Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver

BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease(NAFLD)and its predisposing risk factors,but the conclusions from these studies have been conflicting.More challenging is the fact that no effective treatment is currently available for NAFLD.AIM To determine the effects of proprotein convertase subtilisin/kexin type-9(PCSK9)inhibitors on fatty infiltration of the liver.METHODS This retrospective,chart review-based study was conducted on patients,18-yearold and above,who were currently on PCSK9 inhibitor drug therapy.Patients were excluded from the study according to missing pre-or post-treatment imaging or laboratory values,presence of cirrhosis or rhabdomyolysis,or development of acute liver injury during the PCSK9 inhibitor treatment period;the latter being due to false elevation of liver function markers,alanine aminotransferase(ALT)and aspartate aminotransferase(AST).Radiographic improvement was assessed by a single radiologist,who read both the pre-and post-treatment images to minimize reading bias.Fatty infiltration of the liver was also assessed by changes in ALT and AST,with pre-and post-treatment levels compared by paired t-test(alpha criterion:0.05).RESULTS Of the 29 patients included in the study,8 were male(27.6%)and 21 were female(72.4%).Essential hypertension was present in 25(86.2%)of the patients,diabetes mellitus in 18(62.1%)and obesity in 15(51.7%).In all,patients were on PCSK9 inhibitors for a mean duration of 23.69±11.18 mo until the most recent ALT and AST measures were obtained.Of the 11 patients who received the radiologic diagnosis of hepatic steatosis,8(72.73%)achieved complete radiologic resolution upon use of PCSK9 inhibitors(mean duration of 17.6 mo).On average,the ALT level(IU/L)decreased from 21.83±11.89 at pretreatment to 17.69±8.00 at posttreatment(2-tailed P=0.042)and AST level(IU/L)decreased from 22.48±9.00 pretreatment to 20.59±5.47 post-treatment(2-tailed P=0.201).CONCLUSION PCSK9 inhibitors can slow down or even completely resolve NAFLD.

The proprotein convertase subtilisin/kexin type 9 geneE670G polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

Background The association of E670G polymorphism in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene and serum lipid profiles is inconsistent in dif- ferent ethnic groups.Bai Ku Yao is a special subgroup of the Yao minority in China.The present study was undertaken association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.Methods A total of 649 subjects of Bai Ku Yao and 646 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples.Genotyping of the PCSK9 E670G polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis,and then confirmed by direct sequencing. Results The levels of serum total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C) and apolipoprotein(Apo) AI were lower in Bai Ku Yao than in Han(P【0.01 for all).The frequency of A and G alleles was 98.00%and 2.00%in Bai Ku Yao,and 95.20%and 4.80%in Han(P【0.01);respectively. The frequency of AA,AG and GG genotypes was 95.99%,4.01%and 0%in Bai Ku Yao,and 91.02%, 8.36%and 0.62%in Han(P【0.01);respectively.There were also significant differences in the genotypic and allelic frequencies between n and the ratio of ApoAI to ApoB in Han Chinese but not in Bai Ku Yao were different between the AA and AG/GG genotypes(P【0.05 for all).The G allele carriers had higher serum HDL-C and higher ApoAI to ApoB ratio than the G allele noncarriers.When serum lipid parameters in Han were analyzed according to sex,the G allele carriers had higher serum HDL and ApoAI levels in males (P【0.05),and lower ApoB level and higher ApoAI to ApoB ratio in females(P【0.05 for all).Multiple linear regression analysis showed that serum HDL-C levels were correlated with genotypes in both ethnic groups(P【0.05 each).Serum lipid parameters were also correlated with sex,age,body massindex,alcohol consumption,cigarette smoking,and blood pressure in both ethnic groups(P【0.05-0.001).Conclusions These results suggest that the PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population,both gender show different relations to different serum lipid parameters.The G allele carriers might have higher serum lipid profiles than the G allele noncarriers. ormal LDL-C(≤3.20 mmol/L) and high LDL-C subgroups (】 3.20 mmol/L,P【0.01;respectively) in Bai Ku Yao, and between normal ApoB(≤1.14 g/L) and high ApoB subgroups(】 1.14 g/L,P 【 0.01;respectively) in Han.

