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............................................................................................................................................................................. 9.10.2 Carotid artery disease While there are currently no randomized studies that have assessed whether lipid-lowering treatments reduce the incidence of CV events in patients enrolled on the basis of carotid atherosclerotic disease and without previous CV events, lipid-lowering therapy had reduced stroke in numerous studies. In a meta-analysis of RCTs enrolling >90 000 patients, statin therapy did lead to a 21% reduction in the incidence of all strokes in different populations; this effect was mainly driven by the extent of LDL-C reduction.460

9.10.3 Retinal vascular disease Atherosclerotic changes of retinal arteries correlate with TC, LDL-C, TG, and apoB levels and also with CAD.516 Fenofibrate reduces the progression of diabetic retinopathy.517,518

9.10.4 Secondary prevention in patients with abdominal aortic aneurysm The presence of an abdominal aortic aneurysm represents a riskequivalent condition for CAD and is associated with age, male gender, personal history of atherosclerotic CVD, smoking, hypertension, and dyslipidaemia;519 in contrast, diabetic patients are at decreased risk. There are currently no available clinical trials on the reduction of CV risk with lipid-lowering therapy in patients affected by this condition. Systematic reviews,520 mostly based on retrospective non-randomized studies, have reported that there is still inconclusive evidence that statin therapy reduces peri-operative CV morbidity and mortality. In an RCT comparing atorvastatin 20 mg with placebo, the composite endpoint of cardiac death, MI, stroke, and unstable angina was significantly reduced in 100 patients undergoing vascular non-cardiac surgery, including abdominal aortic aneurysm repair.521 In another double-blind, placebo-controlled trial in 497 patients undergoing vascular surgery, peri-operative fluvastatin therapy (80 mg/day) was associated with an improvement in post-operative cardiac outcome.522

9.10.5 Renovascular atherosclerosis Lipid-lowering therapy has never been tested in an RCT in patients affected by renovascular atherosclerosis; however, a recent nonrandomized population-based study showed that in patients older than 65 years of age with atherosclerotic renovascular disease raised the hypothesis that such treatment may yield cardiorenal benefits; the risk of a major cardiorenal composite endpoint (MI, stroke, HF, acute renal failure, dialysis, and death) was significantly lower in statin users than in non-users.523 9.11 Other special populations at risk of

atherosclerotic cardiovascular disease In general, the effects of lowering LDL-C are determined by the absolute risk of ASCVD and the achieved reduction in LDL-C, so it is important to identify and treat all those at increased risk of ASCVD. There are a few specific groups of patients in whom an underlying disease confers such increased risk, and in addition in whom the standard treatments may themselves cause dyslipidaemia that may contribute to the risk of ASCVD. These include: (i) chronic immunemediated inflammatory disease, (ii) patients with human immunodeficiency virus (HIV), and (iii) patients with severe mental illness. The management principles are the same in these patient groups, but their management may need to address specific issues related to individual dyslipidaemias and drug safety. Details are provided in the Supplementary Data document.

10 Inflammation

Recent advances in basic science have established a fundamental role for low-degree chronic inflammation in mediating all stages of atherosclerosis, from initiation through progression and, ultimately, to the rupture of plaque and ensuing thrombotic complications of atherosclerosis. The cellular and molecular interactions involved during atherogenesis are fundamentally not different from those in chronic inflammatoryfibroproliferative diseases, such as rheumatoid arthritis (RA), glomerulosclerosis, or pulmonary fibrosis.525 Almost all cell types of the immuno-inflammatory system, such as macrophages, and T- and B-cells, as well as many pro- and anti-inflammatory cytokines and chemokines, have been identified during the process of atherosclerosis.526 Interestingly, cholesterol accumulation in cells triggers the inflammasome response and results in the production of inflammatory mediators such as interleukin (IL)-1b. Numerous animal studies, using the knockout model, have demonstrated that inflammation and the immune system both play crucial roles during atherogenesis.527 During inflammatory processes, large numbers of acute-phase proteins have been identified, and several clinical studies have reported C-reactive protein528 to be the most useful serum marker of inflammation, even though it has poor specificity for any particular inflammation process, including atherosclerosis. The high-sensitivity C-reactive protein diagnostic test was developed to detect very low levels of C-reactive protein, and thereby enable a more accurate and precise measure of chronic inflammation compared with standard Creactive protein.529 This diagnostic tool differs only in the range of Creactive protein levels that it can detect. Several studies have found that elevated levels of high-sensitivity C-reactive protein in the blood are associated with an increased risk of CV events and could be used to predict clinical outcomes independently of cholesterol levels.530,531 Other studies have not been able to show any relationship between low-grade chronic inflammation, as indicated by high-sensitivity C-reactive protein levels, and increased risk of CV.532535 Finally, genetic studies of large population cohorts have not demonstrated that chronic elevated high-sensitivity C-reactive protein increases the risk of atherosclerotic events.536 Nevertheless, in some guidelines, high-sensitivity C-reactive protein has been added to traditional risk factors for prognostic information, especially for patients at intermediate risk.537,538

Recommendations for lipid-lowering drugs in patients with peripheral arterial disease (including carotid artery disease)

Recommendations Classa Levelb

In patients with PAD, lipid-lowering therapy, including a maximum tolerated dose of statin, plus ezetimibe or a combination with a PCSK9 inhibitor if needed, is recommended to reduce the risk of ASCVD events.512,524 I A

ASCVD = atherosclerotic cardiovascular disease; PAD = peripheral arterial disease; PCSK9 = proprotein convertase subtilisin/kexin type 9. aClass of recommendation. bLevel of evidence. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026