Lipid-modifying Therapy Research Articles

PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study

Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C). This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients. HeFH patients (n=42) who were aged 8-17years, had body weight (BW) ≥25kg, and had LDL-C ≥130mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30mg (<50kg) or 50mg (≥50kg) every 2weeks (Q2W), #2: 40mg (<50kg) or 75mg (≥50kg) Q2W, #3: 75mg (<50kg) or 150mg (≥50kg) every 4weeks (Q4W), #4: 150mg (<50kg) or 300mg (≥50kg) Q4W. Primary endpoint was LDL-C % change from baseline to week8. Mean age was 12.4years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9mg/dL and free PCSK9 was 186.4-201.7ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2ng/mL and 8.6ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events. In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.

CME-Laboratory 61: New European Consensus Recommendations on Dyslipidemia

CME-Laboratory 61: New European Consensus Recommendations on Dyslipidemia Abstract. The lipid status primarily serves to estimate the risk of atherosclerotic cardiovascular diseases (ASCVD). LDL cholesterol (LDL-C) is the primary target of lipid-lowering therapies. NonHDL cholesterol and apolipoprotein B are secondary targets. The European Cardiology and Atherosclerosis Societies have lowered their treatment targets for all risk groups. Triglycerides and HDL cholesterol are also recommended for risk assessment, but are not therapeutic goals. Lipoprotein (a) is a strongly genetically determined ASCVD risk factor and contains a statin-resistant part of LDL-C. The quality of laboratory diagnostics for all lipid risk factors is in need of improvement due to the fact that it is too dependent on methods and in view of the indication of new and expensive lipid-modifying therapies.

Interaction between Sex and LDLR rs688 Polymorphism on Hyperlipidemia among Taiwan Biobank Adult Participants.

Hyperlipidemia is one of the strong risk factors for ischemic heart disease. Using the Taiwan Biobank (TWB) database, we evaluated the risk of hyperlipidemia and its interaction with sex and rs688 polymorphism on the low-density lipoprotein receptor (LDLR) gene. Data collection in the biobank started in 2008 and is ongoing. Data analysis was performed on the participants’ data collected between 2008 and 2015. In general, 27.92% of the 9237 female participants and 32.65% of the 8690 male participants were identified with hyperlipidemia. Compared to the C/C genotype, C/T and T/T genotypes were not significant risk factors for hyperlipidemia (OR = 1.061, CI: 0.976–1.153 for C/T and OR = 1.052, CI: 0.845–1.309 for T/T genotype) in the general model. However, there was a significant interaction between sex and rs6888 on hyperlipidemia risk (p-interaction = 0.0321). With the male sex/CC genotype being the reference group, only the female sex/CT and T/T genotypes were closely associated with hyperlipidemia, with respective ORs of 1.153 (CI: 1.014–1.311) and 1.423 (CI: 1.056–1.917). Our data indicate that rs688 C/T and T/T genotypes may be associated with increased risk of hyperlipidemia in Taiwanese women. These findings may be relevant in lipid-modification therapy.

Achievement of the low-density lipoprotein cholesterol goal among patients with dyslipidemia in South Korea.

