European Lipid Guidelines and Cardiovascular Risk Estimation: Current Status and Future Challenges.

PURPOSE OF REVIEW: Genetic, experimental, epidemiologic, and clinical data support the causal role of elevated levels of low-density lipoprotein cholesterol (LDL-C) in atherosclerosis and cardiovascular disease (CVD). The recommendations of the 2019 European guidelines are based on the concept of differential CV risk, which in turn defines the LDL-C goals that should be achieved. RECENT FINDINGS: The 2019 ESC/EAS guidelines for dyslipidaemia use the Systematic COronary Risk Evaluation (SCORE) model to assess CV risk, which provides a 10-year risk of fatal CV event. The SCORE model has recently been updated to reflect current rates of cardiovascular disease in Europe. The new SCORE2 model provides estimates of the 10-year risk of fatal and non-fatal CVD events in people aged 40-69 years, thus improving the identification of individuals at higher risk of a CVD event. However, as in the SCORE age is the main determinant of risk, young people have a relatively low estimated 10-year risk of a CV event even with high levels of one or more causal risk factors. Individuals with familial hypercholesterolaemia, who have elevated LDL-C levels from birth and have a high risk of premature CVD, are one example. The concept of cumulative LDL exposure is thus becoming increasingly important. This is also supported by Mendelian randomisation studies showing that carrying genetic variants associated with lower LDL-C levels reduces CV risk. These observations have introduced the concept of "cholesterol-years", which takes into account both LDL-C levels and time of exposure. It is crucial that future European guidelines pay more attention to this point.

Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society.

Cardiovascular disease is the leading cause of death in women and men globally, with most due to atherosclerotic cardiovascular disease (ASCVD). Despite progress during the last 30 years, ASCVD mortality is now increasing, with the fastest relative increase in middle-aged women. Missed or delayed diagnosis and undertreatment do not fully explain this burden of disease. Sex-specific factors, such as hypertensive disorders of pregnancy, premature menopause (especially primary ovarian insufficiency), and polycystic ovary syndrome are also relevant, with good evidence that these are associated with greater cardiovascular risk. This position statement from the European Atherosclerosis Society focuses on these factors, as well as sex-specific effects on lipids, including lipoprotein(a), over the life course in women which impact ASCVD risk. Women are also disproportionately impacted (in relative terms) by diabetes, chronic kidney disease, and auto-immune inflammatory disease. All these effects are compounded by sociocultural components related to gender. This panel stresses the need to identify and treat modifiable cardiovascular risk factors earlier in women, especially for those at risk due to sex-specific conditions, to reduce the unacceptably high burden of ASCVD in women.

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance.

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.

Pleiotropy of PCSK9: Functions in Extrahepatic Tissues.

PURPOSE OF REVIEW: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a central role in the metabolism of LDL receptors and mainly acts in the liver. However, there are accumulating data that PCSK9 involves in several functions in different organs beyond the liver. Herein we aimed to summarize the effects of PCSK9 in tissues other than the liver. RECENT FINDINGS: PCSK9 has crucial roles in heart, brain and kidney in addition to the cholesterol metabolism. Targeting PCSK9 for the treatment of hypercholesterolemia is effective in the prevention from cardiovascular diseases and PCSK9 inhibitors are getting to be administered in more cases. Therefore understanding the effects of PCSK9 in other tissues gained importance in the use of PCSK9 inhibitors era. PCSK9 participates in cardiac, renal, and neurologic functions however, current literature reveals that use of PSCSK9 inhibitors have beneficial or neutral effects on these organs. Inhibition of PCSK9 is assigned to be associated with new onset diabetes in experimental studies whereas real world data with PCSK9 inhibitors established no relationship between PCSK9 inhibitors and new onset diabetes. PCSK9 might be used as a target for the treatment of nephrotic syndrome and heart failure in the future.

The dawn of a new era of targeted lipid-lowering therapies.

