Unit 1: Lipids

Explain the physiological roles of cholesterol in the body, including its importance in cell membrane structure, hormone synthesis, and bile acid production.

• Cholesterol is essential for cell membrane structure and fluidity, acts as a precursor for synthesizing steroid hormones like cortisol, aldosterone, and sex hormones (also used to produce Vitamin D), and is crucial for producing bile acids that aid in fat digestion.

• It is integrated into cell membranes to modulate their fluidity and integrity, provides the building blocks for the body's steroid hormones (e.g., estrogens, testosterone), and is converted by the liver into bile acids that emulsify fats (break large fat globules into smaller particles that can be absorbed in the body) in the small intestine

Differentiate the 5 major lipoproteins (chylomicrons, VLDL, IDL LDL, HDL) based on their composition and primary function.

• Lipoproteins are complex particles that transport fats and cholesterol in the blood

1. Chylomicrons: take fat from what we eat and transport it; transport dietary fat from the small intestine to the rest of the body 

   1. Highest lipid content (90% triglycerides) and lowest protein content

2. VLDL (very low-density lipoprotein cholesterol): delivers TGs to peripheral tissues (muscles, skin, organs, bones, blood vessels, lymphoid tissues- outside of the CNS (brain/spinal cord) from liver

3. LDL (low-density lipoprotein cholesterol): transports cholesterol to tissues "dominant form of atherogenic cholesterol"; deemed “bad cholesterol” because high levels are linked to atherosclerosis 

4. HDL (high-density lipoprotein cholesterol): reverse cholesterol transport back to liver; good cholesterol; transports cholesterol from the tissues back to the liver

5. IDL (intermediate-density lipoprotein): transition between VLDL and LDL

Define dyslipidemia.

• Dyslipidemia: abnormal levels of lipids in the blood

  1. Elevated total cholesterol

  2. Elevated LDL

  3. Decreased HDL

  4. Elevated TGs

• Causes:

  • Genetics

  • Lifestyle factors (e.g., unhealthy diet, lack of exercise, smoking)

  • Medical conditions (e.g., diabetes, obesity, hypothyroidism)

  • Certain medications (e.g., birth control pills, corticosteroids)

• Dyslipidemia is diagnosed through a blood test that measures lipid levels. 

• Treatment

  • Lifestyle changes (e.g., weight loss, exercise, smoking cessation)

  • Medications (e.g., statins, fibrates, niacin)

Describe common lipid abnormalities.

1. Total cholesterol

2. LDL-C

3. HDL-C

4. Triglycerides

• lipid abnormalities are a primary risk factor for clinical atherosclerosis

  • coronary artery disease

  • cerebrovascular disease

  • peripheral artery disease

• Abnormalities include

  • high levels of LDL-C: deposits cholesterol in arteries, forming plaques that causes blockages

  • high levels of TGs: a type of fat that can also contribute to artery plaque

  • low levels of HDL-C: high levels of HDL can help remove cholesterol from arteries

• Metabolic syndrome: a cluster of conditions that includes high TGs, low HDL, high BP, and high blood sugar

Describe the common etiologies of dyslipidemia including primary and secondary.

• Primary (familial): caused by inherited genetic abnormalities

  1. Significant cholesterol elevations at an early age that accelerates atherosclerosis

  2. Increases risk of premature clinical ASCVD

  3. Types include: hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, HDL metabolism disorders, lipoprotein excess, familial hypercholesterolemia

• Secondary (acquired): triggered by environmental including lifestyle, diet, medications, or underlying diseases

  1. Can occur independently or alongside genetic disorders

  2. 4D classification

     1. Diet, drugs, disorders, diseases

  1. Managed by addressing the underlying abnormality

1. Dietary causes:

   1. Weight gain, excessive carb intake, high saturated fat intake, excessive alcohol use, anorexia

2. Medications:

   1. Atypical antipsychotics, glucocorticoids, oral estrogen and progestin, diuretics, beta blockers, tacrolimus, cyclosporine

3. Diseases and disorders

   1. Hypercholesterolemia: hypothyroidism, liver disease, nephrotic syndrome, anorexia nervosa

Describe the exogenous pathway by which cholesterol is transported in the body via lipoproteins.

• Exogenous Cholesterol Pathway - 20% outside of body

  1. Lipid synthesis and transport

     1. Dietary fats: arrive to small intestines as lipid droplets

     2. Lipid droplets and cholesterol absorbed into intestinal cells

  1. Intestinal cells make chylomicrons (large lipoprotein particles produced in the intestine that transport dietary fats, cholesterol, and fat-soluble vitamins throughout the body) (high in lipid content)

     1. Fatty acids, cholesterol, apolipoproteins

  2. Chylomicrons circulate fatty acids and triglycerides to tissues for energy

  3. Chylomicrons remnants are transported to the liver and bind to LDL receptors to be removed from the blood

Describe the endogenous pathway by which cholesterol is transported in the body via lipoproteins.