Changes in proprotein convertase subtilisin/kexin type 9 mRNA expression in rat cortex after cerebral ischemia

Oxidized low density lipoprotein is a risk factor for cerebrovascular disease. Proprotein convertase subtilisin/kexin type 9 （PCSK9） can increase the level of low density lipoprotein. Therefore, this study assumed that PCSK9 plays important roles in ischemic cerebrovascular disease. The present study established transient focal cerebral ischemia models after 100 minutes of middle cerebral artery occlusion. In situ hybridization demonstrated that PCSK9 mRNA expression increased gradually with prolonged reperfusion time in ischemic cortices. This indicated that transient focal cerebral ischemia upregulated PCSK9 mRNA expression in ischemic cortices.

Proprotein convertase subtilisin/kexin type 9 inhibitor non responses in an adult with a history of coronary revascularization:A case report

BACKGROUND Familial hypercholesterolemia(FH)is an autosomal dominant disorder that is characterized by severely increased low-density lipoprotein(LDL)cholesterol levels.At the same time,elevated LDL levels accelerated the development of coronary heart disease.Several classes of drugs are currently in use to treat FH.Proprotein convertase subtilisin/kexin type 9 inhibitor(PCSK9i)is novel one of these.CASE SUMMARY This manuscript reports a case of FH that responded modestly after treatment with PCSK9i and statin drugs.Of even more concern is that the patient frequently admitted to the hospital during a 12-year follow-up period.Subsequently,we identified a heterozygous mutation,1448G>A(W483X)of the LDL receptor(LDLR)in this patient.The serum levels of PCSK9(proprotein convertase subtilisin/kexin type 9)in the patient was 71.30±26.66 ng/mL,which is close the average level reported in the literature.This LDLR mutation affects LDLR metabolism or structure,which may make it unsuitable for use of PCSK9i.CONCLUSION Our outcome demonstrates that LDLR-W483X represents a partial loss-of-function LDLR and may contribute to PCSK9i ineffective. In the meanwhile, additional measures aretherefore required (particularly with gene sequencing or change the treatment plan) must beinitiated as early as possible. Genetic testing for clinically challenging cases who do not respond toPCSK9i therapy is very helpful.

Proprotein convertase subtilisin/kexin type 9 inhibitors in peripheral artery disease:A review of efficacy,safety,and outcomes

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.

Association of Remnant-like Particle Cholesterol with Major Adverse Cardiovascular Events in Subjects with Different Levels of Proprotein Convertase Subtilisin/Kexin 9:A 9.5-year Follow-up Study in a Beijing Community Population