Lipid risk factors for cardiovascular disease depend in part on lifestyle, but optimum control of lipids often demands additional measures. Low-density lipoprotein (LDL) doubtless contributes causally to atherosclerosis. Recent human genetic findings have substantiated a number of novel targets for lipid-lowering therapy including apolipoprotein C-III, angiopoietin-like protein 3 and 4, apolipoprotein V, and ATP citrate lyase. These discoveries coupled with advances in biotechnology development afford new avenues for management of LDL and other aspects of lipid risk. Beyond LDL, new treatments targeting triglyceride-rich lipoproteins and lipoprotein(a) have become available and have entered clinical development. Biological and RNA-directed agents have joined traditional small-molecule approaches, which themselves have undergone considerable refinement. Innovative targeting strategies have increased efficacy of some of these novel interventions and markedly improved their tolerability. Gene-editing approaches have appeared on the horizon of lipid management. This article reviews this progress offering insight into novel biological and therapeutic discoveries, and places them into a practical patient care perspective.

The year in cardiovascular medicine 2021: dyslipidaemia.

The past year was an exciting time for clinical lipidology when we learnt more about existing therapies as well as therapies targeting novel pathways discovered through genetic studies. LDL cholesterol remained the main target and a variety of drugs to lower LDL cholesterol through different mechanisms were explored. Emerging evidence on the atherogenity of triglyceride-rich lipoproteins led to renewed interest in lowering them with new treatments. Lp(a) was back in focus with evidence on causality and new targeted therapeutics which dramatically lower Lp(a) levels. We will be able to personalise lipid lowering therapy further with this enriched armamentarium once we have the results of the cardiovascular outcome studies with some of these new agents.

Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement.

This 2022 European Atherosclerosis Society lipoprotein(a) [Lp(a)] consensus statement updates evidence for the role of Lp(a) in atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis, provides clinical guidance for testing and treating elevated Lp(a) levels, and considers its inclusion in global risk estimation. Epidemiologic and genetic studies involving hundreds of thousands of individuals strongly support a causal and continuous association between Lp(a) concentration and cardiovascular outcomes in different ethnicities; elevated Lp(a) is a risk factor even at very low levels of low-density lipoprotein cholesterol. High Lp(a) is associated with both microcalcification and macrocalcification of the aortic valve. Current findings do not support Lp(a) as a risk factor for venous thrombotic events and impaired fibrinolysis. Very low Lp(a) levels may associate with increased risk of diabetes mellitus meriting further study. Lp(a) has pro-inflammatory and pro-atherosclerotic properties, which may partly relate to the oxidized phospholipids carried by Lp(a). This panel recommends testing Lp(a) concentration at least once in adults; cascade testing has potential value in familial hypercholesterolaemia, or with family or personal history of (very) high Lp(a) or premature ASCVD. Without specific Lp(a)-lowering therapies, early intensive risk factor management is recommended, targeted according to global cardiovascular risk and Lp(a) level. Lipoprotein apheresis is an option for very high Lp(a) with progressive cardiovascular disease despite optimal management of risk factors. In conclusion, this statement reinforces evidence for Lp(a) as a causal risk factor for cardiovascular outcomes. Trials of specific Lp(a)-lowering treatments are critical to confirm clinical benefit for cardiovascular disease and aortic valve stenosis.

Meta-analysis of the Current Research on the Relationship Between Blood Lipid Levels and the Occurrence of Atrial Fibrillation.

