Optimal LDL-C Research Articles

Optimal LDL cholesterol levels in young and old patients with type 2 diabetes for secondary prevention of cardiovascular diseases are different.

Real-world-based population data about the optimal low-density lipoprotein cholesterol (LDL-C) level for preventing cardiovascular disease in very high-risk populations is scarce. From 2009 to 2012, 26,922 people aged ≥ 40 years with type 2 diabetes mellitus (T2DM) who had a history of percutaneous coronary intervention (PCI) were analyzed. Data from the Korean National Health Insurance System were used. They were followed up to the date of a cardiovascular event or the time to death, or until December 31, 2018. Endpoints were recurrent PCI, newly stroke or heart failure, cardiovascular death, and all-cause death. Participants were divided into the following categories according to LDL-C level: <55 mg/dL, 55-69 mg/dL, 70-99 mg/dL, 100-129 mg/dL, 130-159 mg/dL, and ≥ 160 mg/dL. Compared to LDL-C < 55 mg/dL, the hazard ratios (HR) for re-PCI and stroke increased linearly with increasing LDL-C level in the population < 65 years. However, in ≥ 65 years old, HRs for re-PCI and stroke in LDL-C = 55-69 mg/dL were 0.97 (95% CI: 0.85-1.11) and 0.96 (95% CI: 0.79-2.23), respectively. The optimal range with the lowest HR for heart failure and all-cause mortality were LDL-C = 70-99 mg/dL and LDL-C = 55-69 mg/dL, respectively, in all age groups (HR: 0.99, 95% CI: 0.91-1.08 and HR: 0.91, 95% CI: 0.81-1.01). LDL-C level below 55 mg/dL appears to be optimal in T2DM patients with established cardiovascular disease aged < 65 years, while an LDL-C level of 55-69 mg/dL may be optimal for preventing recurrent PCI and stroke in patients over 65 years old.

Role of bempedoic acid in patients with hypercholesterolemia and statin intolerance

introduction: Atherosclerotic cardiovascular disease is a leading cause of death and disability worlwide. The LDL-C causes atherosclerosis and therefore lowering the levels of these lipoproteins reduces the risk of acute myocardial infarction and other cardiovascular events. Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and are the most cost-effective medicines for lowering LDL-C. Up to 80% of patients treated with statins do not achieve optimal LDL-C levels, explained by high baseline LDL-C levels, aggressive LDL-C treatment goals, lack of sufficient statin efficacy or drug intolerance. Objective: This review discusses the characteristics of statin intolerance and the mechanism of action, efficacy, and safety of Bempedoic Acid as a lipid-lowering agent. Methods: We searched PubMed, ScienceDirect, the Virtual Health Library and Latin American and Caribbean Health Sciences Literature for articles published in the last five years using the following health descriptors: “bempedoic” OR “ATP-citrate lyase” AND hypercholesterolemia AND “coronary artery disease”. Results: Bempedoic acid is a prodrug that is converted to its active form (bempedoyl-CoA) by the acyl-CoA synthetase-1 enzyme. Acts two steps upstream from HMG-CoA reductase, the target of statins, in the same metabolic pathway, representing an additional lipid-lowering therapy. Conclusions:Bempedoic Acid’s active metabolite is an effective treatment option, alone or in combination with statin or ezetimibe, to lower LDL-C and reduce hsCRP, which is a marker of systemic inflammation associated with future risk of cardiovascular events, suggesting an anti-inflammatory response. Outcomes and cost-effectiveness are currently being investigated in the CLEAR Outcomes study, with results expected in 2023.

Abstract 10997: Reduction in Dietary Saturated Fat Intake Lowers LDL-C but Increases Lp(a) Levels in African Americans: Findings From the GET-READI Randomized Controlled Crossover Feeding Trial

