Aggressive low-density lipoprotein (LDL) lowering for primary prevention: still an elusive goal.

Cardiovascular disease (CVD) is the leading cause of mortality globally. Low-density lipoprotein (LDL) plays an important role in CVD pathophysiology. Research has shown the safety and efficacy of keeping LDL at very low levels for CVD prevention. Therefore, experts recommend intense LDL-lowering approaches starting at young ages, promoting the mantras "the lower, the better" and "the earlier, the better." This commentary discusses the challenges regarding applying aggressive LDL-lowering approaches in the general population, including pharmacological efficacy and side effects, the cost-effectiveness of interventions, and patient adherence to treatment regimens.

Why make it if you can take it: review on extracellular cholesterol uptake and its importance in breast and ovarian cancers.

Cholesterol homeostasis is essential for healthy mammalian cells and dysregulation of cholesterol metabolism contributes to the pathogenesis of various diseases including cancer. Cancer cells are dependent on cholesterol. Malignant progression is associated with high cellular demand for cholesterol, and extracellular cholesterol uptake is often elevated in cancer cell to meet its metabolic needs. Tumors take up cholesterol from the blood stream through their vasculature. Breast cancer grows in, and ovarian cancer metastasizes into fatty tissue that provides them with an additional source of cholesterol. High levels of extracellular cholesterol are beneficial for tumors whose cancer cells master the uptake of extracellular cholesterol. In this review we concentrate on cholesterol uptake mechanisms, receptor-mediated endocytosis and macropinocytosis, and how these are utilized and manipulated by cancer cells to overcome their possible intrinsic or pharmacological limitations in cholesterol synthesis. We focus especially on the involvement of lysosomes in cholesterol uptake. Identifying the vulnerabilities of cholesterol metabolism and manipulating them could provide novel efficient therapeutic strategies for treatment of cancers that manifest dependency for extracellular cholesterol.

Influence of statin use on progression of postoperative fatty infiltration in the arthroscopic rotator cuff repair.

PURPOSE: The purpose of this study was to determine the influence of hyperlipidemia and statin (hydroxyl-methylglutaryl-coenzyme-A reductase inhibitors) use on fatty infiltration (FI) of the rotator cuff muscle after arthroscopic rotator cuff repair (ARCR). The presence or absence of statin use and type of statins used (type 1 naturally derived statins and type 2 synthetic statins) were examined. METHODS: This was a retrospective review of 620 cases (620 shoulders) who underwent arthroscopic rotator cuff repair. Total cholesterol (TC), low-density lipoprotein (LDL), triglycerides (TG) levels, and statin use were reviewed with the medical records. FI of the cuff muscles and repair integrity were assessed by MRI. A generalized linear model was used to analyze the progression of fatty infiltration. Repair integrity was determined according to the Sugaya classification, with types 4 and 5 as retears. RESULTS: The mean age was 66.9 years (272, females). The overall retear rate was 16.1%. There was no significant difference in retears between statin use and non-use with a trend toward higher retear rates in the type 2 statins. FI progressed postoperatively, and multivariate regression showed that type 2 statin use was a significant risk factor (p = 0.006). Other significant risk factor were large-to-massive tear (p = 0.02) and retear (p < .0001). CONCLUSIONS: The progression of FI after ARCR was observed. The new generation of strong statins (type 2 statins) was a significant risk factor for the progression of postoperative fatty infiltration, while neither serum lipid level (TC, LDL, and TG) was significant.

Lipid management strategies for diabetic patients align with an evidence-based guideline.

