Dyslipidemia Flashcards
what is LDL goal for someone with DM?
<100mg/dl or 70mg/dl optional
what is the LDL goal for someone with CAD?
<100mg/dl or 70mg/dl optional
what is the evidence for primarily targeting LDL?
Total cholesterol has been found to be correlated with CHD. Most of total cholesterol is found in LDL. Studies have shown LDL is the most atherogenic lipoprotein. Atherogenesis of LDL is confirmed in genetic disroders in which LDL is high vs other risk factors, i.e. familial hypercholesterolemia
People with familial hypobetalipoprotenemia have documented longevity
Three studies: Framingham heart study, the Multiple Risk Factor Intervention Trial (MRFIT) and LIPID research clinics (LRC) trial . Direct relationship between LDL or TC and new onset CHD.
Populations with LDL levels <100 throughtout life, show near absesne of CHD
people with genetic hypercholesterolemia show premature CHD and atherosclerosis in the absence of other risk factors
12 Clinical trials have shown a reduced incidence of CHD and CHD mortality with LDL lowering (by statins)
what is the evidence fro primarily targeting HDL or triglycerides?
For targeting triglycerides: epidemiological studies found a correlation with TGs and incidence of CHD. However, multivariate analyses didnt find TG to be an independent risk factor for CHD. Other variables are linked such as High LDL, TC, HDL, obesity, DM , smoking etc So if high TG, still at higher risk even cannot be shown to be an independent risk factor. However now, New meta-analyses show some TG rich lipoproteins are atherogenic .
Data from the ACCORD Lipid trial suggest that adding fenofibrate to a low-dose statin does not further reduce the risk of cardiovascular events in people with diabetes, although a post-hoc analysis showed there may be benefit in those with high triglycerides (>200 mg/dL) and low HDL cholesterol (<35 mg/dL). This has been shown in post-hoc analyses of other trials as well.7,8 More data are needed to solidify any benefits of add-on therapy in this situation.
HDL: angiographc trials have shown that ppl with low HDL treated with fluvastatin, they have reduced progression of atherosclrosis (LCAS trial). The Post Coronary Artery Bypasss graft rial showe the satme thing with lovastatin.
Another piece of evidence was the VA-HIT study (see card below) . HDL increase partly repsonsible for dec major CHD events
PROVE-IT trial
Design: Randomized, double-blind, trial
Population: 4000 ACS patient (MI or UA) in 8 countries
I: aggressive lipid lowering vs. moderate therapy
C: Atorvastatin 80mg vs Pravastatin 40mg
O: Death composite ( Major CV events) , stroke, UA, revascularization,
LDL
Results: Atrovastatin 106 –> 62
Pravastatin 106 –> 95
Overall greater reduction in UA, MI, death composite in aggressive therapy vs. moderate therapy. All except stroke (low event rate)
Importance: sparked controversy regarding the equivalence of different statin forumulation and target levels of LDL. How low of LDL is too low? 100? is going low problematic? Aggressive therapy seems to have improved outcomes vs moderate therapy.
REVERSAL 2003
Design: Randomized, double-blind, MC trial
Population: 654 patients
I: aggressive lipid lowering vs. moderate therapy
C: Atorvastatin 80mg vs Pravastatin 40mg
O: % change in atheroma volume (follow up minus basline)
Results: Atrovastatin 150 –> 110
Pravastatin 150 –> 79
** significantly lower proegression rate of atheroma in atorvastatin group. Progression to atheroscleroisis in 2.7% pravastatin and 0.4% progresssion in atorvastatin group
Importance: Showed that you can essentially halt atherosclerosis progression to ~0. Although highest dose of lipitor necessary
HEART PROTECTION STUDY **
Design
P: 20,000 patients with coronary disease, DM or occlussive arterial disease (40-80 years old), with at least of a total cholesterol of 135
excluded: pts with chornic liver dsiease, >1.5 ULN for ALT, sever renal disease or cratinine > 200 mcg/l, evidence of muslce sisease, child bearing ptoential
I /C: simvastatin 40mg vs matched placebo
O: all cause mortaily
first events of nonfatal MI, coronary deat, fatal/non fatal strokes, coronary revascularization
Results: decrease in all the outcomes
Importance: lowering LDL with statin produces substanial reduction of major vascular disease. It has benefit in patients who already have coronary disease but also thos whtough diagonsed coronary disease who have cerebrovascular dsiease, peripherarl artherial disease or diabetes irrespective of what lipid concentrations pts had before treatment was initiated
study included older people and more women so that the study can be extrapolated more widely.