• Endogenous - 80% from inside body

  1. Dietary glucose absorbed and delivered to the liver

  2. Glycolysis occur:  glucose --> pyruvate --> Acetyl -CoA

  3. Acetyl - CoA --> cholesterol

     1. HMG-CoA reductase

  4. Acetyl-CoA also forms fatty acids and ultimately TGs

Explain the pathophysiology of atherosclerosis including:

1. Lipoprotein involvement in plaque formation

2. Composition and formation of atherosclerotic plaques

3. Definition and implications of vulnerable plaque

4. Consequences of plaque rupture

• LDL accumulates in artery wall and triggers inflammatory response

• macrophages engulf these lipids forming foam cells (filled with cholesterol lipids)

• over time, the foam cells form into a plaque with a lipid core and a fibrous cap which can rupture

• rupture of the plaque (collagen and other tissue factors) leads to a blood clot which can grow to completely block blood flow through the artery and potentially a heart attack or stroke

Describe lipoprotein synthesis and function

• Lipoproteins are synthesized primarily in the liver and intestines as protein and lipid packages that transport cholesterol, TGs, and fatty acids throughout the bloodstream.

• Liver makes 2 lipoproteins - VLDL & HDL (move lipids to tissues that need them for energy or building blocks)

  1. VLDL (very LDL): transports fatty acids and TGs to muscles and adipose tissues

  2. VLDL --> IDL --> LDL

     1. Converted via lipase

  3. LDL transports cholesterol to body tissues to carry out essential functions

  4. LDL returns to the liver

     1. Recycled in the golgi apparatus

        1. Excreted into the bile (excess)

• Reverse cholesterol transport (carry cholesterol back to the liver for disposal)

  1. Empty HDL:

     1. Secreted from the liver

     2. Transported to the cells to remove excess cholesterol

     3. Return to liver for recycling or excretion

     4. picks up bad cholesterol and brings it back to liver

Explain how dyslipidemia contributes to atherosclerosis.

• Dyslipidemia contributes to atherosclerosis through several mechanisms involving inflammation, oxidative stress, and the accumulation of lipoproteins within artery walls.

• Excess LDL is the primary driver of plaque formation

Discuss complications of atherosclerosis.

• stable/unstable angina

  • chest pain from reduced blood flow to the heart muscle

• myocardial infarction

  • heart attack

• stroke

  • blockage to blood flow in brain

• peripheral arterial disease

  • plaque in arteries of the extremities, especially legs

• aortic aneurysm

  • weakened/bulging area of the wall of the aorta, which may rupture or dissect

Define clinical ASCVD

• group of conditions that affect the arteries and increase the risk of CV events such as heart attacks and strokes

• ASCVD, or Atherosclerotic Cardiovascular Disease, is caused by the buildup of plaque within the arteries, limiting the flow of blood to important organs

Identify examples of diagnoses classified as clinical ASCVD

• Acute coronary syndrome (ACS)

  • range of conditions where blood flow to the heart is suddenly blocked, such as a heart attack

• Myocardial infarction (MI)

  • a heart attack (blocked blood flow to the heart muscle)

  • specific type of ACS

• Stroke

  • a cerebrovascular event caused by a blocked or ruptured blood vessel in the brain

• Peripheral Artery Disease (PAD)

  • atherosclerosis in the arteries of the limbs

• Angina

  • chest pain or discomfort that can occur with stable or unstable angina, a symptom of reduced blood flow to the heart

• Revascularization Procedures

  • patients who have undergone procedures to restore blood flow to the heart or other arteries

• Aortic Aneurysm

  • a bulge or swelling in the aorta, the body’s main artery

Describe how LDL-C lowering reduces the risk ASCVD. 

• by decreasing the formation and growth of atherosclerotic plaques in arteries 

• By keeping LDL-C levels low, fewer LDL particles become trapped  in the artery wall, which slows the progression of atherosclerosis 

  • positive relationship exists between elevated LDL-C and ASCVD risk

  • Risk of ASCVD rises more steeply with increasing LDL-C concentrations

  • LDL-C is the primary target of lipid-lowering strategies to reduce ASCVD risk

  • Treatment goal depends on level of individual risk of each patient 

Define cardiovascular-kidney-metabolic (CKM) syndrome

• a disorder connecting heart disease, kidney disease, type 2 diabetes, and obesity, where these conditions can worsen each other and lead to poor health outcomes

• It is defined as a health disorder due to the interconnectedness of these four conditions, leading to an increased risk for heart attack, stroke, heart failure, and abnormal heart rhythms. The American Heart Association (AHA) recently defined this syndrome to emphasize the relationship between these conditions, which were previously often managed separately. 

Introduce the concept of cardiovascular-kidney-metabolic (CKM) syndrome and its relevance to dyslipidemia. 

• a cluster of interconnected metabolic, kidney, and cardiovascular diseases that exacerbate each other. 

• It includes conditions like obesity, diabetes, chronic kidney disease (CKD), and cardiovascular disease (CVD), and is defined by the presence of at least two of these conditions. 

• Dyslipidemia, a key metabolic factor characterized by high triglycerides, low HDL cholesterol, or high blood pressure, is a significant component of CKM syndrome and contributes to its progression by driving inflammation, hemodynamic overload, and neurohormonal dysregulation

Describe the clinical implications of CKM syndrome, including its impact on ASCVD risk.