BACKGROUND: Diabetes mellitus (DM) increases the risk of cardiovascular diseases (CVD) significantly. Statins are recommended for all diabetic patients aged ≥ 40 years to alleviate this risk. OBJECTIVES: This study aimed to determine the status of the implementation of the recommendations of lipid management strategies for diabetic patients. METHODS: In this cross-sectional study, 500 patients with DM, aged ≥ 40 referring to a public pharmacy with at least one diabetic medication in their prescription, were enrolled. Patients' demographics, lipid panel data, medications, personal and family history of atherosclerotic cardiovascular disease (ASCVD), and risk factors for ASCVD were documented. The appropriateness of stain dosing intensity was judged based on the American Diabetes Association (ADA) guideline. RESULTS: The mean ± SD of the age of patients was 61.39 ± 10.49 years. Among patients, 238 (47.6) were men. More than half of the patients were subject to receiving primary prevention (59.8%, n = 299). For 80.8% (n = 404) of patients, a statin, most frequently atorvastatin (61.8%), was prescribed. The appropriate statin dose based on the guideline for 470 patients (94%), was high-intensity statin. In 70.6% (n = 353) of patients, lipid management was not in accordance with the guideline. Patients with ASCVD were more likely to receive the statins and the appropriate doses compared to patients without ASCVD (p-value < 0.001). CONCLUSION: Despite a relatively high percentage of patients who received statins, the lipid management in most patients was not in accordance with the guideline. The profound problem was the suboptimal dosage of statins. Investigating the reasons and barriers of the appropriate management can be helpful. Additionally, since patients without ASCVD who should receive statins for primary prevention were significantly less likely to receive statins and evidence-based doses, more attention is needed for this population.

Association of elevated baseline bilirubin caused by preadmission statin use with cardiovascular prognosis in patients undergoing elective percutaneous coronary intervention.

Bilirubin is widely recognized to possess antioxidant and anti-inflammatory characteristics. However, the relationship between bilirubin and coronary artery disease (CAD) remains controversial, particularly in individuals receiving Percutaneous Coronary Intervention (PCI). Given that statins may enhance the production of heme oxygenase-1 (HO-1) and bilirubin, we investigated the long-term cardiovascular prognostic role of bilirubin levels elevated by statin use in patients undergoing PCI. Data of 6945 subjects undergoing PCI were enrolled in this study. We divided the patients into two groups based on serum total bilirubin (TB) levels detected prior to PCI. The high TB group consisted of patients with serum TB values > 8.4 µmmol/L, while the low TB group consisted of patients with serum TB values ≤ 8.4 µmmol/L. The median follow-up time was 836 days. Cox proportional hazards models were performed to evaluate the hazard ratios (HRs) and 95% confidence interval (CI) for the incidence of major adverse cardiovascular event (MACE) associated with bilirubin levels. The association between TB levels and risk of MACE was significant [adjusted HR = 0.557, 95% CI (0.59-0.96), p = 0.020). Linear analysis was performed to determine the association between preadmission usage of statin and bilirubin level. The preadmission usage of statin independently linearly increases TB [adjusted-ß = 0.371, 95% CI (0.134-0.608), p = 0.002] and direct bilirubin (DB) [adjusted-ß = 0.411, 95% CI (0.300-0.522), p < 0.001). Mediation analysis demonstrated a direct protective role of preadmission statins treatment (ß = - 0.024, p < 0.01), TB (ß = - 0.003, p < 0.05) and DB (ß = - 0.009, p < 0.05). Furthermore, it was found that TB (4.0%) and DB (12.0%) mediated the relationship between preadmission statins therapy and MACE. Bilirubin has a protective effect against MACE. In patients with normal bilirubin level undergoing elective PCI, preadmission statin use elevated bilirubin levels, which were independently associated with a lower incidence of MACE over the long-term follow-up period.

Rosuvastatin-Induced Myopathy: A Case Series.

Statins are one of the most crucial drugs used for the prevention of atherosclerotic coronary artery disease. A wide spectrum of symptoms ranging from myalgia to symptoms of rhabdomyolysis with or without weakness of the upper and lower limbs are indicative of statin-induced rhabdomyolysis or myopathy. The current case series which represents three patients who developed statin-induced myopathy after starting rosuvastatin is one of a few if not the first case series. All three patients had recently started rosuvastatin 40mg once daily post-percutaneous transluminal coronary angioplasty (PTCA) for secondary prevention of atherosclerotic cardiovascular diseases (ASCVDs). Shortly after starting the medication, they were hospitalized due to bilateral lower limb pain and weakness. On further evaluation, they were diagnosed to have rosuvastatin-induced myopathy with acute kidney injury and/or liver injury. In all cases, myopathy, acute renal injury, and liver injury were caused by rosuvastatin, regardless of the presence of a vitamin D deficiency. Despite the documented risk of myopathy and renal toxicity associated with rosuvastatin, the drug remains highly popular worldwide in the modern period. Although all the cases discussed were successfully treated by stopping rosuvastatin and switching it with another class of lipid-lowering agent, it significantly increased morbidity and raised medical expenses. Hence, this case series not only adds to existing safety disputations associated with rosuvastatin but also calls for more pharmacovigilance when recommending this medication.