BACKGROUND: There is still debate in the literature about the relationship between lipid profile and the occurrence of atrial fibrillation (AF). In order to assess the association between blood lipid profiles and incidence of AF, this review was conducted to perform a meta-analysis of all available studies. METHODS: This review analysed all studies up to 28 February 2023 in PubMed, Google Scholar, and the Cochrane Library that included data regarding blood lipid levels and incidence of AF. For the purpose of calculating pooled estimates, the hazard ratios were extracted from all studies. RESULTS: Fourteen studies including 19 cohorts with 3,990,484 patients were included in this meta-analysis. An elevation of one standard deviation in total cholesterol (TC) level was associated with an 8% reduction (HR=0.92, 0.88-0.96; p<0.01) in the risk of developing AF. Although increased low-density lipoprotein cholesterol levels were associated with a 7% reduction in the development of AF (HR=0.93, 0.87-1.00; p=0.04), there was high heterogeneity in the random effects model (I2=92%). Changes in high-density lipoprotein cholesterol and triglyceride levels were not found to be associated with AF risk in the pooled analysis. Dose-response meta-analysis showed that TC was inversely linearly associated with the risk of AF (p<0.001). CONCLUSIONS: Higher TC levels were shown to be independently attributed to an increased risk of AF in individuals without cardiovascular disease. There was no association between the incidence of AF and triglyceride, high-density lipoprotein cholesterol, or low-density lipoprotein cholesterol blood levels.

A Review of Statin Intolerance: a Focus on Statin-Attributed Muscle Symptoms.

PURPOSE OF REVIEW: To provide a systematic approach to management of the patient with statin-attributed muscle symptoms. RECENT FINDINGS: We examined the prevalence of statin intolerance, the role of the nocebo effect, key findings in the patient's history and laboratory studies, the potential value of coronary calcium scoring, and the importance of shared decision-making in considering statin re-initiation. Most patients with statin-attributed muscle symptoms can be successfully treated with statins or a combination of statins and non-statins to achieve successful ASCVD risk reduction.

PCSK9 Inhibition and Risk of Diabetes: Should We Worry?

PURPOSE OF REVIEW: Since the clinical benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors occurs in a setting of reducing low-density lipoprotein-cholesterol (LDL-C) to unprecedentedly low levels, it becomes of interest to investigate possible adverse effects pertaining to the risk of new-onset diabetes (NOD). RECENT FINDINGS: While safety results reported in either meta-analyses or cardiovascular outcome trials FOURIER (with evolocumab) and ODYSSEY (with alirocumab) did not rise the incidence of NOD, Mendelian randomization analyses were almost concordant in showing an increased risk of NOD. This evidence was in line with post-marketing safety reports highlighting that evolocumab and alirocumab were primarily related to mild hyperglycaemia rather than diabetes, with most of the hyperglycaemic events occurring during the first 6 months of treatment. Considering the different nature of genetic studies and of randomized controlled trials, with careful monitoring of patients, particularly in the earlier phases of treatment, and the identification of those more susceptible to develop NOD, treatment with PCSK9 inhibitors should be of minimal concern.

Diet, Lifestyle, Smoking.

Cardiovascular disease is the leading cause of death globally The past few decades have shown that especially low- and middle-income countries have undergone rapid industrialization, urbanization, economic development and market globalization. Although these developments led to many positive changes in health outcomes and increased life expectancies, they all also caused inappropriate dietary patterns, physical inactivity and obesity. Evidence shows that a large proportion of the cardiovascular disease burden can be explained by behavioural factors such as low physical activity, unhealthy diet and smoking. Controlling these risk factors from early ages is important for maintaining cardiovascular health. Even in patients with genetic susceptibility to cardiovascular disease, risk factor modification is beneficial.Despite the tremendous advances in the medical treatment of cardiovascular risk factors to reduce overall cardiovascular risk, the modern lifestyle which has led to greater sedentary time, lower participation in active transport and time spent in leisure or purposeful physical activity, unhealthy diets and increased exposure to stress, noise and pollution have diminished the beneficial effects of contemporary medical cardiovascular prevention strategies. Therefore attenuating or eliminating these health risk behaviours and risk factors is imperative in the prevention of cardiovascular diseases.

Triglyceride-rich lipoproteins and their remnants: metabolic insights, role in atherosclerotic cardiovascular disease, and emerging therapeutic strategies-a consensus statement from the European Atherosclerosis Society.

