An Update on Statin Alternatives and Adjuncts

Matthew J Sorrentino


Clin Lipidology. 2012;7(6):721-730. 

In This Article

Intestinal Agents

The bile acid sequestrants (resins) bind bile acids in the GI tract preventing the return of bile acids to the liver through the enterohepatic circulation. To produce more bile acids, the liver increases synthesis of cholesterol and upregulates LDL receptors, increasing the clearance of LDL-C from the circulation. The resins can reduce LDL-C by 10–20% when used as monotherapy. These agents are especially useful as adjunct agents to low doses of statins in individuals that cannot tolerate higher doses of these agents. An additional 20–25% reduction in LDL-C can be achieved with the addition of a resin to a statin. Colesevelam has also been shown to improve glycemic control in patients with Type 2 diabetes mellitus with a mean reduction in hemoglobin A1c between 0.5 and 1% compared with placebo.[44]

Ezetimibe is a selective cholesterol absorption inhibitor that prevents the absorption of dietary and biliary cholesterol through the intestinal wall. The selectivity of ezetimibe does not affect absorption of triglycerides, bile acids or fat soluble vitamins. The target of ezetimibe is the NPC1L1 protein.[45] The binding of ezetimibe to this receptor blocks cholesterol uptake in the brush border membrane of the enterocyte. Following absorption, ezetimibe is glucoronidated in the intestinal wall and undergoes enterohepatic recirculation. The drug is then returned to its primary site of action in the intestine, limiting systemic exposure. Ezetimibe lowers LDL-C by between 15 and 20% as monotherapy, but may be more useful as adjunct therapy to lower-dose statins in a similar way to the resins. Outcome studies to determine if combination therapy with statins will achieve further cardiovascular risk reduction are ongoing.