Sex specific analysis of patients with and without reported statin intolerance referred to a specialized outpatient lipid clinic.

BACKGROUND: Lowering LDL-cholesterol is a fundamental goal for both primary and secondary prevention of atherosclerotic cardiovascular diseases. Our study aims to analyse potential sex disparities regarding the tolerability and effectiveness of lipid-lowering therapy in patients with and without reported statin intolerance who are being treated at a lipid-outpatient clinic. METHODS: From 2017 to 2022, n = 1062 patients (n = 612 men, n = 450 women) at high-risk were referred to our lipid-outpatient clinic because of difficulties in lipid control by primary healthcare providers. The main therapeutic objective was to optimize lipid-lowering therapy according to current treatment guidelines. RESULTS: Patients presented with high LDL-C baseline levels (4.97 ± 1.81 mmol/l (192 ± 70 mg/dL) in men and 5.46 ± 2.04 mmol/l (211 ± 79 mg/dL) in women). Intolerance towards statins was reported more frequently by women (48.2%) than by men (38.9%, p = 0.004). LDL-C continuously decreased with individual treatment adjustments across follow-up visits. In total, treatment goals (LDL < 1.4 mmol/l (< 55 mg/dl) or < 1.8 mmol/l (< 70 mg/dl)) were accomplished in 75.8% of men and 55.5% of women after the last follow-up visit (p < 0.0001). In men, these data are almost identical in subjects with statin intolerance. In contrast, treatment goals were reached less frequently in women with statin intolerance compared to women tolerant to statin therapy. CONCLUSION: Even if treated in a specialized lipid clinic, women are less likely to reach their target LDL-C than men, particularly when statin intolerant. Nevertheless, many patients with statin intolerance can be successfully treated using oral combination and PCSK9 inhibitor therapy. However, ongoing follow-up care to monitor progress and to adjust treatment plans is necessary to reach this goal.

We investigated patients at high cardiovascular risk who were referred to our specialized lipid outpatient clinic because of elevated lipid levels and difficulties in lipid-lowering treatment in the primary care setting. The primary goal of such a clinic is to help patients to achieve optimal lipid levels through personalized treatment plans. We focused on prescription behavior and differences in treatment tolerability and effectiveness between men and women.A large proportion of patients (more frequently women (48.2%) than men (38.9%)) reported intolerance towards statins and most patients' LDL-cholesterol levels were far away from treatment goals. However, when treated at a specialized lipid clinic providing ongoing follow-up care to monitor progress and to adjust treatment plans if necessary, many of those patients were able to tolerate lipid lowering medication to achieve better lipid control and to maintain their lipid levels within target ranges.However, women were less likely to reach LDL-cholesterol treatment targets compared to men, especially if they reported intolerance towards statins. Ongoing follow-up care to monitor progress and to adjust treatment plans is necessary to reach treatment goals.

Short-Term and Long-Term Fluvastatin Inhibit Effects of Thrombospondin-1 on Human Vascular Smooth Muscle Cells.