Recent advances in human genetics, together with a large body of epidemiologic, preclinical, and clinical trial results, provide strong support for a causal association between triglycerides (TG), TG-rich lipoproteins (TRL), and TRL remnants, and increased risk of myocardial infarction, ischaemic stroke, and aortic valve stenosis. These data also indicate that TRL and their remnants may contribute significantly to residual cardiovascular risk in patients on optimized low-density lipoprotein (LDL)-lowering therapy. This statement critically appraises current understanding of the structure, function, and metabolism of TRL, and their pathophysiological role in atherosclerotic cardiovascular disease (ASCVD). Key points are (i) a working definition of normo- and hypertriglyceridaemic states and their relation to risk of ASCVD, (ii) a conceptual framework for the generation of remnants due to dysregulation of TRL production, lipolysis, and remodelling, as well as clearance of remnant lipoproteins from the circulation, (iii) the pleiotropic proatherogenic actions of TRL and remnants at the arterial wall, (iv) challenges in defining, quantitating, and assessing the atherogenic properties of remnant particles, and (v) exploration of the relative atherogenicity of TRL and remnants compared to LDL. Assessment of these issues provides a foundation for evaluating approaches to effectively reduce levels of TRL and remnants by targeting either production, lipolysis, or hepatic clearance, or a combination of these mechanisms. This consensus statement updates current understanding in an integrated manner, thereby providing a platform for new therapeutic paradigms targeting TRL and their remnants, with the aim of reducing the risk of ASCVD.

The relationship between retinal microcirculation and right heart catheterization and echocardiography findings in patients with idiopathic pulmonary arterial hypertension.

OBJECTIVE: To determine the possible alterations of retinal microcirculation associated with right-sided intracardiac pressures in patients with IPAH. METHODS: Twenty patients with IPAH and 20 age- and sex-matched healthy controls were included in the study. Hemodynamic data were obtained from the most recent right heart catheterization. Echocardiographic examination was performed within 24 h of ophthalmological examination. For the right eyes of all participants, high-resolution scans of chorioretinal microvascular networks at different depths of the retina were captured via OCT angiography. RESULTS: The perfusion of the superficial and deep capillary plexus (SCP and DCP), and choriocapillaris (CCP) flow area were significantly lower than those in healthy control subjects (p < .05 for all). In IPAH group, PVR and mPAP were correlated significantly with the perfusion measurements at SCP and DCP (r = .461, r = .626 and r = .625, r =0.730, respectively, p < .05). sPAP and TRV were positively correlated with the perfusion measurements at SCP and DCP (r = .600, r = .662 and r = .670, r = .655 p < .05). CONCLUSIONS: The positive correlation of retinal perfusion at SCP and DCP with right-sided echocardiographic and hemodynamic measurements unveiled that retinal microcirculation is affected by the pressure alterations in the pulmonary circulation of IPAH patients.

Should We Target Global Risk or Risk Factors?

PURPOSE OF REVIEW: Recent evidence has shaped the new guidelines for the management of dyslipidemia. The importance of accurate risk estimation, subclinical disease detection, and contemporary dyslipidemia management approaches are discussed in this review. RECENT FINDINGS: Risk prediction helps determine the intensity of management strategies and identify high-risk patients. To overcome the pitfalls of the current risk prediction systems, incorporating genetic scores, biomarkers, and imaging is being explored. Key initiating event in atherogenesis is low-density lipoprotein cholesterol (LDL-C) retention in the arterial wall. Recent dyslipidemia guidelines agree that LDL-C is the primary target, but management approaches vary. Guidelines are shaped by new studies that show the benefits of high-intensity lipid lowering, especially for patients at very high-risk. Global risk assessment should be performed in all individuals for cardiovascular disease prevention. Main target should be the causal risk factors, particularly LDL-C which is one of the most important modifiable causal factors. Lower LDL-C goals will help prevent further events in very high-risk patients.

