Class Of Lipid-lowering Drugs Research Articles

Comparing the effects of CETP in East Asian and European ancestries: a Mendelian randomization study

CETP inhibitors are a class of lipid-lowering drugs in development for treatment of coronary heart disease (CHD). Genetic studies in East Asian ancestry have interpreted the lack of CETP signal with low-density lipoprotein cholesterol (LDL-C) and lack of drug target Mendelian randomization (MR) effect on CHD as evidence that CETP inhibitors might not be effective in East Asian participants. Capitalizing on recent increases in sample size of East Asian genetic studies, we conducted a drug target MR analysis, scaled to a standard deviation increase in high-density lipoprotein cholesterol. Despite finding evidence for possible neutral effects of lower CETP levels on LDL-C, systolic blood pressure and pulse pressure in East Asians (interaction p-values < 1.6 × 10−3), effects on cardiovascular outcomes were similarly protective in both ancestry groups. In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries.

Impact of national drug price negotiation policy on the accessibility and utilization of PCSK9 inhibitors in China: an interrupted time series analysis

BackgroundPCSK9 inhibitors are a novel class of lipid-lowering drugs that have demonstrated favorable efficacy and safety. Evolocumab and alirocumab have been added to China’s National Reimbursement Drug List through the National Drug Price Negotiation (NDPN) policy. This study aims to evaluate the impact of the NDPN policy on the utilization and accessibility of these two PCSK9 inhibitors.MethodsThe procurement data of evolocumab and alirocumab were collected from 1,519 hospitals between January 2021 and December 2022. We determined the monthly availability, utilization, cost per daily defined dose (DDDc), and affordability of the two medicines. Single-group interrupted time series (ITS) analysis was performed to assess the impact of the NDPN policy on each drug, and multiple-group ITS analysis was performed to compare the differences between them.ResultsThe NDPN policy led to a significant and sudden increase in the availability and utilization of PCSK9 inhibitors, along with a decrease in their DDDc. In the year following the policy implementation, there was an increase in the availability, utilization, and spending, and the DDDc remained stable. The affordability of PCSK9 inhibitors in China have been significantly improved, with a 92.97% reduction in out-of-pocket costs. The availability of both PCSK9 inhibitors was similar, and the DDDc of alirocumab was only $0.23 higher after the intervention. The market share of evolocumab consistently exceeded that of alirocumab. Regional disparities in utilization were observed, with higher utilization in the eastern region and a correlation with per capita disposable income.ConclusionsThe NDPN policy has successfully improved the accessibility and utilization of PCSK9 inhibitors in China. However, regional disparities in utilization indicate the need for further interventions to ensure equitable medicine access.

Estimating the effect of lipid-lowering agents on novel subtypes of adult-onset diabetes.

The aims of the present study were to assess the effects of lipid-lowering drugs [HMG-CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 inhibitors, and Niemann-Pick C1-Like 1 (NPC1L1) inhibitors] on novel subtypes of adult-onset diabetes through a Mendelian randomisation study. We first inferred causal associations between lipid-related traits [including high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoproteins A-I, and apolipoproteins B] and novel subtypes of adult-onset diabetes. The expression quantitative trait loci of drug target genes for three classes of lipid-lowering drugs, as well as genetic variants within or nearby drug target genes associated with LDL-C, were then utilised as proxies for the exposure of lipid-lowering drugs. Mendelian randomisation analysis was performed using summary data from genome-wide association studies of LDL-C, severe autoimmune diabetes, severe insulin-deficient diabetes (SIDD), severe insulin-resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes. There was an association between HMGCR-mediated LDL-C and the risk of SIRD [odds ratio (OR)=0.305, 95% confidence interval (CI)=0.129-0.723; p=0.007], and there was an association of PCSK9-mediated LDL-C with the risk of SIDD (OR=0.253, 95% CI=0.120-0.532; p<0.001) and MOD (OR=0.345, 95% CI=0.171-0.696; p=0.003). Moreover, NPC1L1-mediated LDL-C (OR=0.109, 95% CI=0.019-0.613; p=0.012) and the increased expression of NPC1L1 gene in blood (OR=0.727, 95% CI=0.541-0.977; p=0.034) both showed a significant association with SIRD. These results were further confirmed by sensitivity analyses. In summary, the different lipid-lowering medications have a specific effect on the increased risk of different novel subtypes of adult-onset diabetes.

