Lipid Disorders Flashcards
What are some modifiable risk factors for atherosclerosis?
Low HDL-C (<40) High HD-C Hypertriglyceridemia Diabetes Inactivity
What are some non-modifiable risk factors associated with atherosclerosis?
Age
Gender
Family history of CHD
How do you calculate LDL? In what circumstances?
LDL = total cholesterol - (HDL + TG/5)
Have to fast 9-12 hours
Can only use if triglycerides are < 400 mg/dL
What is TG/5?
VLDL
How do you determine an estimate of all atherogenic particles?
Non-HDL = total cholesterol - HDL
If you are not fasting, what can be interpreted?
Only TG and HDL
How often should you check cholesterol levels?
- Every 5 years for those 20+
- For children between 2-8 if positive family history or CV risk factors (MI in 40’s for a parent, elevated BMI)
- Universal 1X screening for those 9-11
What is the optimal total cholesterol level?
< 200 mg/dL
What is the optimal LDL level?
< 100 mg/dL
What is the optimal HDL level?
~ 60mg/dL
What is the optimal TG level?
< 150 mg/dL
What does familial hypercholesterolemia increase the risk of?
It reduces LDL receptors, which increases LDL.
What is the difference between homozygous and heterozygous familial hypercholesterolemia?
HoFH can have CHD by age 20, HeFH by age 40, and normal healthy individuals by 60.
What are xanthomas?
Deposits of lipids under the skin or cornea
What are secondary causes of dyslipidemia?
Diet/lifestyle
drugs
diseases
disorders and altered metabolism
What could thiazide diuretics do to cholesterol levels?
It could elevate LDL or triglycerides.
What could beta-blockers do to cholesterol levels?
They could elevate triglyceride levels
What could oral estrogens do to cholesterol levels?
Elevate triglycerides.
What can progestins or anabolic steroids do to cholesterol?
They can elevate LDL levels
What can bile acid sequestrates do to triglyceride levels?
They can elevate triglyceride levels
What disease states can elevate LDL-C? Elevate triglycerides?
LDL-C: autoimmune disorders, chronic kidney disease, obesity
TG: diabetes, metabolic syndrome, HIV, pregnancy, alcoholism, obesity
What is clinical ASCVD?
Any disease caused by atherosclerosis, such as cerebrovascular disease/accident, transient ischemic attack, CAD, PAD, chronic stable angina, intermittent claudication, heart failure (but only ischemic)
What lifestyle changes can lower the risk of atherosclerosis?
Smoking cessation Alcohol in moderation Healthy body weight Limit saturated fats and cholesterol Consume fish regularly Fruits/veggies intake increase Control HTN/DM
and yes, it works
What activities are beneficial to the health of both CAD patients and general population cohort studies?
Smoking cessation, physical activity, moderate alcohol intake, combined dietary changes.
What does glycemic control do for MI?
It decreases the risk (not really sure what the slide is saying exactly)
What are the changes in the guidelines from the NCEP in 2001 to the ACC/AHA in 2013?
In 2001, the guidelines were to primarily red the LDL levels, with a goal of <100mg/dL. The non-HDL-C was a secondary target.
In 2003, an optional goal was added of <70mg/dL for high-risk patients
In 2013, the ACC and AHA collaborated on guidelines. Specific LDL treatment goals are no longer there, and there is a focus on four high-risk groups most likely to benefit from statins. Only meds proven to reduce ASCVD risk are used.
What is the Framingham risk test?
It is an old measurement used to estimate risk of ASCVD, now replaced by a pooled cohort equation used to estimate 10-yr risk.
Why is there no longer a level of LDL to treat to?
Because the only evidence was from observational trials, rather than randomized controlled trials.
Is it more effective for primary or secondary prevention to lower the LDL level?
Secondary prevention, because their risk is higher. Secondary prevention applies to people who already have clinical ASCVD - a previous event. Primary prevention people have a much lower event rate, even if their LDL level is just as high.
What are the four groups that can benefit from statin use as defined by the ACC/AHA? What intensity of statin should they use?
- Clinical ASCVD (high intensity, or moderate if not a candidate for high)
- LDL > 190 mg/dL (high-intensity statin)
- Diabetes age 40-75 (Moderate intensity statin, or high if 10-yr risk is > 7.5%)
- No diabetes, but have 10-yr ASCVD risk of 7.5% and age 40-75 (moderate to high intensity statin)
What drugs are included with high-intensity?
Atorvastatin 40-80mg
Rosuvastatin 20-40mg
What drugs are included in moderate intensity?
Atorvastatin 10-20mg Rosuvastatin 5-10mg Simvastatin 20-40mg Lovastatin 40mg Pravastatin 40-80mg
When are low-intensity statins recommended by the guidelines?
