Pharm Week 15 (Dyslipidemias)

What is cholesterol?

Fatty substance manufactured in the liver and is carried throughout the body in the bloodstream

Cholesterol (in excess) will eventually go and deposit in ourbody

What are the major lipids in the body?

Cholesterol, triglycerides, phospholipids

How are the major lipids of the body transported?

They are insoluble in the plasma

Transported in circulation as lipoproteins (complex of lipid and specialized proteins, apolipoproteins)

How are lipoproteins classified?

Based on density

- HDL = high density lipoprotein (good cholesterol)

- Non-HDLs = bad cholesterol, VLDL, IDL, LDL

What is total cholesterol the combination of?

Total cholesterol = LDL + HDL + VLDL

How can we calculate VLDL from TGD?

VLDL = TGD / 5

When is the formula to calculate VLDL from TGDs not valid?

When TGDs are over 400 mg/dL

Your patient receives a non-fasting cholesterol panel. Their results are as follows:

Total cholesterol = 234 mg/dL

HDL = 48 mg/dL

TG = 350 mg/dL

What is the value of LDL?

LDL = Total cholesterol - HDL - (TG/5)

LDL = 234 - 48 - (350/5)

LDL = 116 mg/dL

Which laboratory value do we use to examine a patient's cholesterol levels, and make sure their medications are working properly?

LDL levels!!

Total cholesterol can be in the "normal" range, but not be a good number for the patient (because of comorbidities, age, other risk factors, etc.)

What are some risk factors for hypercholesterolemia?

- Diet high in saturated fats and cholesterol

- Family hx of high cholesterol

- Being overweight or obese

- Getting older (we start accumulating fat and cholesterol)

What are some secondary causes of hypercholesterolemia?

- Hypothyroidism (slow metabolism, cannot metabolize fats properly)

- Obstructive liver disease

- Nephrotic syndrome

- Anorexia nervosa

- Drugs

What are some secondary causes of hypertriglyceridemia?

- Obesity

- Diabetes mellitus

- Lipodystrophy

- Glycogen storage disease

- Ileal bypass surgery

- Sepsis

- Pregnany

- Acute hepatitis

- Systemic lupus erythematous

- Multiple myeloma

- Lymphoma

- Drugs

What are some drugs/medications that can cause hypercholesterolemia?

- Progestins

- Protease inhibitors

- Cyclosporine

What are some drugs/medications that can cause hypertriglyceridemia?

- Alcohol

- Estrogen

- Bile acid resins

- Interferons

- Azole antifungals

- Anabolic steroids

What are some drugs/medications that can cause both hypercholesterolemia and hypertriglyceridemia?

- Isotretinoin

- Beta-blockers

- Glucocorticoids

- Thiazide diuretics

- Mirtazapine

- Sirolimus

Why do we care about high cholesterol?

- One of the major risk factors for coronary artery disease, heart attacks and strokes (because it is atherosclerotic)

- Boosts risk of Alzheimer's

What are symptoms of high cholesterol?

Usually does not cause any symptoms

Some patients may not know they have high cholesterol until they develop arterial problems

What are some physical exam findings in individuals with high cholesterol?

- Usually scarce

- Extreme elevation can prevent with xanthomas (fat accumulation on fingers, joints, around eyes)

- Other physical exam findings can be found after the plaque forms and ruptures --> CV problems

What is an evidence-based treatment strategy to reduce risk of atherosclerotic CV disease (ASCVD)?

Lowering LDL cholesterol

What are the primary agents used to treat patients with hypercholesterolemia?

Statins

What LDL concentration do we aim for in our treatment of hypercholesterolemia?

60-70 mg/dL

What is the optimal level of total cholesterol?

<200 mg/dL

What is the optimal level of triglycerides?

<150 mg/dL

What are the main guidelines for treatment of hypercholesterolemia (5)?

- Diet and lifestyle modifications

- Statins

- LDL-C thresholds

- Non-statin add ons

- CAC imaging

What are the 2 major categories for prescribing statins?

- Secondary prevention (pts in who already have clinical ASCVD, like prior MI, stroke)

- Primary prevention (pts who have not had any ASCVD yet, but are at risk of developing)

What are the 3 subgroups of primary prevention statin therapy?