INTRODUCTION: Vascular smooth muscle cells are important in intimal hyperplasia. Thrombospondin-1 is a matricellular protein involved in the vascular injury response. Statins are cholesterol lowering drugs that have beneficial cardiovascular effects. Statis have been shown to inhibit smooth muscle migration through the mevalonate pathway. This effect is thought to be mediated by small G protein Ras and Rho turnover which requires many hours. While many patients undergoing treatment for vascular disease are on statins, many are not. Thus immediate pretreatment with statins before surgery may be beneficial. We hypothesized that statins have effects independent of the mevalonate pathway and thus have an immediate effect. METHODS: Human vascular smooth muscle cells were pretreated for 20 h (long-term) or 20 min (short-term) with fluvastatin, or mevalonolactone plus fluvastatin. Thrombospondin-1-induced migration, activation of p42/p44 extracellular signal-regulated kinase, c-Src, focal adhesion kinase and PI3 kinase was determined. The effect of fluvastatin on thrombospondin-1-induced expression of THBS1, FOS, HAS2 and TGFB2 was examined. RESULTS: Both treatments inhibited thrombospondin-1-induced chemotaxis back to the control group. Mevalonolactone reversed the long-term statin effect by increasing migration but had no effect on the short-term statin response. p42/p44 extracellular signal-regulated kinase was activated by thrombospondin-1 and both treatments augmented activation. Neither treatment affected c-Src activity, but both inhibited focal adhesion kinase and PI3 kinase activity. Only long-term statin treatment inhibited THBS1 expression while both treatments inhibited FOS and TGFB2 expression. Neither treatment affected HAS2. FOS knockdown inhibited thrombospondin-1-induced HAS2 but not TGFß2 gene expression. CONCLUSION: Long-term fluvastatin inhibited thrombospondin-1-induced chemotaxis through the mevalonate pathway while short-term fluvastatin inhibited chemotaxis through an alternate mechanism. Short-term stains have immediate effects independent of the mevalonate pathway. Acute local treatment with statins followed by longer term therapy may limit the vascular response to injury.

Statins, but not proprotein convertase subtilisin-kexin type 9 inhibitors, lower chemerin in hypercholesterolemia via low-density lipoprotein receptor upregulation.

Hypercholesterolemia is characterized by elevated low-density lipoprotein (LDL)-cholesterol levels and an increased risk of cardiovascular disease. The adipokine chemerin is an additional risk factor. Here we investigated whether cholesterol-lowering with statins or proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) affects chemerin. Both statins and PCKS9i lowered plasma LDL-cholesterol, triglycerides and total cholesterol in hypercholesterolemic patients, and increased high-density lipoprotein (HDL)-cholesterol. Yet, only statins additionally reduced chemerin and high-sensitivity C-reactive protein (hsCRP). Applying PCSK9i on top of statins did not further reduce chemerin. Around 20% of chemerin occurred in the HDL2/HDL3 fractions, while >75% was free. Statins lowered both HDL-bound and free chemerin. Pull-down assays revealed that chemerin binds to the HDL-component Apolipoprotein A-I (ApoA-I). The statins, but not PCSK9i, diminished chemerin secretion from HepG2 cells by upregulating LDL receptor mRNA. Furthermore, chemerin inhibited HDL-mediated cholesterol efflux via its chemerin chemokine-like receptor 1 in differentiated macrophages. In conclusion, statins, but not PCSK9i, lower circulating chemerin by directly affecting its release from hepatocytes. Chemerin binds to ApoA-I and inhibits HDL-mediated cholesterol efflux. Statins prevent this by lowering HDL-bound chemerin. Combined with their anti-inflammatory effect evidenced by hsCRP suppression, this represents a novel cardiovascular protective function of statins that distinguishes them from PCSK9i.

A Neuropathy Mimic: Statin-Induced Myopathy Presenting as Guillain-Barré Syndrome.

Statins are widely used to manage dyslipidemia and prevent cardiovascular diseases due to their effectiveness and general safety profile. However, they can sometimes cause severe muscle-related adverse effects, presenting diagnostic challenges when symptoms overlap with other conditions. This case report describes a middle-aged woman who presented to the emergency department with bilateral lower limb weakness, initially suggesting Guillain-Barré syndrome (GBS). Despite her history of low-grade fever and diarrhea, primary and secondary surveys, including electrocardiogram, blood gas analysis, and nerve conduction studies, showed no definitive signs of GBS. The patient had a recent history of percutaneous transluminal coronary angioplasty and was on dual antiplatelet therapy and rosuvastatin. Elevated creatine kinase levels and exclusion of other differential diagnoses led to the diagnosis of statin-induced myopathy, a rare but severe adverse effect of statins. The patient was treated with intravenous fluids, cessation of statins, and sessions of hemodialysis and plasmapheresis, resulting in significant improvement and eventual recovery of muscle power and neurological function. This case highlights the importance of recognizing statin-induced myopathy in patients with muscle weakness and emphasizes the need for thorough clinical evaluation to differentiate it from other conditions such as GBS. Further research is warranted to understand the pathophysiology of statin myopathy and identify at-risk populations.

