Reduction of increased plasma cholesterol has many health benefits, one of which is lowering the risk of cardiovascular events. There are numerous medications that help to reduce cholesterol levels in the blood.Statins have been introduced into clinical use in 1980s and since then became number one drug with hypolipidemic properties. Currently, there are five statin medications in clinical use: simvastatin, pravastatin, atorvastatin, fluvastatin, and ovastatin (1).
Statins target liver cells and inhibit HMG-CoA reductase – a special enzyme converting HMG-CoA into mevalonic acid, which is a cholesterol precursor. Besides that, when statins bind to the enzyme’s active site they modify its conformation preventing HMG-CoA reductase from reaching a functional structure (1).Atorvastatin and simvastatin can reduce LDL levels in patients with homozigous family hypercholesterolemia with not functional LDL receptors are not functional which can be explained by another mechanism of statins’ action. They are capable of inhibiting hepatic syntesis of apolipoprotein B-100.
Apolipoprotein B-100 not only determines a reduction of triglyceride rich lipoproteins’ synthesis and secretion but it also production of receptors for apolipoproteins B/E (1).Niacin (nicotinic acid) is an effective medication for treating cardiovascular disease and lipid disorders. Nicotinic acid positively affects apolipoprotein B-containing lipoproteins and increases apo A-I-containing lipoproteins. It directly inhibits hepatocyte diacylglycerol acyltransferase-2 – a key enzyme for TG synthesis, which leads to accelerated intracellular hepatic apo B degradation and the reduced secretion of VLDL and LDL particles.
Vascular endothelial cell redox state is also stimulated by niacin, as a result oxidative stress and vascular inflammatory genes (involved in the process of atherosclerosis formation) are inhibited. Prostaglandins D(2) and E(2) stimulation by subcutaneous Langerhans cells via the G protein-coupled receptor 109A niacin receptor leads to intensive niacin flush. Niacin decreases triglycerides (TGs) through decreased free fatty acid mobilization from adipose tissue via the G protein-coupled receptor 109A niacin receptor (2).Fibrates are commonly used lipid-modifying agents that lower triglycerides levels in plasma and slightly increase HDL cholesterol concentrations. Fibrates stimulate specific transcription factors pertaining to the nuclear hormone receptor superfamily PPARs (peroxisome proliferator-activated receptors).
The alpha form of PPAR mediates the action fibrates have on HDL cholesterol levels through transcriptional initiation of synthesis of the major HDL apolipoproteins (apoA-I and apoA-II). They also initiate uptake of cellular fatty acid, conversion to acyl-CoA derivatives, and catabolism by the beta-oxidation pathways. All of these processes combined together with decreased fatty acid and triglyceride synthesis lead to a decreased VLDL production. Thus, the hypotriglyceridemic effect of fibrates can be explained by induced catabolism of triglyceride-rich particles and reduced secretion of VLDL (3).Colestipol is a non-absorbed, lipid-lowering compound binding to the bile acids in the intestine with the formation of a complex that is excreted from the body through defecation (8).Torcetrapib is a potent cholesteryl ester transfer protein (CETP) binding specifically to CETP with 1:1 stoichiometry and blocking neutral lipid and phospholipid (PL) transfer activities (9).Avasimibe is an ACAT ((Acyl Co A cholesterol acyl transferase) inhibitor reducing foam cell formation through the enhancing of free cholesterol efflux and the inhibition of modified LDL uptake.
Avasimibe use can contribute to the increased plaque stability since its molecules reduce lipids’ accumulation in the arteries, inhibit infiltration of macrophage into the media and reduce the expression and activity of matrix metalloproteinase. In the combination therapy with statins, avasimibe can not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol (4).Implitapide is an inhibitor of the microsomal triglyceride transfer protein (MTP) required for the synthesis of chylomicron in the intestine as well as very low-density lipoprotein in the liver. Implitapide inhibites the increase in plasma TG levels and total cholesterol levels, which explains the antiatherosclerotic effects of this compound (5).
Praluent (or Alirocumab) represents a new class of cholesterol-lowering medications that inactivate a protein in the liver called PCSK9. When protein PCSK9 binds to low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, it promotes the degradation of these receptors by the liver. Since LDLR is the main receptor clearing LDL circulating in the blood, a decreased number of LDLR levels by PCSK9 leads to higher levels of LDL-C in plasma. Praluent prevents binding of PCSK9 to LDLR, which increases the number of LDLRs available to clear LDL and lowers LDL-C levels in plasma (6).Ezetimibe results in significant decrease of the LDL-C and nonhigh-density lipoprotein cholesterol levels in plasma due to its ability to inhibit absorption of intestinal cholesterol by selectively blocking the NPC1L1 protein in the jejunal brush border.
This effect of Ezetimibe can be reached when it’s used alone or in combination with statin therapy (7).