Hypolipidemic therapy

Main pharmacological effects

The action of anti-atherosclerotic agents targets various links of the lipid profile. The main and most clinically significant effect is reduction of LDL-C levels. It is this indicator that is primarily affected by statins, ezetimibe, PCSK9 inhibitors, and bile acid sequestrants.

Another important task is lowering triglyceride levels. Fibrates and nicotinic acid preparations handle this best. These same two drug classes are responsible for increasing HDL-C levels (the so-called "good" cholesterol). In addition, nicotinic acid has the ability to reduce VLDL levels.

Pleiotropic (additional) effects of statins deserve special attention. In addition to a direct lipid-lowering effect, they help improve vascular endothelial function, exert a systemic anti-inflammatory effect, reliably stabilize already formed atherosclerotic plaques, and possess a pronounced antithrombotic effect.

Classification and mechanisms of action

Modern pharmacology distinguishes several main drug groups, each with its unique site of action:

• HMG-CoA reductase inhibitors (statins) (atorvastatin, rosuvastatin, simvastatin). They block the synthesis of endogenous cholesterol directly in the liver. In response, a compensatory increase in LDL receptor expression occurs on the surface of hepatocytes, which leads to enhanced clearance of LDL-C from plasma.
• Cholesterol absorption inhibitors (ezetimibe). The drug selectively blocks the NPC1L1 sterol transport protein in the small intestine. As a result, the influx of both exogenous (dietary) and biliary cholesterol into chylomicrons is sharply reduced.
• Bile acid sequestrants (cholestyramine). These agents bind bile acids in the lumen of the gastrointestinal tract, interrupting their normal enterohepatic circulation. To compensate for the deficit, the liver begins to actively consume cholesterol stores for the synthesis of new portions of bile acids.
• Fibrates (gemfibrozil). The mechanism is based on the activation of nuclear PPAR-α receptors. This stimulates the synthesis of the enzyme lipoprotein lipase, which ultimately leads to a drop in triglyceride levels and an increase in HDL.
• Nicotinic acid preparations (niacin). They inhibit the enzyme triglyceride lipase, thereby inhibiting lipolysis processes in adipose tissue. As a consequence, the formation of VLDL and triglycerides is reduced in the body.
• PCSK9 inhibitors. These include monoclonal antibodies (alirocumab, evolocumab) and small interfering RNA (inclisiran). They block the PCSK9 protein itself or the synthesis of its mRNA, which halts the degradation of LDL receptors on liver cells and causes a powerful, pronounced elimination of LDL from the bloodstream.

Stepwise therapy and target values

The treatment of atherosclerosis requires strict adherence to the stepwise therapy algorithm.

1. Step one always implies prescribing monotherapy with a statin at the maximally tolerated dosage.
2. Step two is applied if the goal is not achieved: ezetimibe is necessarily added to the statin.
3. Step three is justified only if dual therapy is ineffective. It represents a triple combination: a statin, ezetimibe, and a PCSK9 inhibitor.

The effectiveness of treatment is evaluated by achieving the target LDL-C level, which directly depends on the patient's baseline risk:

• For individuals at very high risk, the indicator should be less than 1.4 mmol/L.
• At high risk, the goal is less than 1.8 mmol/L.
• At moderate risk, a level of no more than 2.6 mmol/L is permitted.
• For low-risk patients, the upper limit of normal is no more than 3.0 mmol/L.

Proven clinical effects

Anti-atherosclerotic agents have a powerful evidence base. Their use reliably ensures a reduction in the risk of cardiovascular complications and overall mortality within the framework of both primary and secondary prevention.

They are critically necessary to reduce the risk of recurrent ischemic events in patients with diagnosed coronary artery disease (CAD), as well as in those who have already suffered a myocardial infarction or ischemic stroke. Meta-analysis data on PCSK9 inhibitors are particularly noteworthy: in patients with concomitant renal dysfunction, these drugs are capable of providing an impressive 38% reduction in mortality.

Class and exam questions

What else to study on this topic

• Pleiotropic effects of statins: mechanisms of plaque stabilization and improvement of endothelial function
• Features of bile acid metabolism and enterohepatic circulation
• The role of PPAR-α receptors in lipid metabolism and the mechanism of action of fibrates
• PCSK9 protein: functions and targeted therapy with monoclonal antibodies
• Assessment of cardiovascular risk to determine the target LDL-C level

Other topics in the "Additional Topics" section

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