Lipids, lipid-modifying drug target genes and migraine: a Mendelian randomization study

IntroductionMigraine, a prevalent headache disorder with unclear mechanisms and limited treatments, may be influenced by dyslipidemia and genetic factors. Statins and emerging lipid-modifying agents show potential but lack evidence for migraine management. Mendelian Randomization analysis offers insights into causal relationships and therapeutic targets. This study aims to explore genetically predicted lipid traits, drug targets, and their association with migraine risk.MethodWe conducted Mendelian randomization (MR) analyses utilizing genetic variants associated with lipid traits and variants in genes encoding the protein targets of various classes of lipid-lowering drugs. The specific drug classes investigated included HMGCR, PCSK9, NPC1L1, ABCG5/ABCG8, LDLR, LPL, ANGPTL3, APOB, CETP, and APOC3. To determine the effects on migraine risk, we meta-analyzed MR estimates for regional variants using data from two large sample sets. The genetic variants were weighted based on their associations with specific lipid traits, such as low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), Apolipoprotein A1, and Apolipoprotein B. To obtain association weights, we utilized data from lipid genetics consortia. For lipid-modifying drug targets that exhibited suggestive significance, we further employed expression quantitative trait locus (eQTL) data. Additionally, we performed colocalization analysis to assess genetic confounding.ResultThe use of genetic proxies for HMGCR inhibition demonstrated a significant association with a decreased risk of migraine in the FinnGen dataset (OR = 0.64, 95% CI: 0.46–0.88, p = 0.0006) and a nearly significant association in the Choquet dataset (OR = 0.78, 95% CI: 0.60–1.01, p = 0.06). When pooling the estimates, the overall effect size showed a reduced risk of migraine (OR = 0.73, 95% CI: 0.60–0.89, p = 0.0016). Similarly, genetic mimicry of LPL enhancement was associated with a lower risk of migraine in the FinnGen dataset (OR = 0.82, 95% CI: 0.69–0.96, p = 0.01) and the Choquet dataset (OR = 0.91, 95% CI: 0.83–0.99, p = 0.03). Pooling the estimates showed a consistent effect size (OR = 0.89, 95% CI: 0.83–0.96, p = 0.002). Sensitivity analyses yielded no statistically significant evidence of bias arising from pleiotropy or genetic confounding.ConclusionIn the study, it was observed that among the 10 lipid-lowering drug targets investigated, LPL and HMGCR showed significant associations with migraine risk. These findings indicate that LPL and HMGCR have the potential to serve as candidate drug targets for the treatment or prevention of migraines.

Association of Statin Therapy on Clinical Outcomes in Covid-19 Patients: An Updated Systematic Review and Meta-Analysis on All Related Evidences