They aren’t. However, they are used when helping patients titrate up to their full levels. A family care doctor may titrate up, while a cardiologist might just assign a high intensity statin to start out with.
If a patient does not have LDL levels greater than 190 mg/dL, no ASCVD, no diabetes, and their 10-yr risk is less than 7.5% and more than 5%, what should you do?
You should talk to the patient and explain the risks and benefits of a moderate-intensity statin.
What are the benefits to the new pooled cohort risk calculator compared to the Framingham calculations?
The new calculator more adequately represents women and African Americans, and includes stroke endpoints.
What are the drawbacks to the new pooled cohort risk calculator?
There is no evidence supporting its use (based on expert opinions and outdated studies)
May overestimate risk, primarily in primary prevention
What factors does the risk assessment calculator take into account?
HDL, total cholesterol, diabetes, age, gender, race, hypertension treatment, BP, and smoking
What is the effect of the new guidelines in terms of number of patients that are recommended for treatment under it?
They increase the number of those who would be eligible from 43 million to 56 million, mostly in the 60-75 age bracket.
Are there people who should not have statin therapy initiated?
Yes, some high-risk groups of people such as heart failure and hemodialysis patients have not been found to have benefit.
If people do not fall within a statin benefit group, what are some factors to consider?
Family history
Elevated lifetime risk
LDL > 160
Other markers of inflammation (CRP > 2mg/dL, coronary artery calcium)
What are some of the controversies associated with the ACC/AHA guidelines?
- A lot of evidence may be excluded if only RCT’s are used
- People on max statins no longer have goal to work towards
- There is observational data supporting treat to target
- Patients and providers may have less to check and may not support compliance
What other guidelines are out there? How are they different than the ACC/AHA guidelines?
National Lipid Association (NLA) - Focused on numbers to treat to (<100 for LDL)
United States Preventative Services Task Force (USPTF) - recommends low to moderate dose statins.
For primary prevention, what seems to be the 10-year risk percentage that needs to be crossed in order to have clinical value?
at least 10% on the 10-year risk
What is the age cut-off for safety using statins?
<76 years. Not enough data, risk of side effects is higher
What is the similarity throughout all of the guidelines?
all support lifestyle interventions
What is the mechanism for statins?
They inhibit the HmG-CoA reductase from forming L-mevalonate
What are the indications for statins?
Familial hypercholesterolemia
Prevention of ASCVD (primary and secondary)
What benefits do statins have on lipid parameters?
Lower LDL 18-55%
Increase HDL 5-15%
Decrease TG 7-30%
They also may reduce inflammation, improve endothelial function, and reduce thrombus formation
They reduce mortality, MI and stroke in those with CHD
What was the result of the IDEAL trial?
It looked at the absolute risk reduction between a moderate dose of one statin and a high dose of another statin. The results were that there was a reduction in nonfatal MI with the higher dose.
What are of SE’s of statins?
myopathy, increased liver enzymes, new-onset diabetes, memory loss.
Contraindicated in active liver disease
What are the different myopathies? Which is the most dangerous?
myopathy- any muscle symptoms
myalgia - muscle ache or weakness
myositis - muscle ache or weakness with CK elevations
Rhabdomyolysis - dangerous one: muscle ache or weakness with CK elevations > 10x ULN with renal necrosis
What are some risk factors for statin-induced myopathy?
Higher dose Age Alcohol abuse Hypothyroidism Grapefruit juice Female
What are medications that may make myopathy more likely when used with statins?
Vibrates
Macrolide
Azole
Verapamil
What are hydrophilic statins?
Pravastatin and rosuvastatin
“Roses like water, praying holy water.”
Also possibly less penetration, less SE’s
What are the lipophilic statins?
Atorvastatin Simvastatin lovastatin fluvastatin pitavastatin
What enzymes are mainly used by statins?
Mostly 3A4, except for pravastatin, pivastatin, and rosuvastatin.
What statins use 2C9? What drug interferes with this enzyme?
Fluvastatin and rosuvastatin. Warfarin interacts with 2C9.
What kind of combination therapy increases the risk of rhabdomyolysis when looking at vibrates?
Gemfibrozil and a statin have a 15-fold increased risk of rhabdo over fenofibrate and a statin. However, not contraindicated.
What lab parameters have to be in place for monitoring for myopathy?
CK + liver function tests (CK normal range is 20-200). Check if presenting with symptoms.
TSH. Patients with hypothyroidism are at an elevated risk of developing myopathy.
What happens to your medication therapy if you get myopathy?
If the muscle symptoms are tolerable, you may continue or reduce dose, stop and re-start once the symptoms go away (or use a different statin), or stop everything, depending on the CK elevation.
