Lipids 2

What are the two big questions a provider asks when managing hyperlipidemia?

(1) How do we use screening tools and assessment scores to determine when to initiate treatment? (2) Which medication(s) do we prescribe?

What is primordial prevention?

Preventing or delaying the onset of dyslipidemia.

What is the focus and timeframe of primordial prevention?

Childhood through adulthood - establishing and sustaining healthy habits, focusing on diet and physical activity.

What is primary prevention (of ASCVD)?

Prevention of clinical ASCVD - reducing future risk before an event occurs.

What three events count as an ASCVD event?

Myocardial infarction, ischemic stroke, and symptomatic peripheral artery disease.

What factors are considered in primary prevention decisions?

Calculated risk, comorbidities, life expectancy, and patient preferences.

ASCVD risk is reduced in proportion to what?

The reduction in LDL cholesterol.

When lifestyle interventions are not enough, which therapy is most effective for lipid-lowering?

Statins.

What is secondary prevention?

Reducing the risk of a subsequent event in a patient who has already had at least one clinical event.

What is the first question to ask in secondary prevention?

Is the patient considered 'at very high risk'?

In a low-risk patient (<3% 10-yr risk), when is a statin started?

If LDL-C is 160-189 mg/dL or the 30-year ASCVD risk is ≥10% - start a moderate-intensity statin; otherwise health behavior counseling.

What is the statin goal for a low-risk patient who qualifies for treatment?

≥30% LDL-C reduction, LDL-C <100, and non-HDL-C <130 mg/dL.

How is a borderline-risk patient (3-<5%) managed?

Decide whether to start lipid-lowering therapy; if yes, a moderate-intensity statin (goal ≥30% reduction, LDL <100, non-HDL <130).

How is an intermediate-risk patient (5-<10%) managed?

Start a moderate- to high-intensity statin (goal ≥30-50% reduction, LDL <100, non-HDL <130).

What is used in an intermediate-risk patient when the decision to start therapy is uncertain?

CAC assessment: CAC >0 → initiate statin; CAC 0 → health behavior counseling and repeat CAC in 3-7 years.

How is a high-risk patient (≥10%) managed?

Start a high-intensity statin (goal ≥50% reduction, LDL <70, non-HDL <100); if goals aren't met, add ezetimibe, then a PCSK9 mAb or bempedoic acid.

What LDL-C level defines severe hypercholesterolemia?

>190 mg/dL.

How is severe hypercholesterolemia (LDL >190) treated?

A high-intensity statin, regardless of calculated risk.

What LDL reduction defines a high-intensity statin?

≥50% LDL reduction.

What LDL reduction defines a moderate-intensity statin?

30-49% LDL reduction.

What LDL reduction defines a low-intensity statin?

<30% LDL reduction.

Which statins/doses are high-intensity?

Atorvastatin 80 mg (40 mg if not tolerated) and rosuvastatin 20-40 mg daily.

Which statins/doses are moderate-intensity?

Atorvastatin 10-20 mg, rosuvastatin 5-10 mg, simvastatin 20-40 mg, pravastatin 40-80 mg, and lovastatin 40-80 mg.

Which statins/doses are low-intensity?

Simvastatin 10 mg, pravastatin 10-20 mg, and lovastatin 20 mg.

In secondary prevention, what does 'very high risk' include?

ASCVD with CKD (among other very-high-risk features).

What statin is started in secondary prevention?

A high-intensity or maximally tolerated statin.

What are the LDL goals for a very-high-risk secondary-prevention patient?

≥50% LDL reduction, LDL-C <55, and non-HDL-C <85 mg/dL (optional apoB <55).

If a very-high-risk patient isn't at goal on a maximal statin, what is added?

Ezetimibe and/or a PCSK9 mAb.

If a secondary-prevention patient can't tolerate a PCSK9 mAb, what is used?

Inclisiran.

If a very-high-risk patient still isn't at goal after ezetimibe and PCSK9 therapy, what is added?

Bempedoic acid.

What are the LDL goals for a NOT-very-high-risk secondary-prevention patient?

≥50% LDL reduction, LDL-C <70, and non-HDL-C <100 mg/dL (optional apoB <70).

