From the Guidelines
Crestor (rosuvastatin) works by inhibiting HMG-CoA reductase, the key enzyme responsible for cholesterol synthesis in the liver, leading to increased expression of LDL receptors on liver cell surfaces and removal of more LDL cholesterol from the bloodstream. This mechanism of action is supported by the fact that HMG-CoA reductase inhibitors, including rosuvastatin, decrease cholesterol synthesis in hepatic cells, resulting in upregulation of LDL receptors and mainly lowering LDL cholesterol, with some decrease in triglycerides and modest increase in HDL cholesterol 1. The key effects of rosuvastatin include:
- Lowering LDL cholesterol
- Decreasing triglyceride levels
- Modestly increasing HDL cholesterol
- Having pleiotropic effects such as anti-inflammatory properties, improved endothelial function, and plaque stabilization, which contribute to its cardiovascular benefits. It is worth noting that rosuvastatin is particularly potent compared to other statins due to its high affinity for the enzyme and its selective uptake by liver cells, and it is typically dosed once daily with a long half-life allowing for 24-hour efficacy, and maximum cholesterol-lowering effects are usually seen within 2-4 weeks of consistent use. As stated in the guidelines, HMG-CoA reductase inhibitors, including rosuvastatin, are approved as an adjunct to diet to lower LDL cholesterol in adolescent boys and postmenarcheal girls aged 10–18 y with heFH and LDL cholesterol $190 mg/dL, or $160 mg/dL with family history of premature CVD and $2 CVD risk factors in the pediatric patient 1.
From the FDA Drug Label
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. Inhibition of HMG-CoA reductase by rosuvastatin accelerates the expression of LDL-receptors, followed by the uptake of LDL-C from blood to the liver, leading to a decrease in plasma LDL-C and total cholesterol.
The mechanism of action (MOA) of Crestor (rosuvastatin) is the inhibition of HMG-CoA reductase, which is the rate-limiting enzyme responsible for converting 3-hydroxy-3-methylglutaryl coenzyme A to mevalonate, a precursor of cholesterol. This inhibition leads to an increase in the expression of LDL-receptors, resulting in the uptake of LDL-C from the blood to the liver, and ultimately decreasing plasma LDL-C and total cholesterol 2.
Key points:
- HMG-CoA reductase inhibition
- Increased LDL-receptor expression
- Decreased plasma LDL-C and total cholesterol
From the Research
Mechanism of Action (MOA) of Crestor (Rosuvastatin)
- Crestor (rosuvastatin) is a synthetic statin that works by inhibiting the enzyme HMG-CoA reductase, which plays a key role in the production of cholesterol in the liver 3, 4.
- Rosuvastatin has a high affinity for the active site of HMG-CoA reductase and exhibits greater potency in inhibiting enzyme activity and cholesterol synthesis in vitro than other statins 4.
- The drug is selectively taken up by hepatic cells, where it inhibits the production of cholesterol, and has minimal uptake by nonhepatic tissues 3, 4.
- Rosuvastatin is relatively hydrophilic and is not extensively metabolized by the cytochrome P450 (CYP 450) enzyme system, which reduces the risk of drug interactions 3, 5.
Effects on Lipid Profiles
- Rosuvastatin has been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels by up to 63% and increase high-density lipoprotein cholesterol (HDL-C) levels by up to 14% 3.
- The drug also reduces triglycerides (TG) by up to 28% and slows the progression of atherosclerosis in coronary and carotid arteries 3, 6.
- Rosuvastatin has been shown to be more effective than other statins, such as atorvastatin, simvastatin, and pravastatin, in reducing LDL-C levels and improving lipid profiles 3, 5.
Clinical Efficacy and Tolerability
- Rosuvastatin has been shown to be effective in reducing the risk of major cardiovascular events in patients with normal LDL-C levels and elevated high-sensitivity C-reactive protein (hsCRP) levels 7.
- The drug is generally well tolerated, with a safety profile comparable to other statins, and the most common adverse events are myalgia, constipation, asthenia, abdominal pain, and nausea 3, 5.