From the Guidelines
Statins work by inhibiting the enzyme HMG-CoA reductase, the rate-limiting step in cholesterol synthesis, leading to an up-regulation of LDL receptors in the liver, as evidenced by a study published in 2020 1. Specifically, statins:
- Lower LDL ("bad") cholesterol levels
- Reduce cardiovascular events, with a 1 mM drop in LDL-cholesterol associated with a 21% drop in major vascular events, as shown in a recent meta-analysis 1
- Have beneficial effects across all age groups, with no effect on non-vascular mortality, cancer death, or cancer incidence 1 The mechanism of action of statins involves competitive inhibition of HMG-CoA reductase, which leads to a reduction in cholesterol production in the liver. By reducing cholesterol production, statins help prevent the buildup of plaque in arteries, lowering the risk of heart attacks and strokes. Regular monitoring of liver function is recommended when using statins, as they can occasionally cause liver enzyme elevations, due to their mechanism of action in the liver 1.
From the FDA Drug Label
Atorvastatin is a selective, competitive inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of sterols, including cholesterol Rosuvastatin is an inhibitor of HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol.
The mechanism of action of statins (HMG-CoA reductase inhibitors) is to inhibit HMG-CoA reductase, the rate-limiting enzyme that converts 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor of cholesterol. This inhibition leads to a decrease in cholesterol synthesis in the liver and an increase in the number of LDL receptors on the cell surface, resulting in enhanced uptake and catabolism of LDL 2 3.
- Key points:
- Inhibition of HMG-CoA reductase
- Decrease in cholesterol synthesis
- Increase in LDL receptors
- Enhanced uptake and catabolism of LDL
From the Research
Mechanism of Action of Statins
The mechanism of action of statins, also known as HMG-CoA reductase inhibitors, involves the inhibition of the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which is a key enzyme in the synthesis of cholesterol 4, 5, 6. This inhibition leads to a reduction in the production of cholesterol in the liver, resulting in lower plasma levels of low-density lipoprotein cholesterol (LDL-C) 4, 7.
Inhibition of HMG-CoA Reductase
Statins competitively inhibit the active site of the HMG-CoA reductase enzyme, preventing cholesterol synthesis and reducing the risk of developing cardiovascular disease 5. This inhibition also leads to a decrease in the synthesis of isoprenoids, which are important lipid attachments for intracellular signaling molecules, such as Rho, Rac, and Cdc42 6.
Pleiotropic Effects of Statins
In addition to their cholesterol-lowering effects, statins have been shown to have pleiotropic effects, including proangiogenic and antiangiogenic properties, which could offer new therapeutic applications 5, 6. These effects are thought to be mediated by the inhibition of small GTP-binding proteins, such as Rho, Rac, and Cdc42 6.
Nonenzymatic Mechanism of Statins
Recent studies have also shown that statins can modulate the formation of LDL and HDL cholesterol particles in vitro, indicating a novel nonenzymatic mechanism of statins 8. This mechanism involves the ability of statins to induce high-density cholesterol particle formation in buffer solution with or without the addition of human serum 8.
Key Findings
- Statins inhibit HMG-CoA reductase, leading to a reduction in cholesterol synthesis and lower plasma levels of LDL-C 4, 5, 6, 7.
- Statins have pleiotropic effects, including proangiogenic and antiangiogenic properties, which could offer new therapeutic applications 5, 6.
- Statins can modulate the formation of LDL and HDL cholesterol particles in vitro, indicating a novel nonenzymatic mechanism of statins 8.
- The use of more potent statins, such as atorvastatin and simvastatin, can lead to greater lowering of LDL-C and triglyceride levels, allowing more patients to achieve target goals 4.