It is important to achieve the low-density lipoprotein cholesterol (LDL-C) goal recommended by clinical guidelines in managing the risk of cardiovascular (CV) events, however, the current management of LDL-C in actual clinical settings is suboptimal. We examined the LDL-C level among patients with dyslipidemia against the 2015 Korean guidelines, the crude rates of CV events based on LDL-C goal achievement, and the factors associated with LDL-C goal achievement. This was a retrospective cohort study using the National Health Insurance Service-National Health Screening Cohort (NHIS-HEALS) database from 2006 to 2013. Patients who had a health examination with LDL-C measurement between January 1, 2007, and December 31, 2011 were identified. Patients were required to have at least one diagnosis of dyslipidemia during the 1 year before the index date, defined as the first date of LDL-C measurement. The 2015 Korean guidelines were used to measure LDL-C goal achievement based on the CV risk level. Crude CV event rates were calculated for total and individual CV events as the number of events divided by person-years (PYs) during the follow-up period. CV events included acute coronary syndrome, ischemic stroke, peripheral artery disease, CV death, and all-cause death. Factors associated with LDL-C goal achievement were assessed using logistic regression. In the NHIS-HEALS database, 69,942 patients met the eligibility criteria: 36.7%, 22.5%, 20.1%, and 20.6% were among the very high-, high-, moderate-, and low-risk groups for the CV events, respectively, as defined by the 2015 Korean guidelines. Approximately half of the patients with dyslipidemia (47.6%) achieved their recommended LDL-C goal, but the achievement rates were substantially different across CV risk levels (17.6%, 47.2%, 66.9%, and 82.4% for very high-, high-, moderate-, and low-risk groups, respectively; P<0.0001). The crude event rate of total CV events during the follow-up period in the LDL-C goal non-achievers was higher than that in the LDL-C goal achievers (24.35/100 PYs vs. 11.93/100 PYs; P<0.0001). LDL-C goal achievement was significantly associated with patient characteristics, including age, sex, body mass index, lipid-modifying therapy, and CV risk level. In South Korea, LDL-C goal achievement among patients with very high or high CV risk was suboptimal. Patients who did not achieve the goal showed a higher rate of CV events during the follow-up period than patients who achieved the goal. LDL-C management strategies should be highlighted in dyslipidemia patients who are less likely to achieve the goal, such as female, overweight or obese patients, patients not adherent to statin, or patients with very high or high CV risk.

Familial Hypercholesterolaemia in a Bulgarian Population of Patients with Dyslipidaemia and Diabetes: An Observational Study.

IntroductionPatients with diabetes and familial hypercholesterolaemia (FH) are at very high risk of cardiovascular events, but rates of FH detection are very low in most countries, including Bulgaria. Given the lack of relevant data in the literature, we conducted a retrospective observational study to (1) identify individuals with previously undiagnosed FH among patients being treated at Bulgarian diabetes centres, and (2) gain insight into current management and attainment of low-density lipoprotein cholesterol (LDL-C) goals in such patients.MethodsFrom a database of diabetes centres across Bulgaria we retrieved medical records from patients aged ≥ 18 years with type 1/2 diabetes mellitus (T1DM/T2DM) who were being treated with insulin/insulin analogues, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists and/or sodium-glucose co-transporter-2 inhibitors. Patients with FH (Dutch Lipid Clinic Network score ≥ 3) were identified, and their data analyzed (lipid-modifying therapy (LMT), diabetes treatment, cardiovascular events and glycaemic and lipid parameters).ResultsA total of 450 diabetic patients with FH (92.0% with T2DM; 52.4% receiving insulin/insulin analogues) were included in the analysis. LMT consisted of statin monotherapy (86% of patients; 18% receiving high-intensity statin monotherapy), statin-based combination therapy (13%) or fenofibrate (< 1%). Median LDL-C was 4.4 mmol/L. Although 30% of patients had a glycated haemoglobin level of ≤ 7%, only one patient (< 1%) achieved the LDL-C target recommended in 2016 European guidelines for very high-risk patients (< 1.8 mmol/L). Previous cardiovascular events were documented in 40% of patients.ConclusionTo our knowledge, this is the first study to specifically explore lipid target achievement in diabetic patients with FH. In this preselected Bulgarian population, < 1% of patients achieved the 2016 European guideline-defined LDL-C target. These data highlight the importance of identifying FH in diabetic patients as early as possible so that they can receive appropriate treatment.Electronic Supplementary MaterialThe online version of this article (10.1007/s13300-019-00748-2) contains supplementary material, which is available to authorized users.

PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9): A Narrative Review

Coronary artery disease (CAD), the most common type of heart disease, is the leading reason for mortality in both developing and developed countries. Increased cholesterol and fatty deposits (called plaques) may cause hardening or narrowing of the arteries which supply blood to heart muscles. Triglycerides, low density lipoproteins (LDL), high density lipoproteins (HDL) are different types of cholesterols found in the blood and LDL is the main target for lipid modifying therapy, with the aim of improving long term CAD prognosis. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) is one of the candidate genes with expression of PCSK9 protein and PCSK9 inhibitors are coming up as newer lipid lowering therapy. This narrative review highlights the journey of drug development from recognition of PCSK9 gene to the recent approvals of PCSK9 targeting LDL lowering pharmacotherapy. A bibliographic survey was made with titles PCSK9, PCSK9 inhibitors and coronary artery disease in different search engines from year 2000 to 2019 and filtered with review, preclinical and clinical studies. Retrieved articles were revisited and it was observed that PCSK9 is expressed mainly in hepatocytes and to some extent in mesenchymal cells of kidney, intestinal ileum, colon epithelia and in telencephalon neurons of embryonic brain. In hepatocytes, loss-of function mutations of PCSK9 leads to higher levels of LDL receptors. These receptors make LDL receptor-LDL cholesterol complex, which is directed to the lysosome for degradation of LDL in hepatocytes and lowers LDL cholesterol levels, ultimately resulting in protection from CAD. Gain-of-function mutations hamper LDL degradation. PCSK9 research has proposed an exciting new area for cholesterol management and CAD risk reduction. Different PCSK9 inhibitors with different therapeutic targets for CAD are evolving day by day from bench to bedside. This review could be valuable for helping researchers acquire a deeper insight for PCSK9 and its Inhibitors.

Lipid-modifying therapy in chronic kidney disease: Pathophysiological and clinical considerations.

Chronic kidney disease (CKD), which affects >10% of the population worldwide, is associated with a dramatically increased rate of cardiovascular disease (CVD). More people with CKD will die from CVD than develop end-stage renal disease with dialysis-dependency. However, the contribution of classical atherosclerotic cardiovascular risk factors is less evident than in the general population. Particularly, the relationship between dyslipidemia and CVD morbidity and mortality in CKD patients is not as evident as in the general population. While LDL cholesterol-lowering drugs such as statins significantly reduce the rate of cardiovascular events in the general population, their role in patients with end-stage renal disease has been questioned. This could be caused by a shift from atherosclerotic to non-atherosclerotic CVD in patients with advanced CKD, which cannot be effectively prevented by lipid-lowering drugs. In addition, many lines of evidence suggest that impaired renal function directly affects the metabolism, composition and functionality of lipoproteins, which may affect their responsiveness to pharmacological interventions. In this review, we highlight the challenges for the therapeutic application of lipid-lowering treatment strategies in CKD and discuss why treatment strategies used in the general population cannot be applied uncritically to CKD patients.

Safety of Proprotein Convertase Subtilisin/Kexin Type 9 Monoclonal Antibodies in Regard to Diabetes Mellitus: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

Evidence shows a positive association between the use of statins and new-onset diabetes. There is, however, contradictory evidence as to whether a similar association exists for the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. The aim of this study was to investigate the safety of PCSK9 monoclonal antibodies (PCSK9-mAbs) in regard to incident diabetes. Randomized controlled trials that reported data on the incidence of new-onset diabetes mellitus or the worsening of pre-existing diabetes were searched, and risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare the endpoints. Twenty-three studies including 65,957 participants were identified. Compared with controls, PCSK9-mAb treatment was not associated with the adverse event of diabetes (RR 0.97, 95% CI 0.91-1.02; p = 0.22). When we analysed the trials in terms of PCSK9-mAb type, alirocumab was associated with a significant reduction in the risk of diabetes (RR 0.91, 95% CI 0.85-0.98; p = 0.01), whereas no significant reduction was observed in participants receiving evolocumab or bococizumab. Interestingly, compared with ezetimibe, which was actively used as lipid-modifying therapy in the control group, PCSK9-mAbs seem to have a lower risk of incident diabetes (RR 0.60, 95% CI 0.37-0.99; p = 0.04). This meta-analysis also revealed a noticeable increase in the risk of incident diabetes in the evolocumab and alirocumab pool (RR 2.14, 95% CI 1.12-4.07; p = 0.02) when the use of statins was equivalent between the experimental and active comparator arms. Compared with placebo or any other comparator, PCSK9-mAb treatment was not associated with the adverse event of diabetes. However, evolocumab and alirocumab show high risk of incident diabetes when there is no interference from unbalanced use of statins. The imbalance in background lipid modifying therapy or different comparators used in the control arms of the studies might have masked the effect of PCSK9-mAb therapy on diabetes.

