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............................................................................................... 8.11.3 New approaches to increase high-density lipoprotein cholesterol Although genetic studies suggest that low HDL-C levels are not a cause of ASCVD, casting doubt on the possibilities of future treatment options to raising HDL-C levels with attenuation of CVD, major developments in the search for efficacious agents to raise HDL-C and ApoA1 levels with concomitant benefits on atherosclerosis and CV events are on the horizon. On the one hand, interest is focused on ApoA1 mimetic peptides and recombinant forms of HDL possessing potential for in vivo HDL particle remodelling and enhanced cardioprotective activity.350 On the other, agents that enhance catabolism of TG-rich lipoproteins, such as the antisense oligonucleotide to ApoC-III, and which lead to a concomitant reduction in TGs (70%) and a marked elevation in HDL-C (40%) in hypertriglyceridemia, are under development.351 Importantly, however, we currently lack understanding of the relationship between the modality of raising HDL/ApoA-I levels and a possible antiatherogenic function of HDL particles.

8.11.4 New approaches to reduce lipoprotein(a) levels Another approach under study is the selective decrease of Lp(a) concentrations. RNA-based therapies are now being evaluated in clinical settings. Results from studies of an antisense oligonucleotide in patients with normal Lp(a) values as well as in patients with elevated Lp(a) concentrations have shown a reduction of >90%.352 These approaches are currently being evaluated in phase IIIII studies and an outcome trial is planned to study whether Lp(a) reduction translates into risk reduction.

8.12 Strategies to control plasma

cholesterol Although LDL-C goals are attained with monotherapy in many patients, a significant proportion of patients at high-risk or with very high LDL-C levels need additional treatment. In this case, combination therapy is reasonable. In patients at very-high risk and with persistent high-risk despite being treated with a maximally tolerated statin, combination with ezetimibe is recommended and, if still not at goal, the addition of a PCSK9 inhibitor is recommended (see Figure 4 and Recommendations for pharmacological low-density lipoprotein cholesterol lowering). Of note, addition of a PCSK9 inhibitor directly to a statin is also feasible120,290 (Figure 4).

As shown in Figure 3, the expected clinical benefit of treatment to lower the LDL-C level of any person can be estimated; it depends on the intensity of therapy, the baseline LDL-C level, and the baseline estimated risk of ASCVD. This simple algorithm can be used to help clinicians select the appropriate therapy and quantify the expected benefits of LDL-C-lowering therapy to help inform discussions with patients. For ease of reference, Supplementary Table 3 provides a summary of the absolute LDL-C reductions that can be achieved with various therapeutic approaches at particular baseline levels of LDL-C.

8.13 Strategies to control plasma

triglycerides Although CVD risk is increased when fasting TGs are >1.7 mmol/L (>150 mg/dL),56 the use of drugs to lower TG levels may only be considered in high-risk patients when TGs are >2.3 mmol/L (>200 mg/dL) and TGs cannot be lowered by lifestyle measures. The available pharmacological interventions include statins, fibrates, PCSK9 inhibitors, and n-3 PUFAs. A meta-analysis of 10 trials included people treated with various agents that reduce serum TGs (fibrates, niacin, and n-3 PUFAs) and reported a 12% reduction in CV

Recommendations for pharmacological low-density lipoprotein cholesterol lowering

Recommendations Classa Levelb

It is recommended that a high-intensity statin is prescribed up to the highest tolerated dose to reach the goals set for the specific level of risk.32,34,38 I A If the goalsc are not achieved with the maximum tolerated dose of a statin, combination with ezetimibe is recommended.33 I B For primary prevention patients at very-high risk, but without FH, if the LDL-C goal is not achieved on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor may be considered. IIb C For secondary prevention, patients at very-high risk not achieving their goalc on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended.119,120 I A For very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goalc on a maximum tolerated dose of a statin and ezetimibe, a combination with a PCSK9 inhibitor is recommended. I C If a statin-based regimen is not tolerated at any dosage (even after rechallenge), ezetimibe should be considered.197,265,353 IIa C If a statin-based regimen is not tolerated at any dosage (even after rechallenge), a PCSK9 inhibitor added to ezetimibe may also be considered.197,265,353 IIb C If the goalc is not achieved, statin combination with a bile acid sequestrant may be considered. IIb C

ASCVD = atherosclerotic cardiovascular disease; FH = familial hypercholesterolaemia; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/ kexin type 9. aClass of recommendation. bLevel of evidence. cFor definitions see Table 7. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026