Inhibition of the mevalonate pathway: benefits beyond cholesterol reduction?

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG-CoA RIs) reduce plasma total and low-density lipoprotein cholesterol.1 Clinical studies with HMG-CoA RIs have shown a reduction in severity of arterial lesions and frequency of cardiovascular disease events.2,3 It is usually assumed that the beneficial effects of HMG-CoA RIs result from competitive inhibition of cholesterol synthesis.4 However, cholesterol is only one among many products of mevalonate, the product of HMG-CoA reductase. Mevalonate metabolism yields a series of isoprenoid compounds, including farnesyl, geranylgeranyl, and dolichol.4 Isoprenoids are necessary for cell proliferation and other important cell funtions.4 We hypothesise that reduction of isoprenoids may explain some of the beneficial effects of HMG-CoA RIs.