Textbook of Cardiology

Atherosclerosis: Difference between revisions

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In primary prevention, pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors (statins), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In the clinical setting, statins are widely used, being the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower levels of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet.
 
In primary prevention, pharmacologic agents are the second option when lifestyle modifications fail to achieve targeted lipid profile. There are several groups of lipid-altering medicines such as HMG-CoA reductase inhibitors ('''statins'''), niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents. In the clinical setting, statins are widely used, being the most cost-effective LDL-lowering drugs. They reduce intracellular cholesterol concentration by inhibiting HMG-CoA reductase, which is an enzyme that synthesizes cholesterol. This results into increased LDL-receptor expression and therefore leads to higher clearance of LDL molecules from blood. They also affect the liver and thereby lower the rate of VLDL synthesis, which results into lower levels of serum triglyceride. Statins also raise HDL, but this mechanism is not fully understood yet.




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Inhibiting HMG-CoA reductase results in several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, the anti-thrombotic and anti-inflammatory profile is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to the anti-inflammatory profile. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α.  Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation. <br />
Inhibiting HMG-CoA reductase results in several mechanisms that explain the beneficial effect of using statins. One beneficial mechanism is via lowering LDL and raising HDL. This results into less lipid content in atherosclerotic plaques and improve their biologic activity. Furthermore, the anti-thrombotic and anti-inflammatory profile is enhanced by other mechanisms such as increased NO synthesis and fibrinolytic activity, inhibition of smooth muscle proliferation and monocyte recruitment, and reduced production of matrix-degrading enzymes by macrophages. Several studies suggest that other mechanisms also contribute to the anti-inflammatory profile. For example, statins reduce endothelial expression of leukocyte adhesion molecules and macrophage tissue factor production by inhibiting the macrophage cytokines or by activating PPAR-α.  Another anti-inflammatory action of statins, supported by clinical trials is reducing the serum level of C-reactive protein, which is a marker of inflammation. <br />


Although statin therapy can reduce the risk of atherosclerotic cardiovascular disease by about one third, there is still a need for additional risk-reducing therapies. Thus, a new idea was developed to raise HDL cholesterol as a treatment for atherosclerosis. With the finding of the high-HDL phenotype of a human genetic deficiency of cholesteryl ester transfer protein (CETP), a new class of drugs was developed, which inhibits CETP. CETP functions as a mediator for transfer of cholesteryl ester from HDL to VLDL/LDL, which is then cleared by LDL receptors in liver. Thus when CETP is inhibited, this transfer process is inhibited and the direct hepatic HDL clearance pathway takes over. This leads to less fractional clearance of HDL from plasma, which is beneficial for atherosclerosis. Although the absolute clearance rate of HDL remains the same, the key step for atherosclerosis, which is the removal of cholesterol from macrophage foam cells in artery wall by HDL, is reduced. <br />
Despite the effectiveness of statins, niacin, fibric acid derivatives, cholesterol intestinal absorption inhibitors, and bile acid-binding agents in managing serum lipid levels, further advancements in pharmacologic lipid management have introduced additional options for reducing cardiovascular risk associated with atherosclerosis. Two notable additions to the lipid-lowering arsenal are PCSK9 inhibitors and bempedoic acid.
 
Proprotein convertase subtilisin/kexin type 9 '''(PCSK9) inhibitors''' are a novel class of medications that significantly lower low-density lipoprotein cholesterol (LDL-C). PCSK9 is a protein that binds to LDL receptors on the liver surface, leading to their degradation and preventing them from removing LDL cholesterol from the blood. By inhibiting PCSK9, these drugs increase the number of LDL receptors available to clear LDL from the blood, thus lowering LDL-C levels.
 
Clinical trials have demonstrated that PCSK9 inhibitors, such as evolocumab and alirocumab, can reduce LDL-C levels by up to 60% when used alone or in combination with statins. This significant reduction in LDL-C levels has been associated with a decreased risk of cardiovascular events, making PCSK9 inhibitors an important option for patients who are statin-intolerant or for whom statins alone are insufficient to achieve LDL-C targets.
 
'''Bempedoic acid''' represents another innovative approach to lowering LDL-C levels. It acts by inhibiting ATP citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway. This inhibition leads to reduced hepatic cholesterol synthesis and upregulation of LDL receptors, resulting in decreased LDL-C levels. Bempedoic acid has the advantage of being metabolized in the liver, sparing muscle tissue and potentially offering a safer alternative for patients who experience muscle-related side effects with statins.


The most recently investigated CETP inhibitors are torcetrapib, anacetrapib, and dalcetrapib. In the Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) trial, involving 15,000 patients at high risk for coronary heart disease, torcetrapib was clinically investigated. Unfortunately this trial was prematurely stopped due to the finding of an increase in cardiovascular events associated with an undiscovered off-target effect. Anacetrapib and dalcetrapib are still under active clinical investigation, since they lack the off-target effects of torcetrapib.
In clinical trials, bempedoic acid has been shown to lower LDL-C levels by up to 20% when used as monotherapy and has shown additional LDL-C lowering when used in combination with statins. Furthermore, bempedoic acid has been associated with reductions in biomarkers of inflammation, such as high-sensitivity C-reactive protein (hsCRP), suggesting potential anti-inflammatory benefits beyond its lipid-lowering effects.


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