• its most significant clinical implication is a dramatically heightened risk for atherosclerotic cardiovascular disease (ASCVD), heart failure, and premature death. 

  
  

Interpret a fasting lipid panel.

• dyslipidemia is diagnosed with a lipid panel

  • measures or estimates amount of “cholesterol” within lipoprotein

• a lipid panel is a simple blood draw

• most adults should have a lipid panel every 4 to 6 years

• Presence of heart disease, diabetes, family history of high cholesterol, lowering require more frequent checks

Identify commonly used ASCVD risk calculators

• ACC/AHA Pooled Cohort Equations (use this one)

• AHA PREVENT calculator

Recognize limitations of ASCVD risk calculators.

• Population-based limitations

  • racial and ethnic diversity (POOLED was on white and black individuals)

  • socioeconomic status: may overestimate risk in individuals with a higher socioeconomic status and healthier lifestyles and underestimate risk in those with lower socioeconomic status

  • older adults: not valid for adults over the age of 75

• Incomplete inclusion of risk factors

  • family history

  • inflammatory and autoimmune conditions

  • specific biomarkers

Explain the rationale for ASCVD risk stratification (arranging in groups) in clinical practice.

• The rationale for atherosclerotic cardiovascular disease (ASCVD) risk stratification is to classify patients into risk categories to guide the intensity of preventative therapy. The higher a patient's risk, the more intensive their treatment plan should be, ensuring that prevention efforts are targeted, effective, and efficient

Differentiate between primary and secondary prevention of ASCVD. 

• primary prevention (patient’s with no known clinical ASCVD, aim is to prevent or delay the onset of clinical ASCVD, shared decision-making around treatment goals and options, predict future risk of ASCVD events with a validated calculator)

  • assess patient’s ASCVD risk, if indicated

  • lifestyle modifications

  • medications

• Active disease

  • lifestyle modifications

• secondary prevention

  • lifestyle modifications

  • medications

Describe how lipid goals and treatment decisions differ based on risk group classification (e.g., low, borderline, intermediate, high)

• Low risk (<5%)

  • Lifestyle is key: heart-healthy diet and regular exercise; statin is not usually recommended unless the patient has a very high LDL-C level (>/= 190 mg/dL)

• Borderline risk (5% - < 7.5%)

  • personalized approach: a moderate-intensity statin may be considered especially if the patient has additional “risk-enhancing factors”; factors include a FH of premature ASCVD, chronic kidney disease, or elevated lipoprotein(a)

• Intermediate risk (7.5% - < 20%)

  • moderate-intensity statin therapy: decision to initiate or intensity statin therapy is based on a discussion between the clinician and the patient; presence of risk-enhancing factors favors starting statin therapy

• High risk (>/= 20% or other specific conditions)

  • high-intensity statin therapy: goal of reducing LDL-C by 50% or more; also includes individuals with severe hypercholesterolemia (LDL-C >/= 190 mg/dL) and most people with diabetes who are 40-75 years old

List ASCVD risk-enhancing factors.

• family history of premature ASCVD

  • first degree relative: male <55 years, female <65 years

• primary hypercholesterolemia

  • LDL-C of 160-189 mg/dL

• persistently elevated primary hypertriglyceridemia (>/= 175 mg/dL)

• Chronic Kidney Disease

  • eGFR 15-59 and not treated with dialysis or kidney transplantation

• premature menopause (before age 40 years)

• history of preeclampsia

• south asian ancestry

• Chronic inflammatory conditions

  • psoriasis, rheumatoid arthritis, HiV/AIDS

• metabolic syndrome (have to have 3)

  • metabolic waist circumference (>40 inches males, > 35 inches females

  • elevated TGs >150 mg/dL

  • elevated BP >130/85 mmHg

  • elevated blood glucose levels (fasting >/=100 mg/dL)

  • low HDL-C of <40 mg/dL in men and <50 mg/dL in women

What is primary (familial) hypercholesterolemia?

• caused by inherited genetic abnormalities

• significant cholesterol elevations at an early age that accelerates atherosclerosis

• increases risk of premature clinical ASCVD

What are types of primary hypercholesterolemia?

• hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, HDL metabolism disorders, lipoprotein excess, familial hypercholesterolemia

What is secondary (acquired) hypercholesterolemia?

• triggered by environmental including lifestyle, diet, medications, or underlying diseases

• Can occur independently or alongside genetic disorders

• Classification (4D): Diet, Drugs, Disorders, Disease

• managed by addressing the underlying abnormality

What are dietary causes for secondary hypercholesterolemia?

• weight gain

• excessive carb intake

• high saturated fat intake

• excessive alcohol use

• anorexia

What medications cause secondary hypercholesterolemia?

• increase both LDL-C and triglycerides 

  • atypical antipsychotics

  • glucocorticoids

  • oral estrogen and progestin

  • diuretics

  • beta-blockers

  • tacrolimus

  • cyclosporine

What diseases and disorders cause secondary hypercholesterolemia?

Explain how ASCVD risk-enhancing factors (REFs) inform treatment decisions.

• The presence of multiple REFs favors statin therapy for patients at intermediate or borderline risk

• REFs allow clinicians to move beyond the general risk predicted by equations to provide a more personalized cardiovascular risk assessment.

