Ezetimibe does not appear to be a substrate for cytochrome P450 enzymes. Experience to date reveals a low incidence of reversible impaired hepatic function with a small increase in incidence when given with a reductase inhibitor. Myositis has been reported rarely.
Microsomal triglyceride transfer protein (MTP) plays an essential role in the addition of triglycerides to nascent VLDL in liver, and to chylomicrons in the intestine. Its inhibition decreases VLDL secretion and consequently the accumulation of LDL in plasma. An MTP inhibitor, lomitapide, is available but is currently restricted to patients with homozygous familial hypercholesterolemia. It causes accumulation of triglycerides in the liver in some individuals. Elevations in transaminases can occur. Patients must maintain a low fat diet to avoid steatorrhea and should take steps to minimize deficiency of essential fat-soluble nutrients. Lomitapide is given orally in gradually increasing doses of 5-to 60-mg capsules once daily 2 hours after the evening meal. It is available only through a restricted (REMS) program for patients with homozygous familial hypercholesterolemia.
Mipomersen is an antisense oligonucleotide that targets apo B-100, mainly in the liver. It is important to note that the apo B-100 gene is also transcribed in the retina and in cardiomyocytes. Subcutaneous injections of mipomersen reduce levels of LDL and Lp(a). Mild to moderate injection site reactions and flu-like symptoms can occur. The drug is available only for use in homozygous familial hypercholesterolemia through a restricted (REMS) program.
Development of inhibitors of proprotein convertase subtilisin/ kexin type 9 (PCSK9) followed on the observation that loss of function mutations result in very low levels of LDL and no apparent morbidity. Therapeutic agents currently available in this class are humanized antibodies to PCSK9 (evolocumab, alirocumab). LDL reductions of up to 70% at the highest doses have been achieved with these agents when administered subcutaneously every two weeks. (Evolocumab can also be given monthly at a higher dose). Triglycerides and apo B-100 are reduced, and Lp(a) levels decrease by about 25%. Rarely, hypersensitivity reactions have occurred. Local reactions at the injection site, upper respiratory and flu-like symptoms have been observed more frequently. Use of these agents is restricted to patients who have familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional reduction of LDL. They are given with diet and maximal tolerated statin and/or ezetimibe. Development of small molecules and antisense oligonucleotides to inhibit PCSK9 is underway. Studies of PCSK9 inhibition should be approached with caution because of its established role in normal cell biology. These agents are very expensive.
Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from mature, large diameter HDL particles to triglyceride-rich lipoproteins that ultimately deliver the esters to liver whence both cholesterol and bile acids can be eliminated into the intestine. Inhibition of CETP leads to accumulation of mature HDL particles and diminution of the transport of cholesteryl esters to liver. The accumulation of large HDL particles does not have the cardioprotective effect anticipated on the basis of epidemiologic studies. Some reduction of LDL-C can be achieved and cholesterol efflux capacity enhanced. Thus far no drug (eg, torcetrapib, anacetrapib) in this class has been approved.