If a not-very-high-risk patient isn't at goal, what is added?

Ezetimibe, a PCSK9 mAb, and/or bempedoic acid.

What dietary pattern is recommended for hypercholesterolemia?

Emphasize vegetables, fruits, whole grains, healthy protein sources, and fiber; limit sugars, simple carbohydrates, and red meats.

What is the recommended exercise prescription for hypercholesterolemia?

Aerobic physical activity 3-4 sessions per week for 30-40 minutes.

What is the weight loss target for hypercholesterolemia?

A loss of 5-10% of body weight.

Besides diet, exercise, and weight loss, what other lifestyle measures are recommended?

Smoking cessation, reduced alcohol consumption, and optimizing comorbidities.

At what triglyceride range is CV risk highest?

500-880 mg/dL.

At what triglyceride level does pancreatitis risk increase, and when is it particularly high?

Risk increases with TG >500 mg/dL and is particularly high with TG >1000 mg/dL.

If triglycerides are >1000 mg/dL, what takes priority?

Lowering TG to reduce the risk of pancreatitis.

What is first-line therapy for all patients with hypertriglyceridemia?

Lifestyle modifications.

When are statins first-line pharmacologic therapy in hypertriglyceridemia?

When TG <1000 mg/dL, to reduce ASCVD risk.

How do statins lower triglycerides?

Modestly, by inhibiting VLDL assembly and secretion.

In hypertriglyceridemia, what determines the need for additional therapy beyond general measures?

The TG level and prior history of pancreatitis.

What defines 'high risk' in hypertriglyceridemia management?

Established ASCVD or diabetes mellitus PLUS two additional risk factors.

Name additional risk factors used to define high risk in hypertriglyceridemia.

Age >50, smoking, HTN, ABI <0.9, retinopathy, albuminuria, HDL <40 (males)/<50 (females), CRP >3 mg/L, and CrCl <60 mL/min.

What triglyceride level is normal?

<150 mg/dL.

What triglyceride range is moderate?

150-499 mg/dL.

What triglyceride range is moderate-to-severe?

500-999 mg/dL.

What triglyceride level is severe?

>1000 mg/dL.

What is the key goal in managing moderate hypertriglyceridemia (150-499)?

Reduce the risk of ASCVD events.

How is moderate hypertriglyceridemia managed initially?

ASCVD risk assessment, LDL management, and nonpharmacologic measures; reassess the need for further therapy after 4-12 weeks.

In moderate hypertriglyceridemia with high ASCVD risk, what is added?

High-dose marine omega-3 fatty acid (icosapent ethyl).

In moderate hypertriglyceridemia without high risk, what is done?

Continue general measures and LDL optimization.

What is the key goal in moderate-to-severe hypertriglyceridemia (500-999)?

Reduce the risk of both ASCVD and pancreatitis.

When is additional therapy added in moderate-to-severe hypertriglyceridemia?

If TG remains moderate-to-severe despite 12 weeks of lifestyle modifications and optimal lipid-lowering medications.

In moderate-to-severe hypertriglyceridemia with high risk, what is the initial agent and next step?

Initial agent is icosapent ethyl; if insufficient, add fibrate therapy.

In moderate-to-severe hypertriglyceridemia without high risk, what is the initial agent and next step?

Initial agent is a fibrate; if insufficient, add omega-3 fatty acids.

What is the key goal in severe hypertriglyceridemia (>1000)?

Reduce the risk of both ASCVD and pancreatitis.

What genetic condition should be tested for in severe hypertriglyceridemia?

Familial chylomicronemia syndrome (FCS).

How is severe hypertriglyceridemia managed without FCS?

Strict dietary adherence until TGs are <1000, then initiate triglyceride-specific therapy (fibrates, omega-3s).

How is severe hypertriglyceridemia managed with FCS?

Olezarsen.

How does olezarsen work?

It reduces production of apolipoprotein C-III (apoC-III), which regulates triglyceride metabolism.

Give example statins.

Atorvastatin, rosuvastatin, simvastatin, pravastatin, lovastatin.

What is the mechanism of statins?