• Guide statin therapy: When an individual's 10-year risk falls into borderline (5−7.5%) or intermediate (7.5−20%) categories, REFs are used to help decide whether to initiate or intensify statin therapy.

• Trigger more aggressive treatment: The presence of multiple or significant REFs can lead a clinician to recommend a more aggressive approach, such as starting a moderate- to high-intensity statin, even if the 10-year risk score is lower than typically recommended for that intensity.

• Refine treatment decisions: REFs can be used to advocate for statin therapy in borderline-risk patients or for more intense therapy in intermediate-risk patients, particularly when the standard risk score may not fully capture the individual's risk. 

Describe the role of coronary artery calcium (CAC) scoring in cardiovascular risk assessment.

• Coronary artery calcium (CAC) scoring is a tool in cardiovascular risk assessment that measures calcified plaque in the coronary arteries using a CT scan to predict future heart events

• Its role is to refine risk assessment for asymptomatic individuals, providing more accurate predictions than traditional risk factors alone by identifying those with low risk (CAC score of 0) and high risk (higher CAC scores)

• It can guide clinical decisions, such as the need for statins and more aggressive lifestyle changes, particularly for those at intermediate risk. 

What are the blood cholesterol patient management groups?

• Primary prevention

  • LDL-C >/= 190 mg/dL

  • 40-75 with diabetes

  • > 75 age group

  • 40-75 age group

  • 20-39 age group

  • 0-19 age group

• Secondary prevention

  • patients with ASCVD

Identify nonpharmacologic therapy for ASCVD-risk reduction. 

How to treat lipoprotein disorders (primary prevention)?

• therapeutic lifestyle changes are first-line for any lipoprotein disorder 

• Lipid lowering agents are chosen based on individual’s ASCVD risk

Identify nonpharmacologic therapy for ASCVD-risk reduction.

• The cornerstone of ASCVD risk reduction

• Recommended in all patients even when receiving lipid lowering therapy

• 12 week trial of lifestyle modifications

  1. Recommended BEFORE lipid lowering therapy in patients without ASCVD or diabetes

  1. Lifestyle modification ALONE is inappropriate for patients with established ASCVD or diabetes due to benefit of statin therapy

• Weight and BMI should be determined at each visit

• See chart for dietary patterns, physical activity, and tobacco

What are some recommendations to modify select lipid parameters (lower LDL-C, increase HDL-C, lower TGs)?

• lower LDL-C

  • increase soluble fiber intake (goal 25 g/day)

    • fiber binds to cholesterol and bile in small intestines

      • reduces total and LDL-C

      • 12 g/day of soluble fiber decrease LDL-C up to 12 mg/dL

    • fruits, vegetables, legumes, barley, oats/oat bran

  • phytosterol (2g/day) supplementation

    • found in various plant foods

    • can decrease LDL-C by 5-15%

    • vegetable oils, nuts/seeds, whole grains, fruits, legumes

• increase HDL-C

  • increase physical activity

  • smoking cessation

• lower triglycerides

  • lose weight (5%-10% body weight loss)

  • increase physical activity

  • abstain from alcohol

  • reduce intake of refined carbs and sugars

What is the MOA for statins (atorvastatin, rosuvastatin, simvastatin, lovastatin, pravastatin, fluvastatin, pitavastatin)?

• inhibits HMG-CoA reductase

  • prevents conversion of HMG-CoA to mevalonate

• it is the rate limiting step in cholesterol biosynthesis

• reduced LDL synthesis

• enhanced LDL catabolism (mediated through LDL receptors)

• principal mechanisms for lipid-lowering effects

What is the first-line lipid lowering therapy?

• “statins” - HMG-CoA reductase inhibitors

  • reduction in the risk of first CV event (primary prevention)

  • reduction in the risk of recurrent CV events (secondary prevention)

What are the effects of statins on the lipid profile (LDL, HDL, TG, VLDL)

• reduces LDL-C by 20%-60%

• increases HDL-C by 6%-12%

• decreases TG by 10%-30%

• reduces risk of ASCVD events

  • primary and secondary prevention

Explain why some statins require evening dosing. 

• Longer half life statins can be taken whenever (atorvastatin and rosuvastatin stay in the body for a full 24 hour cycle); pravastatin, simvastatin, lovastatin, fluvastatin need to be taken in the evening because of short half life (around 6 hours)

• you produce the most cholesterol while you sleep

Describe how statins structure affects its absorption, distribution, metabolism, and excretion (ADME) profile.

• atorvastatin, lovastatin, simvasatin

  • CYP3A4 enzyme metabolism

  • all are lipophilic (ability to dissolve in fats)

• fluvastatin (CYP2C9); lipophilic

• pitavastatin (moderate lipophilic), rosuvastatin (not lipophilic)

  • minimal CYP2C9

• pravastatin

  • no CYP

  • not lipophilic

What are the ADRs of statins?