Reduction in dietary saturated fatty acids (SFA) intake results in a significant clinically meaningful lowering of LDL-C across ethnicities. In contrast, the role of dietary SFA reduction in modulating emerging risk factors for cardiovascular disease (CVD) in different ethnic groups remains poorly understood. An elevated level of lipoprotein(a) [Lp(a)], an independent casual risk factor for CVD, disproportionally affects African Americans. In this study, we assessed the responses in Lp(a) to dietary SFA reduction specifically in African Americans (N=166) enrolled in GET-READI (The Gene-Environment Trial on Response in African Americans to Dietary Intervention), a randomized controlled feeding trial. Men and women with above optimal LDL-C were fed two diets in a random order for five weeks each: (1) the average American diet (AAD) (37% total fat: 16% SFA), and (2) a diet similar to the Dietary Approaches to Stop Hypertension (DASH) combination diet (25% total fat: 6% SFA). The mean age of participants was 33 years (range: 18-64 years), 70% were women, the mean BMI was 28.4 kg/m 2 and LDL-C was 116 mg/dL. At the end the 5-week intervention period with the DASH diet, compared with the end of the AAD diet, LDL-C was significantly reduced (mean change: -12.4 mg/dL, p &lt;0.0001), as were the levels of total cholesterol (-16.6 mg/dL, p &lt;0.0001), HDL-C (-5 mg/dL, p &lt;0.0001), apoA-1 (-8.7 mg/dL, p &lt;0.0001) and apoB-100 (-5.7 mg/dL, p &lt;0.0001). In contrast, Lp(a) levels were significantly increased following the DASH diet compared to AAD (from a median value of 44 mg/dL with AAD to 58 mg/dL with DASH; mean change: +11.2 mg/dL, p &lt;0.0001). As LDL-C measurements typically include Lp(a)-cholesterol, the “true” LDL-C decrease is estimated at -16 mg/dL, i.e., an underestimation by about 30%. In conclusion, in a large cohort of African Americans, an ethnic group with a high burden of elevated Lp(a), reductions in SFA intake significantly increased Lp(a) while reducing LDL-C. These findings suggest that dietary SFA reduction exerted an opposing effect on the circulating levels of two highly-atherogenic lipoproteins. Future studies are warranted to elucidate mechanism(s) underlying the SFA reduction-induced increase in Lp(a) and its role in CVD risk across population groups.

The challenge of lipid-modifying therapies in the achievement of optimal LDL-C levels in high and very high CV risk patients: Still an open question

Background and Aims : Hypercholesterolemia is one of the main modifiable atherosclerotic cardiovascular (CV) disease’s risk factors. The aim was to evaluate the efficacy of the currently available lipid lowering therapy (LLT) and the achievement of treatment targets (TT) in a cohort of high and very-high CV risk patients treated with maximum tolerated LLT.

Apolipoprotein B Displays Superior Predictive Value Than Other Lipids for Long-Term Prognosis in Coronary Atherosclerosis Patients and Particular Subpopulations: A Retrospective Study

Accumulating evidence that apolipoprotein B (apoB) plays a critical role in predicting coronary heart disease (CHD) and future outcomes. The 2019 European Society of Cardiology/European Atherosclerosis Society guidelines suggest that apoB can be an alternative to non-HDL-C or LDL-C in patients with high triglyceride levels, diabetes, obesity, metabolic syndrome, or very low LDL-C levels. This study explores whether apoB can also serve as predictive value for long-term major adverse cardiovascular events (MACEs) in normal people and specific coronary atherosclerosis patients. A total of 826 patients were followed up over 10 years, and the risk factors for MACEs were retrospectively analyzed in patients with CHD and particular subpopulations. All statistical analyses were performed in R software. Cox regressions were performed to assess independent risk factors of long-term MACEs in the atherosclerosis group and CHD subgroups. Kaplan-Meier survival curves were used to evaluate the survival rate for patients in different apoB quartiles, and receiver-operating characteristic curves were used to compare apoB and other lipids in predicting the presence of long-term MACE. apoB could be a "risk-enhancing factor" in patients with coronary atherosclerosis disease, whereas in the Normal population, LDL-C still acted as a major risk factor for predicting MACEs. apoB was a good risk predictor for long-term cardiovascular events in coronary atherosclerosis (AS) patients, including the AS group and CHD subpopulations (including CHD+triglyceride ≥2.3 mmol/L, CHD+diabetes mellitus, CHD+body mass index ≥25 kg/m2, or CHD+metabolic syndrome). In patients with CHD whose condition was complicated with diabetes, obesity, and metabolic syndrome, apoB performed better than other lipids in predicting the presence of myocardial infarction, hospitalization due to angina, and cardiac death. Despite achieving optimal LDL-C or non-HDL-C levels, patients with CHD are still at risk of worse survival if they are unable to reach a low apoB level (lower cut points such as 65 mg/dL). More attention should be paid to special populations with residual elevations of atherogenic particle numbers, and greater focus should be placed on lowering baseline apoB to achieve long-term benefits. However, given that this was an observational study, the association of baseline apoB level and long-term MACEs only was evaluated; it is unclear whether the emergence of MACEs would be influenced by the dynamic changes of apoB. Because this was a retrospective and observational analysis, bias in data analysis was unavoidable; thus, the results cannot be used to generalize implications to broader patient populations, and more large-scale clinical trials are required to verify these findings. (Clin Ther. 2022;44:1071-1092) © 2022 Elsevier HS Journals, Inc.