Assessing the role of statin therapy in bladder cancer: evidence from a Mendelian Randomization study.

Background: Statins, which are medications that lower lipid levels, are extensively used to decrease cardiovascular disease risk. Recently, the use of statins in cancer prevention has attracted considerable interest. However, it is still unclear whether the use of statins has a causal effect on bladder cancer. Methods: The two-sample Mendelian Randomization (MR) was performed to infer the causal relationship between statin therapy (atorvastatin, simvastatin, and rosuvastatin) and bladder cancer. Single-nucleotide polymorphisms (SNP)-based genome-wide association studies (GWAS) of statins (atorvastatin, simvastatin, and rosuvastatin) were gathered from the UK Biobank, involving 462,933 participants. We acquired summary-level genetic data on bladder cancer from a European cohort of 175,121 individuals. The inverse variance weighted (IVW) method was the main analytical technique used, supplemented by MR-Egger, weighted median, weighted mode, and simple mode to estimate causal effects. Additionally, sensitivity analyses were conducted to verify the robustness and reliability of our findings. Results: Based on the IVW analysis, we identified a significant causal association between rosuvastatin use and a decreased risk of bladder cancer, with genetic analysis inferring the substantial reduction in odds (OR = 3.52E-19, 95% CI: 5.48E-32-2.26E-06, p = 0.005). In contrast, the IVW results did not reveal a statistically significant relationship between the genetically estimated use of atorvastatin (OR = 7.42E-03, 95% CI: 6.80E-06-8.084, p = 0.169) or simvastatin (OR = 0.135, 95% CI: 0.008-2.330, p = 0.168) and bladder cancer risk. Conclusion: We investigated the causal link between statin therapy (atorvastatin, simvastatin, and rosuvastatin) and bladder cancer using a two-sample Mendelian Randomization analysis among the European population. Our findings indicated that genetically predicted use of rosuvastatin was associated with a decreased risk of bladder cancer, whereas no significant genetically predicted causal effects were observed for atorvastatin and simvastatin use.

Frequency and determinants of lipid management target achievement in primary prevention of cardiovascular disease in type 2 diabetes.

Aims: This study aimed to clarify the real-world status of lipid management in outpatients with type 2 diabetes (T2DM) following the 2022 revision of the Japan Atherosclerosis Society Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases. It also aimed to evaluate characteristics associated with the failure to achieve management targets. Materials and Methods: In this post-hoc analysis of a multicenter, cross-sectional study, we included Japanese outpatients with T2DM undergoing primary prevention of atherosclerotic cardiovascular diseases (ASCVD) who provided fasting blood samples. The frequency and determinants of achieving low-density lipoprotein cholesterol (LDL-C) and non-high-density lipoprotein cholesterol (non-HDL-C) targets were assessed. Results: Among 223 participants with a mean age of 67 and mean HbA1c of 7.1%, 61 had no history of peripheral arterial disease, microvascular complications, or smoking. Out of the 223 participants, 64.1% (95% CI: 57.6-70.1%) achieved the LDL-C target. In multivariate logistic regression analysis, being female (odds ratio [OR] 3.139, P = 0.0011), having diabetic nephropathy (OR 2.868, P = 0.0021), smoking (OR 2.292, P = 0.0281), and non-use of statins (OR 4.857, P < 0.0001) were independently associated with non-achievement. For non-HDL-C, 65.6% (95% CI: 58.1%-70.6%) of patients met the target. Having diabetic neuropathy (OR 2.428, P = 0.0054), smoking (OR 2.008, P = 0.0478), and non-use of statins (OR 2.277, P = 0.0112) were identified as factors associated with non-achievement. Conclusions: Low achievement rate of revised lipid management targets for ASCVD primary prevention in T2DM was unveiled. Assessing comorbidities, encouraging smoking cessation, and prioritizing statin use are considered.