• SAMs (statin-associated muscle symptoms)

  • reported by 10-25% of users; often a reason for discontinuation

  • myalgia (bilateral muscle achiness, weakness or cramps of larger muscle groups 

  • rhabdomyolysis (rare): rapid breakdown of skeletal muscle

    • dark urine, AKI, N/V, confusion, coma, cardiac arrhythmias, electrolyte disturbances 

• elevations in serum transaminase levels

  • mild elevations in ALT

  • contraindication in decompensated cirrhosis or acute liver failure

• new-onset diabetes

  • <1% increased risk of new-onset diabetes

  • common attributes of statin users who develop new-onset diabetes

    • higher statin doses and presence of other risk factors for diabetes

      • obesity

      • impaired fasting glucose

      • A1c >6%

      • metabolic syndrome 

Which statins are high intensity therapies? What does that mean?

• high intensity statins daily dose lowers LDL >/= 50%

• rosuvastatin 20-40 mg

• atorvastatin 40-80 mg

Which statins are moderate intensity therapies? What does that mean?

• moderate intensity therapies daily dose lowers LDL from 30% to <50%

• Rosuvastatin 5-10 mg

• atorvastatin 10-20 mg

• pitavastatin 2-4 mg

• simvastatin 20-40 mg

• lovastatin 40 mg

• pravastatin 40-80 mg

• fluvastatin XL 80 mg

• fluvastatin 40 mg BID

Which statins are low intensity therapies? What does that mean?

• low intensity statin therapy daily dose lowers LDL <30%

• pitavastatin 1 mg

• simvastatin 10 mg

• lovastatin 20 mg

• pravastatin 10-20 mg

• fluvastatin 20-40 mg

Risk factors for SAMs

• advanced age

• female gender

• low BMI

• frequent heavy exercisers

• increased serum statin concentrations due to drug-drug interactions

What are some medications that are CYP3A4 inhibitors? What does this do?

• CYP3A4 inhibitors will increase serum statin concentrations and increase the risk for SAMS

• CYP3A4 inhibitors: ketoconazole, itraconazole, ritonavir, clarithromycin, erythromycin, diltiazem & verapamil (Non-DHP CCB)

How to prevent SAMS?

• for patients with multiple risk factors

  • lower starting doses

  • dose titration to the desired potency once the initial dose is tolerated

Explain statin intolerance.

• 5%-30% of patients will have satin intolerance

  • most common intolerance is SAMS

• side effect that

  • resolves or improves after a dose decrease or discontinuation of statin therapy

  • after attempting at least two statins, with one at the lowest approved dose

• complete inability to tolerate any statin dose

• inability to tolerate dose required to achieve desired LDL-C level

• nonstatin therapies may be considered in patients who fail multiple statins

What are nonstatin therapies?

• ezetimibe

• bile acid sequestrants

  • colestipol, colesevelam, cholestyramine

• PCSK9 inhibitors

  • monoclonal antibodies (mAbs) molecules: evolocumab and alirocumab

  • small interfering ribonucleic acid (siRNA) molecule: Inclisiran

• Bempedoic acid

When is ezetimibe preferred and why?

• preferred adjunct therapy

• reduces the risk of recurrent CV events in combo with statins (secondary prevention)

• statin intolerance 

What is the MOA for ezetimibe?

• inhibits the NPC1L1 transporter protein in the small intestine from transporting cholesterol from the gut into the body; decreases the amount of cholesterol that reaches the liver so liver starts taking up LDL from the bloodstream

  • NPC1L1 protein absorbs dietary cholesterol and cholesterol from bile

• prevents the absorption of cholesterol

• leads to a reduction in circulating LDL-C

What are the lipid lowering effects of ezetimibe?

• reduces LDL-C by 18%

• higher LDL-C reductions achievable when used in combination with statin therapy (up to 25%)

What are ADRs for ezetimibe?

• well tolerated

• mild GI complaints (diarrhea)

• myalgia and ALT elevations when used with statins

• ezetimibe has not effects on the CYP450 enzyme

Role of ezetimibe in ADME?

• Prodrug itself is converted into a more active form in the body. After absorption in the small intestine and liver, it is extensively converted into its pharmacologically active glucuronide metabolite( ezetimibe−glucuronide)

• This metabolite is what exerts the cholesterol-lowering effects by inhibiting cholesterol absorption. 

• Conversion process:

  Ezetimibe is converted into its glucuronide metabolite through a process called glucuronidation, mainly in the liver and small intestine. 

• Active metabolite:

  The resulting ezetimibe-glucuronide is the primary active form of the drug circulating in the body and is responsible for the therapeutic effect. 

• Role of the prodrug:

  The initial ezetimibe is the prodrug that, after being absorbed, is converted into the active compound to perform its function. 

• Pharmacokinetics:

  The glucuronide metabolite is largely responsible for the prolonged plasma half-life of the drug. 

What place in therapy are Bile Acid Sequestrants (BAS)?

• first line during pregnancy

  • not systemically absorbed and pose no risk to the fetus

• combination therapy with statins when desired LDL-C levels are not achieved with monotherapy

• used when intolerance to statins and ezetimibe

What is MOA in Bile Acid Sequestrants (BAS)?