Applying an LDL-C threshold-based approach to identify individuals with familial hypercholesterolemia

Familial hypercholesterolemia (FH) remains underdiagnosed and undertreated. The optimal electronic health record (EHR) screening strategy for FH is unclear. To evaluate an LDL-C threshold-based approach of identifying patients with FH from the EHR to determine the optimal LDL-C range for FH consideration. Individuals from UT Southwestern Medical Center with an LDL-C level ≥190mg/dL at any time were enrolled in an FH registry. These 5,786 patients were divided into four categories of LDL-C (190- 219, 220 - 249, 250 - 299, and ≥ 300mg/dL) with 100 individuals randomly selected for manual chart review in each category. Chart review included 1) the presence of secondary causes of dyslipidemia, 2) diagnosis of possible/definite FH by modified Simon Broome criteria, and 3) probable/definite FH by modified Dutch Lipid Clinic Network (DLCN) criteria. Of the 400 individuals with an LDL-C level ≥190mg/dL (mean age 52 years ± 14), the presence of secondary causes increased across each LDL-C category (p < 0.001) with the greatest prevalence in those ≥ 300mg/dL (52%). The prevalence of possible/probable or definite FH also varied by LDL-C category, with the highest prevalence of FH by Simon Broome criteria in the 220 - 249mg/dL category (52%) and by DLCN criteria in the 250 - 299mg/dL category (46%). Among those with LDL-C ≥ 190mg/dL, the prevalence of secondary causes increased markedly with higher LDL-C, while the diagnosis of FH has a parabolic relationship. Patients with intermediate LDL-C (220 - 299mg/dL) may be the optimal group to prioritize for FH screening.

Characterization of residual lipid-rich plaques despite achieving LDL-C &amp;lt;1.8mmol/l with a statin in patients with coronary artery disease: insights from the REASSURE-NIRS registry

Abstract Introduction Recent studies have demonstrated favourable modification of lipidic plaque materials under achieving LDL-C &amp;lt;1.8mmol/l with a statin, which potentially accounts for its clinical benefit. However, coronary events still occur even under optimal LDL-C management. This may suggest the presence of residual lipid-rich coronary plaque despite on-treatment LDL-C &amp;lt;1.8mmol/l. Given that near-infrared spectroscopy (NIRS) enables quantitative evaluation of lipidic plaque in vivo, we employed this imaging modality to investigate characteristics and drivers of residual lipid-rich plaques in statin-treated patients with coronary artery disease (CAD) who achieved LDL-C &amp;lt;1.8mmol/l. Purpose To clarify the frequency, clinical demographics and factors associated with residual lipid-rich plaques under LDL-C &amp;lt;1.8mmol/l. Methods The REASSURE-NIRS registry is an on-going multi-center registry to enroll CAD subjects receiving NIRS/intravascular ultrasound-guided PCI. The current analysis included 133 statin-treated stable CAD patients with on-treatment LDL-C &amp;lt;1.8mmol/l from August 2015 to December 2020. The maximum 4-mm lipid core burden index (maxLCBI4mm) at culprit lesions was measured by NIRS imaging prior to PCI. Clinical characteristics were compared in patients with and without maxLCBI4mm ≥400 at culprit lesions. Results In the current study, 45% (=58/128) of study subjects exhibited maxLCBI4mm ≥400 at culprit lesions under on-treatment LDL-C &amp;lt;1.8 mmol/l. They were more likely to be female, whereas there were no differences in age and the frequency of risk factors. Most of study subjects received moderate to high-intensity statin (p=0.79), and over one-fourth of them were treated with ezetimibe (p=0.56). Under these lipid-lowering therapies, LDL-C level was significantly higher in patients with maxLCBI4mm ≥400 (Table). Additionally, a lower frequency of LDL-C &amp;lt;1.4mmol/l was observed in those exhibiting maxLCBI4mm ≥400 (31.0 vs. 45.7%), but this comparison failed to meet statistical significance (p=0.09). Despite LDL-C control with a statin, deterioration of coronary flow after PCI with stent implantation more frequently occurred in patients with maxLCBI4mm ≥400 (Table). Multivariate analysis demonstrated that an independent factor associated with maxLCBI4mm ≥400 was LDL-C level (OR=1.05; 95% CI=1.00–1.10, p=0.03), but not other lipid and clinical parameters. Conclusion Almost half of CAD subjects who achieved LDL-C level &amp;lt;1.8mmol/l still exhibited the accumulation of lipidic plaque materials within vessel wall. Given that LDL-C level was associated with this residual lipid-rich plaque features, our findings support current ESC-guideline recommended LDL-C goal (&amp;lt;1.4mmol/l) to optimize the secondary prevention in stable CAD patients. Funding Acknowledgement Type of funding sources: None.