Risk of cardiovascular outcomes with bempedoic acid in high-risk statin intolerant patients: a systematic review and meta analysis.

Aim: Statin intolerance and myopathy is a major issue with prolonged use of statins myopathy. Bempedoic acid can be a good alternative for those intolerant to statins. This systematic review aims to observe incidence of major adverse cardiovascular events (MACE) and other adverse events, in high-risk statin intolerant patients receiving bempedoic acid. Methods: Literature search was conducted via Google Scholar, Science Direct and PubMed, after which screening, selection and data extraction of articles was done. Meta-analysis was performed on RevMan 5.4. Subgroup analysis was also conducted and heterogeneity was evaluated. Risk of bias was performed using ROB2 assessment scale. (CRD42024536827). Results: Only six randomized controlled trials were used in final analysis consisting of 17,844 patients. Treatment with bempedoic acid was associated with a reduced risk of MACE compared with placebo (RR 0.86; 95% CI [0.79, 0.94] p = 0.0005), with myocardial infarction significantly reduced. Incidence of adverse effects was increased with bempedoic acid (RR: 1.02; 95% [1.00, 1.03] p = 0.01) but no significant difference was observed. Incidence of myalgia was reduced in bempedoic group as well. Conclusion: Bempedoic acid is a safe and effective alternative to statins in high-risk patients intolerant to statins, decreasing the risk of MACE.

What is this summary about? Low density lipoprotein (LDL-C) also known as 'bad cholesterol', is the culprit behind many heart diseases. Statins are first-line treatment to reduce LDL-C. Despite being extremely effective, some people are intolerant and experience side effects such as sleep disorders, intestinal diseases and most commonly, effects on muscles ranging from muscle pain to breakdown of muscles leading to kidney damage. Bempedoic acid is a once-a-day medication, increasing LDL-C clearance from blood, reducing the risk of heart attack and diabetes and is effective for patients intolerant to statins. This article provides insights into incidences of major heart-related, and other adverse events in patients receiving bempedoic acid.What were the results? Muscle pain and major heart-related events were reduced (especially heart attack) in patients receiving bempedoic acid as compared with those receiving placebos. Muscle weakness and other adverse events were seen in patients receiving bempedoic acid, but serious adverse events were not significantly different from those receiving placebos.What do the results mean? Bempedoic acid is a safe and effective treatment that can be given to patients who cannot tolerate statins or develop side effects to it, as it reduces the risk of heart-related adverse events.

Pitavastatin is Well-Tolerated with no Detrimental Effects on Physical Function.

BACKGROUND: Little is known about the potential benefits or harms of statins on physical function among people with HIV (PWH). METHODS: REPRIEVE was a double-blind randomized controlled trial evaluating pitavastatin for primary prevention of major adverse cardiovascular events (MACE) in PWH. Time to complete ten chair rises, 4-meter gait speed, grip strength, and a modified short physical performance test were assessed annually for up to 5 years in the ancillary study PREPARE and analyzed using linear mixed models. FINDINGS: Of 602 PWH, 52% were randomized to pitavastatin and 48% to placebo. Median age was 51 years; 18% were female at birth; 2% transgender; 40% Black, and 18% Hispanic. Median PREPARE follow-up was 4.7 (4.3, 5.0) years. Muscle symptoms (grade ≥3 or treatment-limiting) occurred in 5% of both groups. There was no evidence of decline in chair rise rate in either treatment group, and no difference in the pitavastatin group compared to placebo (estimated difference -0.10 [95% CI: -0.30, 0.10] rises/min/year; p=0.31). Small declines over time were observed in other physical function tests in both treatment groups, with no apparent differences between groups. INTERPRETATION: We observed minimal declines in physical function over 5 years of follow-up among middle-aged PWH, with no differences among PWH randomized to pitavastatin compared to placebo. This finding, combined with low prevalence of myalgias, supports the long-term safety of statin therapy on physical function, when used for primary prevention of MACE among PWH.