• cholesterol is a precursor of bile acid

• BAS bind bile acids in the intestinal lumen forming an insoluble complex that is excreted in the feces; prevents reabsorption of bile acids causing the liver to use more cholesterol to produce new bile acids. This process lowers cholesterol levels in the blood by reducing the amount of cholesterol in the liver which leads to an increase in LDL receptors on the liver surface

  • removes more LDL cholesterol from the circulation

    • stimulates hepatic synthesis of bile acids from cholesterol

    • increases cholesterol biosynthesis and the number of LDL receptors on hepatocyte membranes

    • more LDL receptors enhances the rate of LDL catabolism from plasma and lowers LDL-C levels

What are the lipid lowering effects of BAS?

• reduces LDL-C by 13% to 20%

What are some BAS drugs?

• Colesevelam (Welchol)

• Colestipol (Colestid)

• Cholestyramine (Question)

• Do not administer in dry form; requires mixing with water or juice to create a slurry for oral administration

• maintenance dose often based on patient tolerability

What are ADRs for BAS?

• tablet formulations are generally better tolerated than resin powders

• General GI complaints

  • constipation, bloating, epigastric fullness, nausea, flatulence

  • effects can be minimized by increasing fluid intake, increasing dietary bulk, and softeners

  • GI obstruction

  • Vitamin deficiencies due to impaired absorption of fat-soluble vitamins A, D, E, K

  • Hypertriglyceridemia

    • avoid when TG > 300 mg/dL

What are BAS drug-drug interactions?

• reduced bioavailability of other drugs such as warfarin, levothyroxine, and phenytoin.

• drug-drug interactions may be avoided by taking other mediations at least 1 hour before or 4 hours after BAS administration

What are PCSK9 Inhibitors?

• PCSK9 drugs are a class of cholesterol-lowering medications that work by blocking the PCSK9 protein to help the liver remove more LDL (bad) cholesterol from the blood

• used for individuals whose cholesterol is not controlled by diet and statins, including those with familial hypercholesterolemia

• monoclonal antibody injections alirocumab (Praluent) and evolocumab (Repatha),

  • preferred in high-risk patients unable to achieve desired LDL-C levels with a statin + ezetimibe therapy

  • both drugs are FDA approved for use as monotherapy in patients with primary hyperlipidemia

• small interfering RNA (siRNA) drug inclisiran (Leqvio)

  • reserved for patients unable to tolerate PCSK9 mAbs

  • FDA approved as additional therapy to be added to maximally tolerated statin therapy to further lower LDL-C

What is the MOA for PCSK9 inhibitors?

• Target PCSK9 protein: PCSK9 drugs inhibit the PCSK9 protein, which normally breaks down LDL receptors on the liver.

• Increase LDL receptors: By blocking PCSK9, the drugs allow more LDL receptors to remain active on the liver cells.

• Lower LDL cholesterol: More active LDL receptors are able to capture and remove more LDL cholesterol from the bloodstream, resulting in significantly lower levels

• Alirocumab and Evolocumab MOA

  • fully human monoclonal antibodies (mAbs) to PCSK9

  • prevents LDL receptors from being marked for degradation

  • more LDL-C is cleared from the blood lowering levels 

• Inclisiran MOA

  • small interfering RNA (siRNA) molecule complementary to the PCSK9 mRNA strand

  • binds to the PCSK9 mRNA strand resulting in degradation of PCSK9 mRNA leading to less PCSK9

  • allows for greater LDL receptor availability to remove LDL-C from circulation 

What are the lipid lowering effects of PCSK9 drugs?

• Alirocumab and evolocumab (injections given every two weeks)

  • reduces LDL-C (60%) when added to statin therapy

  • reduces recurrent CV events when added to statin therapy

• Inclisiran (small interfering RNA - siRNA)

  • reduces LDL-C (40%-50%) when added to statin therapy

  • effect on CV event rates is currently being investigated

  • given SUBQ injection twice per year

What are the ADRs of PCSK9 drugs?

• injection site reactions

  • minimize by allowing the medication to come to room temperature and icing the injection site

• flulike symptoms

• headache (evolocumab)

• nasophyngitis (evolocumab)

• urinary track infections (evolocumab)

What is bempedoic acid (Nexletol)?

• an oral, non-statin medication used to lower low-density lipoprotein (LDL) cholesterol. It is particularly valuable for patients who cannot tolerate statins due to side effects like muscle pain. 

• patients take if unable to achieve desired LDL-C goal on statin + ezetimibe who prefer a noninjectable option 

Bempedoic acid and ADME?

• Bempedoic acid is a prodrug that is activated in the liver, not in muscle tissue, which is why it generally avoids the muscle-related side effects associated with statins

• has a high plasma protein binding (99%)

• activated in the liver by enzyme ACSVL1 to form an active coenzyme A ester, which inhibits ATP citrate lyase metabolism to form an inactive metabolite

• absorbed in small intestines

• metabolic pathway is hepatic (liver-based)

• elimination is through metabolism in the liver and over 95% of the drug is excreted as metabolites

• It is an adenosine triphosphate-citrate lyase (ACL) inhibitor

• ACL is a cytoplasmic enzyme that generates acetylcholine coenzyme A

What is the MOA of bempedoic acid?

• It works by inhibiting an enzyme called adenosine triphosphate-citrate lyase (ACL), which is involved in the cholesterol synthesis pathway.