Medical Treatment in Coronary Patients: Is there Still a Gender Gap? Results from European Society of Cardiology EUROASPIRE V Registry.

PURPOSE: This study is aimed at investigating gender differences in the medical management of patients with coronary heart disease (CHD). METHODS: Analyses were based on the ESC EORP EUROASPIRE V (European Survey Of Cardiovascular Disease Prevention And Diabetes) survey. Consecutive patients between 18 and 80 years, hospitalized for a coronary event, were included in the study. Information on cardiovascular medication intake at hospital discharge and at follow-up (≥ 6 months to < 2 years after hospitalization) was collected. RESULTS: Data was available for 8261 patients (25.8% women). Overall, no gender differences were observed in the prescription and use of cardioprotective medication like aspirin, beta-blockers, and ACE-I/ARBs (P > 0.01) at discharge and follow-up respectively. However, a statistically significant difference was found in the use of statins at follow-up, in disfavor of women (82.8% vs. 77.7%; P < 0.001). In contrast, at follow-up, women were more likely to use diuretics (31.5% vs. 39.5%; P < 0.001) and calcium channel blockers (21.2% vs. 28.8%; P < 0.001), whereas men were more likely to use anticoagulants (8.8% vs. 7.0%; P < 0.001). Overall, no gender differences were found in total daily dose intake (P > 0.01). Furthermore, women were less likely than men to have received a CABG (20.4% vs. 13.2%; P < 0.001) or PCI (82.1% vs. 74.9%; P < 0.001) at follow-up. No gender differences were observed in prescribed (P = 0.10) and attended (P = 0.63) cardiac rehabilitation programs. CONCLUSION: The EUROASPIRE V results show only limited gender differences in the medical management of CHD patients. Current findings suggest growing awareness about risk in female CHD patients.

Familial Hypercholesterolemia: Global Burden and Approaches.

PURPOSE OF REVIEW: Familial hypercholesterolemia (FH) is the most common genetic metabolic disorder characterized by markedly elevated LDL-C levels from birth leading to atherosclerotic cardiovascular disease (ASCVD) and premature deaths. The purpose of this review is to share the current knowledge in the diagnosis, risk estimation, and management of patients with FH in the light of recent evidence and guideline recommendations. RECENT FINDINGS: Recent registries underscored the prevalence of FH as 1/200-250 translating to an almost 1500 million subjects suffering from FH worldwide. However, only a minority of FH patients are identified early and effectively treated. In most cases, mutations in the LDL-receptor (LDLR) gene and to a lesser degree in the apolipoprotein B-100 (APOB), proprotein convertase subtilisin/kexin type 9 (PCSK9), and the LDL-receptor adaptor protein 1 (LDLRAP1) genes cause FH. Diagnostic scores such as Dutch Lipid Clinic Network criteria using clinical manifestations are helpful in identifying FH. Traditional risk factors and high lipoprotein(a) affect the course of the disease. Vascular ultrasound imaging and coronary calcium scoring are helpful for further risk estimation of these patients. Getting to LDL-C goals is possible with currently available treatments including statins, ezetimibe, and PCSK9 inhibitors, as well as lipoprotein apheresis, lomitapide, and mipomersen in more severe phenotypes. Additionally, novel agents bempedoic acid, inclisiran, and evinacumab expanded the treatment choices for some patients with FH. Early diagnosis and initiation of LDL-C lowering are still required to achieve the greatest reduction in ASCVD morbidity and mortality in patients with FH. FH is a common genetic disorder characterized by markedly elevated LDL-C levels from birth onward, resulting in significantly increased risk for ASCVD. Despite major advances in our understanding of the disease and effective therapies, FH is still underdiagnosed and undertreated. Early initiation of LDL-C lowering by increased awareness of FH among the healthcare professionals, patients, and the public is necessary to achieve meaningful reduction in ASCVD morbidity and mortality in these patients.