Association of daily fish intake with serum non-high-density lipoprotein cholesterol levels and healthy lifestyle behaviours in apparently healthy males over the age of 50 years in Japanese: Implication for the anti-atherosclerotic effect of fish consumption

Background and aimHigher fish consumption has been reported to be associated with a lower incidence of coronary artery disease (CAD). We hypothesized that higher fish intake may be associated with lower serum level of non-high-density lipoprotein cholesterol (non-HDL-C) levels, representing the entire dyslipidemia spectrum, and a healthy lifestyle. Methods and resultsThis cross-sectional study was conducted in a population of 1270 apparently healthy males over the age of 50 years without lipid-modifying therapy at the Health Planning Center of Nihon University Hospital between April and August 2018. The average number of days of fish intake per week was 2.6 ± 1.4. We performed analysis of variance using fish consumption as a categorical variable (0–1 day, 2–3 days, 4–5 days, or 6–7 days per week). The serum non-HDL-C levels in the 6–7 days fish intake group were significantly lower than those in the 0–1 and 2–3days fish intake groups. Furthermore, with increasing frequency of fish intake per week, the proportion of subjects with cigarette smoking decreased (p = 0.026), that of subjects engaging in habitual aerobic exercises increased (p = 0.034), and the sleep duration of the subjects increased (p < 0.0001). ConclusionsThese results suggest that a high frequency of fish intake, that is a fish intake of 6–7 days per week, was associated with healthier lifestyle behaviours as well as lower non-HDL-C levels, and thus may represent a component of a healthy lifestyle associated with a lower risk of CAD in Japanese males over the age of 50. Clinical trial registrationUMIN (http://www.umin.ac.jp/). Study IDUMIN000035899.

The challenge of multiple cardiovascular risk factor control outside Western Europe: Findings from the International ChoLesterol management Practice Study.

BackgroundComprehensive control of multiple cardiovascular risk factors reduces cardiovascular risk but is difficult to achieve.DesignA multinational, cross-sectional, observational study.MethodsThe International ChoLesterol management Practice Study (ICLPS) investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in patients receiving lipid-modifying therapy in countries outside Western Europe. We examined the rate of, and association between, control of multiple risk factors in ICLPS participants with dyslipidaemia, diabetes and hypertension (N = 2377).ResultsMean (standard deviation) age of patients was 61.4 (10.4) years; 51.3% were male. Type 2 diabetes was the most common form of diabetes (prevalence, 96.9%). The prevalence of metabolic syndrome was 67.8%, obesity 40.4%, atherosclerotic disease 39.6% and coronary artery disease 33.5%. All patients were at high (38.2%) or very high (61.8%) cardiovascular risk according to ESC/EAS guidelines. Body mass index (BMI) was <25 kg/m2 in 20.3% of patients, 62.8% had never smoked and 25.2% were former smokers. Overall, 12.2% achieved simultaneous control of LDL-C, diabetes and blood pressure. Risk factor control was similar across all participating countries. The proportion of patients achieving individual guideline-specified treatment targets was 43.9% for LDL-C, 55.5% for blood pressure and 39.3% for diabetes. Multiple correspondence analysis indicated that control of LDL-C, control of blood pressure, control of diabetes, BMI and smoking were associated.ConclusionComprehensive control of multiple cardiovascular risk factors in high-risk patients is suboptimal worldwide. Failure to control one risk factor is associated with poor control of other risk factors.

【論文摘要】How to Reach Precision Medicine in Lipid Management: What Data? Which Patients?

