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This joint expert review by the Obesity Medicine Association (OMA) and National Lipid Association (NLA) provides clinicians an overview of the pathophysiologic and clinical considerations regarding obesity, dyslipidemia, and cardiovascular disease (CVD) risk. This joint expert review is based upon scientific evidence, clinical perspectives of the authors, and peer review by the OMA and NLA leadership. Among individuals with obesity, adipose tissue may store over 50% of the total body free cholesterol. Triglycerides may represent up to 99% of lipid species in adipose tissue. The potential for adipose tissue expansion accounts for the greatest weight variance among most individuals, with percent body fat ranging from less than 5% to over 60%. While population studies suggest a modest increase in blood low-density lipoprotein cholesterol (LDL-C) levels with excess adiposity, the adiposopathic dyslipidemia pattern most often described with an increase in adiposity includes elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-C), increased non-HDL-C, elevated apolipoprotein B, increased LDL particle concentration, and increased small, dense LDL particles. Obesity increases CVD risk, at least partially due to promotion of an adiposopathic, atherogenic lipid profile. Obesity also worsens other cardiometabolic risk factors. Among patients with obesity, interventions that reduce body weight and improve CVD outcomes are generally associated with improved lipid levels. Given the modest improvement in blood LDL-C with weight reduction in patients with overweight or obesity, early interventions to treat both excess adiposity and elevated atherogenic cholesterol (LDL-C and/or non-HDL-C) levels represent priorities in reducing the risk of CVD. [Display omitted] [ABSTRACT FROM AUTHOR]

• Triglyceride-rich lipoproteins (TRLs) were independently associated with GlycA. • Medium and large TRLs were the main TRL subclasses related to GlycA. • Medium, large, and very large TRLs were associated with circulating leukocytes. • TRLs were more strongly related to neutrophils and lymphocytes than monocytes. • The total number of TRLs was not associated with C-reactive protein. Experimental studies have linked triglyceride-rich lipoproteins (TRLs) to inflammation, but the extent of this phenomenon in vivo has not been completely elucidated. We investigated the association between TRL subparticles and inflammatory markers (circulating leukocytes, plasma high-sensitivity C-reactive protein [hs-CRP], and GlycA) in the general population. This was a cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). TRLs (number of particles per unit volume) and GlycA were measured by nuclear magnetic resonance spectroscopy. The association between TRLs and inflammatory markers was determined by multiple linear regression models adjusted for demographic data, metabolic conditions, and lifestyle factors. Standardized regression coefficients (beta) with 95% confidence intervals are reported. The study population comprised 4,001 individuals (54% females, age 50 ± 9 years). TRLs, especially medium and large subparticles, were associated with GlycA (beta 0.202 [0.168, 0.235], p <0.001 for total TRLs). There was no association between TRLs and hs-CRP (beta 0.022 [-0.011, 0.056], p = 0.190). Medium, large, and very large TRLs were associated with leukocytes, with stronger connections with neutrophils and lymphocytes than monocytes. When TRL subclasses were analyzed as the proportion of the total pool of TRL particles, medium and large TRLs were positively related to leukocytes and GlycA, whereas smaller particles were inversely associated. There are different patterns of association between TRL subparticles and inflammatory markers. The findings support the hypothesis that TRLs (especially medium and larger subparticles) may induce a low-grade inflammatory environment that involves leukocyte activation and is captured by GlycA, but not hs-CRP. [Display omitted] [ABSTRACT FROM AUTHOR]

• Thyroid hormones modulate LDL metabolism. • Subclinical hypothyroidism and hyperthyroidism did not change LDL particle distribution. • However, LDL size decreases as TSH levels increase. LDL appears to drive atherogenesis in overt hypothyroidism, but in subclinical dysfunction, its role is not completely elucidated. The aim of this study was to evaluate subfractions of LDL in subclinical (SC) thyroid disorders. Individuals were divided into three groups by baseline thyroid function (SC hypothyroidism, euthyroidism, and SC hyperthyroidism). LDL particle (LDL-P) subfractions were analyzed by Nuclear Magnetic Resonance (NMR) spectroscopy. The association between LDL-P subfractions and thyroid groups and quintiles was evaluated by linear regression models. We evaluated 3304 participants (54.1% women, 51.2% white, mean age 50.6 ± 8.7 years). In the univariate analysis, small LDL particle concentrations (SLDL-P) were not different between SC hypo- and hyperthyroidism compared to euthyroid individuals (p = 0.485 and p = 0.314, respectively). Large LDL-P (LDL-P) levels also did not differ in SC hyperthyroidism and SC hypothyroidism compared to euthyroidism (p = 0.698 and 0.788 respectively). Intermediate LDL-P levels were not different across the groups. These numbers did not materially change in multivariate analysis. However, we also analyzed LDL subfractions according to quintiles of TSH. We showed that in the higher TSH quintile LDL subfractions presented a significantly smaller mean size of LDL subfractions compared to the first quintile. SC thyroid disorders are not associated with significant changes in LDL-P subfractions measured by NMR spectroscopy. However, it seems that the LDL mean size decreases as TSH levels increase, which may represent a more atherogenic lipid profile. [ABSTRACT FROM AUTHOR]