• By blocking this enzyme, it inhibits the conversion of Acetyl-CoA, reduces the amount of cholesterol produced in the liver, which leads to a corresponding increase in LDL receptors that clear "bad" LDL cholesterol from the bloodstream.

What are the lipid lowering effects of bempedoic acid?

• reduces LDL-C by 15%-20%

• bempedoic acid + ezetimibe results in a 36% reduction in LDL-C

What are the ADRs of bempedoic acid?

• well tolerated

• hyperuricemia

• tendon rupture (rare)

What are fatty acids?

• long chain of carbon atoms with carbons attached with carboxylic acid; saturated fatty acid has no double bonds; unsaturated fatty acids have double bonds (cis double bonds)

  -trans fatty acids can stick to each other better which enabled melting points to be higher; bad for the heart like saturated fatty acids

  -unsaturated fatty acids tend to be healthier (from plant sources)

  -saturated fatty acids come from red meat

  -a cell would want to utilize fatty acids for secondary energy source; cell uses carbohydrates to convert into glucose for energy; run out of fat – uses muscle (protein)

Why are fatty acids important?

• they are a form of energy

• play a role as structural components of cells (cell membranes)

What are triglycerides?

• glycerol is the backbone of a triglyceride (have 3 fatty acids); not water soluble- won’t go through blood easily; very lipophilic (want to clump together); simple lipids

What is a phospholipid?

• have glycerol backbone with 2 fatty acids (very lipophilic) and phosphate (PO4-) component (very polar); simple lipids – composed of fatty acids

What are sterols?

• lipophilic in nature and complex lipids; not made through fatty acids;

  has one OH group

• sterols have a fused four-ring core, while fatty acids consist of a long hydrocarbon chain with a carboxyl group at one end.

• cholesterol is the most abundant sterol in animals

  • key component of animal cell membranes and a precursor for steroid hormones, vitamin D, and bile acids

    
    

Do sterols require transport?

• Yes, sterols (lipids) require transport within cells and in the bloodstream because they are insoluble in water.

• transport in the plasma as solubilized lipoproteins so necessary tissue gets the necessary lipids. 

• lipoproteins (carry cholesterol) consist of a central core of hydrophobic lipid encased in a more hydrophilic coat of polar phospholipids, free cholesterol, and associated proteins called apolipoproteins. 

What is chylomicron?

• Chylomicrons are the largest lipoprotein particles that transport dietary fats, including TGs, cholesterol, and fat-soluble vitamins from the small intestines to the rest of the body.

• They are assembled in intestinal cells, then enter the lymphatic system before reaching the bloodstream, where they deliver their fatty acid contents to tissues.

• Enzymes in the capillaries break down the triglycerides, and the remaining particles, called chylomicron remnants, are eventually taken up by the liver

What are chylomicrons composed of?

• 1% protein

• 88% TGs

• 3% cholesterol

• transports dietary fats

What is VLDL (transporter) composed of?

• 10% protein

• 56% TGs

• 15% cholesterol

• transports fats in the body (from liver)

What does LDL (bad cholesterol) consist of?

• 20% protein, 13% TGs, 48% cholesterol

• transports fats in the body

What does HDL (good cholesterol) consist of?

• 50% protein

• 13% TGs

• 30% cholesterol

What are the two main sources of lipids?

• exogenous (diet) - 20%

• endogenous (hepatic biosynthesis) - 80%

What are the type of lipoproteins?

• Chylomicron

• VLDL

• LDL

• HDL

• lipoproteins transport lipids through the bloodstream

What are TGs broken down by? Why are they broken down?

• TG (stored form of fatty acid) is broken down by lipoprotein lipase (LPL) to form glycerol and fatty acids

• TG are large, insoluble molecules that cannot be absorbed directly in the bloodstream.

• Broken down to be absorbed in the body; Fatty acids can be taken up by cells

How do you get lipids from exogenous pathway?

• The exogenous lipid process begins with dietary fats being digested in the small intestines by bile salts and pancreatic lipase.

• These break down fats into absorbable components which are then reassembled into TGs inside the intestinal cells

• These triglycerides, along with cholesterol and fat-soluble vitamins, are packaged into chylomicrons, which are secreted into the lymphatic system before entering the bloodstream to be delivered to tissues (muscle) for energy or storage (adipose tissue)

• After binding to lipoproteins, ApoC-II acts as a crucial cofactor for lipoprotein lipase (LPL). LPL is anchored to the interior surface of capillaries in tissues that require fatty acids, such as adipose tissue and muscle. 

  • It is on the surface of blood vessels which breaks down chylomicrons, releasing lipids for use by cells.

• The ApoC-II present on the chylomicron interacts with and activates LPL, triggering the enzyme to begin hydrolyzing the triglycerides (TGs) contained within the core of the chylomicron. 

• After releasing most of its triglycerides, the chylomicron shrinks and becomes a cholesterol-rich chylomicron remnant.

• ApoE: The chylomicron remnant is recognized and taken up by the liver. This clearance process is mediated by ApoE on the remnant, which binds to specific receptors (like the LDL receptor) on liver cells.

• The liver then processes the remnants, and the components can be recycled or converted into bile acids

What is the endogenous pathway?