Lipid lowering therapy to reduce LDL-C level is the cornerstone to reduce the cardiovascular disease (CVD) risks, but it should not be one size fits all. Precision medicine is an emerging field that calls for individualization of treatment strategies based on characteristics unique to each patient. Over the past few years, more evidences about new treatments and which patients may benefit from them were uncovered. Therefore, the latest clinical practice guidelines provide recommendations applicable to patients with different CVD risks. Clinicians can now treat their patients individually according to the presence of cardiovascular diseases, traditional risk factors, family history, ethnicity, certain health conditions such as metabolic syndrome, chronic kidney disease, chronic inflammatory conditions, or the coronary calcium score. In addition, several genetic predictors of statin response have already been identified, which might further identify patients who are more likely to benefit from lipid-modifying therapy as opposed to those who likely will suffer from its side effects using precision medicine tools.

Lipid management in rheumatoid arthritis: a position paper of the Working Group on Cardiovascular Pharmacotherapy of the European Society of Cardiology.

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity, partly due to alterations in lipoprotein quantity, quality and cell cholesterol trafficking. Although cardiovascular disease significantly contributes to mortality excess in RA, cardiovascular prevention has been largely insufficient. Because of limited evidence, optimal strategies for lipid management (LM) in RA have not been determined yet, and recommendations are largely based on expert opinions. In this position paper, we describe abnormalities in lipid metabolism and introduce a new algorithm for estimation of cardiovascular risk (CVR) and LM in RA. The algorithm stratifies patients according to RA-related factors impacting CVR (such as RA activity and severity and medication). We propose strategies for monitoring of lipid parameters and treatment of dyslipidaemia in RA (including lifestyle, statins and other lipid-modifying therapies, and disease modifying antirheumatic drugs). These opinion-based recommendations are meant to facilitate LM in RA until more evidence is available.

Systematic Review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

The 2013 American College of Cardiology/American Heart Association guidelines for the treatment of blood cholesterol found little evidence to support the use of nonstatin lipid-modifying medications to reduce atherosclerotic cardiovascular disease (ASCVD) events. Since publication of these guidelines, multiple randomized controlled trials evaluating nonstatin lipid-modifying medications have been published. We performed a systematic review to assess the magnitude of benefit and/or harm from additional lipid-modifying therapies compared with statins alone in individuals with known ASCVD or at high risk of ASCVD. We included data from randomized controlled trials with a sample size of >1 000 patients and designed for follow-up >1 year. We performed a comprehensive literature search and identified 10 randomized controlled trials for intensive review, including trials evaluating ezetimibe, niacin, cholesterol-ester transfer protein inhibitors, and PCSK9 inhibitors. The prespecified primary outcome for this review was a composite of fatal cardiovascular events, nonfatal myocardial infarction, and nonfatal stroke. The cardiovascular benefit of nonstatin lipid-modifying therapies varied significantly according to the class of medication. There was evidence for reduced ASCVD morbidity with ezetimibe and 2 PSCK9 inhibitors. Reduced ASCVD mortality rate was reported for 1 PCSK9 inhibitor. The use of ezetimibe/simvastatin versus simvastatin in IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) reduced the primary outcome by 1.8% over 7 years (hazard ratio: 0.90; 95% CI: 0.84-0.96], 7-year number needed to treat: 56). The PSCK9 inhibitor evolocumab in the FOURIER study (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) decreased the primary outcome by 1.5% over 2.2 years (hazard ratio: 0.80; 95% CI: 0.73-0.88; 2.2=year number needed to treat: 67). In ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab), alirocumab reduced the primary outcome by 1.6% over 2.8 years (hazard ratio: 0.86; 95% CI: 0.79-0.93; 2.8-year number needed to treat: 63). For ezetimibe and the PSCK9 inhibitors, rates of musculoskeletal, neurocognitive, gastrointestinal, or other adverse event risks did not differ between the treatment and control groups. For patients at high risk of ASCVD already on background statin therapy, there was minimal evidence for improved ASCVD risk or adverse events with cholesterol-ester transfer protein inhibitors. There was no evidence of benefit for the addition of niacin to statin therapy. Direct comparisons of the results of the 10 randomized controlled trials were limited by significant differences in sample size, duration of follow-up, and reported primary outcomes. In a systematic review of the evidence for adding nonstatin lipid-modifying therapies to statins to reduce ASCVD risk, we found evidence of benefit for ezetimibe and PCSK9 inhibitors but not for niacin or cholesterol-ester transfer protein inhibitors.

