**6. Treatment strategies**

#### **6.1 Impact of diet and lifestyle modifications on lipid levels**

Consistent evidence from epidemiological studies indicates that saturated fatty acids (SFAs) and trans unsaturated fatty acids are the dietary factors with the greatest elevating impact on LDL-C levels [5]. Therefore, current dietary guidelines uniformly recommend reducing intakes of saturated and trans fatty acids with replacement by increasing intake of mono- and polyunsaturated fatty acids [35]. Moreover, recommended food choices to lower LDL-C and improve the overall lipoprotein profile include higher consumption of non-starchy vegetables, fruit, legumes, nuts, fish, vegetable oils, yoghurt, and wholegrains, along with a lower intake of red and processed meats, foods higher in refined carbohydrates, and salt [36, 37]. Dietary patterns that may have a role in the prevention and management of dyslipidemia are the Mediterranean diet and the DASH diet [38, 39]. Excessive body weight loss exhibits the LDL-C decreasing effect, but the magnitude of the effect is small. In people with obesity, a decrease in LDL-C concentration of 0.2 mmol/L is observed for every 10 kg of weight reduction [40, 41]. Regular physical exercise results in even smaller reduction of LDL-C levels [42, 43]. Overall, through dietary changes and weight loss, LDL-C can be lowered by approximately 10–15% [44].

#### **6.2 Drugs for treatment of dyslipidemias**

Statin treatment, targeting LDL cholesterol reduction, remains the cornerstone of dyslipidemia management. There is a clear linear relationship between the degree of LDL-cholesterol lowering achieved with statins and CV benefits, pointing out

that a reduction of 1 mmol/L of LDL-C is associated with a 20–25% reduction in the relative risk of major CV events including cardiovascular mortality, non-fatal myocardial infarction and non-fatal stroke [45]. Statins reduce the biosynthesis of cholesterol in the liver by competitively inhibiting the enzyme hydroxymethylglutaryl CoA (HMG-CoA) reductase, the rate-limiting step in the production of cholesterol. The reduction in intracellular cholesterol promotes up-regulation of LDL receptor (LDLR) at the surface of the hepatocytes, which in turn results in increased hepatic uptake of LDL from the blood, thereby lowering plasma concentrations of LDLand other ApoB-containing lipoprotein particles. The degree of LDL-C reduction is dose-dependent and varies between the different statins. A high intensity statin, on average, reduces LDL-C by >50%, while, moderate-intensity therapy is defined as the dose expected to reduce LDL-C by 30-50% [35]. Statins should be initiated with the highest tolerated dose to reach the LDL-C goal determined by the individual's risk category. There are abundant data supporting the concept of 'the lower LDL-C, the better' in the primary and secondary cardiovascular disease prevention. Statins are generally safe and well tolerated apart from myalgia which is the most commonly reported statin adverse effect, although its frequency is higher in everyday clinical practice than in RCTs [46]. However, due to low adherence to statin therapy or statin intolerance, many patients do not reach LDL-C target levels. Because the LDL-C targets suggested in guidelines, currently <1.4 mmol/L in patients with very-high CV risk, < 1.8 in patients with high CV risk and < 2.6 mmol/L in those with moderate CV risk respectively, are often not achieved, additional and more aggressive LDL-C lowering therapies are needed [35].

Ezetimibe inhibits dietary and biliary cholesterol absorption by interacting with the Niemann-Pick C1-Like 1 protein (NPC1L1), thereby lowering the amount of cholesterol delivered to the liver. In response to reduced cholesterol delivery, the liver reacts by upregulating LDL receptor expression, which in turn leads to increased clearance of LDL from the blood. A large clinical trial evaluating the addition of ezetimibe to statins in patients with prior acute coronary syndrome found a 24% reduction in LDL-C levels and a 6.4% reduction in the relative risk of CV death, major coronary events, or nonfatal stroke at 7 years [47]. Statinezetimibe combination treatment is the first choice for managing elevated LDL-C in very-high-risk patients with high LDL-C unlikely to reach goal with a statin, and in primary prevention familial hypercholesterolaemia patients [48].

A new class of drugs, PCSK9 inhibitors, that targets a proprotein convertase subtilisin/kexin type 9 (PCSK9) is recommended by current guidelines for the secondary prevention of very high-risk individuals not at LDL-C goal despite maximally tolerated statin doses and ezetimibe [35]. This protein regulates plasma concentrations of LDL-C by interacting with LDL receptors on hepatocytes. After binding to an LDL receptor, PCSK9 directs it to lysosomal degradation. Consequently, it inhibits recycling of the receptor to the surface of the hepatocyte and delays catabolism of LDL particles [49]. Currently approved PCSK9 inhibitors are the human monoclonal antibodies, alirocumab and evolocumab. The mechanism of action relates to the reduction of the plasma level of PCSK9, which in turn results in decreased intracellular degradation and increased expression of LDL receptors at the cell surface and therefore in a reduction of circulating LDL-C levels [50]. Co-administration with statin treatment has a sound rationale because statins upregulate PCSK9. In clinical trials, PCSK9 inhibitors either alone or in combination with statins, and/or other lipid-lowering therapies have been shown to significantly reduce LDL-C levels on average by 60%, depending on dose. In contrast to statins, inhibiting PCSK9 with monoclonal antibodies also reduces Lp(a) plasma levels.