Objective::The purpose of this study was to determine the relationship between remnant-like particle cholesterol(RLP-C)and major adverse cardiovascular events(MACEs)in patients with different levels of proprotein convertase subtilisin/kexin 9(PCSK9).Methods::From September 2007 to January 2009,1,859 subjects in Pingguoyuan communities in Beijing were initially screened.After excluding those with bedridden status,mental illness,severe systemic diseases,and missing data,1,680 subjects were recruited for follow up.All recruited subjects were followed up from February 2013 to September 2013(181 subjects were lost to follow-up)and from June 2017 to September 2018(174 subjects were lost to follow up).Finally,1,325 subjects were included in the study.General demographic characteristics,lifestyle and behaviors,disease history and use of medication was collected.Levels of total cholesterol,triglycerides,high-density lipoprotein cholesterol,low-density lipoprotein cholesterol,fast blood glucose,RLP-C,low-density lipoprotein triglycerides and PCSK9 were measured.The levels of RLP-C(low:RLP-C≤157 mg/L;high:RLP-C>157 mg/L)and PCSK9(low:PCSK9≤135.87μg/L;high:PCSK9>135.87μg/L)were represented using quartiles.Subjects were categorized into 4 groups according to their RLP-C and PCSK9 levels:Q4,high levels of RLP-C with high levels of PCSK9;Q3,high levels of RLP-C with low levels of PCSK9;Q2,low levels of RLP-C with high levels of PCSK9;and Q1,low levels of RLP-C with low levels of PCSK9.The association of RLP-C with MACEs in subjects with different PCSK9 levels was evaluated.Results::After a median follow-up of 9.5 years,1,325 subjects were included in the study and a total of 191 MACEs had occurred.The incidence of MACEs was higher in the RLP-C>157 mg/L group than the RLP-C≤157 mg/L group(18.40%vs.10.42%).Cox proportional hazards regression model analysis showed that increased RLP-C levels were associated with an increased risk of MACEs(hazard ratio:1.405;95%confidence interval:1.005-1.964;P<0.005).The incidence of MACEs was higher in the high RLP-C/PCSK9 group vs.the low RLP-C/PCSK9 group(20.68%vs.8.76%).Cox proportional hazards regression model analysis showed that RLP-C was associated with an increased risk of MACEs in subjects with high PCSK9 levels independent of traditional risk factors(hazard ratio:1.791;95%confidence interval:1.168-2.825;P=0.001),but not in those with low PCSK9 levels.Conclusions::RLP-C was identified as a risk factor for MACEs,particularly in subjects with high PCSK9 levels.Lowering PCSK9 levels may reduce residual risk in subjects with elevated plasma RLP-C levels.

PCSK9 inhibitors: A new era of lipid lowering therapy

Hyperlipidemia is a well-established risk factor for developing cardiovascular disease(CVD). The recent American College of Cardiology and American Heart Association guidelines on lipid management emphasize treatment of individuals at increased risk for developing CVD events with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors(statins) at doses proven to reduce CVD events. However, there are limited options for patients who are either intolerant to statin therapy, develop CVD despite being on maximally tolerated statin therapy, or have severe hypercholesterolemia. Recently the Food and Drug Administration approved two novel medications for low-density lipoprotein(LDL)-cholesterol reduction: Evolocumab and Alirocumab. These agents target and inactivate proprotein convertase subtilsinkexin type 9(PCSK9), a hepatic protease that attaches and internalizes LDL receptors into lysosomes hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone. This review explores PCSK-9 biology and the mechanisms available to alter it; clinical trials targeting PCSK9 activity, and the current state of clinically available inhibitors of PCSK9.

PCSK9 and carbohydrate metabolism:A double-edged sword

Proprotein convertase subtilisin/kexin type 9(PCSK9) plays a paramount role in the degradation of lowdensity lipoprotein(LDL) receptors(LDLR) on the hepatic cells surface and subsequently affects LDL particles catabolism and LDL cholesterol(LDL-c) levels. The anti-PCSK9 monoclonal antibodies lead to substantial decrease of LDL-c concentration. PCSK9(which is also expressed in pancreatic delta-cells) can decrease LDLR and subsequently decrease cholesterol accumulation in pancreatic beta-cells, which impairs glucose metabolism and reduces insulin secretion. Thus, a possible adverse effect of PCSK9 inhibitors on carbohydrate metabolism may be expected by this mechanism, which has been supported by the mendelian studies results. On the other hand, clinical data have suggested a detrimental association of PCSK9 with glucose metabolism. So, the inhibition of PCSK9 may be seen as a double-edged sword regarding carbohydrate metabolism. Completed clinical trials have not shown a detrimental effect of PCSK9 inhibitors on diabetes risk, but their short-term duration does not allow definite conclusions.

A novel mutation in proprotein convertase subtilisin/kexin type 9 gene leads to familial hypercholesterolemia in a Chinese family

