levels and relative risk for CHD
-data suggests that for every 30mg/dL change in LDL-C, the RR of CHD is changed in proportion by about 30%
All adults of what age should have a fasting lipid screen? What 4 things should it include?
->20 -TGs, total cholesterol, HDL cholesterol. LDL cholesterol (usually calculated)
Evolution of lipid management guidelines
-increasing aggressiveness of cholesterol-lowering therapy and now analyze lipid panel more thoroughly
Primary and secondary goals of lipid therapy
-primary therapeutic target is a reduction in LDL cholesterol to an appropriate level -decreasing TGs and non-HDL (if elevated) or raising HDL (if reduced) are secondary goals
Classification of fasting plasma TG levels
Borderline High: 150-200
Very high 500
Non-HDL cholesterol represents all ______ lipid particles. How is it calculated and what is the target?
-atherogenic: VLDL, VLDL remnant, IDL, LDL, dense LDL -Non-HDL: total cholesterol- HDL -target is 30 mg/dL higher than LDL-C target
Definition of low HDL-C
-<50 in premenopausal women; <40 in men
Therapeutic Lifestyle Changes (TLC) for lipid disorders
-diet management -aerobic exercise -weight loss -avoidance/moderation in alcohol intake
2 main categories of drugs used in the rx of lipid disorders
-reduced LDL-C -treat TG-HDL axis (tend to be inversely related)
3 classes of drugs used to reduce LDL-C
-HMG CoA reductase inhibitors (statins) -Cholesterol absorption inhbitors (CAI; ezetimibe) -Bile acid sequestrants (BAS)
Why target HMG CoA reductase?
-rate limiting step in cholesterol formation
6 HMG CoA Reductase Inhibitors
1. lovastatin (mevacor) 2. Simvastatin (Zocor) 3. Pravastatin (Pravachol) 4. Atorvastatin (Lipitor) 5. Fluvastatin (lescol) 6. Rosuvastatin (crestor)
Statins mechanism of action
-have an appendage that mimics HMG CoA that is recognized as a pseudosubstrate. -binding of the drug inhibits binding of the true substrate -Competitive inhibitor (reversible) but the inhibitors have >> affinity for the enzyme
How does statins cause reduction in LDL-C?
-LDLRs on hepatic cells are regulated by intracellular levels of cholesterol. -so blocking cholesterol synthesis causes an increase in LDLR and uptake from the blood, decreasing LDL levels!! Main mechanism! -HMG CoA Reductase expression is also increased.
The Rule of 6%
-in general, each doubling of statin dose produces approximately a 6% decrease in LDL-C, but biggest decrease in first dose! -ex: atorvastatin 10/80 dose is 37% reduction at 10, 43% at 20, 49% at 40 and 55% at 80.
The more you reduce a patient's LDL, the more you reduce event rate. However, even if LDL is below 50, some will still have risk of recurrent events. What does this tell us?
-LDL is not the only picture; we need to treat beyond LDL reduction -22% reduction per 40 mg/dL lower LDL-C
_______ are the first line therapy for LDL-C reduction
Adverse effects of statins
1. elevated hepatic transaminases 2. muscle-related adverse effects!! most important reason for discontinuation! Myalgias, myopathy, rhabdomyolysis
Myalgia vs myopathy vs rhabdomyolysis
1. myalgia: msucle ache or weakness without CK elevation 2. muscle symptoms with increased CK levels > 10 ULN^2 3. Rhabdomyolysis: muscle sxs with marked CK elevation (>10) and with creatinine elevation (usually with brown urine and urinary myoglobin)
Factors that increase risk of statin-induced myopathy
1. pt characteristics: age, female gender, frailty/low body weight, renal insufficiency, hepatic dysfunction, hypothyroidism, diet (grapefruit juice), polypharmacy 2. statin properties: high systemic exposure, lipophilicity, high bioavailability, limited protein binding, potential for drug-drug interactions metabolized by CYP3A4
When do doctors use cholesterol absorption inhibitors or bile acid sequestrants?
-when statin intolerant pt or need further LDL
The small intestine plays a role in cholesterol balance. Where does the cholesterol come from?
-25% diet -75% biliary ~50% absorbed
Plasma cholesterol levels depend on balance of ______ and _______.
-cholesterol production and intestinal absorption
-cholesterol absorption inhibitor -localizes and acts at the brush border of the small intestine, where it inhibits the absorption of cholesterol by binding to and inhibiting the cholesterol transporter NPC1L1
Why are CAIs such a good idea?
-they not only block uptake, but by doing so, decrease hepatic cholesterol stores which results in upregulation of LDLRs to remove even more from the blood -work especially well with statins which will block the body's response to CAIs to just make more Cholesterol
Efficacy of Ezetimibe
-reduces LDL-C by 18-20% as monotherapy or in combo with a statin -minimal effects on TG or HDL-C -not yet shown to reduce CV events
Primary indication for ezetimibe and adverse effects
-indications: add to statin therapy to achieve LDL-C goal, statin intolerant patients -adverse: elevated transaminases
Bile Acid Sequestrants aka resins mechanism of action
-they are large MW, insoluble anion exchange resins -bind bile acids in intestine to prevent their recycling -causes liver to use more cholesterol to make more bile salts!
3 types of BAS
-cholestyramine -colestipol -colesevelam