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4.6.3.1.3. Statins. Statins decrease LDL-C, thereby reducing ASCVD morbidity and mortality as well as the need for coronary artery interventions. Statins also lower triglycerides, and may reduce pancreatitis risk. Therefore, they are the drug of first choice in patients at increased risk of ASCVD.3

4.6.3.1.3.1. Adverse effects, interactions, and adherence to statin therapy The most frequent adverse effect of statin therapy is myopathy, but this is rare. A meta-analysis ruled out any contribution to an increase in non-CV mortality.522 Increased blood sugar and HbA1c levels (i.e. increased risk of type 2 DM) can occur after treatment initiation and are dose dependent, in part linked to slight weight gain, but the benefits of statins outweigh the risks for the majority of patients.527 Adhering to lifestyle changes when prescribed a statin should lessen the risk of DM. Increased levels of liver enzymes may occur during statin therapy, and are usually reversible. Routine monitoring of liver enzyme values is not indicated. Although 510% of patients receiving statins complain of myalgia, in most cases it is not attributable to statins.3 The risk of myopathy (severe muscular symptoms) can be minimized by identifying vulnerable patients and/or by avoiding statin interactions with specific drugs. Rhabdomyolysis is extremely rare. As statins are prescribed on a long-term basis, possible interactions with other drugs deserve particular and continuous attention, as many patients will receive pharmacological therapy for concomitant conditions. In practice, management of a patient with myalgia but without a major increase in creatine kinase is based on trial and error, and usually involves switching to a different statin or use of a very low dosage several days a week, with a gradual increase in frequency and dosage. A management algorithm may help to manage these patients.3

4.6.3.1.4. Cholesterol absorption inhibitors (ezetimibe). The combination of statin with ezetimibe brings a benefit that is in line with meta-analyses showing that LDL-C reduction has benefits independent of the approach used.3,21 The beneficial effect of ezetimibe is also supported by genetic studies.528 Together, these data support the position that ezetimibe should be considered as second-line therapy, either on top of statins when the therapeutic goal is not achieved, or when a statin cannot be prescribed.

4.6.3.1.5. Proprotein convertase subtilisin/kexin type 9 inhibitors. PCSK9 inhibitors (monoclonal antibodies to PCSK9) decrease LDL-C by up to 60%, either as monotherapy or in addition to the maximum tolerated dose of statin and/or other lipid-lowering therapies, such as ezetimibe. Their efficacy appears to be largely independent of background therapy. In combination with high-intensity or maximum tolerated statins, alirocumab and evolocumab reduced LDL-C by 4673% more than placebo, and by 30% more than ezetimibe.516,517 Among patients in whom statins cannot be prescribed, PCSK9 inhibition reduced LDL-C levels when administered in combination with ezetimibe.529 Both alirocumab and evolocumab effectively lower LDL-C levels in patients who are at high or very high CVD risk, including those with DM, with a large reduction in future ASCVD events.516,517 PCSK9 inhibitors also lower triglycerides, raise HDL-C and apolipoprotein A-I, and lower lipoprotein(a), although the relative contributions of these lipid modifications remain unknown. PCSK9 inhibitors are costly, and their cost-effectiveness, long-term safety, and effect in primary prevention are as yet unknown. We recommend considering cost-effectiveness in a loco-regional context before implementing recommendations that involve their use. Recommendations for the use of PCSK9 inhibitors are described in the Recommendations for pharmacological LDL-C lowering. Inclisiran is a long-acting hepatic PCSK9 synthesis inhibitor that also lowers LDL-C levels considerably.530 Its effect on clinical outcomes remains to be established.

4.6.3.2 Strategies to control plasma triglycerides Although CVD risk is increased when fasting triglycerides are >1.7 mmol/L (150 mg/dL),531 the use of drugs to lower triglyceride levels may only be considered in high-risk patients when triglycerides are >2.3 mmol/L (200 mg/dL) and triglycerides cannot be lowered by lifestyle measures. The available pharmacological interventions include statins, fibrates, PCSK9 inhibitors, and n-3 PUFAs (in particular icosapent ethyl in doses of 24 g/day; see section 4.3.2.4.4). Recommendations for the treatment of hypertriglyceridaemia are shown in the Recommendations below.

4.6.3.2.1. Fibrates. Fibrates are used primarily for triglyceride lowering and, occasionally, for increasing HDL-C. Evidence supporting the use of these drugs for CVD event reduction is limited, and given the strong evidence favouring statins, routine use of these drugs in CVD prevention is not recommended.3 To prevent pancreatitis, when

For secondary prevention patients not achieving their goals on a maximum tolerated dose of a statin and ezetimibe, combination therapy including a PCSK9 inhibitor is recommended.516,517 I A For very-high-risk FH patients (that is, with ASCVD or with another major risk factor) who do not achieve their goals on a maximum tolerated dose of a statin and ezetimibe, combination therapy including 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.515,523525 IIa B If a statin-based regimen is not tolerated at any dosage (even after rechallenge), a PCSK9 inhibitor added to ezetimibe may be considered.523,524,526 IIb C If the goal is not achieved, statin combination with a bile acid sequestrant may be considered. IIb C Statin therapy is not recommended in premenopausal female patients who are considering pregnancy or are not using adequate contraception. III 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. cA stepwise approach to LDL-C targets is recommended; see section 3.2.3.1 and Figures 6 and 7. Adapted from 3 ESC 2021 Downloaded from academic.oup.com/eurheartj/article/42/34/3227/6358713 by guest on 07 October 2026