Peripheral artery disease (PAD) is a common condition characterized by atherosclerosis in the peripheral arteries, associated with concomitant coronary and cerebrovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a class of drugs that have shown potential in hypercholesterolemic patients. This review focuses on the efficacy, safety, and clinical outcomes of PCSK9 inhibitors in PAD based on the literature indexed by PubMed. Trials such as FOURIER and ODYSSEY demonstrate the efficacy of evolocumab and alirocumab in reducing cardiovascular events, offering a potential treatment option for PAD patients. Safety evaluations from trials show few adverse events, most of which are injection-site reactions, indicating the overall safety profile of PCSK9 inhibitors. Clinical outcomes show a reduction in cardiovascular events, ischemic strokes, and major adverse limb events. However, despite these positive findings, PCSK9 inhibitors are still underutilized in clinical practice, possibly due to a lack of awareness among care providers and cost concerns. Further research is needed to establish the long-term effects and cost-effectiveness of PCSK9 inhibitors in PAD patients.

Elevated low-density lipoprotein cholesterol (LDL-C) is a major causal factor for atherosclerotic cardiovascular disease (ASCVD), the leading cause of mortality worldwide. Statins are the recommended first-line lipid-lowering therapy (LLT) for patients with primary hypercholesterolemia and established ASCVD, with LLT intensification recommended in the substantial proportion of patients who do not achieve levels below guideline-recommended LDL-C thresholds with statin treatment alone. The proprotein convertase subtilisin/kexin type 9 inhibitor monoclonal antibody evolocumab has demonstrated significant LDL-C reductions of > 60% in the clinical trial and open-label extension settings, with LDL-C reductions observed early post-evolocumab initiation and maintained long term, during up to 8.4 years of follow-up. Evolocumab therapy, when added to a statin, also conferred a significant reduction in major cardiovascular (CV) events, including a 20% reduction in the composite of CV death, myocardial infarction (MI), or stroke. The absolute benefits were enhanced among various patient types at high and very high risk for secondary ASCVD (e.g., with recent MI, multiple events or peripheral artery disease). Importantly, evolocumab treatment resulted in incremental CV risk reductions during the extended follow-up, including a 23% reduction in CV mortality and no apparent LDL-C level below which there is no further CV risk reduction. Hence, the evolocumab clinical data support the need for early and significant LDL-C lowering, especially in vulnerable ASCVD patients, in order to derive the greatest benefit in the long term. Importantly, evolocumab had no impact on any treatment emergent adverse events apart from a small increase in local injection site reactions. A growing body of real-world evidence (RWE) for evolocumab in heterogeneous populations is consistent with the trial data, including robust LDL-C reductions below guideline-recommended thresholds, a favourable safety profile even at the lowest levels of LDL-C achieved, and a high treatment persistence rate of > 90%. Altogether, this review highlights findings from 50 clinical trials and RWE studies in > 51,000 patients treated with evolocumab, to demonstrate the potential of evolocumab to address the healthcare gap in LDL-C reduction and secondary prevention of ASCVD in a variety of high- and very high-risk patients.

Lipid-lowering therapy (LLT) is a cornerstone of atherosclerotic cardiovascular disease prevention. Although LLT might lead to different reductions in low-density lipoprotein cholesterol (LDL-C) levels in women and men, LLT diminishes cardiovascular risk equally effectively in both sexes. Despite similar LLT efficacy, the use of high-intensity statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 inhibitors is lower in women compared to men. Women achieve the guideline-recommended LDL-C levels less often than men. Greater cholesterol burden is particularly prominent in women with familial hypercholesterolemia. In clinical practice, women and men with dyslipidemia present with different cardiovascular risk profiles and disease manifestations. The concentrations of LDL-C, lipoprotein(a), and other blood lipids differ between women and men over a lifetime. Dissimilar levels of LLT target molecules partially result from sex-specific hormonal and genetic determinants of lipoprotein metabolism. Hence, to evaluate a potential need for sex-specific LLT, this comprehensive review (i) describes the impact of sex on lipoprotein metabolism and lipid profile, (ii) highlights sex differences in cardiovascular risk among patients with dyslipidemia, (iii) presents recent, up-to-date clinical trial and real-world data on LLT efficacy and safety in women, and (iv) discusses the diverse medical needs of women and men with dyslipidemia and increased cardiovascular risk.

Acute coronary syndrome (ACS) remains a major cause of morbidity and mortality, despite many improvements in its prevention and management. Lipid management is an important aspect of secondary prevention after ACS. Previous studies indicate that the early use of intensive statin therapy in patients with ACS may alleviate the risk of recurrent cardiovascular events and mortality. However, many patients do not reach the target low-density lipoprotein cholesterol (LDL-C) level of < 55 mg/dL with statin monotherapy, and muscle-related adverse effects caused by statins hinder adherence to treatment. Novel non-statin agents are recommended for patients who cannot achieve the target LDL-C levels with high-intensity statin therapy and those with statin intolerance. The combination of statins and non-statins may synergistically affect intensively lowering LDL-C through different mechanisms, which could lead to better cardiovascular outcomes than statin monotherapy. However, it remains uncertain whether the early use of combination lipid-lowering therapy is more beneficial. The present review summarizes the benefits of intensive statin monotherapy and their early combination with non-statin medications including ezetimibe, PCSK9 inhibitors, inclisiran, and bempedoic acid (BDA) in the management of ACS.

