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"Medical Journeys" is a set of clinical resources reviewed by physicians, meant for the medical team as well as the patients they serve. Each episode of this journey through a disease state contains both a physician guide and a downloadable/printable patient resource. "Medical Journeys" chart a path each step of the way for physicians and patients and provide continual resources and support, as the caregiver team navigates the course of a disease.

While bile acid sequestrants and other agents had some modest impact on cholesterol levels, statins ushered in the modern era of lipid management and remain the cornerstone of treatment.

Statins cut endogenous cholesterol production by inhibiting the hydroxymethylglutaryl-CoA reductase enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. This reduces hepatocyte cholesterol concentration, which triggers hepatic low density lipoprotein (LDL) receptor expression and clears LDL and its precursors from the circulation.

Clinical atherosclerotic cardiovascular disease (ASCVD) or severely elevated LDL (≥190 mg/dL) on their own should prompt statin treatment based on American Heart Association/American College of Cardiology (AHA/ACC) , and "moderate intensity generic statins allow for efficacious and cost-effective primary prevention in patients with a 10-year risk of ASCVD ≥7.5%," the guidelines note.

Those with an intermediate LDL level of 70-189 mg/dL are also candidates based on pooled cohort equations estimated risk of ASCVD of 5% or higher over 10 years in the absence of clinical ASCVD or diabetes.

Risk Enhancers

For patients with intermediate levels of risk based on LDL cholesterol and the risk-prediction score, risk-enhancing factors that can play into the discussion about whether to initiate treatment include:

• Family history of premature ASCVD (before age 55 for males and 65 for females)

• Persistently elevated LDL cholesterol ≥160 mg/dL

• Chronic kidney disease

• Metabolic syndrome

• Preeclampsia or premature menopause

• Inflammatory diseases, especially rheumatoid arthritis, psoriasis, and HIV

• South Asian ancestry

• Triglycerides persistently ≥175 mg/dL

While not recommended for routine measurement, other markers of elevated risk that can weigh in if measured in select individuals are a high-sensitivity C-reactive protein level of at least 2.0 mg/L, lipoprotein (a) levels over 50 mg/dL, apolipoprotein B of at least 130 mg/dL, and an ankle-brachial index less than 0.9.

If the risk decision remains uncertain, coronary artery calcium levels can be informative for selected adults. Finding a level of zero can move the decision toward no statin treatment, while anything higher favors prescription, especially after age 55 and definitely when the level reaches 100 or the 275th percentile.

Under U.S. guidelines, the impact of statins is tracked as a percentage reduction rather than a numerical target, with each 1% drop about a 1% reduction in ASCVD risk. The target is a 50% or greater reduction in LDL cholesterol for those with a predicted 10-year ASCVD risk of 20% or greater, which can typically be achieved by 80-mg atorvastatin or 20-mg rosuvastatin.

The goal is 30-49% LDL reduction for those with a 10-year risk of 7.5-19%, which can be achieved by 10-mg atorvastatin, 10-mg rosuvastatin, 20- to 40-mg simvastatin, 40-mg pravastatin, 40-mg lovastatin, and so forth.

Lipid-lowering therapy has been shown to be as in younger people.

Other Options

A range of other drugs can have a complementary role in LDL lowering.

For ASCVD patients, guidelines recommend adding non-statin agents to intensive statin therapy if LDL cholesterol levels remain at or above 70 mg/dL.

Most prominent among the non-statin lipid-lowering agents is ezetimibe (Zetia). This agent blocks absorption of cholesterol in the intestines and lowers LDL cholesterol by 13-20% when added to a statin regimen. It carries a low risk of side effects.

Bile acid sequestrants like colesevelam, colestipol, and cholestyramine bind to negatively charged bile acids in the intestines to block cholesterol absorption. As the liver makes more bile acid from circulating cholesterol, this lowers cholesterol levels typically by 15-30% depending on the dose.

Because bile acid sequestrants are excreted without being absorbed, they do not cause systemic side effects, although constipation and other gastrointestinal symptoms are not uncommon. These drugs can also exacerbate hypertriglyceridemia and must be used cautiously with regular monitoring for patients with triglyceride levels approaching 300 mg/dL so as not to cause pancreatitis.

PCSK9 inhibitors block these proteins from breaking down LDL receptors on the surface of liver cells so more LDL receptors remain available to bind to LDL cholesterol. These drugs can dramatically lower LDL levels by 43-46% when added to a statin therapy regimen.

This class of medications include the injectable monoclonal antibodies alirocumab (Praluent) and evolocumab (Repatha) and the injectable small interfering RNA agent inclisiran (Leqvio). They are generally well tolerated.

Evolocumab is approved for primary and secondary prevention; alirocumab and inclisiran are approved atop a statin for those with clinical ASCVD who need further lowering of LDL cholesterol. While a has suggested that inclisiran holds clinical outcome benefits like the other two, the randomized trials to prove it are ongoing. Guidelines give a class IIa recommendation to use in clinical ASCVD patients who are judged to be "very high risk" and still have LDL of 70 mg/dL or higher despite maximally tolerated statin therapy if the cost-to-benefit ratio is favorable.

Bempedoic acid (Nexletol) is an ATP citrate lyase inhibitor that targets cholesterol synthesis upstream of the enzyme inhibited by statins but similarly reduces hepatic cholesterol synthesis and raises LDL receptor expression to boost clearance of LDL cholesterol from the circulation. Bempedoic acid and its combination ezetimibe (Nexlizet) are approved for adults with either established atherosclerotic cardiovascular disease (CVD) or are at high risk for a CVD event to reduce the risk of myocardial infarction and coronary revascularization. Approval does not require patients to be on existing statin therapy. However, the drug has not yet been adopted into U.S. treatment guidelines.

While fibrates and niacin have a mild LDL-lowering effect, these triglyceride-lowering drugs have failed to show add-on benefit to statins in randomized controlled trials. "They may be useful in some patients with severe hypertriglyceridemia," according to the AHA/ACC guidelines, but that document does not include them among LDL-lowering medication options.

Read previous installments in this series:

Part 1: Hypercholesterolemia: A Complex System

Part 2: Consequences of Hypercholesterolemia

Part 3: Genetics of Hypercholesterolemia

Part 4: Case Study: High Lipoprotein(a) Levels in Younger Patients Are Not So Clear Cut

Part 5: The Shifting Epidemiology of Hypercholesterolemia

Part 6: Diagnosing Hypercholesterolemia

Part 7: Primary Prevention in Hypercholesterolemia

Part 8: Case Study: Teenage Girl's Shortness of Breath and Chest Pain

Up next: Familial Hypercholesterolemia Management