Description

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. (500 word min)

For your replies, select the threads of at least 2 classmates that discuss a drug other than the class you selected and contrast the mechanism of that drug with the mode of action of PCSK-9 inhibitors (discussed in the second website). Which one seems to be better for patients? (200 word min for each reply)

Here is the post that i need you to do a reply on :

first post:

The presence of blood cholesterol comes from two sources – hepatic cholesterol excretion and dietary intake. While cholesterol from the liver makes up about 75% of blood cholesterol, intestinal absorption accounts for the remaining 25%. Because of this, my proposal includes adding an intestinal-absorption-prevention medication to a statin-resistant patient’s medication regimen.

An example of this type of medication is Ezetimibe. This drug functions to reduce intestinal uptake of cholesterol, reducing blood cholesterol levels by up to 25%. Typically, the intestines absorb cholesterol through enterocyte membrane sterol influx transporters. There is a particular class of these transporters, a protein referred to as the Niemann-Pick C1-like protein, referred to as NPC1L1. NPC1L1 facilitates the transport of cholesterol-containing micelles from the intestinal lumen to the enterocyte. It works in conjunction with another protein, adaptor protein 2 (AP2), and clathrin in a complex micelle uptake system. (Phan et. Al., 2012)

Ezetimibe binds to NPC1L1, specifically in the jejunal brush border, inhibiting the protein’s transporting duties. Specifically, it is thought to disrupt the NPC1L1/AP2/clathrin bond, disabling the ability of NPC1L1 to bind with micelles. (Phan et. Al., 2012)

The inhibition of NPC1L1 creates a cascade of events. Cholesterol absorption into enterocytes is limited, chylomicron creation and secretion are thus reduced, and hepatic pools of cholesterol are depleted in an attempt to maintain enterocytic cholesterol levels. After depletion, the result is reduced serum LDL. (Phan et. Al., 2012)

When used alone (rather than in conjunction with statins as it is typically used), Ezetimibe reduces LDL by an average of 18.5%. HDL increases by an average of 3%, triglycerides reduce by 8%, and total cholesterol reduces by 13%. Therefore, an overall improvement in patient health can be expected. (Phan et. Al., 2012)

Unwanted physiological effects of Ezetimibe are limited to an increase in liver enzymes, such as transaminase. Adverse events related to Ezetimibe are infrequent. Liver failure while taking this medication has been documented but in minimal quantities. Long-term side effects that may occur when taking Ezetimibe include drowsiness, and temporary side effects include diarrhea, joint pain, and viral susceptibility. (Ezetimibe: Side effects, dosages, uses and more, 2018)

In comparison, statins’ mechanism of action includes the inhibition of MHG-CoA reductase. This enzyme’s responsibility is catalyzing the step of the cholesterol synthesis pathway comprising the conversion of HMG-CoA to mevalonate. This means that in the presence of statins, the synthesis of cholesterol will be reduced.

The cholesterol-lowering effects of statins are an average of 35% reduction in LDL, an average of 8% increased HDL, and 23% overall reduction in cholesterol. (Sizar et. Al., 2021)

Unwanted physiological effects of statins include elevated transaminases, myopathy, rhabdomyolysis, diabetes mellitus, and hepatotoxicity. Side effects that may be experienced by a patient taking statins include muscle joint and muscle pain, inflammation, confusion, headache, drowsiness, dizziness, diarrhea, bloating, and less common symptoms include hair loss, nausea, numbness, stomach and liver pain, rashes, low sex drive, and erectile dysfunction. (Side effects of cholesterol-lowering statin drugs, 2012)(Kapur, 2008)

Statins appear to be more effective in improving LDL, HDL, and overall cholesterol levels in patients with cholesterol-related pathology. However, the side effects of Ezetimibe are much less numerous and severe than those of statins. Additionally, as mentioned in the prompt, some patients do not respond as they should to statins. Therefore, Ezetimibe is an excellent alternative as it still demonstrates efficacy (though reduced) and has more minor side effects. (Ezetimibe: Side effects, dosages, uses and more, 2018)

References

Ezetimibe: Side effects, dosage, uses, and more. (2018). https://www.healthline.com/health/ezetimibe-oral-tablet

Kapur, N. (2008). Clinical efficacy and safety of statins in managing cardiovascular risk. Vascular Health and Risk Management, 4(2), 341-353. https://10.2147/VHRM.S1653

Phan, B. A. P., Dayspring, T. D., & Toth, P. P. (2012). Ezetimibe therapy: Mechanism of action and clinical update. Vascular Health and Risk Management, 8, 415-427. https://10.2147/VHRM.S33664

Side effects of cholesterol-lowering statin drugs. (2021) https://www.webmd.com/cholesterol-management/side-effects-of-statin-drugs

Sizar, O., Khare, S., Jamil, R. T., & Talati, R. (2021). Statin medications. StatPearls (). StatPearls Publishing.