Native Low-Density Lipoproteins Act in Synergy with Lipopolysaccharide to Alter the Balance of Human Monocyte Subsets and Their Ability to Produce IL-1 Beta, CCR2, and CX3CR1 In Vitro and In Vivo: Implications in Atherogenesis.

Increasing evidence has demonstrated that oxidized low-density lipoproteins (oxLDL) and lipopolysaccharide (LPS) enhance accumulation of interleukin (IL)-1 beta-producing macrophages in atherosclerotic lesions. However, the potential synergistic effect of native LDL (nLDL) and LPS on the inflammatory ability and migration pattern of monocyte subpopulations remains elusive and is examined here. In vitro, whole blood cells from healthy donors (n = 20) were incubated with 100 μg/mL nLDL, 10 ng/mL LPS, or nLDL + LPS for 9 h. Flow cytometry assays revealed that nLDL significantly decreases the classical monocyte (CM) percentage and increases the non-classical monocyte (NCM) subset. While nLDL + LPS significantly increased the number of NCMs expressing IL-1 beta and the C-C chemokine receptor type 2 (CCR2), the amount of NCMs expressing the CX3C chemokine receptor 1 (CX3CR1) decreased. In vivo, patients (n = 85) with serum LDL-cholesterol (LDL-C) >100 mg/dL showed an increase in NCM, IL-1 beta, LPS-binding protein (LBP), and Castelli’s atherogenic risk index as compared to controls (n = 65) with optimal LDL-C concentrations (≤100 mg/dL). This work demonstrates for the first time that nLDL acts in synergy with LPS to alter the balance of human monocyte subsets and their ability to produce inflammatory cytokines and chemokine receptors with prominent roles in atherogenesis.

Lipoprotein(a): a genetic marker for cardiovascular disease and target for emerging therapies.

Lipoprotein(a) [Lp(a)] is an established cardiovascular risk factor, and growing evidence indicates its causal association with atherosclerotic disease because of the proatherogenic low-density lipoprotein (LDL)-like properties and the prothrombotic plasminogen-like activity of apolipoprotein(a) [apo(a)]. As genetics significantly influences its plasma concentration, Lp(a) is considered an inherited risk factor of atherosclerotic cardiovascular disease (ASCVD), especially in young individuals. Moreover, it has been suggested that elevated Lp(a) may significantly contribute to residual cardiovascular risk in patients with coronary artery disease and optimal LDL-C levels. Nonetheless, the fascinating hypothesis that lowering Lp(a) could reduce the risk of cardiovascular events - in primary or secondary prevention - still needs to be demonstrated by randomized clinical trials. To date, no specific Lp(a)-lowering agent has been approved for reducing the lipoprotein levels, and current lipid-lowering drugs have limited effects. In the future, emerging therapies targeting Lp(a) may offer the possibility to further investigate the relation between Lp(a) levels and cardiovascular outcomes in randomized controlled trials, ultimately leading to a new era in cardiovascular prevention. In this review, we aim to provide an updated overview of current evidence on Lp(a) as well as currently investigated therapeutic strategies that specifically address the reduction of the lipoprotein.

Cardiovascular Risk Factor Modification in Asymptomatic Adults and Implications for Pilots.