Association of Non-LDL Indices with Recurrent Stroke Risk while on Lipid-Modifying Therapy.

Aims: Low-density lipoprotein (LDL)-lowering statin therapy is an established secondary stroke prevention strategy. However, the differential impact of key non-LDL levels on recurrent stroke risk, while on lipid-modifying therapy (LT), remains unclear.Methods: We analyzed the dataset of a multicenter trial involving 3640 recent (< 4 months) noncardioembolic stroke patients followed for 2 years. Participants were categorized into four groups of presumed improving lipid profile: level 0, no LT prescribed; level I, LT use with low high-density lipoprotein cholesterol (HDL-C) (< 40 mg/dL for men; < 50 mg/dL for women); level II, LT use with high HDL-C (≥ 40 mg/dL and ≥ 50 mg/dL, respectively); and level III, level II with low triglycerides (< 150 mg/dL). Independent associations of LT category with stroke, major vascular events (MVEs; stroke/coronary heart disease/vascular death), and all-cause death were assessed.Results: LTs were mostly statins (> 95%). The unadjusted recurrent stroke rate declined with LT category level (9.2% for level 0; 8.4% for level I; 7.5% for level II; and 5.7% for level III). Compared with level 0, the adjusted hazard ratio of stroke for level I was 0.78 (95% confidence interval (CI), 0.59–1.03), level II 0.80 (0.54–1.18), and level III 0.63 (0.43–0.91). Multivariable analyses of MVEs and all-cause death followed a similar pattern of declining risk with higher LT category level.Conclusions: Compared with the nonuse of LT, there may be a hierarchy of residual vascular risk after stroke by non-LDL type and target, while on LT. Particularly, stroke patients with low HDL-C levels on LT may benefit from additional therapeutic strategies to improve their outcomes.

Risk of acute pancreatitis after glucagon-like peptide-1 receptor agonists

Despite available medications for dyslipidemia, many treated patients still have suboptimal lipid levels. The aim of this study was to examine the extent of residual dyslipidemia in United States adults. Of 2509 United States adults aged ≥18 years from the National Health and Nutrition Examination Survey (NHANES) 2009-2010, 1,129 (41.8% weighted) had hyperlipidemia on the basis of modified treatment guidelines for low-density lipoprotein (LDL) cholesterol according to risk category or pharmacologic treatment. Of these, 484 (42.4%) were treated with lipid-modifying therapy, and the proportions of subjects who still had LDL cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, or non-HDL cholesterol not at recommended levels were examined. In this cohort treated for hyperlipidemia, the mean age was 60.1 ± 14.9 years, and 52% were men. Only 36.5% of subjects receiving treatment for hyperlipidemia were at goal or normal levels for all 3 lipids (LDL cholesterol, HDL cholesterol, and triglycerides). LDL cholesterol remained higher than goal for 37.5% of subjects, 28.9% had low HDL cholesterol, and 36.3% had elevated triglycerides. One, 2, and 3 lipid parameters were at abnormal levels in 32.4%, 23.0%, and 8.2% of subjects, respectively; 36.5% had no lipid disorder. In addition, 38.6% of treated subjects were above non-HDL cholesterol goal, and even in those at LDL cholesterol goal, 12.9% were not at non-HDL cholesterol goal. Those with cardiovascular disease conditions had poorer goal attainment of LDL cholesterol, HDL cholesterol, and composite all lipids than those without cardiovascular disease. In conclusion, despite widely available treatments for dyslipidemia, many patients remain at suboptimal lipid levels, indicating need for greater adherence to lifestyle and medical therapies to address these gaps in the management of dyslipidemia.