What kinds of strategies are there for reducing risk of myopathies?
Low dose statin, creative dosing intervals, different statin choices, intensify lifestyle. Don’t try Coenzyme Q10.
Which statin does not need renal adjustment?
Atorvastatin. All others need to be really dosed.
Are over enzymes needed periodically while using statins?
No, only at baseline now. Pretty rare for injury to occur to liver.
If you notice confusion or memory loss in statin users, what should you be aware of?
That cognitive SE’s are possible with statin users.
What monitoring is required with statin use?
Fasting lipid profile (4-12 weeks @ first, then every 3-12 months)
CK (creatine kinase) w/ muscle symptoms
Screen for DM
Hepatic ALT levels at baseline only, and during therapy if suggested hepatotoxicity
Which statins do you not have to take at bedtime?
The long-acting ones: atorvastatin and rosuvastatin.
What enzyme does grapefruit juice interact with?
3A4. So avoid atorvastatin, simvastatin, fluvastatin, lovastatin.
Should pregnant or breastfeeding women be on this medication?
No
What is the view of ACC/AHA on combination therapy to improve ASCVD outcomes? NLA?
No evidence, so don’t do it. If they still have LDL > 190, or in patients who are statin intolerant. NLA guidelines recommend combination therapy if atherogenic cholesterol goals are not met on moderate or high intensity statin therapy.
Is there evidence that combination therapy may have a greater effect on the lipid profile/
No clinical evidence, although it may help. Adverse effects increase though.
What SE’s happen with a statin and niacin?
Hepatic enzymes are increased, with a myopathy risk
What SE’s happen with a statin and a fibrate?
Increased myopathy and rhabdo.
AIM-HIGH, ACCORD and HPS2-THRIVE trials were analyzed with the result of what?
That there was no increased benefit from lowering TG’s and increasing HDL’C in terms of reducing the cardiovascular risk. Therefore statin combo therapy with either fibrates or niacin was no longer suggested.
How does niacin or nicotinic acid work?
Mechanism not clear, but reduces TG synthesis, increases breakdown of Apo B which lowers VLDL, IDL, and TG levels. Also inhibits release of free fatty acids from adipose and increases lipoprotein lipase (LPL) activity, which enhances removal of chylomicrons from plasma.
What effects do niacin have?
Lowers TG 20-50%, and elevated HDL 12-35%
Decreases LDL 5-25%
SE’s: hepatotoxicity, flushing, itching. Contraindicated in liver disease, gout, diabetes, and peptic ulcer disease
What does the AIM-HIGH trial conclude about niacin?
That it may actually increase the incidence of ischemic stroke.
What did the CDP trial find on niacin?
It found that niacin may have benefit in mono therapy for MI and stroke.
What did the HPS2-THRIVE trial find about niacin?
That the addition of niacin to a statin did not reduce the risk of major cardiovascular events, but did increase adverse effects.
What is the problem with immediate-release niacin? Sustained-release niacin? Extended release?
IR - Flushing results from IR
SR - Hepatotoxicity results from the sustained release formulation.
ER - Reduced flushing and reduced hepatotoxicity
What monitoring is required for niacin?
What if ALT is >2-3X ULN?
What if bilirubin is >3?
ALT every 8-12 weeks during first 6-12 months, then every 6 months thereafter. Reduce dose is ALT > 2-3X ULN, or if bilirubin is >3
What can you pre-medicate with to reduce the flushing symptoms?
aspirin 325mg 30 minutes before IR niacin. NSAIDS can also help. Can chew an aspirin during flushing to decrease severity
Should this medication be used to lower TG’s?
There are other meds out there, this is last line (after fibrate or omega-3)
What is the mechanism of fibrates?
- Decrease VLDL secretion
- Increase catabolism of TG-rich particles
- Decrease hepatic app C-III production
- Increase lipoprotein lipase-mediated lipolysis
What are fibrates used to treat?
To lower TG’s (20-50%) and increase HDL 5-20%
What are the SE’s of fibrates?
Dyspepsia, gallstones, myopathy
Which fibrate do you dose once daily? Twice daily?
Fenofibrate once daily, depending on formulation
Gemfibrozil twice daily,
What do the FIELD STUDY and the ACCORD trial say about fibrate efficacy?
FIELD STUDY - Reduction in non-fatal MI’s
ACCORD TRIAL - no reduction in cardiovascular events in combo vs statin only. Also, there was a possibility of benefit in subgroup of people who had decreased HDL (<34) and increased triglycerides (over 204)
If the patient is really impaired, what fibrate is better for the patient? What if the pt is also on a statin?
Gemfibrozil is best for renal impairment, unless a statin is also being used. Then fenofibrate is preferred.