This study aims to examine the available evidence that supports a more aggressive approach to managing asymptomatic people with low to intermediate cardiovascular risks; to evaluate the appropriate threshold for initiating pharmacologic interventions to treat hyperglycaemia, hyperlipidaemia, and hypertension; and to describe the implications for airline pilots. A systematic search was performed employing an OvidSP interface, including all EBM Reviews, EMBASE, and Ovid MEDLINE databases. Data, including sixteen randomised controlled trials, on the appropriate threshold for initiating pharmacologic interventions were extracted. Studies on the treatment of hyperlipidaemia indicated that the threshold for initiation of intervention in intermediate-risk people is a LDL-C level of 3.36 mmol/l (130 mg/dl). There was no lower limit or optimal LDL-C level below which further reduction was no longer beneficial. Studies on the treatment of hyperglycaemia suggested that a threshold of fasting plasma glucose of ≥5.3 mmol/l (95 mg/dl) and 2-hour postprandial glucose level of 7.8 mmol/l (140 mg/dl) is reasonable for initiating pharmacologic intervention. Initiating treatment to people with a blood pressure of ≥130/≤89 mmHg or ≤139/≥85 mmHg significantly reduced the risk of developing stage 1 hypertension. Multifactorial intervention studies showed that, in hypertensive patients (BP ≥160/≥100 mmHg), initiating treatment to those with a total cholesterol of 6.5 mmol/l (251.35 mg/dl) or higher resulted in a significant reduction in the risk of developing fatal and non-fatal cardiovascular events. The available evidence from large quality trials supports a more aggressive approach to managing hyperglycaemia, hyperlipidaemia, and hypertension in asymptomatic pilots with a 5-year CVD risk of 5-10% and 10-15%.

P5327Are we being able to meet current guidelines LDL-cholesterol goals in very high risk patients? How many of them could benefit of PSCK9 inhibition by the FOURIER/ODYSSEY and NICE criteria?

Abstract Background/Introduction With increasing evidence of LDL-cholesterol (LDL-c) lowering and a subsequent reduction in cardiovascular events, guidelines of different parts of the world aim for lower LDL-c goals by risk stratification. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition has been able to reduce up to 60% LDL-c levels, with further reduction in cardiovascular outcomes. Purpose Our aim was to evaluate the proportion of very high risk patients in a tertiary cardiology center that met LDL-c goal of less than 50mg/dL proposed by the Brazilian Society of Cardiology (BSC) guidelines. Furthermore, we assessed the number of patients that were receiving adequate statin intensity therapy and could benefit from PCSK9 inhibition by the FOURIER/ODYSSEY and by the National Institute for Health and Care Excellence (NICE) criteria. Methods We screened 2180 consecutive patients from March, 2018 to February, 2019 for cardiovascular risk factors, cholesterol and glycemic levels, and current medical therapy at use. Patients were stratified by level of risk, and compliance to recommended statin therapy was evaluated. We then analyzed how many of the very high risk patients, that were in use of high intensity statin therapy, met the inclusion LDL-c levels of the FOURIER/ODYSSEY trials (≥70mg/dL) and the NICE recommendations (≥140mg/dL) for the introduction of PCSK9 inhibitors. Results Of the 2180 patients enrolled to our study, 1225 (56.2%) patients were at very high cardiovascular risk level. Of these patients, 136 (11.1%) met LDL-c BSC guideline levels. Using the LDL-c target of 70mg/dL, an additional 320 (26.1%) patients were below target range. When analyzing statin therapy at use, 913 (74,5%) were receiving adequate statin therapy. Of the very high risk patients in adequate statin treatment, 617 (65.9%) by the FOURIER/ODYSSEY criteria and 88 (9.4%) patients by the NICE criteria would benefit from PCSK9 inhibitors. Conclusions With lower LDL-c goals, achievement of optimal LDL-c levels is now a challenge for current clinical practice. Even though many patients are receiving adequate guideline-based statin therapy, difficulty remains in achieving optimal treatment, especially in the higher risk stratum. These patients would benefit from PCSK9 inhibition, being the NICE criteria, a more cost-effective strategy, still applicable in a substantial portion of our patients.

LDL-Cholesterol Lowering of Plant Sterols and Stanols-Which Factors Influence Their Efficacy?

The LDL-cholesterol (LDL-C) lowering effect of plant sterols/stanols (PSS) is summarized in several meta-analyses showing a dose-response relationship with intakes of 1.5 to 3 g/day lowering LDL-C by 7.5% to 12%. This review summarizes evidence for the impact of various factors potentially influencing the LDL-C-lowering efficacy of PSS. PSS are efficacious in all food formats and in food supplements. Some factors related to food format, e.g., solid vs. liquid foods, seem to impact efficacy, while there is no difference between free PSS and esters. Compared to multiple daily intakes, once-a-day intake of PSS, especially in the morning with light breakfast, leads to a sub-optimal LDL-C lowering. However, intake frequency seems influenced by intake occasion, i.e., with or without a meal, and time of day. Meal intake is a critical factor for an optimal LDL-C lowering efficacy of PSS. While age has no impact, gender is suggested to influence the LDL-C lowering effect of PSS with greater reductions reported for men than women; but overall evidence is inconclusive and larger studies show no gender by treatment interaction. In conclusion, PSS are efficacious in all foods and food supplements; for optimal efficacy they should be consumed with a (main) meal and twice daily.

