Low Density Lipoprotein (LDL)

Low density lipoprotein (LDL) is one of several lipoprotein particles that transport cholesterol (a lipophilic molecule) through the aqueous environment of the blood. Other cholesterol carriers include high-density lipoprotein (HDL), very low density lipoprotein (VLDL) and chylomicrons. [Huff 2020;1b; Grundy 2018;7a]

Cholesterol has several essential functions, including modulating cell membrane fluidity and serving as a metabolic precursor for the synthesis of vitamin D, steroid hormones and sex hormones. [Huff 2020;1a] The liver packages endogenously synthesized and exogenously acquired cholesterol into VLDL particles, which are then converted into LDL particles in the bloodstream. The LDL particles are taken up in peripheral tissues by endocytosis. [Luo 2019;1a]

Despite its central role in several metabolic processes, elevated levels of serum cholesterol (hypercholesterolemia) are associated with increased risk for atherosclerotic cardiovascular disease (ASCVD). [Pirahanchi 2020;2b; Grundy 2018;8a] LDL and VLDL are the primary atherogenic particles; HDL appears to not be atherogenic, while the atherogenicity of chylomicrons is unknown. [Grundy 2018;7a] When present in excess, LDL cholesterol (LDL-C) is deposited within blood vessel walls. Smooth muscle cells infiltrate these lesions and encapsulate the lipid deposits, leading to formation of atherosclerotic plaque. Plaques are pathogenic via two major mechanisms: 1) progressive atherosclerotic obstruction of the vessel (causing ischemia); and 2) plaque rupture with thrombus formation. [Huff 2020;2b]

Population studies from the United States suggest that the optimal level of LDL-C to minimize CV risk is below 100 mg/dL. [Grundy 2018;7b] According to the Adult Treatment Panel III (ATP III), the standard levels for LDL-C are as follows: [Lee 2020;2a-b]

• Optimal: less than 100 mg/dL
• Near optimal/above optimal:100 to 129 mg/dL
• Borderline high: 130 to 159 mg/dL
• High: 160 to 189 mg/dL
• Very high: greater than 190 mg/dL

Because LDL-C is the primary driver of atherosclerosis, lowering LDL-C has become a major focus of primary and secondary ASCVD preventive patient care. [Grundy 2018;8a; Huff 2020;2a]

Interventions to lower LDL-C

In addition to a heart-healthy lifestyle, which includes a diet rich in fruits, vegetables and healthy protein sources, avoidance of weight gain and regular physical exercise, there are several pharmacological options to lower LDL-C levels. [Grundy 2018;9a]

By far the most important LDL-C-lowering medications are the HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase inhibitors — or statins. Statins inhibit the conversion of HMG-CoA to mevalonate, a metabolic precursor of cholesterol. [Pirahanchi 2020;2c] Other efficient LDL-C-lowering drugs include ezetimibe, which inhibits cholesterol absorption in the small intestine; bile acid sequestrants, which channel more cholesterol to bile acid synthesis to replace the sequestered bile acids, reducing the amount of LDL in the circulation; and PCSK9 inhibitors, which inactivate LDL receptors on target tissues. [Grundy 2018;10b-c] The triglyceride-lowering drugs — fibrates and niacin— also have a mild LDL-C-lowering effect. [Grundy 2018;10c] Bempedoic acid, a once-daily LDL-C-lowering therapy that is designed to work in the liver to inhibit cholesterol biosynthesis, was approved by the FDA in February 2020. Inclisiran, a twice-yearly small-interfering RNA therapy for LDL-C lowering, was approved by the FDA in December 2021.

The indications for the use of statins and other LDL-C-lowering medications depend on several factors, including the absence or presence of clinically evident ASCVD (ie, primary or secondary prevention), the presence of other comorbidities and LDL-C levels. The 2018 American College of Cardiology/American Heart Association guidelines on blood cholesterol management include the following “take-home messages” to reduce ASCVD on the basis of LDL-C levels:

• In patients with clinical ASCVD, reduce LDL-C with high-intensity statin therapy or maximally tolerated statin therapy. [Grundy 2018;3b]
• In very high-risk ASCVD, use an LDL-C threshold of 70 mg/dL to consider the addition of non-statins to statin therapy. [Grundy 2018;3c]
• In patients with severe primary hypercholesterolemia (LDL-C level ≥ 190 mg/dL), begin high-intensity statin therapy without calculating 10-year ASCVD risk. [Grundy 2018;3d]
• In patients aged 40 to 75 years with type 2 diabetes and LDL-C of at least 70 mg/dL, start moderate-intensity statin therapy without calculating 10-year ASCVD risk. [Grundy 2018;3e]
• In adults aged 40 to 75 years without diabetes and with LDL-C levels of at least 70 mg/dL, at a 10-year ASCVD risk of 7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy. [Grundy 2018;3f]

The guidelines also state that adherence and percentage response to LDL-C–lowering medications and lifestyle changes should be assessed with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, and repeated every 3 to 12 months as needed. [Grundy 2018;4b]

References:

• Grundy SM, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.11.003.
• Huff T, et al. Physiology, Cholesterol. [Updated 2021 Mar 2]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-.
• Lee Y, et al. Cholesterol Levels. 2021 Jul 26. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.
• Luo J, et al. Nat Rev Mol Cell Biol. 2020;doi:10.1038/s41580-019-0190-7.
• Pirahanchi Y, et al. LDL Cholesterol. 2021 Aug 15. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.