BACKGROUND: Statins are the most widely used drugs for decreasing elevated serum LDL-cholesterol (LDL-C) and thus for the prevention of atherosclerotic cardiovascular disease (ASCVD), but they have also some pleiotropic effects, including anti-inflammatory properties. Atherosclerosis is a low-grade inflammatory disease, and elevated ferritin is considered to be one of the markers of inflammation. Since the results of studies on the effects of statins on serum ferritin levels are conflicting, this meta-analysis was performed.
METHODS: A literature search was performed using major electronic databases (MEDLINE/PubMed, Scopus, Embase, and ISI Web of Science) from inception up to 5 March 2022 to find studies evaluating the effect of different statins on serum ferritin levels. The effect size was determined using weighted mean differences (WMDs) and the corresponding 95% confidence intervals (CIs).
RESULTS: The meta-analysis of nine studies (1611 patients) analyzing the effects of statins on serum ferritin levels that were included showed a significant decrease in circulating ferritin levels caused by statins. The results did not suggest any significant association between the changes in concentrations of serum ferritin and the duration of treatment with statins.
CONCLUSIONS: Statin therapy decreases the circulating concentrations of ferritin, which might be beneficial for the prevention and/or progression of ASCVD. This effect might be explained by the anti-inflammatory effects and maybe some other pleiotropic effects of statins and not by their lipid-lowering effects.

OBJECTIVE: Women are less often recognized to have cardiovascular disease (CVD) risk and are underrepresented in randomized trials of lipid-lowering therapy. Here, we summarize non-pharmacologic and pharmacologic strategies for lipid-lowering in women of childbearing age, lipid changes during pregnancy and lactation, discuss sex-specific outcomes in currently available literature, and discuss future areas of research.
RESULTS: While lifestyle interventions form the backbone of CVD prevention, some women of reproductive age have an indication for pharmacologic lipid-lowering. Sex-based evidence is limited but suggests that both statin and non-statin lipid-lowering agents are beneficial regardless of sex, especially at high cardiovascular risk. Pharmacologic lipid-lowering therapies, both during the pregnancy period and during lactation, have historically been and continue to be limited by safety concerns. This oftentimes limits lipid-lowering options in women of childbearing age. In this review, we summarize lipid-lowering strategies in women of childbearing age and the impact of therapies during pregnancy and lactation. The limited sex-specific data regarding efficacy, adverse events, and cardiovascular outcomes underscore the need for a greater representation of women in randomized controlled trials. More data on lipid-lowering teratogenicity are needed, and through increased clinician awareness and reporting to incidental exposure registries, more data can be harvested.

Lipid-lowering guidelines emphasize shared decision-making between clinicians and patients, resulting in patients anticipating the degree of response from diet or drug therapy. Challenging for physicians is understanding the sources of variability complicating their management decisions, which include non-adherence, genetic considerations, additional lipid parameters including lipoprotein (a) levels, and rare systemic responses limiting benefits that result in non-responsiveness to monoclonal antibody injection. In this narrative review, we focus on the variability of low-density lipoprotein cholesterol (LDL-C) response to guideline-directed interventions such as statins, ezetimibe, bile acid sequestrants, fibrates, proprotein/convertase subtilisin-kexin type 9 inhibitors, and LDL-C-lowering diets. We hypothesize that the variability in individual lipid responses is multifactorial. We provide an illustrative model with a check list that can be used to identify factors that may be present in the individual patient.

Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the mainstay of treatment for hypercholesterolemia as they effectively reduce LDL-C levels and risk of atherosclerotic cardiovascular disease. Apart from hyperglycemia, dyslipidemia and HDL dysfunction are known risk factors for neuropathy in people with obesity and diabetes. Although there are case reports of statin-induced neuropathy, ad hoc analyses of clinical trials and observational studies have shown that statins may improve peripheral neuropathy. However, large randomized controlled trials and meta-analyses of cardiovascular outcome trials with statins and other lipid-lowering drugs have not reported on neuropathy outcomes. Because neuropathy was not a prespecified outcome in major cardiovascular trials, one cannot conclude whether statins or other lipid-lowering therapies increase or decrease the risk of neuropathy. The aim of this review was to assess if statins have beneficial or detrimental effects on neuropathy and whether there is a need for large well-powered interventional studies using objective neuropathy end points.

Aggressive lipid-lowering lifestyle modifications and pharmacologic therapies are the cornerstones of the primary and secondary prevention of atherosclerotic cardiovascular disease events. While statins are highly effective, inexpensive, and generally well-tolerated medications, many clinicians and patients express uncertainty regarding the necessity of statin treatment in older adults. Citing concerns such as polypharmacy, muscle symptoms, and even potential cognitive changes with statins, many patients and health care providers elect to de-intensify or discontinue statin therapy during the process of aging. A lack of clear representation of older individuals in many clinical trials and practice guidelines may contribute to the ambiguity. However, the recently prevailing data and practice patterns supporting the benefits, safety, and tolerability of a variety of lipid-lowering therapeutics in older adults are discussed here, with particular mention of a potential protective effect from incident dementia among a statin-treated geriatric population and an admonishment of the historical concept of \"too-low\" low-density lipoprotein cholesterol (LDL-C) levels.

The seasonal variations of blood lipids have recently gained increasing interest in this field of lipid metabolism. Elucidating the seasonal patterns of blood lipids is particularly helpful for the prevention and treatment of cardiovascular and cerebrovascular diseases. However, the previous results remain controversial and the underlying mechanisms are still unclear. This mini-review is focused on summarizing the literature relevant to the seasonal variability of blood lipid parameters, as well as on discussing its significance in clinical diagnoses and management decisions.