Hypertriglyceridemia (HTG) is associated with increased cardiovascular disease (CVD) risk. However, the cost burden of HTG-related CVD in high-risk US adults on statins has not been well characterized. We estimated the HTG-related health care cost burden among US adults with CVD or diabetes taking statin therapy. We estimated population sizes and annual health care costs among US adults aged ≥45 years with diabetes or CVD taking statin therapy with normal triglycerides (TGs) defined as TG < 150 mg/dL compared with those with HTG defined as TG ≥ 150 mg/dL. Population sizes were estimated from the 2007-2014 National Health and Nutrition Examination Surveys. Adjusted mean total annual health care costs in 2015 US dollars were estimated using the Optum Research Database. The annual total health care cost burden was estimated by multiplying the population size by the mean annual total incremental health care costs overall and within subgroups. There were 6.2 (95% confidence interval [CI], 5.4 - 7.1) million and 12.0 (95% CI, 11.1 – 12.9) million US adults aged ≥45 years with diabetes and/or CVD on statin therapy with TG ≥ 150 mg/dL and TG < 150 mg/dL, respectively. The mean adjusted incremental total one-year health care costs in adults with TG ≥ 150 mg/dL compared with those with TG < 150 mg/dL was $1730 (95% CI, $1160 - $2320). This leads to a projected annual incremental cost burden associated with HTG in patients with diabetes or CVD on statins of $10.7 billion (95% CI, $6.8 B - $14.6 B). In US adults on statins and at high risk for CVD, the health care costs associated with HTG are substantial. • HTG is associated with an increased risk of cardiovascular events. • HTG prevalence in US adults with cardiac comorbidities on statins is 6.2 million. • Projected annual incremental cost burden associated with HTG is $10.7 billion. • Older adults, men, and diabetics are most impacted by the cost burden of HTG. • In adults on statins and high risk, the costs associated with HTG are substantial. [ABSTRACT FROM AUTHOR]

Background Statin therapy remains the primary treatment for mixed dyslipidemia, even with moderate triglyceride (TG) elevations. Objective We examined the prevalence of elevated TG levels in adults with and without statin use and the associated 10-year predicted atherosclerotic cardiovascular disease (ASCVD) risk. Methods We studied 9593 US adults aged ≥20 years (219.9 million projected) in the US National Health and Nutrition Examination Surveys, 2007 to 2014. We determined the proportions of TG categories (<150, 150–199, 200–499, and ≥500 mg/dL) according to statin use, as well as the 10-year estimated ASCVD risk and number of events. Results Among those not taking statin therapy, the prevalence of TG < 150, 150 to 199, and ≥200 mg/dL was 75.3%, 12.8%, and 11.9%; among statin users, these proportions were 68.4%, 16.2%, and 15.4%, respectively. Among persons with low-density lipoprotein cholesterol <100 mg/dL (or <70 mg/dL in those with ASCVD), despite statin use, 27.7% had TG ≥ 150 mg/dL. The odds of TG ≥ 150 mg/dL in statin users was associated with greater age, higher body mass index, lower high-density lipoprotein cholesterol, higher low-density lipoprotein cholesterol, and diabetes. Estimated mean 10-year ASCVD risk from TG < 150 to ≥500 mg/dL, ranged from 11.3% to 19.1% in statin users and 6.0% to 15.6% in nonusers, with an overall 3.4 million ASCVD events expected in the next 10 years. Conclusions One-fourth of US adults overall, including nearly one-third of those on statin therapy, have suboptimal TG levels. More than 3 million ASCVD events are expected to occur over the next decade in those with TG ≥ 150 mg/dL, with approximately 1 million events expected in statin users. Highlights • We examined the prevalence of hypertriglyceridemia in US adults by statin use. • We also examined the 10-year estimated ASCVD risk and number of events. • In non-statin users 24.7% had TG ≥150 mg/dL versus 31.6% in statin users. • Mean 10-year ASCVD risk ranged from 7.1% to 16.1% with TG<150–≥500 mg/dL. • We estimate >3 million ASCVD events in 10 years in those with TG ≥ 150 mg/dL. [ABSTRACT FROM AUTHOR]

