Question

Work from the Brown and Goldstein lab provided insights into cholesterol homeostasis that were used to develop several of the LDL cholesterol-lowering therapies, including statins that remain in use today. However, in some patients, statins were not as effective as expected, suggestive of additional mechanisms regulating the LDL receptor. Investigate other LDL cholesterol-lowering therapies (other than PCSK-9 inhibitors), select 1, and compare and contrast the mechanisms of action between the class of drug you select and statins. Include side effects for both types of drugs and information on their efficacy.

Answer 1

The types of LDL cholesterol lowering thereapies other than statins and PCSK-9 inhibitors are by using

-Bile acid sequestrons which function by lowering the absorption of bile acids in the intestine, but these are not preferred as it results in absorption of many other drugs and have many undesirable GI side effects. It also lowers theglycemic levels.

- Ezetimibe therapy, ezetimibe is a non statin drug functions to lower the LDL cholestrol by blocking the NPC1L1 protein. This drug causes a reduction in the intestinal cholesterol absorption. It is less active when used seperately but is very effective when coupled with statin therapy.

- Mipomersan therapy, this is an oligonucleotide therapy which specifically binds to apolipoprotein B-100 mRNA resulting in reduction or non availability of apolipoprotein B resulting in reduction of hepatic LDL. But this is not preferred as it causes severe liver damage and can be used only with a risk management plan

-Lomitapide therapy, MTP inhibitor used in HoFH patients where statins have poor efficiency. the side effects are mostly based on GI tract.

I am selecting lomitapide against statins, as it is very efficient in patients where statins have not much of a use, like in homozygous familial hypercholesterolaemia - HoFH patients because they have minimal LDL receptor activity.

Statins function by inhibiting the HMG CoA reductase in the liver which causes a reduction in the liver cholesterol levels and thereby leading to an increase in the LDL receptors expression which in turn results in a reduction in the plasma cholesterol levels.The major side effects are muscle complications like myalgia and increased risk of diabetes. Statins are not effective in patients where LDL receptor activity is least. The efficacy in reducing LDL cholesterol is around 30-50% in patients where stains are effective.

Comparitively lomitapide functions by inhibiting microsomal triglyceride transfer protein resulting in reduction of VLDL release and VLDL mediated triglyceride secretion, leading to a decrease in plasma LDL concentration. It is very effective in HoFH patients where statins are not effective as these patients have very little receptor activity. The side effects are mostly GI tract disturbances. The efficacy is 40% in HoFH patients and hence a good alternative to statins.