Background Familial hypercholesterolemia （FH） is an autosomal disorder associated with elevated plasma low density lipoprotein （LDL） levels leading to premature coronary heart disease （CHD）. As a result of long-term hyperlipemia, FH patients will present endarterium thickening and atherosclerosis. In the present study we scanned the related gene of a clinically diagnosed autosomal genetic hypercholesterolemia family for the possible mutations and established eukaryotic expression vector of mutation of proprotein convertase subtilisin/kexin type 9 （PCSK9） gene with gene recombination technique to investigate the contributions of the variation on low density lipoprotein receptor （LDL-R） metabolism and function alternation.Methods Mutation detection was conducted for LDL-R, apolipoprotein B100 （apoB100） and PCSK9 gene with nucleotide sequencing in a Chinese FH family. The full-length cDNA of wild type PCSK9 gene （WT-PCSK9） was obtained from Bel-7402. Site mutagenesis was used to establish the recombinant eukaryotic expression vector carrying pathogenic type of PCSK9 gene and the inserted fragment was sequenced. With the blank vector as control, liposome transfection method was used to transfect the Bel-7402 cells with recombinant plasmid. The expression of LDL-R mRNA was examined by RT-PCR. PCSK9 and the expression of LDL-R protein were determined by Western blotting. Results The G→T mutation at the 918 nucleotide of PCSK9 gene resulted in the substitution of the arginine by a serine at the codon 306 of exon 6. After sequencing, it was confirmed that the inserted fragment of established expression vector had correct size and sequence and the mutant was highly expressed in Bel-7402 cells. There was no significant variation in the levels of LDL-R mRNA. LDL-R mature protein was decreased by 57% after the cells were transfected by WT-PCSK9 plasmid. Mature LDL-R was significantly decreased by 12% after the cells were transfected by R306S mutant as evidenced by gray scale scanning, suggesting that the new mutant R306S can significantly decrease the expression of mature LDL-R protein.Conclusions A novel missense mutation of PCSK9 gene, R306S, was found and the eukaryotic expression vectors of mutant and wild-type of PCSK9 gene were established. There was no significant variation in the levels of LDL-R mRNA. The R306S mutation could significantly lead to the decrease of LDL-R mature protein expression, which might be the pathogenic gene of the FH family.

Effects of Hedan Tablet(荷丹片)on Lipid Profile, Proprotein Convertase Subtilisin/Kexin Type 9 and High-Density Lipoprotein Subfractions in Patients with Hyperlipidemia:A Primary Study

Objective： To investigate the effects of Hedan Tablet（荷丹片） on serum lipid profile, proprotein convertase subtilisin/kexin type 9（PSCK9） and high-density lipoprotein（HDL） subfractions in patients with hyperlipidemia. Methods： Thirty-seven patients with hyperlipidemia were randomized to treatment with Hedan Tablet 4.38 g/day as Hedan group（18 cases） or placebo（19 cases） as control group for 8 weeks. The lipid profile, PCSK9 and HDL subfractions were determined at day 0 and week 8 in both groups respectively. Results： Hedan treatment for 8 weeks mildly decreased serum low-density lipoprotein cholesterol（LDL-C） levels, while no changes were found in total cholesterol（TC）, triglycerides（TG） and PCSK9 concentrations. Furthermore, Hedan treatment increased the concentration of large high-density lipoprotein cholesterol（HDL-C） and the percentage of large HDL subfraction, while decreased the concentration of small HDL-C and the percentage of small HDL subfraction without changing serum HDL-C levels in patients with hyperlipidemia. Conclusion： Hedan treatment of 4.38 g per day for 8 weeks could confer a favorable effects on serum LDL-C concentration as well as HDL subfractions.

Short-andLong-Term Effects of Xuezhikang(血脂康),An Extract of Cholestin,on Serum Proprotein Convertase Subtilisin/Kexin Type 9 Levels

