Statins represent a class of cholesterol-lowering agents used for the treatment of dyslipidemia (abnormal amount of lipids) and the reduction of atherosclerotic cardiovascular disease risk. Their broad and potent effects on the lipid profile and cholesterol-independent pleiotropic cardioprotective effects positioned them among the most prescribed medications worldwide.

Statins were introduced in the late 1980s and early 1990s as a novel group of cholesterol-lowering drugs in attempt to offer patients with hypercholesterolemia a safe and effective means of reducing their plasma cholesterol. Research has shown that they not only have an important effect in reducing blood lipid levels, but also an individual’s risk of vascular disease in general.

Chemical structure and pharmacokinetics

The chemical structure of statins is constituted by two components; the pharmacophore, which is a dihydroxyheptanoic acid segment, and its moiety composed of a ring system with diverse substituents. Different statin groups can have certain differences in the structure, which in turn governs their water solubility and influences their absorption, distribution, metabolism and excretion.

Upon oral administration all statins are well absorbed from the intestine, albeit extensive first-pass metabolism occurs in the liver with the subsequent reduction of systemic bioavailability from 5 to 50%. Most statins are administered as beta-hydroxy-acids, except for lovastatin and simvastatin, which are pro-drugs that necessitate hepatic metabolism for their activation.

Lovastatin, simvastatin and pravastatin are derived from fungal metabolites with elimination half-lives between 1 and 3 hours. Atorvastatin, rosuvastatin, fluvastatin and pitavastatin are fully synthetic compounds, with elimination half-lives ranging from 1 hour for fluvastatin to 19 hours for rosuvastatin.

Lovastatin, simvastatin, atorvastatin, fluvastatin and pitavastatin are relatively lipophilic compounds. Lipophilic statins are more susceptible to metabolism by the cytochrome P(450) system, with the exception of pitavastatin which undergoes limited metabolism via this pathway. Liver and kidney are key players in the elimination of statins from the circulation through the bile and into the feces.

Mechanism of action

The beneficial effects of statins stem from their capacity to reduce cholesterol biosynthesis, predominantly in the liver where they are selectively distributed, as well as the propensity to modulate lipid metabolism via competitive, reversible inhibition of HMG-CoA (3-hydroxy-3-methyl-glutaryl-CoA) reductase – the rate-limiting step in cholesterol biosynthesis.

HMG-CoA reductase catalyzes the conversion of HMG-CoA to L-mevalonate and coenzyme A through four-electron reductive deacetylation. The pharmacophore of all statins bears resemblance to the endogenous HMG-CoA moiety, thus it competitively binds to the catalytic domain of HMG-CoA reductase, causing steric hindrance and halting HMG-CoA from accessing the active site.

Their antiatherosclerotic effects positively correlate with the percent decrease in LDL cholesterol, but such effects can be exerted independently of their hypolipidemic action. Such non-lipid effects at least partly reflect statins’ ability to block the synthesis of significant isoprenoid intermediates, which act as lipid attachments for a plethora of intracellular signaling molecules.

Because the mevalonate metabolism generates a series of isoprenoids pivotal for different cellular functions – from cholesterol synthesis to the control of cell growth and differentiation – HMG-CoA reductase inhibition has beneficial pleiotropic effects, i.e.effects on vascular function and hemostasis, anti-inflammatory effects and stabilizing effects on the atherosclerotic plaques.

Furthermore, it has been reported that statins inhibit the migration and proliferation of vascular smooth cells and macrophages, and also decrease interleukin-6 and inducible nitric oxide synthase expression. These agents may affect erythrocyte deformability, thrombus formation and levels of plasminogen activator inhibitor-1, with possible significant differences among the different molecules.

These drugs also significantly reduce the incidence of coronary events, both in primary and secondary prevention, reducing in turn the rate of mortality in coronary patients. Independent of their hypolipidemic properties, it has been shown that statins interfere with events involved in bone formation and impede tumor cell growth.