Rationale and Design of Randomized Evaluation of Aggressive or Moderate Lipid Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) Trial.

Large-scale clinical trials in patients in Western countries with coronary artery disease (CAD) have found that aggressive lipid-lowering therapy using high-dose statins reduces cardiovascular (CV) events further than low-dose statins. However, such evidence has not yet been fully established in Asian populations, including in Japan. The Randomized Evaluation of Aggressive or Moderate Lipid-Lowering Therapy with Pitavastatin in Coronary Artery Disease (REAL-CAD) study addresses whether intensification of statin therapy improves clinical outcomes in Japanese patients with CAD.REAL-CAD is a prospective, multicenter, randomized, open-label, blinded-endpoint, physician-initiated phase 4 trial in Japan. The study will recruit up to 12,600 patients with stable CAD. Patients are assigned to receive either pitavastatin 1 mg/day or pitavastatin 4 mg/day. LDL-C levels are expected to reach approximate mean values of 100 mg/dL in the low-dose pitavastatin group and 80 mg/dL in the high-dose group. The primary endpoint is the time to occurrence of a major CV event, including CV death, non-fatal myocardial infarction, non-fatal ischemic stroke, and unstable angina requiring emergency hospitalization during an average of 5 years. The large number of patients and the long follow-up period in the REAL-CAD study should ensure that there is adequate power to definitively determine if reducing LDL-C levels to approximately 80 mg/dL by high-dose statin can provide additional clinical benefit.After the study is completed, we will have categorical evidence on the optimal statin dose and target LDL-C level for secondary prevention in Japanese patients.

Combining LDL-C and HDL-C to predict survival in late life: The InChianti study

BackgroundWhile the relationship between total cholesterol (TC) and cardiovascular disease (CVD) progressively weakens with aging, several studies have shown that low TC is associated with increased mortality in older individuals. However, the possible additive/synergic contribution of the two most important cholesterol rich fractions (LDL-C and HDL-C) to mortality risk has not been previously investigated. Our study aimed to investigate the relationship between baseline LDL-C and HDL-C, both separately and combined, and 9-years mortality in a sample of community dwelling older individuals from the InCHIANTI study.Methods and findings1044 individuals over 64 years were included. CVD and cancer mortality were defined by ICD-9 codes 390–459 and 140–239, respectively. LDL-C <130 mg/dL (3.36 mmol/L) was defined as “optimal/near optimal”. Low HDL-C was defined as <40/50 mg/dL (1.03/1.29 mmol/L) in males/females, respectively. Nine-years mortality risk was calculated by multivariate Cox proportional hazards model. We found that, compared to subjects with high LDL-C and normal HDL-C (reference group), total mortality was significantly increased in subjects with optimal/near optimal LDL-C and low HDL-C (H.R.:1.58; 95%CI:1.11–2.25). As regards the specific cause of death, CVD mortality was not affected by LDL-C/HDL-C levels, while cancer mortality was significantly increased in all subjects with optimal/near optimal LDL-C (with normal HDL-C: H.R.: 2.49; with low HDL-C: H.R.: 4.52). Results were unchanged after exclusion of the first three years of follow-up, and of subjects with low TC (<160 g/dL—4.13 mmol/L).ConclusionsOur findings suggest that, in community dwelling older individuals, the combined presence of optimal/near optimal LDL-C and low HDL-C represents a marker of increased future mortality.

Statin combination therapy and cardiovascular risk reduction.

In numerous clinical trials, lowering LDL-C with statin therapy has been demonstrated to reduce the risk of cardiovascular disease (CVD) in primary and secondary prevention settings. Guidelines recommend statins for first-line therapy in cholesterol-lowering management of patients with CVD risk. Despite increased statin monotherapy use over the last decade, a number of patients with high CVD risk do not achieve optimal LDL-C lowering. Guidelines recommend consideration of statin combination therapy with nonstatin agents for these patients. However, combination therapy approaches have been hampered by neutral findings. Recently, ezetimibe added to simvastatin therapy reduced cardiovascular events in acute coronary syndrome patients, more than simvastatin alone. This article provides an overview of various agents in combination with statin therapy on cardiovascular outcomes. Other lipid-lowering agents in development, including PCSK9 and CETP inhibitors in development, are also described.

Effect of Ezetimibe on LDL-C Lowering and Atherogenic Lipoprotein Profiles in Type 2 Diabetic Patients Poorly Controlled by Statins.