Objective：To investigate the short- and long-term effects of Xuezhikang（血脂康,XZK）,an extract of Cholestin,on proprotein convertase subtilisin/kexin type 9（PCSK9） level.Methods：Thirty rats were randomly divided into three groups and were given saline,XZK 1,200 mg/kg or lovastatin 10 mg/kg respectively by daily gavage for 3 days（n=10 for each）.Sixteen patients without previous iipid-lowering drug treatment for dyslipidemia received XZK 1,200 mg daily for 8 weeks.Fasting blood samples and liver tissue were collected at day 3 for rats,while the blood samples were obtained at baseline and week 8 from patients.The serum PCSK9 and lipid profile were measured.The expression of hepatic low density lipoprotein（LDL） receptor and sterol regulatory element binding protein 2（SREBP-2） were measured by real time-PCR.Results：PCSK9 levels in rats were significantly increased in the XZK and lovastatin groups（P=0.002,P=0.003 vs.control） at day 3,while no significant differences were found in the levels of lipid parameters.PCSK9 levels in patients increased by34%（P=0.006 vs.baseline） accompanied by total cholesterol and LDL-cholesterol decreased by 22%and 28%（P=0.001,P=0.002 vs.baseline）.The hepatic mRNA levels of LDL-receptor and SREBP-2 were significantly increased in the XZK and lovastatin groups.Conclusion：XZK has significant impact on PCSK9 in a short- and long-term manner in both rats and humans.Moreover,the data indicated that as lovastatin,XZK increased PCSK9 levels through SREBP-2 pathway.

Research on Hepatocyte Regulation of PCSK9-LDLR and Its Related Drug Targets

The prevalence of hyperlipidemia has increased significantly due to genetic, dietary, nutritional and pharmacological factors, and has become one of the most common pathological conditions in humans. Hyperlipidemia can lead to a range of diseases such as atherosclerosis, stroke, coronary heart disease, myocardial infarction, diabetes, and kidney failure, etc. High circulating low-density lipoprotein cholesterol (LDL-C) is one of the causes of hyperlipidemia. LDL-C in the blood binds to LDL receptor (LDLR) and regulates cholesterol homeostasis through endocytosis. In contrast, proprotein convertase subtilisin/kexin type 9 (PCSK9) mediates LDLR degradation via the intracellular and extracellular pathways, leading to hyperlipidemia. Targeting PCSK9-synthesizing transcription factors and downstream molecules are important for development of new lipid-lowering drugs. Clinical trials regarding PCSK9 inhibitors have demonstrated a reduction in atherosclerotic cardiovascular disease events. The purpose of this review was to explore the target and mechanism of intracellular and extracellular pathways in degradation of LDLR and related drugs by PCSK9 in order to open up a new pathway for the development of new lipid-lowering drugs.

Intensive lipid-lowering therapy,time to think beyond low-density lipoprotein cholesterol

Statins have been shown to be effective in reducing cardiovascular events.Their magnitude of benefits has been proportionate to the reduction in low-density lipoprotein cholesterol(LDL-c).Intensive lipid-lowering therapies using ezetimibe and more recently proprotein convertase subtilisin kexin 9 inhibitors have further improved clinical outcomes.Unselective application of these treatments is undesirable and unaffordable and,therefore,has been guided by LDL-c level.Nonetheless,the residual risk in the post-statin era is markedly heterogeneous,including thrombosis and inflammation risks.Moreover,the lipoprotein related risk is increasingly recognised to be related to other non-LDL-c markers such as Lp(a).Emerging data show that intensive lipid-lowering therapy produce larger absolute risk reduction in patients with polyvascular disease,post coronary artery bypass graft and diabetes.Notably,these clinical entities share similar phenotype of large burden of atherosclerotic plaques.Novel plaque imaging may aid decision making by identifying patients with propensity to develop lipid rich plagues at multi-vascular sites.Those patients may be suitable candidates for intensive lipid lowering treatment.

Effect of Quercetin on Atherosclerosis Based on Expressions of ABCA1, LXR-α and PCSK9 in ApoE-/- Mice