• Formation:

  The liver packages synthesized lipids (triglycerides, cholesterol) and apoB-100 into VLDL particles. 

• Modification:

  VLDL is released into the bloodstream, where it is matured by receiving apolipoproteins like apoC-II and apoE from high-density lipoproteins (HDL). 

• Lipolysis:

  ApoC-II activates lipoprotein lipase (LPL), which breaks down VLDL's triglycerides into free fatty acids for tissue use. 

• Remnant formation:

  As VLDL loses triglycerides, it becomes an intermediate-density lipoprotein (IDL). 

• Clearance:

  IDL can be taken up by the liver via the apoE receptor or further converted into low-density lipoprotein (LDL) by hepatic lipase

What is the primary site of cholesterol synthesis in the body?

• Liver

What do LDL receptors do? 

• Interaction leads to uptake of the whole LDL particle;

• it is broken down from LDL particle into its components and returned to LDL receptor to surface

Blood Cholesterol Patient Management Groups for primary prevention of ASCVD chart

What are the treatment plans for primary prevention (severe primary hypercholesterolemia - LDL-C >/= 190)?

• Do not calculate 10 year ASCVD risk

• Begin high intensity statin therapy

  1. Achieve goal of 50% reduction in LDL-C

  2. Goal LDL-C <100 mg/dL

• If goal is not achieved

  1. Add ezetimibe FIRST then a PCSK9 inhibitor

Treatment plan for 40-75 year olds with diabetes?

• Diabetes is a major risk factor for ASCVD

• Leading cause of death in persons with diabetes is ASCVD

1. Persons with diabetes are at greater risk of morbidity and mortality following an ASCVD event than those without diabetes

2. 10 Year ASCVD risk score is used to determine appropriate statin therapy

   1. less than 7.5% - start moderate intensity statin; goals: achieve >/= 30-49% reduction in LDL-C and LDL-C <100 mg/dL

   2. greater than or equal to 7.5% - start high intensity statin; goals: achieve 50% reduction in LDL-C and LDL-C <70 mg/dL

3. If the goal is not achieved

   1. Increased to high intensity statin (if not already on)

   2. Can add ezetimibe FIRST then a PCSK9 inhibitor

What is the treatment plan for patients >75 years old?

• Most ASCVD events occur in the 6th and 7th decade of life

• Older patients respond to therapy as well as younger patients

• The gain in life expectancy may be small

  1. Depends on age at the start of treatment and the magnitude of LDL-C reduction

• Benefits of statins for primary prevention is debated

  1. Patients >75 is poorly represented in clinical trials

What is the treatment plan for patients 40-75 years old without diabetes?

Flow chart for patients 40-75 years old without diabetes

• Yellow means to proceed with caution

• Low risk: Lifestyle only

• Borderline risk: lifestyle; most discussion with patient; possible moderate intensity statin; reduce LDL-C by 30-49% and goal LDL-C <100 mg/dL; considering getting CAC score

• Intermediate risk: same as borderline but more discussion in borderline

• High risk: high intensity therapy; reduce LDL-C by 50%; Goal LDL-C <70 mg/dL

What should a risk discussion include?

• Clinicians and patients should engage in a risk discussion:

  1. Determine if ASCVD risk factors have been addressed

  2. Evaluate if lifestyle modifications have been implemented

  3. Review potential for adverse effects and DDI with lipid lowering therapy

  4. Consider patient preferences

• Consideration given to "risk enhancers" and CAC scoring

  1. Used to favor initiation or intensification of statin therapy

What are ASCVD risk enhancers?

• Family history of premature ASCVD

  • First degree relative: Male <55 years, female < 65 years

• Primary hypercholesterolemia

  • LDL-C of 160-189 mg/dL

• Persistently elevated primary hypertriglyceridemia (>/= 175 md/dL)

• CKD

  • eGFR < 60

  • ASCVD event reduction is less robust than patients without CKD

  • Moderate intensity statins are preferred to minimize the risk of adverse effects

  • Ezetimibe may also be used in combination with statin therapy

  • Current guidelines do not advocate for routine use of other nonstatin therapies

• Premature menopause (before age 40 years)

• History of preeclampsia

• South Asian ancestry

• Chronic inflammatory conditions

  • Psoriasis, rheumatoid arthritis, HIV/AIDS

• Metabolic syndrome (need 3 to make diagnosis)

  • Increased waist circumference

    • >40 inches males; >35 inches females

  • Elevated triglycerides >150 mg/dL

  • Elevated blood pressure (>130/85 mmHg)

  • Elevated blood glucose (fasting >/=100 mg/dL)

  • Low HDL-C of <40 mg/dL in men or <50 mg/dL in women

What is CAC?

• CAC (Coronary Artery Calcification)

  1. Predicts future ASCVD events

  2. Atherosclerotic plaques consists of cholesterol, fat, calcium, fibrin, and other cellular waster products

     1. CAC = 0; delay or withhold statin therapy Unless DM, and those with strong family history of premature ASCVD

     2. CAC = 1-99; favors statin therapy

     3. CAC >/= 100; statin therapy is indicated

What is treatment for patients 20-39 years old without diabetes?