Patients with:

- LDL >= 190 mg/dL

- Diabetes that are between 40-75 y/o and LDL >= 70 mg/dL

- 10 year risk assessment score of >= 7.5%, who are also around 40-75 y/o

What is primary prevention in statin therapy?

Reducing the risk of ASCVD by implementing a statin early

In which patients would you initiate high-intensity statin therapy?

- Primary prevention: those with LDL-C >= 190 mg/dL

- Secondary prevention: those less than 75 y/o

What is the Framingham risk score?

Gender specific criteria for estimation of 10 year risk of cardiovascular disease

Takes into account age, actual cholesterol, BP, and HDL-C

If a patient has a Framingham risk score of <10%, what is their risk of developing ASCVD?

Low risk

If a patient has a Framingham risk score of 10-20%, what is their risk of developing ASCVD?

Moderate risk

If a patient has Framingham risk score of >20%, what is their risk of developing ASCVD?

High risk

What are high-intensity statins?

Achieve 49% or more reduction in LDL levels

- Atorvastatin 40-80 mg

- Rosuvastatin 20-40 mg

What are moderate-intensity statins?

Achieve 30-50% reduction in LDL levels

- Atorvastatin 10-20 mg

- Rosuvastatin 5-10 mg

- Simvastatin 20-40 mg

- Pravastatin 40-80

- Lovastatin 40 mg

- Fluvastatin XL 80 mg

- Pitavastatin 1-4 mg

What are low-intensity statins?

Achieve <30% reduction in LDL levels

- Simvastatin 10 mg

- Pravastatin 10-20 mg

- Lovastatin 20 mg

- Fluvastatin 20-40 mg

What statin do we give to a pt having a heart attack?

Atorvastatin 80 mg bolus

We want to stabilize the plaque causing the MI

What is a potential consequence of high dose statins?

High incidence of side effects

May need to adjust dosage if pt cannot tolerate side effects

What are the different LDL-C lowering meds?

- Statins (HMG CoA reductase inhibitors)

- Ezetimibe

- Bile acid sequestrants

- PCSK9 inhibitors

- PCSK9 synthesis blockers

- Inclisiran and bempedoic acid

What are the different TG lowering meds?

- Fibric acid derivatives

- Omega-3 fatty acids

What is the mechanism of action of statins?

HMG-CoA reductase inhibitors

Will inhibit cholesterol synthesis by inhibiting HMG-CoA reductase (which converts acetyl-CoA to cholesterol, will eliminate major step)

How do statins affect the lipid profile?

- Decrease LDL-C by 21-63%

- Decrease TG by 10-37%

- Increase HDL by 2-16%

Which statins have greater LDL cholesterol reduction?

Atorvastatin and rosuvastatin

Which statins go through the CYP 3A4 metabolic pathway?

- Lovastatin

- Simvastatin

- Atorvastatin

- Rosuvastatin (minor)

Your patient has just begun atorvastatin to control their cholesterol levels. They are on other medications as well. They begin to experience a major reaction. What is this from and what do you do?

Most likely from reaction with one of the other meds that is a 3A4 inhibitor

From here, must determine if they are high risk or moderate risk pt

If high risk: switch to rosuvastatin (may not have major reaction because it has minor effect on pathway)

If moderate risk: switch to a statin that does not go through 3A4 pathway (pravastatin)

What is the recommended dosing and administration of statins?

- Recommended that statins with shorter T1/2 be administered in evening or at bedtime

- Administer statins at time recommended by manufacturer

- Every other day therapy has been suggested (insufficient clinical data)

What is a potential adverse effect of statins in regards to the liver?

Dose-dependent hepatic transaminase elevation

AST/ALT (liver enzymes) can elevate

Uncertain if this elevation leads to hepatotoxicity, these elevations will normalize with dose reduction or discontinuation

In which patients are statins contraindicated?

Those with cholestasis and active liver disease

What should you measure (labwork wise) when starting a patient on statins?

LFTs!!

Should be measured at baseline, 12 weeks, then periodically after to make sure there aren't any elevations

What are statin-associated muscle symptoms (SAMS)?