Objective:To investigate the effect of quercetin on ATP binding cassette transporter A1(ABCA1),liver X receptor(LXR),and proprotein convertase subtilisin/kexin type 9(PCSK9)expressions in apoE-knockout(ApoE-/-)mice.Methods:The high-fat diet-induced atherosclerosis(AS)in ApoE-/-mice was established.Thirtysix mice were divided into 3 groups using random number table method:model group(n=12),quercetin group(n=12),and atorvastatin group(n=12),with C57BL/6J mice of the same strain and age as the control group(n=12).Quercetin group and atorvastatin group were administrated with quercetin and atorvastatin by oral gavage,with doses of 12.5 and 4 mg/(kg・d),respectively.Animals in the control and model groups were given an equal volume of distilled water by oral gavage once per day for a total of 12 weeks.Western blot and immunohistochemical methods were employed to determine the aortic ABCA1,LXR-a and PCSK9 protein expressi on.En zyme linked imm uno sorbent assay method was used to detect the expressi on of serum total cholesterol(TC),triglyceride(TG),high density lipoprotein-cholesterol(HDL-C),low density lipoproteincholesterol(LDL-C),tumor necrosis factor-a(TNF-a),interleukin-6(IL-6),and IL-10,combined with tissue pathological exami nation.Results:ApoE-/-mice fed with a high-fat diet had no table atherosclerosis lesions,with reduced ABCA1,LXR-a and IL-10 levels(all P<0.01),elevated PCSK9,TNF-a and IL-6 expression,and increased TC and LDL-C con tents(all P<0.01).After querceti n in terventi on,the areas of AS plaques and the expressions of PCSK9,TNF-a and IL-6 were significantly reduced(all P<0.01),while the expressions of ABCA1 and LXR-a were increased significantly(all P<0.01).Conclusion:Quercetin effectively interfered with AS development by regulating the expressions of ABCA1,LXR-a and PCSK9 in ApoE,mice.

Antithrombotic therapy and bleeding risk in the era of aggressive lipid-lowering:current evidence,clinical implications,and future perspectives

The clinical efficacy of proprotein convertase subtilisin/kexin type 9 inhibitors(PCSK9i)in reducing major cardiovascular adverse events related to atherosclerotic cardiovascular disease(ASCVD)has been well established in recent large randomized outcome trials.Although the cardiovascular and all-cause mortality benefit of PCSK9i remains inconclusive,current cholesterol management guidelines have been modified toward more aggressive goals for lowering low-density lipoprotein cholesterol(LDL-C).Consequently,the emerging concept of"the lower the better"has become the paradigm of ASCVD prevention.However,there is evidence from observational studies of a U-shaped association between baseline LDL-C levels and all-cause mortality in population-based cohorts.Among East Asian populations,low LDL-C was associated with an increased risk for hemorrhagic stroke in patients not on antithrombotic therapy.Accumulating evidence showed that low LDL-C was associated with an enhanced bleeding risk in patients on dual antiplatelet therapy following percutaneous coronary intervention.Additionally,low LDL-C was associated with a higher risk for incident atrial fibrillation and thereby,a possible increase in the risk for intracranial hemorrhage after initiation of anticoagulation therapy.The mechanism of low-LDL-C-related bleeding risk has not been fully elucidated.This review summarizes recent evidence of low-LDL-C-related bleeding risk in patients on antithrombotic therapy and discusses potential measures for reducing this risk,underscoring the importance of carefully weighing the pros and cons of aggressive LDL-C lowering in patients on antithrombotic therapy.

Lowering low-density lipoprotein cholesterol: from mechanisms to therapies

Low-density lipoprotein(LDL)is the main carrier of cholesterol and cholesteryl ester in circulation.High plasma levels of LDL cholesterol(LDL-C)are a major risk factor of atherosclerotic cardiovascular disease(ASCVD).LDL-C lowering is recommended by many guidelines for the prevention and treatment of ASCVD.Statins,ezetimibe,and proprotein convertase subtilisin/kexin type 9 inhibitors are the mainstay of LDL-C-lowering therapy.Novel therapies are also emerging for patients who are intolerant to statins or respond poorly to standard treatments.Here,we review the most recent advances on LDL-C-lowering drugs,focusing on the mechanisms by which they act to reduce LDL-C levels.The article starts with the cornerstone therapies applicable to most patients at risk for ASCVD.Special treatments for those with little or no LDL receptor function then follow.The inhibitors of ATP-citrate lyase and cholesteryl ester transfer protein,which are recently approved and still under investigation for LDL-C lowering,respectively,are also included.Strategies targeting the stability of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and cholesterol catabolism can be novel regimens to reduce LDL-C levels and cardiovascular risk.