LDL Cholesterol: Controversies and Future Therapeutic Directions

Perspective:

This article is the first in a series on lipids and cardiovascular disease (CVD). The following are 10 points to remember from a review about low-density lipoprotein (LDL) cholesterol:

1. LDL cholesterol is a key determinant of vascular risk and central to the development of atherothrombosis. The concept of ‘cholesterol years of exposure’ implies that reduction of LDL early in life may lead to significant, long-term gains.

2. Compared to fasting concentrations, nonfasting lipid concentrations are similarly predictive of incident cardiovascular events. Assessment of lipids in the nonfasting state may improve clinical efficiency.

3. There are limitations to both the indirect calculation of LDL cholesterol with the Friedewald equation (which might underestimate the true LDL concentration when triglycerides are high) and direct measurement of LDL cholesterol (which may not be as accurate in patients with hepatic or renal dysfunction, paraproteins, and some heritable hyperlipidemias). These limitations can be potentially overcome with the use of non–high-density lipoprotein cholesterol concentrations for screening purposes and for on-treatment assessment.

4. Although statin therapy may be associated with a small risk of developing diabetes, the benefits of vascular event reduction outweigh the risks in patients both at low and high risk for diabetes.

5. The most recent US guidelines for management of high cholesterol in adults no longer advocate for treatment to specific LDL cholesterol targets. Instead, the guidelines advocate the use of higher-intensity statin agents in those at higher absolute risk. Current European and Canadian guidelines have maintained LDL targets.

6. In addition to assuaging the atherothrombotic process, statins also have anti-inflammatory properties. These anti-inflammatory effects are expressed in the ability of statins to reduce high-sensitivity C-reactive protein (hs-CRP) concentrations. However, the only evidence-based response to persistently elevated hs-CRP despite statin therapy would be to increase the dose of the current statin.

7. Although nonstatin medications (bile acid-binding resins, fibrates, and niacin) can improve lipid profiles in many patients, there is little evidence to support their use as monotherapy or as an adjunct to statins in the general population.

8. Neither the AIM-HIGH nor HPS-2-THRIVE trials showed efficacy for niacin in the reduction of cardiovascular events; both trials demonstrated a hazard for gastrointestinal events and infection.

9. Proprotein convertase subtilisin kexin type 9 (PCSK9), a protein secreted by the hepatocytes and which binds to the LDL receptor, is a promising novel target for LDL cholesterol reduction. PCSK9, once bound to the LDL receptor, leads to its cellular internalization and subsequent lysosomal degradation. Gain-of-function mutations in PCSK9 are associated with severe hypercholesterolemia phenotypes. Phase 3 trials will assess the value of monoclonal antibodies targeting PCSK9 (a strategy that results in large reductions in plasma LDL cholesterol when given as monotherapy or to patients already on statins).

10. Early reduction of LDL cholesterol, as through aggressive diet and lifestyle changes in youth and young adulthood, is most likely to result in the largest absolute risk reduction.

Clinical Topics: Dyslipidemia, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Life Style, Cholesterol, LDL, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hepatocytes, Bile Acids and Salts, Receptors, LDL, Hypercholesterolemia, Mutation, Proprotein Convertases, Fibric Acids, C-Reactive Protein, Subtilisins, Cardiovascular Diseases, Niacin, Diabetes Mellitus


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