George Livingston M.S. in Biochemistry

Introduction

Atherosclerosis, a chronic inflammatory disease, is a leading cause of cardiovascular disease. It involves the buildup of plaque within the arterial walls, leading to reduced blood flow and potentially severe consequences like heart attack and stroke. To manage this condition, lipid-lowering medications, such as statins, fibrates, and niacin, are commonly prescribed. The following discussion seeks to answer the question of “how?” these medications, through different mechanisms, elicit their desired therapeutic effect in the treatment of atherosclerosis.

Statins inhibit the enzyme HMG-CoA reductase, which is involved in cholesterol synthesis in the liver. This leads to a decrease in LDL cholesterol (the “bad” cholesterol) and a slight increase in HDL cholesterol (the “good” cholesterol).

Fibrates activate a nuclear receptor called PPAR-alpha, which affects the liver’s ability to process fats. This can lead to a decrease in triglycerides (another type of fat in the blood) and an increase in HDL cholesterol.

Niacin works by reducing the liver’s production of VLDL cholesterol, a precursor to LDL cholesterol. It also increases HDL cholesterol levels. However, niacin can cause side effects like flushing, liver damage, and digestive upset.

Fibrates versus Statins in Atherosclerosis Treatment

Fibrates and statins are both effective in the treatment of atherosclerosis, but they have different mechanisms for achieving the desired lipid lowering effect to prevent plaque buildup in arteries. Statins are members of the hydroxymethylglutaryl-coenzyme A (HMG CoA) reductase inhibitor drug class, but fibrates are members of the peroxisome proliferator-activated receptor (PPAR) alpha agonists drug class [1]. These two medications can be taken in combination in certain cases, but there is an increased risk of side effects when taking statins in combination with fibrates [2]. Some fibrates, like gemfibrozil, are not advised to be combined with statins because they have a high incidence of muscle pain, weakness, and rhabdomyolysis [2]. Fenofibrate is a safer option when considering combination treatment with statins. Overall, these two medications accomplish the same goal, just via different mechanisms, for they lower lipid levels to prevent arterial plaque accumulation. 

Statins are a first line medication for treating atherosclerosis because they lower serum lipid levels via the inhibition of HMG CoA reductase. Farnesyl pyrophosphate (FPP) is the last intermediate within the metabolic pathway associated with cholesterol synthesis. FPP is the precursor for many different isoprenoid compounds, such as cholesterols (including LDLs). HMG CoA reductase facilitates a much earlier step in the metabolic path, so inhibitors of that enzyme will prevent the continuation of the metabolic path that leads to FPP and, consequently, cholesterol synthesis. 

Fibrates take a different approach to lowering serum lipid levels. Instead of inhibiting an enzyme, they activate a receptor. Fibrates have been proven as potent activating ligands for PPARs. The function of PPARs is to regulate lipid metabolism, and their activation is associated with metabolizing triglycerides, which stimulates the liver to produce more apolipoprotein A-I (ApoA-I) and apoA-II. These proteins are the major components of HDL particles and are essential for HDL assembly [3]. Fibrates have also been associated with uptake of LDLs from the blood because they activate LDL receptors on cell surfaces. This LDL lowering is significantly lesser than that of which is associated with statins. The primary function of fibrates is to decrease triglyceride levels and stimulate HDL production.

Lipid-Lowering Actions of Niacin

Niacin (AKA vitamin B3) has also been used as a lipid lowering treatment for patients with excessive lipid serum levels. It partially accomplishes this by acting as an agonist for PPARs [4]. In this way, it functions similarly to fibrates [3,4]. Niacin also regulates energy metabolism, so it can indirectly affect lipid metabolism [4]. Since levels of free fatty acids become lowered via niacin’s down regulating action of cyclic adenosine monophosphate, there is a prevention of the formation for the required reactants to complete intracellular lipid catabolism [4]. Therefore, the rate at which ApoA-I-containing lipoproteins, such as HDLs, get degraded is decreased [4]. By inhibiting triglyceride synthesis, VLDLs and LDLs cannot be formed because they require triglycerides. This means that VLDLs and LDLs are catabolized for their triglycerides because the liver is not producing them due to the action of niacin. Niacin is being used to treat an array of different chronic issues and diseases alongside high cholesterol. In many cases, it is administered as a pleiotropic agent [4]. 

Known side effects of this water soluble vitamin (B3) are typically not severe because it can easily be filtered and excreted through the nephro-urology system. It is a well tolerated medication, but some common side effects include flushing, liver damage, and stomach upset [1]. Flushing can be counteracted by taking specific NSAIDs beforehand. Liver damage can be prevented by having regular blood tests and not taking excessive amounts of niacin (more than what is prescribed). Nausea can usually be prevented by not taking niacin on an empty stomach.

Conclusion

In conclusion, both statins and fibrates are valuable tools in the management of atherosclerosis. Statins, as first-line therapy, primarily target cholesterol synthesis, while fibrates focus on triglyceride reduction and HDL elevation. While both medications can be used in combination, careful consideration is necessary due to potential side effects, particularly muscle-related adverse events. Niacin, another lipid-lowering agent, can be a useful adjunct therapy, especially in patients with low HDL levels or mixed dyslipidemia. While it can cause side effects like flushing, these can often be mitigated with appropriate dosing and timing. As with any medication, the decision to use niacin should be made on an individual basis, weighing the potential benefits against the risks.

References

[1] Wecker, Lynn. Brody’s Human Pharmacology. Elsevier Health Sciences. Kindle (5th) Edition. 2010.

[2] Staels B, Maes M, Zambon A. Fibrates and future PPARalpha agonists in the treatment of cardiovascular disease. Nat Clin Pract Cardiovasc Med. 2008 Sep;5(9):542-53. doi: 10.1038/ncpcardio1278. Epub 2008 Jul 15. PMID: 18628776.

[3] Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med. 2002;53:409-35. doi: 10.1146/annurev.med.53.082901.104018. PMID: 11818483. 

[4] Djadjo S, Bajaj T. Niacin. [Updated 2023 Mar 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK541036/.