Squalene synthase inhibitors: Clinical pharmacology and cholesterol-lowering potential

HMG-CoA reductase inhibitors (statins) reduce cardiovascular disease morbidity and mortality with a high level of safety. Nonetheless, there are substantial numbers of people who either do not tolerate statins or whose low-density lipoprotein (LDL) levels are not lowered adequately. For these reasons, there is a need to develop other cholesterol-lowering drugs. A target for these new agents is provided by the enzymes distal to HMG-CoA reductase in the cholesterol biosynthesis pathway. Two classes of drugs have been developed: (i) squalene synthase inhibitors, which act at the first committed step in cholesterol biosynthesis, distal to the mevalonate-farnesyl diphosphate pathway; and (ii) oxidosqualene cyclase inhibitors, which act distal to the squalene intermediate. Of these, squalene synthase inhibitors have received more attention and are the subject of this review. Squalene synthase inhibitors decrease circulating LDL-cholesterol by the induction of hepatic LDL receptors in a similar manner to statins. They have fewer secondary effects mediated by a decrease in non-cholesterol products of mevalonate metabolism distal to HMG-CoA reductase, but have the potential to increase intermediates proximal to squalene. Squalene synthase inhibitors are just now entering clinical trials and data on how effectively they lower LDL-cholesterol and how they compliment the actions of statins and other agents is awaited with considerable interest.