Cholesterol Tx Flashcards
Statins are a….
HMG-CoA reductase inhibitors
Statins main effect is on…..
LDL levels in the blood
Statin Examples
Atorvastatin
Fluvastatin
Lovastatin
Pravastatin
Rosuvastatin
Simvastatin
Statin MOA
Inhibits an enzyme in the pathway for intracellular synthesis of cholesterol
Cellular levels of cholesterol become depleted
Cell upregulates LDL receptor
LDL levels in the blood decrease
Primary site of action appears to be hepatic cells liver takes up a bunch of LDL
Statins primary Site of ACtion
Liver - Hepatocytes
Statin Benfits
Clinical benefits of LDL lowering have been demonstrated repeatedly
Similar to HTN control, lipid reduction is NOT a cure for ACVD
The most benefit of statins in….
Greatest absolute benefit occurs in patients with a “statin-indicated condition” due to their high global risk
greater benefits are a reesult of
Greater LDL reductions
Current Strategy of Statin Usage. Why?
Maximize statin dose in everyone who can tolerate it
Trials show that high dose statins are better than low dose statins
Statin effects on other plasma proteins. Are we certain?
HDL may ↑ 5-10% (up to 15% or not at all)
TG ↓ up to 30% (higher baseline TG = greater effect)
Benefits of these effects UNCLEAR
What is the most controversial aspect of statin tx?
One of the MOST controversial aspects of statin therapy is its role in LOW risk patients
Primary prevention
When is benefit of a drug reduced?
If few events are occurring WITHOUT drug, the opportunity for benefit is drastically reduced
NNT in Statin Tx that is acceptable
NNT of <50 to prevent 1 CV event over 5 years is generally accepted as reasonable for statins (threshold for where they think statins are of benefit)
Are the benefits of statins the same for everyone?
For statins, relative benefits seem to be the same in everyone assuming a fixed LDL reduction.
The NNT is often impcated by….
Thus, NNT is generally impacted by the RISK level
The recommended use of statins is based on…
RISK
Why can’t diets/lifestyle be used to reduce LDL?
Diets are terrible at lowering LDL levels
Healthy Lifestyles –> Start way to late –> If you are 60, this is nieve –> Do not have time to change their life as much as a 20 year old
Critical for global CV risk reduction
Limited benefits for LDL specifically
Risk of early onset of dz is reduced when…
Healthy diet/lifestyle throughout life would almost eliminate an individual’s risk (at least for early onset dz)
Is titration needed with statin meds?
NO
High Intesnity Statin Lowers LDL by…. Examples
> than or equal to 50%
Atorvastatin 40/80 mg
Rousuvastatin 20/40
Moderate Intensity Statins Lower LDL by…. Examples
30-49%
Atorvastatin 10mg
Rousuvatstain 10mg
Simvastatin 20-40 mg
Pravastatin 40-80 mg
Lovastatin 40-80 mg
FLuvastatin 40 mg
All rats swim past lakes fast.
Low intensity Stains lower LDL by… Examples
<30%
Simvastatin 10mg
Pravustatin 10-20 mg
Lovastatin 20 mg
Why do all pt’s get high-dose statins?
More intensive LDL reduction is clearly associated with greater protection against ACVD events
Exceptions to high dose strategy?
Intolerance
Drug interactions
Patient preference
What do we do if we don’t reach targets?
Time – wait at least 6-12 weeks to ensure full effect
Adherence - Has Jibby experienced challenges taking it?
Lifestyle – has Jibby implemented lifestyle changes yet?
Statin Time to Effect
6-12 weeks
Chart for Intensifying tx
Study
PCSK9
Evolocumab
Alirocumab
New and expensive
PCSk9 MOA
PCSK is An enzyme that promotes degradation of the LDL receptor on hepatocytes. (antibodies to the enzyme)
Alirocumab and evolucumab are antibodies to PCSK9
Fully “humanized” monoclonal antibodies
Result is increased expression of LDL receptors on hepatocytes and increased clearance of LDL from blood
Are PCSK9 safe to use with statins?
Yes –> Different mechanism
PCSk9 Criteria
40 to 85 years of age
Clinically evident atherosclerotic disease
MI
Ischemic stroke
PAD
LDL 1.8mmol/L or higher (or Non-HDL at least 2.6mmol/L)
Currently taking Atorvastatin equivalent of 20mg/day (why on 20 is b/c most likely could not tolerate the high dose)
Ezetimibe MOA
Inhibits luminal cholesterol absorption in small intestine
↓ cholesterol absorption = ↓ chylomicron formation
↓ chylomicron remnants to the liver = ↓ hepatocyte chol
↑ LDL receptor expression in liver = greater clearance of LDL
LDL reduces LDL by 15% to 20% as monotherapy (weak)
Ezetimibe undergoes….
Despite its local effect, the drug undergoes enterohepatic recirculation
Is ezetimibe used in monotx?
No
Ezetimibe is combined with statins when…..
Statin escalation impossible – tolerability –> Use Atorvo 20 and add ezetimibe can equal high does statin LDL reduction
Statin dose maxed out – LDL still not at goal
Eicosapent Ethyl
Eicosapent Ethyl (n-3 fatty acid) Omega-3 fatty acids
Purified ester of EPA (eicosapentaenoic acid) (fish source) Now in guidelines NOT AN LDL DRUG
Inclisiran
interferes with PCSK9 messenger RNA
Bempedoic Acid
Inhibitor of ATP citrate lyase – reduced cholesterol synthesis
Stain Tolerability Variability
Very Variable
Statin S/e
GI discomfort
Fatigue
Rhabdomyolyisis –> Rare
Muscle effects Rhabdomyolysis (ultimate neg muscle outcome) such inflamed muscles, muscles rupturing and letting go of myoglobin
Diabetes (increased detection) –> VERY LOW –> Increase blood glucose
Cognitive Impairemnt - Low
Myopathy
Muscle Pain
Myalgia
CK < or eqaul to ULN
Myositis
CK > ULN
Rhabdomyolysis
CK > 10 times ULN
CK Tests
ULN
Creatinine Kinase Tests
Upper Limit of Normal
When are CK tests ordered?
Ask about muscle diseases, wasting/frailty may indicate higher risk for statin-myopathy (might consider lowering statin dose)
If the risk for muscle effects is high, consider a baseline CK (i.e., before statin started)
Otherwise, CK levels ONLY ordered if symptoms appear
To ensure muscle sx are from statin?
Ensure it is from the statin
Symptoms resolve when statin d/c
Symptoms recur when statin restarted
Symptoms recur when another statin tried
How to deal with intolerability?
D/c statin for short period, re-challenge after resolution of symptoms
Lower doses / every other day dosing
Lower potency statins (e.g., fluvastatin)
Non-statin drugs
Most likley origin of DI’s for statins
Hepatic Metabolism
All statins undergo the
First Pass effect
All statins are metabolized by…
Liver
Interactions of Statins
3A4 / grapefruit juice
C.I. of Statins
People with muscle disease
Gemfibrozil (fibrates can increase adverse muscular effects)
Dosing of Statins
OD
Which has fewer drug interactions?
Rosuvastatin – fewer drug interactions vs atorva
In renal disease, use this statin?
Atorvostatin
Reduce dose if CrCl <30m/min for ROSUVA —- Atorva does NOT require dose adjustment in renal dysfx
