How do statins work?

Cholesterol plays a myriad of important functions in the body, ranging from cellular membrane physiology and dietary nutrient absorption to reproductive functions and stress responses.¹ However, high cholesterol is a risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), along with other risk factors such as diabetes, smoking, and hypertension. ASCVD includes coronary heart disease (CHD), stroke, and peripheral artery disease, and is one of the leading causes of death in the United States.² According to the 2018 cholesterol guidelines³ by the American College of Cardiology and American Heart Association, varying intensities of statin therapy are recommended as adjunct therapies to a heart-healthy lifestyle and diet for patients with ASCVD. They are also recommended for the primary prevention of ASCVD for patients who have hypercholesterolemia and a high-risk of developing ASCVD. The most potent statins at maximal doses can reduce low-density lipoprotein cholesterol (LDL-C) by 55% to 60% on average.⁴

Statins are a class of medications that lower cholesterol levels by inhibiting hydroxymethyglutaryl-CoA (HMG-CoA) reductase enzyme.^5,6 HMG-CoA reductase enzyme is an early rate-limiting step in cholesterol biosynthesis and converts HMG-CoA to mevalonate in the “mevalonate pathway”. The mevalonate pathway is a multi-branch biosynthetic pathway for cellular cholesterol synthesis. Statins lower cholesterol biosynthesis by acting on a crucial step in this pathway by selectively inhibiting the HMG-CoA reductase enzyme in the liver. This results in reduced mevalonate synthesis and decreased hepatic concentrations of cholesterol. This decrease in intracellular cholesterol biosynthesis leads to upregulated expression of HMG-CoA reductase and LDL-receptors (LDL-R) in hepatic cell membranes.⁷ The increased LDL-R expression facilitates the clearance of LDL-C particles circulating in the blood. In addition to lowering circulating LDL-C levels, statins can increase high-density lipoprotein cholesterol and reduce triglyceride concentration.

There are many other secondary mechanisms by which statins improve the profile of atherogenic lipoproteins in the blood.⁷ Statins inhibit hepatic synthesis of apolipoprotein B100 and the synthesis of triglyceride-rich lipoproteins. In addition to these lipid-modifying properties, statins show cardiovascular benefits by inhibiting nonsteroidal isoprenoid compound synthesis, improving endothelial cell function through vasodilation,⁵ and reducing smooth muscle cell proliferation and cholesterol accumulation. All these secondary effects result in reducing general inflammatory processes that partly decrease levels of C-Reactive Protein (CRP).⁸ Statin-induced decrease in levels of CRP has been linked to lower cardiovascular events even in patients without hypercholesterolemia.

^References

1. Tabas I. Cholesterol in health and disease. J Clin Invest. 2002;110(5):583-590.
2. Kochanek KD, Murphy SL, Xu JQ, Arias E. Mortality in the United States, 2016. NCHS Data Brief, no 293. Hyattsville, MD: National Center for Health Statistics. 2017.
3. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2018.
4. Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol 2019; 39 (2): e38-e81.
5. Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3-11.
6. Lennernas H, Fager G. Pharmacodynamics and pharmacokinetics of the HMG-CoA reductase inhibitors. Similarities and differences. Clin Pharmacokinet. 1997;32(5):403-425.
7. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19(1):117-125.
8. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA. 2001;286(1):64-70.