Introduction: Statins is a class of lipid-lowering drugs and our previous investigations showed that statins have antiviral effects and have a wound healing effect in the lung. This systematic review and meta-analysis aimed to evaluate the effects of statin therapy on mortality and clinical outcomes in COVID-19 patients.&#x0D; Methods: A comprehensive search was conducted in international databases, including MEDLINE, Scopus, Web of Science, and Embase from December 1, 2019 until January 26, 2022 without any restriction in language. The random-effects model was used to estimate the pooled odds ratio (OR).&#x0D; Results: The statin therapy overally was associated with decrease in odds of ventilation [pooled OR (95% CI): 0.85 (0.70 to 0.99)] and mortality [pooled OR (95% CI): 0.73 (0.66 to 0.81)] but had no effects on the ICU admission [pooled OR (95% CI): 0.93 (0.77 to 1.12)], oxygen therapy [pooled OR (95% CI): 0.85 (0.70 to 0.99)], recovery [pooled OR (95% CI): 1.85 (0.35 to 9.92)], kidney failure [pooled OR (95% CI): 1.01 (0.73 to 1.40)], hospitalization [pooled OR (95% CI): 1.45 (0.88 to 2.36)], asymptomatic disease [pooled OR (95% CI): 1.33 (0.24 to 7.44)], and ARDS [pooled OR (95% CI): 1.15 (0.88 to 1.49)].&#x0D; Conclusion: The present meta-analysis showed that statin therapy was associated with a reduced risk of mortality and ventilation in patients with COVID-19 but had no effects on other clinical outcomes.

SIRT3 mediates the effects of PCSK9 inhibitors on inflammation, autophagy, and oxidative stress in endothelial cells.

Background: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors (i) are a class of lipid-lowering drugs suggested to hold a plethora of beneficial effects independent of their LDL cholesterol-lowering properties. However, the mechanism underlying such observations is debated. Methods: Human aortic endothelial cells (TeloHAEC) were pre-treated with 100 µg/mL of the PCSK9i evolocumab and then exposed to 20 ng/mL of IL-6, a major driver of cardiovascular diseases (CVD), in both naïve state and after siRNA-mediated suppression of the NAD-dependent deacetylase sirtuin-3 (SIRT3). Inflammation, autophagy, and oxidative stress were assessed through Western Blots, ELISAs, and/or immunofluorescence coupled by flow cytometry. To explore the human relevance of the findings, we also evaluated the expression of IL-6, SIRT3, IL-1β, the ratio LC3B II/I, and PCSK9 within the plaques of patients undergoing carotid endarterectomy (n=277), testing possible correlations between these proteins. Results: PCSK9i improved a range of phenotypes including the activation of inflammatory pathways, oxidative stress, and autophagy. Indeed, treatment with PCSK9i was able to counteract the IL-6 induced increase in inflammasome activation, the accrual of autophagic cells, and mitochondrial ROS accumulation. Of note, silencing of SIRT3 reverted the beneficial effects observed with PCSK9i treatment on all these phenomena. In atheroma specimens, the expression of PCSK9 was inversely related to that of SIRT3 while positively correlating with IL-6, IL-1β, and the ratio LC3B II/I. Conclusions: Overall, these data suggest that PCSK9i bear intrinsic anti-inflammatory, anti-autophagic, and antioxidant properties in endothelial cells, and that these pleiotropic effects might be mediated, at least in part, by SIRT3. These results provide an additional mechanism supporting the emerging knowledge relative to the benefit of PCSK9i on CVD beyond LDL-lowering and uncover SIRT3 as a putative mediator of such pleiotropy.

Review of the efficacy and safety of PCSK9 inhibitors in the therapy of lipid metabolism disorders

Lipid metabolism disorder with a predominance of very-low-density lipoproteins (VLDL), triglycerides (TG), and cholesterol (CS) in the blood plasma contributes to the development of atherosclerotic diseases, which to date remain the main cause of death among the population, ranking first among all causes of death in the world and claiming the lives of 4 million Earth inhabitants every year. In this regard, there is a need to search for drugs that reduce the level of cholesterol, triglycerides, and VLDL in blood plasma. Such a group of drugs is PCSK9 inhibitors. Purpose of the study: to evaluate the efficacy and safety of the new class of lipid-lowering drugs — PCSK9 inhibitors.

Статины и окислительный стресс при сердечно-сосудистой патологии

Statins are a highly effective class of lipid-lowering drugs for the prevention of the risk of developing cardiovascular pathology. The main mechanism of action of statins is based on the inhibition of cholesterol formation, which leads to a decrease in serum levels of total cholesterol and atherogenic low-density lipoproteins. However, in addition to the main hypolipidemic effect, statins also have a significant effect on oxidative stress. This article discusses in detail the effect of statins on oxidative stress and its significance for cardiovascular pathology.