Low-density lipoprotein cholesterol goal achievement in patients with familial hypercholesterolemia in countries outside Western Europe: The International ChoLesterol management Practice Study

The cross-sectional observational International ChoLesterol management Practice Study study assessed achievement of European Society of Cardiology/European Atherosclerosis Society low-density lipoprotein cholesterol (LDL-C) targets in patients outside Western Europe. The aim of the study was to assess LDL-C goal achievement in International ChoLesterol management Practice Study participants with familial hypercholesterolemia (FH). A total of 334 patients (aged ≥18years) with definite or probable FH (Dutch Lipid Clinic Network score ≥6; 43.1% genetically confirmed) who had been receiving stable lipid-modifying therapy (LMT) for ≥3months were enrolled. The mean±standard deviation age of the patients was 58.5±13.1years, 49.1% were male, and 48.2% had coronary artery disease. Most were receiving statin (∼99%). Of these, 57.6% were on high-intensity statin therapy, 49.1% on the highest dose available, and 13.0% used a statin together with a cholesterol absorption inhibitor (CAI). Mean±standard deviation LDL-C level was 5.6±3.0mmol/L before LMT and 3.3±2.0mmol/L at enrollment. Overall, 32.0% of patients achieved their LDL-C target. Target achievement rates were 36.6% for patients with coronary artery disease, and 27.5% for those without, and 27.9%, 28.0%, and 37.5% for patients treated with a statin plus CAI, highest-dose statin (no CAI), and lower-dose statin (no CAI), respectively. LDL-C target achievement rates were low in patients with FH, even in those receiving intensive LMT. Factors that are likely to have contributed to the low LDL-C target achievement rates include high baseline LDL-C, inadequate statin dosages, and low use of CAI. Many patients would have been eligible for proprotein convertase subtilisin/kexin type 9 inhibitor therapy.

Real-World Data to Identify Hypercholesterolemia Patients on Suboptimal Statin Therapy.

Aim: Statins are generally well-tolerated but some patients develop adverse events and down-titrate or discontinue statins. It is important to understand the frequency of dyslipidemia patients with the inability to continue statins. The aim of the present study was to identify the frequency of high-risk dyslipidemia patients who are unable to take or not taking statins for any reason using Japanese hospital claims database.Methods: 2,527,405 dyslipidemia patients with atherosclerotic cardiovascular disease were investigated between April 2008 and September 2017. Definition 1 included statin discontinuation or down-titration with non-statin lipid modifying therapy (LMT) prescription, rhabdomyolysis or muscle-related symptoms with statin downtitration or discontinuation, or prescription for ≥ 3 statin types. Definition 2 included all components of Definition 1 in addition to statin down-titration or discontinuation for any reason. Patients never given statins but who started non-statin LMT were considered as Definition 3. The achievement rate of the target LDL-C level was investigated.Results: Among 54,296 patients with statin prescription, 2.32% and 48.38% patients were identified as Definition 1 and 2, respectively. Of eligible patients, 13.16% patients were identified as Definition 3. The achievement rate of target LDL-C level was lower in patients meeting each definition than not satisfying each definition.Conclusions: There is a proportion of high-risk dyslipidemia patients unable to take or not taking statins for any reason, and it is associated with lower achievement rates of target LDL-C levels. Suboptimal management of LDL-C is directly associated with residual cardiovascular risk and implementation of alternative therapeutic options in addition to existing LMT is warranted.

Statins in Ischemic Stroke Prevention: What Have We Learned in the Post-SPARCL (The Stroke Prevention by Aggressive Reduction in Cholesterol Levels) Decade?