Safety and Effectiveness of High-Intensity Statins Versus Low/Moderate-Intensity Statins Plus Ezetimibe in Patients With Atherosclerotic Cardiovascular Disease for Reaching LDL-C Goals: A Systematic Review and Meta-Analysis.

BACKGROUND: It remains controversial whether adding ezetimibe to low/moderate-intensity statins has a more beneficial impact on the treatment efficacy and safety of patients with existing atherosclerotic cardiovascular disease (ASCVD) compared to high-intensity statin regimens. HYPOTHESIS: A combination of low/moderate-intensity statins plus ezetimibe might be more effective and safer than high-intensity statin monotherapy. METHODS: We searched databases for randomized controlled trials comparing lipid profile alterations, drug-related adverse events, and MACE components between high-intensity statin monotherapy and low/moderate-intensity statin plus ezetimibe combination therapy. Pooled risk ratios (RR), mean differences (MD), and 95% confidence intervals (95% CI) were estimated using a random-effects model. RESULTS: Our comprehensive search resulted in 32 studies comprising 6162 patients treated with monotherapy against 5880 patients on combination therapy. Combination therapy was more effective in reducing low-density lipoprotein cholesterol (LDL-C) levels compared to monotherapy (MD = -6.6, 95% CI: -10.6 to -2.5); however, no significant differences were observed in other lipid parameters. Furthermore, the combination therapy group experienced a lower risk of myalgia (RR = 0.27, 95% CI: 0.13-0.57) and discontinuation due to adverse events (RR = 0.61, 95% CI: 0.51-0.74). The occurrence of MACE was similar between the two treatment groups. CONCLUSIONS: Adding ezetimibe to low/moderate-intensity statins resulted in a greater reduction in LDL-C levels, a lower rate of myalgia, and less drug discontinuation compared to high-intensity statin monotherapy in patients with existing cardiovascular disease. However, according to our meta-analysis, the observed reduction in LDL-C levels in the combination group did not correlate with a reduction in MACE compared to the high-intensity statin group.

Association of statin use with risk of depression and anxiety: A prospective large cohort study.

OBJECTIVES: To examine associations between regular statin use and the incidence of depression and anxiety. METHODS: This cohort was based on UK Biobank participants without depression/anxiety recruited between 2006 and 2010. The self-reported regular statin use was collected at baseline. Depression and anxiety outcomes were assessed by diagnostic interviews (international classification of diseases codes) and nondiagnostic scales (mental well-being questionnaires). Cox proportional hazards models adjusted for a wide range of confounders were used to estimate associations of statins with incident depression/anxiety. RESULTS: Among 363,551 eligible participants, 55,838 reported regular statin use. During a 13-year follow-up, 14,765 cases of depression and 15,494 cases of anxiety were identified. Compared with non-statin users, statin use was associated with reduced risk of depression (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.81, 0.94) and anxiety (HR: 0.90, 95% CI: 0.84, 0.97). Effects of statins on depression were consistent in sensitivity analyses and may be less influenced by unmeasured confounders. However, results of online survey data showed that statin use might not be associated with incident anxiety (HR: 0.96, 95% CI: 0.85, 1.09). CONCLUSION: Regular statin use was associated with a lower risk of depression. No clear associations between statin use and anxiety were found.

Expression of pro- and anti-inflammatory cytokines during anti-proprotein convertase subtilisin/kexin type 9 therapy in patients with statin-resistant familial hypercholesterolemia.