Pitavastatin Induces Cancer Cell Apoptosis by Blocking Autophagy Flux.

Statins, a class of lipid-lowering drugs, are used in drug repositioning for treatment of human cancer. However, the molecular mechanisms underlying statin-induced cancer cell death and autophagy are not clearly defined. In the present study, we showed that pitavastatin could increase apoptosis in a FOXO3a-dependent manner in the oral cancer cell line, SCC15, and the colon cancer cell line, SW480, along with the blockade of autophagy flux. The inhibition of autophagy by silencing the LC3B gene reduced apoptosis, while blockade of autophagy flux using its inhibitor, Bafilomycin A1, further induced apoptosis upon pitavastatin treatment, which suggested that autophagy flux blockage was the cause of apoptosis by pitavastatin. Further, the FOXO3a protein accumulated due to the blockade of autophagy flux which in turn was associated with the induction of ER stress by transcriptional upregulation of PERK-CHOP pathway, subsequently causing apoptosis due to pitavastatin treatment. Taken together, pitavastatin-mediated blockade of autophagy flux caused an accumulation of FOXO3a protein, thereby leading to the induction of PERK, ultimately causing CHOP-mediated apoptosis in cancer cells. Thus, the present study highlighted the additional molecular mechanism underlying the role of autophagy flux blockade in inducing ER stress, eventually leading to apoptosis by pitavastatin.

PCSK9 as a Target for Development of a New Generation of Hypolipidemic Drugs.

PCSK9 has now become an important target to create new classes of lipid-lowering drugs. The prevention of its interaction with LDL receptors allows an increase in the number of these receptors on the surface of the cell membrane of hepatocytes, which leads to an increase in the uptake of cholesterol-rich atherogenic LDL from the bloodstream. The PCSK9 antagonists described in this review belong to different classes of compounds, may have a low molecular weight or belong to macromolecular structures, and also demonstrate different mechanisms of action. The mechanisms of action include preventing the effective binding of PCSK9 to LDLR, stimulating the degradation of PCSK9, and even blocking its transcription or transport to the plasma membrane/cell surface. Although several types of antihyperlipidemic drugs have been introduced on the market and are actively used in clinical practice, they are not without disadvantages, such as well-known side effects (statins) or high costs (monoclonal antibodies). Thus, there is still a need for effective cholesterol-lowering drugs with minimal side effects, preferably orally bioavailable. Low-molecular-weight PCSK9 inhibitors could be a worthy alternative for this purpose.

How to Use Statins in Secondary Prevention of Atherosclerotic Diseases: from the Beneficial Early Initiation to the Potentially Unfavorable Discontinuation.

Statins, a class of lipid-lowering drugs, reduce morbidity and mortality in patients with established atherosclerosis-related cardiovascular disease. Early initiation of statin therapy after admission for acute coronary syndromes (ACS), stroke, or transient ischemic attack (TIA) is associated with improved cardiovascular outcomes. Moreover, high-dose statin treatment prior to coronary or carotid revascularization has been shown to reduce cardiovascular events in these patients. However, many patients may be undertreated, and a residual cardiovascular risk remains in current clinical practice. Despite the beneficial role of statins, their discontinuation rate among patients is still elevated leading to severe adverse cardiovascular events due to atherosclerotic plaque destabilization. In this review, we summarized the impact of statin treatment among patients, focusing on the initiation time-points as well as the potential harm derived by their discontinuation.

Immune-based therapies in cardiovascular and metabolic diseases: past, present and future.