BackgroundThere exists a subpopulation of T2DM in whom first-line doses of statin are insufficient for optimally reducing LDL-C, representing a major risk of CVD. The RESEARCH study focuses on LDL-C reduction in this population along with modifications of the lipid profiles leading to residual risks.MethodsLipid changes were assessed in a randomized, multicenter, 12-week, open-label study comparing a high-potency statin (10mg of atorvastatin or 1mg of pitavastatin) plus ezetimibe (EAT: n = 53) with a double dose of statin (20mg of atorvastatin or 2mg of pitavastatin) (DST: n = 56) in DM subjects who had failed to achieve the optimal LDL-C targets. Lipid variables were compared with a primary focus on LDL-C and with secondary focuses on the percentage of patients who reached the LDL-C targets and changes in the levels of RLP-C (remnant like particle cholesterol) and sd-LDL-C, two characteristic atherogenic risks of DM.ResultsThe reduction of LDL-C (%), the primary endpoint, differed significantly between the two groups (-24.6 in EAT vs. -10.9 in DST). In the analyses of the secondary endpoints, EAT treatment brought about significantly larger reductions in sd-LDL-C (-20.5 vs. -3.7) and RLP-C (-19.7 vs. +5.5). In total, 89.4% of the patients receiving EAT reached the optimized treatment goal compared to 51.0% of the patients receiving DST. The changes in TC (-16.3 vs. -6.3) and non-HDL-C (-20.7 vs. -8.3) differed significantly between the two groups.ConclusionEzetimibe added to high-potency statin (10 mg of atorvastatin or 1 mg of pitavastatin) was more effective than the intensified-dose statin (20 mg of atorvastatin or 2 mg of pitavastatin) treatment not only in helping T2DM patients attain more LDL-C reduction, but also in improving their atherogenic lipid profiles, including their levels of sd-LDL-C and RLP-C.We thus recommend the addition of ezetimibe to high-potency statin as a first line strategy for T2DM patients with insufficient statin response.Trial RegistrationThe UMIN Clinical Trials Registry UMIN000002593

Persistent lipid abnormalities in statin-treated coronary artery disease patients with and without diabetes in China

BackgroundWe evaluate the prevalence of persistent lipid abnormalities and statin use in Chinese coronary artery disease patients with and without diabetes. Methods and resultsIn this cross-sectional observational study, 8965 outpatients from 200 clinical departments of 122 hospitals in 27 provinces nationwide of China who had coronary artery disease and were taking a statin were consecutively enrolled and divided into two groups based on diabetes status. The European Society of Cardiology/European Arthrosclerosis Society Guidelines for the management of dyslipidemias and the Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults were used to compare the control rates of low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, and triglycerides (TG). Among the 8965 participants, 33.3% had been diagnosed with diabetes mellitus. According to the ESC Guidelines, the percentage of patients with not at goal LDL cholesterol did not differ significantly between patients with diabetes and those without diabetes (71.9% vs. 72.7%, P=0.46). The percentages of patients with not-at-goal levels of HDL and TG were 42.9% vs. 34.4% (P<0.001) and 39.1% vs. 34.3% (P<0.001) among patients with diabetes and those without, respectively. Only approximately 10% of patients in both groups had optimal LDL-C, HDL-C, and TG levels. Compared with patients without diabetes, patients with diabetes were more likely to have mixed dyslipidemia. Atorvastatin (47.0%) and simvastatin (34.4%) were the two most frequently used statins, and the average statin dosage was 29.09mg/day (simvastatin equivalent). Less than 1% of patients were treated with another lipid-lowering drug in combination with a statin. ConclusionsAlthough international guidelines highly recommend intensive lipid modulation in patients with coronary artery disease, persistent dyslipidemia is still prevalent among these patients in China, even with statin treatment.

GW25-e0273 To dynamically observe a severe familial hypercholesterolemia child with seven-year follow up in China: a call for action