They inhibit HMG-CoA reductase, the enzyme used to form cholesterol, reducing its synthesis.

What are the lipid effects of statins?

Decreased LDL, decreased triglycerides, and a modest increase in HDL.

What are the common adverse effects of statins?

GI symptoms, rash, and muscle aches.

What is myositis in the context of statins?

Muscle inflammation with moderately elevated CK levels.

What is rhabdomyolysis in the context of statins?

Severe muscle breakdown with markedly elevated serum CK levels.

What liver-related adverse effects can statins cause?

Liver disease with elevated serum transaminases, and liver failure.

What is the contraindication to statins?

Pregnancy.

Name patient factors that increase the risk of statin-attributed muscle symptoms.

Age ≥65, low BMI, female sex, obesity, hypothyroidism, diabetes, chronic liver disease, CKD, alcohol, vigorous exercise, high-dose statins, myalgia-associated diseases, drug interactions affecting statin metabolism, and gene variants (e.g., SLCO1B1).

What is the mechanism of ezetimibe?

It decreases intestinal absorption of dietary and biliary cholesterol.

How much does ezetimibe lower LDL as monotherapy?

15-20%.

Does ezetimibe affect VLDL or HDL?

No.

When is ezetimibe the first choice?

When a patient is unable to tolerate or unwilling to take statins (it is available PO and inexpensive).

What are the adverse effects of ezetimibe?

Uncommon - GI upset and, very rarely, liver damage.

What are acceptable alternatives to ezetimibe for statin-intolerant patients at high ASCVD risk?

Bempedoic acid or evolocumab (a PCSK9 inhibitor).

What is the mechanism of bempedoic acid?

It targets cholesterol synthesis in the liver (available PO).

How much does bempedoic acid lower LDL when combined with statins?

An additional ~20%.

What are the adverse effects of bempedoic acid?

Hyperuricemia/gout, cholelithiasis, limited muscle aches, and a moderate increase in the risk of tendon rupture.

What does PCSK9 stand for?

Proprotein Convertase Subtilisin/Kexin Type 9.

Give examples of PCSK9 inhibitors.

Alirocumab, evolocumab, and inclisiran.

How are PCSK9 inhibitors administered?

Via subQ injection - the -mab agents every 2-4 weeks; inclisiran as an initial dose, a 3-month dose, then every 6 months.

How much do PCSK9 inhibitors lower LDL?

40-60%.

What effect do PCSK9 inhibitors have on lipoprotein(a)?

Lower it by up to 20-30%.

What are PCSK9 inhibitors FDA-approved for?

Familial hypercholesterolemia, and CVD/high CVD risk requiring further lipid-lowering.

What are the adverse effects of PCSK9 inhibitors?

Injection-site reactions (soreness, infection risk); they are also very expensive.

Give example bile acid-binding resins.

Cholestyramine, colesevelam, colestipol.

What is the mechanism of bile acid-binding resins?

Positively-charged resins bind negatively-charged bile acids in the intestine, reducing plasma LDL.

Why are bile acid resins less effective than statins?

The liver increases HMG-CoA reductase, synthesizing more cholesterol.

How much do bile acid resins lower LDL?

~15-25%.

What happens to triglycerides with bile acid resins?

They tend to increase in some patients.

What are the adverse effects of bile acid resins?

GI symptoms, gallstone formation, interference with fat-soluble vitamin absorption, and binding of other medications (take separately).

What is the contraindication to bile acid resins?

Triglyceride levels >500 mg/dL.

Which lipid-modifying medication is the only one safe in both pregnancy and lactation?

Bile acid-binding resins.

Give an example omega-3 fatty acid medication.

Icosapent ethyl.

What is the mechanism of omega-3 fatty acids?

They reduce VLDL production in the liver and enhance triglyceride clearance from the bloodstream.

What are the adverse effects of omega-3 fatty acids?

Unusual bleeding, arrhythmia, and dizziness/lightheadedness.

In which patients should omega-3 fatty acids be used with caution?

Those with a known allergy or sensitivity to fish and/or shellfish.

Give example fibric acid derivatives (fibrates).

Fenofibrate and gemfibrozil.