Cardiometabolic disorders were originally thought to be driven primarily by changes in lipid metabolism that cause the accumulation of lipids in organs, thereby impairing their function. Thus, in the setting of cardiovascular disease, statins - a class of lipid-lowering drugs - have remained the frontline therapy. In the past 20 years, seminal discoveries have revealed a central role of both the innate and adaptive immune system in driving cardiometabolic disorders. As such, it is now appreciated that immune-based interventions may have an important role in reducing death and disability from cardiometabolic disorders. However, to date, there have been a limited number of clinical trials exploring this interventional strategy. Nonetheless, elegant preclinical research suggests that immune-targeted therapies can have a major impact in treating cardiometabolic disease. Here, we discuss the history and recent advancements in the use of immunotherapies to treat cardiometabolic disorders.

Differential effect of statin use on coagulation markers: an active comparative analysis in the NEO study

BackgroundStatins are a potential treatment for venous thromboembolism (VTE) prophylaxis complementary to conventional anticoagulants without associated bleeding complications. This study aimed to compare pro-thrombotic activities of different classes of lipid-lowering drugs in an active comparator design and determine whether there is a relation between statin versus fibrate/niacin use and pro-coagulant factor outcomes.MethodsThis is a cross-sectional analysis of participants from the Netherlands Epidemiology of Obesity study using any class of lipid-lowering drugs, including any types of statins, niacin, and fibrates. We performed linear regression analyses to determine fibrinogen, factor (F) VIII, FIX, and FXI activity in statins versus fibrate/niacin users and adjusted for age, sex, tobacco smoking, body mass index (BMI), hypertension, diabetes, and prevalent cardiovascular disease.ResultsAmong 1043 participants, the mean age was 58.4 ± 5.2 years, 61% were men, and the mean BMI was 31.3 ± 4.5 kg/m2. Clinical characteristics were balanced between statin and fibrate/niacin users. Statin users had lower mean FXI (18.3 IU/dL, 95% confidence interval (CI) 9.4 to 27.3) levels compared to fibrate/niacin users. The level of FVIII (15.8 IU/dL, 95% CI − 0.003 to 31.6), and FIX (11.3 IU/dL, 95% CI − 0.4 to 23.2) were lower in statin users than fibrate/niacin users with marginal statistical significance.ConclusionCurrent statin use was associated with lower plasma levels of FXI than fibrate/niacin use. The effects on coagulation factors may, in part, explain the benefit of statin therapy rendered in primary and secondary prevention of VTE.

Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients

BackgroundThe coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now. Statins constitute a class of lipid-lowering drugs with proven safety profiles and various known beneficial pleiotropic effects. Our previous investigations showed that statins have antiviral effects and are involved in the process of wound healing in the lung. This triggered us to evaluate if statin use reduces mortality in COVID-19 patients.ResultsAfter initial recruitment of 459 patients with COVID-19 (Shiraz province, Iran) and careful consideration of the exclusion criteria, a total of 150 patients, of which 75 received statins, were included in our retrospective study. Cox proportional-hazards regression models were used to estimate the association between statin use and rate of death. After propensity score matching, we found that statin use appeared to be associated with a lower risk of morbidity [HR = 0.85, 95% CI = (0.02, 3.93), P = 0.762] and lower risk of death [(HR = 0.76; 95% CI = (0.16, 3.72), P = 0.735)]; however, these associations did not reach statistical significance. Furthermore, statin use reduced the chance of being subjected to mechanical ventilation [OR = 0.96, 95% CI = (0.61–2.99), P = 0.942] and patients on statins showed a more normal computed tomography (CT) scan result [OR = 0.41, 95% CI = (0.07–2.33), P = 0.312].ConclusionsAlthough we could not demonstrate a significant association between statin use and a reduction in mortality in patients with COVID19, we do feel that our results are promising and of clinical relevance and warrant the need for prospective randomized controlled trials and extensive retrospective studies to further evaluate and validate the potential beneficial effects of statin treatment on clinical symptoms and mortality rates associated with COVID-19.