We describe the current status of lipid-lowering therapies for ischemic stroke prevention. The SPARCL trial published in 2006 has been a landmark study in vascular neurology. The trial demonstrated that high-dose atorvastatin prevents recurrent stroke, and led the AHA/ASA to recommend statin therapy for patients with stroke or TIA of atherosclerotic origin. Recently, the J-STARS study demonstrated that therapy with low-dose pravastatin reduced atherothrombotic infarction incidence among patients with prior ischemic stroke. Besides, several trials have shown improved stroke outcomes with non-statin lipid-lowering medications: IMPROVE-IT with ezetimibe on top of simvastatin and PCSK9 inhibitors-FOURIER with evocolumab and ODYSSEY-OUTCOMES with alirocumab-on top of statin therapy. LDL-cholesterol remains the primary lipid treatment target for reduction of stroke risk. Randomized trials have shown that each reduction of 40mg/dL in the level of LDL-cholesterol reduces the stroke risk by approximately one quarter, and further, reductions in LDL-cholesterol levels have shown to produce additional reductions in stroke risk. Currently, we have evidence of benefit for adding non-statin lipid-modifying therapies to statins to reduce stroke risk. Surely, these novel strategies to reduce residual lipidic risk will provide future benefits on stroke prevention.

From HDL-cholesterol to HDL-function: cholesterol efflux capacity determinants.

The validity of HDL-cholesterol (HDL-C) elevation as a therapeutic target has been questioned, in comparison to enhancing HDL functionality. Cholesterol efflux capacity (CEC) is an in-vitro assay that measures the ability of an individual's HDL to promote cholesterol efflux from cholesterol donor cells such as macrophages. CEC of HDL is a predictor of cardiovascular risk independent of HDL-C levels. However, molecular determinants of CEC and the effects of diseases and therapeutic interventions on CEC have not been completely defined. We review here recent findings on elevated HDL-C and disease risk, as well as determinants of CEC, from genetics and proteomics to pathophysiology and therapeutic interventions that contribute to our understanding of CEC as a biomarker of HDL functionality. Elevated HDL-C levels are not always protective against cardiovascular disease and mortality. CEC is a heritable trait, and genetic polymorphisms in genes involved in HDL and triglycerides metabolism are associated with CEC. Multiple HDL proteins correlate positively with CEC levels and inversely with noncalcified plaque burden. Differences in CEC assays that make comparisons between studies difficult are also emphasized. CEC should be measured in clinical trials of lipid-modifying and anti-inflammatory therapies to determine whether increases are cardioprotective.

Cardiovascular Risk Factor Burden in People With Incident Type 2 Diabetes in the U.S. Receiving Antidiabetic and Cardioprotective Therapies.

Individualized treatment of patients with diabetes requires detailed evaluation of risk factor dynamics at the population level. This study evaluated the persistent glycemic and cardiovascular (CV) risk factor burden over 2 years after treatment intensification (TI). From U.S. Centricity Electronic Medical Records, 276,884 patients with incident type 2 diabetes who intensified metformin were selected. Systolic blood pressure (SBP) ≥130/140 mmHg and LDL ≥70/100 mg/dL were defined as uncontrolled for those with/without a history of CV disease at TI. Triglycerides ≥150 mg/dL and HbA1c ≥7.5% (58 mmol/mol) were defined as uncontrolled. Longitudinal measures over 2 years after TI were used to define risk factor burden. With 3.7 years' mean follow-up, patients were 59 years; 70% were obese; 22% had a history of CV disease; 60, 30, 50, and 48% had uncontrolled HbA1c, SBP, LDL, and triglycerides, respectively, at TI; and 81% and 69% were receiving antihypertensive and lipid-modifying therapies, respectively. The proportion of patients with consistently uncontrolled HbA1c increased from 31% in 2005 to 41% in 2014. Among those on lipid-modifying drugs, 41% and 37% had consistently high LDL and triglycerides over 2 years, respectively. Being on antihypertensive therapies, 29% had consistently uncontrolled SBP. Among patients receiving cardioprotective therapies, 63% failed to achieve control in HbA1c + LDL, 57% in HbA1c + SBP, 55% in LDL + SBP, and 63% in HbA1c + triglycerides over 2 years after TI. Among patients on multiple therapies for risk factor control, more than one-third had uncontrolled HbA1c, lipid, and SBP levels, and more than one-half had two CV risk factors that were simultaneously uncontrolled after TI.