Second Post

Introduction

Cholesterol is can be found in every cell and synthesized by the liver but possessing to much of it can lead to health problems. Cholesterol is a fat which needs a transport protein travel within the blood. Low density lipoprotein (LDL) and high-density protein (HDL) are what cholesterol attaches to while being transported. Elevated serum LDL-C can cause a buildup that causes arteries to become blocked that may lead to strokes and/or myocardial infarction.

Compare and contrast: Ezetimibe -VS- Statins

Ezetimibe and statins are both a class of drug that inhibits cholesterol from entering serum, reducing the chances of LDL-C building up and lowering the chance of cardiovascular events happening(Bruckert et al., 2003). Ezetimibe inhibits absorption of cholesterol from the small intestine through NPC1L1 (Niemann-Pick C1-like 1 protein), a major site of cholesterol absorption which allows for a moderate decrease of LDL-C. Decreasing cholesterol absorption in the small intestine decreases how much cholesterol is transported to the liver via chylomicrons. While statins reduce the amount of LDL-C is released from the liver through competitive inhibition of the HMA-Coa reductase reducing the amount of LDL receptors that are present on hepatocytes; though ezetimibe is commonly taken with or individuals that have shown an intolerance to statins(Feingold, 2000). Using Ezetimibe as a monotherapy (taken by itself) has not shown any major or significant side effects, though studies have shown when taken as a combination therapy with statins had shown a slight increase in of LDL-C in a liver function test. Statins have shown to increase the risk of developing diabetes and an even greater risk which is dependent on the type of therapy (intensive or moderate); Intensive therapies have shown to increase the risk of diabetes by twelve percent(Feingold, 2000; Preiss et al., 2011). Furthermore, statins increase the risk of muscle disorders, which includes myalgia, myopathy, myositis, myonecrosis, and Rhabdomyolysis. The muscle disorders that may occur with the use of statins may be dishearten, studies have demonstrated that these conditions were found to be rear in nature. But just like any other type of drug an individual may take, the increased risks of these disorders happening are dose dependent, studies have shown that the higher the dose of statins, the more likely an individual begin to develop these side effects(Feingold, 2000).

Efficacy

Ezetimibe mono and combination therapies

Monotherapy treatment of Ezetimibe of 8 studies with 2,722 patients combined has shown a decrease of LDL-C by 18.6 %, triglycerides by 8% and HDL-C by 3%. Furthermore, a combination therapy of 27 studies with 11,714 patients had shown decreasing levels of LDL-C of 15 %, triglycerides by 4.7 %, and an increase in HDL-C by 13.5%. Though a high dose regiment of the combination therapy has shown to lower LDL-C by 70%(Feingold, 2000).

Statin therapies

Statins have different efficacies for different types of statins, for example, 40mg rosuvastatin has shown to reduce LDL-C by 60%. Moreover, taking double the dose of statins has shown to increase the efficacy by 6%. Low starting dose and high starting dose have shown the same percent in decrease of LDL-C, though the higher dose has shown that the absolute decrease has been more impactful than the low starting doses(Feingold, 2000).

References

Bruckert, E., Giral, P., & Tellier, P. (2003). Perspectives in cholesterol-lowering therapy: The role of ezetimibe, a new selective inhibitor of intestinal cholesterol absorption. Circulation, 107(25), 3124–3128. https://doi.org/10.1161/01.CIR.0000072345.98581.24

Feingold, K. R. (2000). Cholesterol Lowering Drugs. In K. R. Feingold, B. Anawalt, A. Boyce, G. Chrousos, W. W. de Herder, K. Dungan, A. Grossman, J. M. Hershman, J. Hofland, G. Kaltsas, C. Koch, P. Kopp, M. Korbonits, R. McLachlan, J. E. Morley, M. New, J. Purnell, F. Singer, C. A. Stratakis, … D. P. Wilson (Eds.), Endotext. MDText.com, Inc. http://www.ncbi.nlm.nih.gov/books/NBK395573/

Preiss, D., Seshasai, S. R. K., Welsh, P., Murphy, S. A., Ho, J. E., Waters, D. D., DeMicco, D. A., Barter, P., Cannon, C. P., Sabatine, M. S., Braunwald, E., Kastelein, J. J. P., de Lemos, J. A., Blazing, M. A., Pedersen, T. R., Tikkanen, M. J., Sattar, N., & Ray, K. K. (2011). Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: A meta-analysis. JAMA, 305(24), 2556–2564. https://doi.org/10.1001/jama.2011.860