What medication interaction is an important for 3A4 enzymatic pathways?
2C9
If your TG’s are above 1,000mg/dL, what is the immediate risk?
Pancreatitis
What is considered severe hypertriglyceridemia?
500-1,000 mg/dL
What mechanism of action does ezetimibe have?
It acts on the NPC1L1 transporter to prevent absorption and dietary and biliary cholesterol. (Interrupts the enterohepatic circulation of biliary FC and chylomicron assembly.
Increases SREBO and up regulates LDL receptors.
What are the benefits of ezetimibe?
10mg daily
Reduces LDL 13-20%, raises HDL 1-3%, reduces TG 1-5%
Alone it has not been able to reduce coronary events
What monitoring is needed for ezetimibe?
Baseline hepatic transaminases (AST, ALT)
Discontinue if persistent ALT elevation > 3x ULN occur
What does the IMPROVE-IT trial say about ezetimibe?
It is the first trial that shows benefit in cardiovascular outcomes, particularly non-fatal
What is the ezetimibe’s place in therapy?
Similar reductions in LDL-c achieved by max statin dose
Well-tolerated
Potential add-on to statin therapy as more data become available from the IMPROVE_IT trial.
1st add-on therapy to lower LDL in high risk patients
How do bile acid seqestrants work?
Interrupts the flow of the bile acids
Reduces recirculation of bile
Increases conversion of cholesterol to bile acid.
Upregulates LDL receptors
What is the counterintuitive thing about BAS?
It lowers LDL and increases HDL, but TG’s may increase.
What are the three types of BAS that are on the market?
Cholestyramine
Colestipol
Colesevelam
SE’s of BAS?
constipation, gas
decreased absorption of other drugs
What BAS has less SE’s?
Colesevelam
At what level of TG’s should you not take BAS?
> 300mg/dL
There was a 19% reduction rate in CHD death or nonfatal myocardial infarction because of what drug?
Cholestyramine
What can colesevelam do?
It can lower plasma glucose and HgA1c levels.
How should you take BAS?
once or twice daily with meal
Increase slowly due to SE’s
When should you use BAS?
High risk ASCVD as add-on therapy
How do omega-3-fatty acids work?
Reduce the rate of VLDL synthesis and TG content: reduces release of FFA, inhibiting FFA synthesis, increasing Apo B degradation, increasing LPL
What does Lovasa contain?
Two ethyl esters: EPA and DHA
At what point should you start therapy of omega-3-fatty acids?
When your TG levels are >500 mg/dL
What SE’s were experienced with omega-3?
eructation (belching), nausea, taste perversion.
If on warfarin, prolonged bleeding times
Is there a benefit to using omega-3fatty acids?
nothing proven for stroke, sudden cardiac death, or other CV events
What is the first line for non-statin add-on?
Ezetimibe
Who should be on non-statin mono therapy?
High CV risk, can’t take statin
Very high triglycerides (fibrates, omega-3)
BAS, gemfibrozil, niacin appear to lower CV events when used alone
How do you get someone to stay on their statin?
Avoid interactions, suggest lower dose, suggest different statin
What summary is presented by the Chronic kidney disease guidelines?
A statin/ezetimibe or statin alone is recommended
If a 19-year-old is not being treated for chronic kidney or dialysis, but has CKD, and diabetes mellitus, what should she get?
Most likely should get a statin
what is the primary goal of hypertriglyceridemia (500-1000)?
To lower TG’s to decrease risk of pancreatitis rather than reducing CV risk.. Use fibrates, omega-3, nicotinic acid to get to <500.
If TG’s are in 200-499 range, what is the goal?
To reduce atherogenic cholesterol (LDL) to lower ASCVD risk using statins.
What can you take for cholesterol if you are pregnant?
Only BAS
If you have familial hypercholesterolemia, what should you take?
- High intensity statin
- High intensity statin + ezitimibe
- three drug combo
- four drug combo plus LDL apheresis
What is a PCSK9 inhibitor?
- Human monoclonal antibodies that inhibit the enzyme PCSK9. This reduces the degradation of the LDL receptor, and lowers the LDL levels in the bloodstream.
- Very effective. Reduces LDL by over 50% from baseline
- cardiovascular morbidity and mortality not yet determined
- Sub Q every 2 weeks
- safety concern: neurocognitive events (too low of cholesterol?
- reduction in all cardiovascular mortality by 50%, but CI may be too wide, too expensive
What are Alirocumab and Evolocumab?
PCSK9 inhibitors
What are PCSK9 inhibitors approved for?
- adjunct to diet for heterozygous familial hypercholesterolemia
- clinical ASCVD who require additional LDL lowering
- Adjunct to other therapies for homozygous familial