Lipid-lowering and anti-thrombotic therapy in patients with peripheral arterial disease.

Patients with peripheral arterial disease (PAD) are at very high risk of cardiovascular events, but risk factor management is usually suboptimal. This Joint Task Force from the European Atherosclerosis Society and the European Society of Vascular Medicine has updated evidence on the management on dyslipidaemia and thrombotic factors in patients with PAD. Guidelines recommend a low-density lipoprotein cholesterol (LDLC) goal of more than 50% reduction from baseline and <1.4 mmol/L (<55 mg/dL) in PAD patients. As demonstrated by randomized controlled trials, lowering LDL-C not only reduces cardiovascular events but also major adverse limb events (MALE), including amputations, of the order of 25%. Addition of ezetimibe or a PCSK9 inhibitor further decreases the risk of cardiovascular events, and PCSK9 inhibition has also been associated with reduction in the risk of MALE by up to 40%. Furthermore, statin- based treatment improved walking performance, including maximum walking distance, and pain-free walking distance and duration. This Task Force recommends strategies for managing statin-associated muscle symptoms to ensure that PAD patients benefit from lipid-lowering therapy. Antiplatelet therapy, either daily clopidogrel 75 mg or the combination of aspirin 100 mg and rivaroxaban (2×2.5 mg) is also indicated to prevent cardiovascular events. Dual pathway inhibition (aspirin and rivaroxaban) may be considered following revascularization, taking into account bleeding risk. This Joint Task Force believes that adherence with these recommendations for lipid-lowering and antithrombotic therapy will improve the morbidity and mortality in patients with PAD.

Evaluation of Low-density Lipoprotein Cholesterol Target Attainment Rates According to the 2016 and 2019 European Society of Cardiology/European Atherosclerosis Society Dyslipidemia Guidelines for Secondary Prevention in Patients with Acute Myocardial Infarction.

BACKGROUND: High-intensity statin (HIS) therapy is widely recommended for secondary prevention after an acute myocardial infarction (AMI). The 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) dyslipidemia guidelines have lowered the target low-density lipoprotein cholesterol (LDL-C) level, which necessitates a more frequent use of nonstatin therapies. OBJECTIVES: The objectives of the study were to investigate the rate of LDL-C target attainment for secondary prevention in AMI patients. METHODS: This retrospective investigation included 1360 patients diagnosed with AMI in a tertiary heart center. Lipid parameters were collected within 24 h of admission and within 1 year after discharge. The medications used were retrieved from medical records, and the lowest LDL-C levels after statin treatment were used to assess the effectiveness of the therapy. LDL-C target attainment was defined according to the 2016 ESC/EAS dyslipidemia guidelines as an LDL-C level of < 70 mg/dL and a ≥ 50% reduction from baseline. In addition, the rate of LDL-C target attainment according to the 2019 fromESC/EAS guidelines was defined as an LDL-C level of < 55 mg/dL and a ≥ 50% reduction baseline. RESULTS: In total, 502 (36.9%) and 247 (18.2%) patients reached the LDL-C targets according to the 2016 and 2019 ESC/EAS guidelines, respectively. The admission LDL-C levels were significantly lower and HIS treatment was used more frequently in patients who subsequently attained the LDL-C goal. Remarkably, 461 (34%) patients failed to reach the LDL-C goals despite HIS treatment. Only 27 (1.9%) patients were prescribed ezetimibe. CONCLUSION: The rate of LDL-C goal attainment in AMI patients was low, which indicates the need for combination statin and non-statin lipid-lowering therapies.

Low-Density Lipoprotein Cholesterol Lowering With Evolocumab and Outcomes in Patients With Peripheral Artery Disease: Insights From the FOURIER Trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk).

BACKGROUND: The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. METHODS: FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. RESULTS: Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. CONCLUSIONS: Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.