**15**

*Dyslipidemia: Current Perspectives and Implications for Clinical Practice*

An alternative approach targeting PCSK9 consists of RNA interference. Recently, the small interfering RNA (siRNA) molecule inclisiran, which inhibits the intracellular hepatic translation of PCSK9, has been approved in Europe based on a robust clinical development program demonstrating effective and sustained LDL-C reduction of up to 52% in patients with elevated LDL-C despite maximally tolerated statin therapy [51, 52]. With two doses a year, this new lipid lowering strategy is

The cholesterol efflux capacity, mainly mediated by HDL-C, from arterial tissues to liver has demonstrated its association with major adverse cardiovascular events [53]. The pharmacological approach that has led to the greatest elevations in HDL-C levels has been direct inhibition of cholesterol ester transfer protein (CETP) by small-molecule inhibitors, which may induce an increase in HDL-C by >100% on a dose-dependent basis. Although CETP inhibitors significantly increased HDL-C levels in trials, they have not displayed benefits on cardiovascu-

Hypertriglyceridemia is a well-described contributor to the residual cardiovascular risk [54]. Statin treatment is recommended as the first drug of choice to reduce CVD risk in high-risk individuals with TG levels >2.3 mmol/L. In high and very high-risk patients with TG levels between 1.5-5.6 mmol/L despite statin treatment, n-3 PUFAs (icosapent ethyl 2x2 g/day) should be considered in combination with a statin. It has been demonstrated that icosapent ethyl, a highly purified and stable eicosapentaenoic acid (EPA), on top of statins was associated with a 25% relative CV risk reduction and a 4.8% absolute risk reduction in major adverse CV events in high-risk individuals [55]. The underlying mechanism how omega-3 fatty acids affect serum lipids and lipoproteins, in particular VLDL concentrations is poorly understood, although it may be related, at least in part, to their ability to interact with peroxisome proliferator-activated receptors (PPARs) and to decreased secretion of ApoB. In primary prevention patients who are at LDL-C goal with TG levels >2.3 mmol/L, fenofibrate may be considered in combination with statins. Fibrates are agonists of PPARs, acting via transcription factors regulating various steps in lipid and lipoprotein metabolism. Consequently, fibrates have good efficacy in lowering fasting and post-prandial TGs and TG-rich lipoprotein remnant par-

Agents that enhance catabolism of TG-rich lipoproteins, such as the antisense oligonucleotide to ApoC-III mRNA, which lead to a concomitant reduction in TGs (>70%) and a marked elevation in HDL-C (>40%) in hypertriglyceridemia, are

Dyslipidemias largely contribute to global cardiovascular disease burden. Consistent evidence from epidemiological and clinical studies, supports the key role of the circulating LDL-C and other apoB containing lipoproteins in the development of atherosclerosis. Therefore, reducing LDL-C and other ApoB-containing lipoproteins is a core component of lipid management for both the primary prevention of CVD and the secondary prevention of recurrent CV events. A major outstanding challenge is how best to implement use of evidence-based therapies in clinical practice, particularly statins and PCSK9 inhibitors. Understanding the important role that metabolic derangements play in the pathogenesis of atherosclerosis pave the way for stronger implementation of current guidelines for CVD risk

*DOI: http://dx.doi.org/10.5772/intechopen.98386*

expected to support long-term adherence.

lar outcomes [22].

ticles [56, 57].

**7. Conclusion**

under development [58].

assessment and prevention.

#### *Dyslipidemia: Current Perspectives and Implications for Clinical Practice DOI: http://dx.doi.org/10.5772/intechopen.98386*

An alternative approach targeting PCSK9 consists of RNA interference. Recently, the small interfering RNA (siRNA) molecule inclisiran, which inhibits the intracellular hepatic translation of PCSK9, has been approved in Europe based on a robust clinical development program demonstrating effective and sustained LDL-C reduction of up to 52% in patients with elevated LDL-C despite maximally tolerated statin therapy [51, 52]. With two doses a year, this new lipid lowering strategy is expected to support long-term adherence.

The cholesterol efflux capacity, mainly mediated by HDL-C, from arterial tissues to liver has demonstrated its association with major adverse cardiovascular events [53]. The pharmacological approach that has led to the greatest elevations in HDL-C levels has been direct inhibition of cholesterol ester transfer protein (CETP) by small-molecule inhibitors, which may induce an increase in HDL-C by >100% on a dose-dependent basis. Although CETP inhibitors significantly increased HDL-C levels in trials, they have not displayed benefits on cardiovascular outcomes [22].

Hypertriglyceridemia is a well-described contributor to the residual cardiovascular risk [54]. Statin treatment is recommended as the first drug of choice to reduce CVD risk in high-risk individuals with TG levels >2.3 mmol/L. In high and very high-risk patients with TG levels between 1.5-5.6 mmol/L despite statin treatment, n-3 PUFAs (icosapent ethyl 2x2 g/day) should be considered in combination with a statin. It has been demonstrated that icosapent ethyl, a highly purified and stable eicosapentaenoic acid (EPA), on top of statins was associated with a 25% relative CV risk reduction and a 4.8% absolute risk reduction in major adverse CV events in high-risk individuals [55]. The underlying mechanism how omega-3 fatty acids affect serum lipids and lipoproteins, in particular VLDL concentrations is poorly understood, although it may be related, at least in part, to their ability to interact with peroxisome proliferator-activated receptors (PPARs) and to decreased secretion of ApoB. In primary prevention patients who are at LDL-C goal with TG levels >2.3 mmol/L, fenofibrate may be considered in combination with statins. Fibrates are agonists of PPARs, acting via transcription factors regulating various steps in lipid and lipoprotein metabolism. Consequently, fibrates have good efficacy in lowering fasting and post-prandial TGs and TG-rich lipoprotein remnant particles [56, 57].

Agents that enhance catabolism of TG-rich lipoproteins, such as the antisense oligonucleotide to ApoC-III mRNA, which lead to a concomitant reduction in TGs (>70%) and a marked elevation in HDL-C (>40%) in hypertriglyceridemia, are under development [58].