Objectives: To evaluate the prevalence of persistent lipid abnormalities and statin use in Chinese patients with coronary artery disease. Methods: This cross-sectional observational study consecutively enrolled 9420 outpatients with coronary artery disease in China. ESC/EAS Guidelines for the management of dyslipidemia and Chinese guidelines on prevention and treatment of dyslipidemia in adults were used to compare the control rate of low density lipoprotein cholesterol, high density lipoprotein cholesterol and triglyceride. Results: Among the 9420 participants, 33.6% was diagnosed as diabetes mellitus. The percentage of patients with not-at-goal LDL cholesterol was significantly lower in patients with diabetes than those without diabetes (72.7% vs 73.2%, P<0.001). The corresponding values for HDL-C and TG were 42.9% vs 34.2% (P<0.001) and 40.6% vs 35.2% (P<0.001), respectively. Only about 10% patients had optimal LDL-C, HDLC and TG. Compared with patients without DM, patients with DM were more likely to have mixed dyslipidemia. Atorvastatin (47.0%) and simvastatin (34.4%) were the two most frequently used statin and the average statin dosage was 29.09 mg/d (simvastatin equivalent). Drug combination with statin to modulate lipid was only 3%. Conclusions: Although international guideline highly recommends intensive lipid modification in patients with coronary artery disease, persistent dyslipidemia was still prevailing in China, even with statin treatment.

Intestinal sterol transporters and cholesterol absorption inhibition

Statin therapy is the mainstay of lipid-lowering therapy; however, many patients, particularly those at high risk, do not achieve sufficient LDL-cholesterol (LDL-C) lowering. Thus, there remains an unmet medical need for more effective and well tolerated lipid-lowering agents. Guidelines recommend combining additional lipid-lowering agents with a complementary mode of action for these patients. One approach to complementing statin therapy is combination with inhibitors that block the intestinal absorption of dietary and biliary cholesterol. This review summarizes what is currently known about intestinal sterol transporters and cholesterol absorption inhibitors (CAIs). The only lipid-lowering agent currently available that specifically targets an intestinal sterol transporter (Niemann-Pick C1-like 1) is the CAI, ezetimibe. It is effective in lowering LDL-C, both when given alone and when combined with a statin. Clinical outcome data with ezetimibe combined with simvastatin have recently become available, and definitive evidence that the incremental LDL-C lowering attributable to the ezetimibe component reduces cardiovascular events beyond simvastatin alone is currently under study. Other novel CAIs have been evaluated based upon the structure and properties of ezetimibe, but none remain in development. Additional lipid-lowering agents are needed to fulfill an unmet medical need for those patients who do not achieve optimal LDL-C goals on statin monotherapy. The inhibition of cholesterol absorption is an important therapeutic strategy to reduce cholesterol levels. Based upon the demonstrated lipid-altering efficacy and safety of ezetimibe, several CAIs have been identified; all to date have been discontinued due to limited efficacy.

Cardiovascular Disease and Dyslipidemia: Beyond LDL

Low-density lipoproteins (LDL) are atherogenic and represent a strong cardiovascular risk factor. Therefore, LDL-cholesterol (LDL-C) remains the primary target in lipid lowering therapy. However, since many cardiovascular events occur despite an optimal LDL-C, it is necessary to focus on the remaining cardiovascular risk. Treatment of low high-density lipoprotein-cholesterol (HDL-C) and high triglycerides (TG) are options to achieve cardiovascular risk reduction beyond LDL. HDL mediates reverse cholesterol transport and exerts several other athero-protective effects. Epidemiologic evidence has shown that low HDL-cholesterol (HDL-C) is a strong and independent cardiovascular risk marker. However, since the anti-atherogenic effects of HDL particles rather depend on their functionality rather than on their cholesterol content, an increase in HDL-C concentration does not always have to result in a clinical benefit. Besides established strategies to increase HDL-C, e.g. with fibrates and nicotinic acid, CETP (Cholesteryl ester transfer protein)-inhibition is a promising new therapeutic option. The failure of torcetrapib, the first CETP-inhibitor, seems to be attributed to "off-target" effects. Treatment with the newer CETP-inhibitors dalcetrapib and anacetrapib has been shown to be efficacious and safe - but their usefulness in clinical practice remains to be determined in ongoing clinical endpoint trials. TG concentrations have been shown to correlate with cardiovascular risk. However, interpretation of plasma TG concentrations remains difficult due to considerable intra-individual variability of plasma concentrations. Post-prandial triglyceride concentrations may be better predictors of cardiovascular risk than fasting TG. In patients with hypertriglyceridemia, achievement of the LDL-C goal remains the primary lipid target. The basis of therapy in patients with hypertriglyceridemia are life style modifications. In addition, non-HDL-C should be addressed. For selected patients, treatment with fibrates, nicotinic acid or omega-3 fatty acids are available to lower TG concentrations. In summary, the focus of lipid therapy is the reduction of cardiovascular risk rather than the modification of lipoprotein sub-fractions. Ongoing research points towards a shift of the focus from the HDL-C concentrations to parameters of HDL function and from fasting TG to TG kinetics.