Background: Some clinical dyslipidemia cases do not respond to statins, known as statin-resistant familial hypercholesterolemia (SR-FH), in which patients are under a high cardiovascular risk despite statin therapy. Therefore, novel therapeutic alternatives are required. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) reduce cholesterol levels and cardiovascular disease risk, particularly in patients with SR-FH, where PCSK9i may differentially affect pro- and anti-inflammatory mediators depending on the clinical setting. Aim: To evaluate the effect of PCSK9i treatment on pro- and anti-inflammatory cytokines in patients with SR-FH. Methods: Before-after comparison, quasi-experimental, single-center study in patients with SR-FH. Blood samples were processed to obtain complete blood counts of glycated hemoglobin and serum lipid levels. Flow cytometry was performed to characterize baseline circulating M1- and M2-macrophages and monocytes. Multiplexing of plasma samples was used to compare plasma fraktaline, interleukins (ILs), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-alpha. The endpoints were lower serum lipid levels and pro-inflammatory mediator modification. Results: Twenty patients with SR-FH, aged 58 years and most of them males, were included, with a mean body-mass index of 26.4 and showing ischemic heart disease and similar values of baseline M1- and M2-macrophages and monocytes. Six-month iPSCK-9 therapy considerably reduced LDLc, increased anti-inflammatory cytokine (IL-4), and modified pro-inflammatory cytokine (TNF-alpha and MCP-1) levels. No notable effects were observed for the other markers. Conclusion: PCSK9i therapy exerted subclinical anti-inflammatory and anti-atherogenic effects, indicating potential benefits for clinical outcomes.

Statin Therapy, Inflammation, and Outcomes in Patients Hospitalized for Covid-19: A Prospective Multicenter Cohort Study.

BACKGROUND: Statins are lipid-lowering agents with with anti-inflammatory effects. Data surrounding the benefits of statins in patients with coronavirus disease 2019 (Covid-19) are conflicting. We sought to better understand the impact of statins in the context of Covid-19-related inflammation. METHODS: We leveraged the International Study of Inflammation in Covid-19, a prospective multicenter cohort of patients hospitalized for Covid-19 between February 2020 and October 2022. Participants underwent systematic assessment of biomarkers of inflammation. We used logistic regression modeling and inverse probability-of-treatment weighting (IPTW) to examine the association between prior statin use and the composite outcome of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS: A total of 4,464 patients were included in the study, of whom 1,364 (27.5%) were taking a statin prior to admission. There were 1,061 primary outcome events, including 540 deaths, 854 mechanical ventilation and 313 renal replacement therapy. Amongst biomarkers of inflammation, statin use was associated solely with lower levels of soluble urokinase plasminogen activator receptor (suPAR) after adjusting for known confounders. In multivariable logistic regression analysis, statin use was associated with lower odds of the composite outcome (adjusted odds ratio (aOR) 0.63, 95%CI[0.53-0.76]) compared to patients not on statins. Findings were consistent with IPTW (aOR 0.92, 95%CI [0.89- 0.95]). The proportion of the effect of statin on the primary outcome mediated by suPAR was estimated at 31.5%. CONCLUSION: Prior-statin use is associated with improved outcomes and lower inflammation as measured by suPAR levels in patients hospitalized for Covid-19.

Off-target effects of statins: molecular mechanisms, side effects and the emerging role of kinases.

Statins are one of the most important classes of drugs. In this analytical review, we elucidate the intricate molecular mechanisms and toxicological rationale regarding both the on- (targeting 3-hydroxy-3-methylglutaryl-coenzyme A reductase [HMGCR]) and off-target effects of statins. Statins interact with a number of membrane kinases, such as epidermal growth factor receptor (EGFR), erb-b2 receptor tyrosine kinase 2 (HER2) and MET proto-oncogene, receptor tyrosine kinase (MET), as well as cytosolic kinases, such as SRC proto-oncogene, non-receptor tyrosine kinase (Src) and show inhibitory activity at nanomolar concentrations. In addition, they interact with calcium ATPases and peroxisome proliferator-activated receptor α (PPARα/NR1C1) at higher concentrations. Statins interact with mitochondrial complexes III and IV, and their inhibition of coenzyme Q10 synthesis also impairs the functioning of complexes I and II. Statins act as inhibitors of kinases, calcium ATPases and mitochondrial complexes, while activating PPARα. These off-target effects likely contribute to the side effects observed in patients undergoing statin therapy, including musculoskeletal symptoms and hepatic effects. Interestingly, some off-target effects of statins could also be the cause of favourable outcomes, relating to repurposing statins in conditions such as inflammatory disorders and cancer.