Cholesterol Metabolism in Neurodegenerative Diseases: Molecular Mechanisms and Therapeutic Targets

Cholesterol is an indispensable component of the cell membrane and plays vital roles in critical physiological processes. Brain cholesterol accounts for a large portion of total cholesterol in the human body, and its content must be tightly regulated to ensure normal brain function. Disorders of cholesterol metabolism in the brain are linked to neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and other atypical cognitive deficits that arise at old age. However, the specific role of cholesterol metabolism disorder in the pathogenesis of neurodegenerative diseases has not been fully elucidated. Statins that are a class of lipid-lowering drugs have been reported to have a positive effect on neurodegenerative diseases. Herein, we reviewed the physiological and pathological conditions of cholesterol metabolism and discussed the possible mechanisms of cholesterol metabolism and statin therapy in neurodegenerative diseases.

Modulatory effect of simvastatin on redox status, caspase-3 expression, p-protein kinase B (p-Akt), and brain-derived neurotrophic factor (BDNF) in an ethanol-induced neurodegeneration model.

Neurodegenerative diseases are a common cause of morbidity and mortality worldwide, with oxidative stress, inflammation, and protein aggregation representing the main underlying mechanisms that ultimately lead to cell death. Ethanol has shown strong neurodegenerative consequences in experimental animal brains. Statins are a class of lipid-lowering drugs with many pleotropic effects. Therefore, the aim of the present study was to explore the modulatory effect of simvastatin (10mg·kg-1·day-1) before and after the development of neurodegeneration (for 55 and 25days, respectively) on redox state, caspase-3 expression, p-protein kinase B (p-Akt), and brain-derived neurotrophic factor (BDNF) in ethanol-induced (15% ethanol solution for 55 days) neurodegeneration. Seventy female Albino Swiss mice were included and randomly divided into five groups: C, control group; E, ethanol group; ES, group treated with simvastatin from the first day of ethanol intake; E+ S, group treated with simvastatin after neurodegeneration development; and S, simvastatin group. Administration of simvastatin from the first day improved the biochemical changes, suppressed apoptosis, and induced autophagy and neurogenesis; however, its administration after the development of neurodegeneration resulted in partial improvement. The histopathological findings confirmed the biochemical changes. In conclusion, simvastatin has a neuroprotective effect against the development of ethanol-induced neurodegeneration and its progression.

Pitavastatin induces apoptosis in oral squamous cell carcinoma through activation of FOXO3a.

Statins are a class of lipid‐lowering drugs that have recently been used in drug repositioning in the treatment of human cancer. However, the underlying mechanism of statin‐induced cancer cell death has not been clearly defined. In the present study, we evaluated the anticancer effect of pitavastatin on oral squamous cell carcinoma (OSCC), SCC15 and SCC4 cells and found that FOXO3a might be a direct target in pitavastatin‐induced cancer cell death. Our data revealed that pitavastatin selectively suppressed cell viability and induced intrinsic apoptosis in a FOXO3a‐dependent manner in SCC15 cells while no effect was observed in SCC4 cells. Notably, treatment with pitavastatin in SCC15 cells induced the nuclear translocation of FOXO3a via dual regulation of two upstream kinases, AMPK and Akt, resulting in the up‐regulation of PUMA, a transcriptional target gene of FOXO3a. Furthermore, our data revealed that FOXO3a‐mediated PUMA induction plays a role in pitavastatin‐induced intrinsic apoptosis in SCC15 cells. Taken together, our findings suggest that pitavastatin activates the FOXO3a/PUMA apoptotic axis by regulation of nuclear translocation of FOXO3a via Akt/FOXO3a or AMPK/FOXO3a signalling. Therefore, these findings might help to elucidate the underlying mechanism of the anticancer effects of pitavastatin on OSCC.

Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors, Reality or Dream in Managing Patients with Cardiovascular Disease

Statins have been a major keystone in the management of patients with atherosclerotic cardiovascular disease. The benefits of inhibiting HMG CoA reductase, via statins, were translated into reduction in LDL-c with proportionate decrease in cardiovascular events in response to the magnitude of LDL-c reduction. Despite major advances in pharmacological treatments, including the use of high-dose statins, there are urgent need to further reduce future cardiovascular risk. This is in particularly important since 1 out of 5 high-risk atherosclerotic patients who achieve low LDL-c return with a second cardiovascular event within five years. Although this residual risk post-statin is largely heterogeneous, lowering LDL-c beyond 'normal' or guidelines-recommended level using novel therapies has resulted in further reduction in cardiovascular events. The current review will discuss the use of PCSK9 inhibitors in patients with atherosclerotic disease. PCSK9 inhibitors are a new class of lipid-lowering drugs that are either fully human monoclonal antibodies (evolocumab and alirocumab) or humanised monoclonal antibodies (bococizumab) that effectively reduce LDL-c to unprecedented level. By blocking circulating PCSK9, these drugs would preserve LDL receptors and prevent them from cellular degradation. This process promotes recycling of LDL receptors back to hepatocytes surface, leading into further reduction of LDL-c. Combining PCSK9 inhibitors with statin have led into lower LDL-c, reduction in plaque volume and more importantly reduction in future cardiovascular events. These drugs are very promising, nonetheless, the unselective approach of applying these monoclonal antibodies may not prove to be cost-effective and potentially exposing some patients to unnecessary side effects.

Statins, myalgia, and rhabdomyolysis.

Statin-associated muscle symptoms (SAMSs) vary considerably in frequency and severity, with a spectrum extending from myalgia with normal creatine kinase (CK) levels or asymptomatic hyperCKemia to potentially life-threatening rhabdomyolysis and necrotizing autoimmune myopathy. Myalgia with CK elevation is the most common presentation. Onset is usually within 1 month after statin initiation or dosage intensification, and the symptoms can be expected to resolve within a few weeks after treatment discontinuation. The mechanism of muscle injury combines statin accumulation within muscles, which varies with the type and dosage of the drug; muscle fragility; abnormalities in statin transport or liver metabolism; drug-drug interactions; and genetic susceptibility. HMG-CoA reductase inhibition in muscles by statins exerts pleiotropic effects that can affect energy metabolism, induce mitochondrial dysfunction, modify lipid oxidation, promote apoptosis and cell membrane lysis, alter muscle protein synthesis, or trigger an autoimmune process. Statins are used to treat several chronic conditions and comorbidities, including inflammatory rheumatic diseases, which are associated with an increased cardiovascular risk. When the cardiovascular risk is high or very high, statin therapy is indispensable and has a very favorable risk/benefit ratio. Otherwise, the risks should be weighed against the benefits before reinitiating statin therapy, and a different statin or lower dosage should be used. If statin therapy cannot be successfully reintroduced, other classes of lipid-lowering drugs should be considered. Severe SAMSs with major weakness and marked CK elevation should suggest the rare eventuality of necrotizing autoimmune myopathy and prompt an anti-HMGCR antibody assay and muscle biopsy to ensure that immunosuppressant therapy is started rapidly if needed.

Combined Lowering Effects of Rosuvastatin and L. acidophilus on Cholesterol Levels in Rat.

Statins are a class of lipid-lowering drugs commonly used in the prevention of cardiovascular diseases. However, statin therapy presents many limitations, which have led to an increased interest in non-drug therapies, such as probiotics, to improve blood cholesterol levels. Indeed, probiotic strains such as Lactobacillus acidophilus have been found to improve blood lipid profiles, especially in reducing total cholesterol and LDL-C levels. In this study, we established a high-cholesterol rat model and studied the effect of Lactobacillus acidophilus administration alone or in conjunction with rosuvastatin. We were able to show that indeed Lactobacillus exerts a cholesterol-lowering effect. Additionally, we observed that when administered together, rosuvastin and Lactobacillus exert a combined cholesterol-lowering effect. Altogether, our data advocate for the possibility of establishing probiotics as non-drug supplements for the treatment of hypercholesterolemia.