Potential side effect of statins on the muscles

Includes:

- Myalgia (muscle pain)

- Myositis/myopathy

- Rhabdomyolysis

- Very rare statin-associated autoimmune myopathy

In which patients is myositis/myopathy likely to occur as a side effect of statins?

Those with complex medical conditions or taking multiple medications

Which medications can cause myopathy to occur in pts taking statins?

- Cyclosporine

- FIBRATES!!!!

- Macrolide antibiotics

- Azole antifungals

- Glucocorticoids

- Daptomycin

- Zidovudine

What is the pathology of myalgia?

Muscle ache or weakness without creatine kinase elevation

What is the pathology of myositis?

Muscle symptoms with increased creatine kinase levels (normally >10x upper limit)

What is the pathology of rhabdomyolysis?

Muscle symptoms with marked creatine kinase elevation (>10x) and with creatine elevation

Which fibrate is preferred in pts who also need to be on a statin?

Fenofibrate

Poses less risk of developing myopathy

Which fibrate has greater potential to cause myopathy with statins?

Gemfibrozil

Has potential to increase plasma levels of statins

What are some examples of CYP 3A4 inhibitors that can affect statin metabolism?

- Non-DHP Ca2+ channel blockers

- HIV protease inhibitors (ritonavir)

- Amiodarone

What is the correlation between statin therapy and new-onset diabetes?

Statins can cause modest 10-12% increase in risk of developing type II DM

BUT: benefits of CV event reduction by 25-35% outweight this risk

Which patients are at risk of developing new-onset diabetes with their statin therapy?

Those who have additional risk factors for diabetes

- BMI of 30 kg/m2 or more

- Fasting blood glucose of 100 mg/dL or more

- Metabolic syndrome

- HbA1C of 6% or more

What are the effects of statins on cognition?

FDA warning about mild impaired cognition with use of statins

Can result in: memory loss, forgetfullness, confusion

Variable onset, sx reversible within a few weeks of stopping statin therapy

Which statins have a greater risk of causing cognitive effects in patients?

Simvastatin and atorvastatin

These are the most lipophilic --> have the most capability of penetrating the blood brain barrier

What are the pleiotropic effects of statins?

- Improve endothelial function (NO regulation)

- Atherosclerotic plaque stabilization

- Inhibition of LDL-C oxidation

- Platelet inhibition and antithrombosis

- Reduced leukocyte adhesiveness

- Effects on circulatory clotting factors

- Reduced ischemia-reperfusion injury

- BP effects

- Enhanced angiogenesis

It is for these reasons that we give bolus doses of statin in CV events

What is the mechanism of action of ezetimibe?

Inhibits cholesterol absorption at brush border of small intestine

Also reduces hepatic cholesterol stores and increases cholesterol clearance from the blood

How does ezetimibe affect a patient's lipid profile?

- Decrease LDL by 13-20%

- Decrease TGDs by 5-11%

- Increase HDL by 3-5%

What is Vytorin?

Combination pill of simvastatin and ezetimibe

Combo of ezetimibe and statin has shown improvement in CV outcomes

What are some adverse effects of ezetimibe?

- GI: diarrhea, abdominal pain

- Increased risk of elevated hepatic transaminases when used with statin

- Muscle-related effects (potentially due to statin when in combination therapy)

What are some drug interactions with ezetimibe?

- Gemfibrozil increases it --> increased risk of cholelithiasis

- Cholestyramine decreases it --> should separate doses

What is ezetimibe's place in therapy?

Most commonly prescribed agent after statins

Available in combination pill with statins --> has shown improvement in CV outcomes

Helpful for avoiding high doses of statins (and susceptibility to muscle injury)

What are bile acid sequestrants?

Medications that inhibit bile acid reabsorption, prolonging its mechanism in the GI tract to break down cholesterol longer

What are some examples of bile acid sequestrants?

- Cholestyramine

- Colestipol

- Colesevelam

What is the effect of BARs on a patient's lipid profile?

- Decrease LDL by 15-30%

- Small increase in HDL (3-5%)

- May increase TG

Why are BARs not used as much anymore?

Have a lot of side effects --> pt compliance is low because of this (about 40% of pts discontinue therapy within 1 year)

What are some adverse effects of BARs?

- GI: bloating, cramping, constipation

- Drug-drug interactions, as it binds to meds/vitamins and decreases its absorption

- Increased triglycerides

Which BAR has less incidence of drug-drug interactions?