definite reduction in the reduction of ischemic stroke and transient ischemic attacks. Reduced needd for revascularization
*** this study demosnstarted that lowering LDL from below 116 to below 77mg/dl reduces vascular diease risk by ~25%. People who were even below 100mg/dl had benefit (surprising) if they lowered their LDL
ENHANCE 2010
Design: Randomized, double-blind, 24 month trial
Population:720 pts with familial hypercholesterolemia
I:
C: Simvastatin 80mg + Placebo/ Simvastatin 80mg + 10mg ezetemibe
O: Atherosclerosis: change in media intima thickness in caroteid aretieres, bulbs, internal carotid arteries
Results: no difference in mean mediate thicnkess between intervetion group vs no intervention
decerase in LDL greater with ezetemibe
decreases TG and CRP
Safety profile about the same
Importance: ezetimibe has been shown to lower LD 15% but hans not been shown to improve clinical outcomes (atherosclerosis)
ppl had assumed that it would improve clinical outcomes because it decreases LDL but not the case in this trial.
JUPITER
Design:
Population: 17,800 patients with LDL < 130 and CRP > 2mg/dl
I:
C: Rosuvastatin 20mg vs placebo
O: combined MI, Stroke, arterial revascularization, hopsitalization for UA, or death from CV cause
Results: LDL decrease 50% vs placebo
dec CRP by 37% vs placeboy
decrease in MI, stroke , revasculariazation, etc for rosuvastatin vs placebo
Importance: Healthy people with low LDL but high CRB can have decreased risk of CV events
CRP contributes to CV disease
Controversial: One pointed out that JUPITER did not tease out the real importance of CRP levels, or whether lowering those levels is useful. Because of its design, it could not (and did not) tell us whether the beneficial outcome is specific to Crestor, or is a class effect of all statins (which seems very likely). It did not tell us whether reducing CRP levels is itself beneficial, or even whether using CRP as a screening tool is actually helpful.
VA-HIT 2001
Design: MC, Randomized , DB, placebo controlled trial
Population: 2000 men with history of CHD and low HLD (mean 32)
I: Fibrate vs placebo
C: Gembfibrozil 1200mg QD or Placebo
O: Lipid levels at baseline and @ 18 months
incidence of CHD death
incidence of non-fatal MI
Results: inverse relationship for HDL and incidence of CHD events ( inc HDL 5mg/dl = dec 11 % CHD events)
TG and LDL levels did not predict CHD events incidence.
Importance: It’s the first lipid intervention trial to show that raising HDL-C concentrations in persons with established CHD and both a low HDL-C and a low LDL-C level will significantly reduce the incidence of major coronary events. it showed that it can be independent of LDL levels and TG levels.
what is the evidence for each for heart attacks and strokes?
HMG COA reductase inhibitors : do dec MI risk inc first heart attacks in ppl without HLD or heart disease (crestor 20) used in studies
fibrates Only statins shown to reduce risk of stroke.. all the others not
niacin when given with simvastatin vs simvastatin, no change in cardiovascular events. So questionalbe. In fact slight increase in ischemic stroke (AIM-HIGH trial) In COronary drug project study showed decrease in stroke risk .
BABRs
ezetemibe. Reduce LDL but no reduction in clinical outcomes
OMEG 3 lowers TG but no evidence with CHD
waht non medication factors increase the risk for myopathy?
renal impairment (acute or chronic renal failure)
hypothyroidism
age >65
-obstructive liver disease
discuss use of statins in patients with muscle symptoms (dose limitations, precautions?)
if patients have muscle symptoms they need to be seen immediately and order a CPK
discuss use of statins in patients with Liver/ALT elvation (fatty liver) (dose limitations, precautions?)
Contraindicated if active liver disease
Need to look at AST and ALT levels and stop medications if they rise >3 ULN
-if patient has baseline elevated liver enzymes due to fatty liver or hepatic steatosis, can still use statins. Studies showed no significant difference in increase in liver enzyme elevation. Just have to monitor patients for symptoms of liver damage PMID 15131789
ok to use in nonalcoholic fatty liver or chronic liver disease
-avoid in patients with acute liver failure or decompensated liver cihrrosis (evidence level C (expert opinion) PMID: 16581333
-pravastatin and pitivastatin and crestor not sig metabolism by cyp450 enzymes
discuss use of statins in patients with elevated CPK (dose limitations, precautions?)
If a patient has symptoms of muscle damage like soreness, pain etc. get a CK level. If level is >10 x upper limit of normal, DC the statin. IF patient previously had rhabdomyolysis do not retry a statin