Colesevelam

What is some guidance we can give to patients on BARs to reduce their incidence of side effects?

- Increase fluid intake (to avoid constipation)

- Modify diet to increase bulk

- Use stool softeners

Which patients should we not give BARs to?

Those with hypertriglyceridemia

They have the potential to increase TGDs, we don't want to increase it any more in these pts

What is the mechanism of action of PCSK9 inhibitors?

Inhibits the PCSK9 enzyme allowing for more receptors to be available to capture LDL for metabolism and removal from the blood

Can lead up to 70% LDL reduction

What is PCSK9?

A protein that degrades LDL receptors on the liver (more LDL will remain in the blood because cannot be transported)

How are PCSK9 inhibitors administered?

As subcutaneous injections every 2-4 weeks (have long half lives)

What are some examples of PCSK9 inhibitors?

- Alirocumab

- Evolocumab

What is the indication for use of PCSK9 inhibitors?

For very high risk patients with ASCVD or with very high baseline LDL-C levels

Also good for pts with familial hypercholesterolemia

Why are PCSK9 inhibitors not first line tx for dyslipidemias?

Injections and very expensive

What is the effect of PCSK9 inhibitors on a patient's lipid profile?

- Decrease LDL by 40-72%

- Small increase in HDL (0-10%)

- Small decrease in TGD (0-17%)

What are some adverse effects of PCSK9 inhibitors?

- Local injection site reactions >10%

- Nasopharyngitis, itching, flu and seriously allergic reactions

- Neurocognitive side effects initially reported, ongoing safety analyses did not show changes

Why do PCSK9 inhibitors cause flu-like symptoms?

Because they are monoclonal antibodies

What is the FDA indication for tx of patients with heterozygous familial hypercholesterolemia?

Combination of diet changes, maximally tolerated statin therapy and PCSK9 inhibitors

Which PCSK9 inhibitor is indicated for homozygous familia hypercholesterolemia?

Evolocumab

Why are PCSK9 inhibitors the drug of choice for familial hypercholesterolemia?

Provide a very rapid decrease in LDL levels

Patients with familial hypercholesterolemia (heterozygous or homozygous) will have super high levels of LDL --> need a very rapid drop to bring them to good level

What were the results of the Fourier and Odyssey trial?

Showed significant benefit of giving PCSK9 inhibitors for LDL cholesterol reduction

Demonstrated LDL-C lowering up to 50% compared to placebo, 50-70% lowering when combined with statins

What is inclisiran? What is its mechanism of action?

Antilipemic Small Interfering Ribonucleic Acid (siRNA) agent

Interferes with PCSK9 to block its synthesis

When is inclisiran used?

In patients who do not meet goals with dietary modifications and other lipid-lowering therapies (statin plus ezetimibe)

What are some adverse reactions to inclisiran?

- Immunologic

- Injection site reactions

- Arthralgias

- Bronchitis

What is bempedoic acid and what is its mechanism of action?

Adenosine Triphosphate-Citrate Lyase inhibitor

Inhibits cholesterol synthesis in the liver

When is bempedoic acid recommended in treatment?

In combination with maximally tolerated statin therapy

What are some adverse reactions of bempedoic acid?

- Hyperuricemia and gout

- Tendon ruptures

What are some significant drug interactions of bempedoic acid?

- Inhibits OATP1B1/1B3 pathway

- Organic anion transporting peptides

- Interactions with antiviral agents

What are cholesteryl ester transfer protein (CETP) inhibitors?

Meds that target low HDL and try to increase it

No benefit seen, many studies terminated early

What are some examples of CETP inhibitors?

- Torcetrapib

- Anacetrapib

- Evacetrapib

- Dalcetrapib

What level of triglycerides puts you at risk for metabolic syndrome?

150 mg/dL or higher

This is linked to hear disease and diabetes!!

What are some causes of high TGD levels in the general population?

- Overweight and obesity

- Physical inactivity

- Cigarette smoking

- Excess alcohol intake

- Very high carb diets (>60% of energy)

- Other disease (diabetes, renal failure, nephrosis)

- Drugs: steroids, protease inhibitors, estrogen, etc.

- Genetic factors