Background Erectile dysfunction complaints among men treated with a statin are not uncommon. Objectives To evaluate the effect of lowering low-density lipoprotein cholesterol (LDL-C) to target levels using varying doses of atorvastatin therapy in hypercholesterolemic male patients on adrenocortical hormones, sexual functions, and serum nitric oxide (NO) levels. Methods Eleven hypercholesterolemic male patients who had LDL-C levels greater than 160 mg/dL were included in the study and 11 healthy male individuals served as controls. Following basal hormone measurements, 1-and 250-mcg adrenocorticotropic hormone stimulation tests were performed in both groups, and blood sampling was performed at 0, 30, and 60 minutes for the determination of blood levels of cortisol, total testosterone (TT), free testosterone (FT), 11-deoxycortisol, and dehydroepiandrostenedione. Depending on baseline LDL-C concentrations, atorvastatin therapy was given to patients with daily doses of 5 or 10 mg and the study procedures were repeated once patients reached risk stratified goal LDL-C levels. LDL-C values after treatment were classified into 3 groups as LDL-C > 160 mg/dL, LDL-C 100 to 130 mg/dL and LDL-C < 100 mg/dL. NO levels were measured at baseline and after statin therapy. Erectile function was assessed both objectively and subjectively by using penile somatosensory evoked potential (SEP) and the International Index of Erectile Function-5 Questionnaire, respectively, at 3 different LDL-C levels. Results With regard to adrenocorticotropic hormone stimulation test (1 or 250 mcg) results, peak cortisol levels before and after statin treatment among 3 LDL-C groups and among controls did not differ significantly. However, peak TT and FT hormone levels decreased in conjunction with decreasing levels of LDL-C among the statin-treated patients, whereas dehydroepiandrostenedione and 11-11-deoxycortisol peak values did not change. N1 latency obtained during SEP, which is the first negative deflection, was prolonged with decreasing levels of LDL-C and a significant decrease in International Index of Erectile Function-5 scores were observed. When LDL-C levels of ≥ 160 mg/dl was reduced to 100 to 130 mg/dl, maximal NO elevations were noted. Conclusions Our results suggest that decreased LDL-C levels caused by different doses of atorvastatin treatment did not associate with significant changes in adrenal hormone levels. In contrast, there was a significant relationship between attained LDL-C on statin therapy and TT and FT levels. Electrophysiologically, abnormal SEP responses obtained in the patient group with LDL-C levels below 100 indicate a negative impact on the integrity of the somatosensory pathway, which plays a role in erectile function. Reducing LDL-C with a statin was associated with both decreased testosterone levels and erectile dysfunction. [ABSTRACT FROM AUTHOR]

Background The National Lipid Association (NLA) selected non-HDL-C as its prime index of the cardiovascular risk associated with the apoB lipoproteins. ApoB was recommended only as an optional secondary target after low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (HDL-C) targets were achieved. Objective The aims of this analysis were to determine whether (1) all relevant uses of apoB were considered by the NLA; (2) all the relevant evidence was considered by the NLA panel; and (3) all the evidence that was considered was interpreted correctly. Results (1) The utility of apoB in the diagnosis of the atherogenic dyslipoproteinemias was not considered. (2) All the relevant observational studies were not identified, and some that were cited were incorrectly interpreted. In particular, an equal hazard ratio for two markers in a group does not mean they will predict risk equally in individuals within the group in whom they are discordant. This matters because discordance analysis consistently demonstrates apoB and LDL particle number are more accurate measures of cardiovascular risk than LDL-C/non-HDL-C. (3) The target levels of apoB selected by the NLA are too high relative to the levels selected for LDL-C and non-HDL-C. Conclusions The review of the evidence by the NLA was incomplete. More complete examination of the evidence indicates that apoB is a more accurate marker of cardiovascular risk than non-HDL-C and that the practice of lipidology would be improved by inclusion of apoB along with lipoprotein lipids in routine clinical care. [ABSTRACT FROM AUTHOR]

Objective To evaluate patient characteristics, treatment patterns, comorbidities, and risk factors associated with the development of acute pancreatitis (AP) in patients with severe hypertriglyceridemia (HTG) in an integrated health care delivery system. Methods We identified a retrospective cohort of severe HTG patients with a fasting triglyceride level ≥ 1000 mg/dL during January 1, 2007 to June 30, 2013 (index date) in an integrated health care delivery system. Patients were aged ≥18 years on index date and had 12 months of continuous membership and drug eligibility before the index date and during postindex including index date. Baseline patient characteristics, comorbidities, and risk factors were evaluated during 12-month preindex. Outcomes such as development of AP, treatment patterns, adherence to index therapy, and change in triglyceride (TG) laboratory levels were evaluated during postindex. Descriptive statistics were used to identify differences between patients developing AP vs no development of AP. A stepwise multivariate logistic regression and backward elimination method were used to assess statistically significant predictive factors associated with development of AP vs no AP. Results We identified 5550 patients with severe HTG, and 5.4% of these patients developed AP during postindex. Patients were mostly male (≥70%) in both groups; however, younger in the AP group (45 years ± 10.6) vs no AP group (50 years ± 11.4) with P value < .0001. The AP group had higher baseline Charslon Comorbidity Index score, alcohol abuse history (42.2%), any pancreatitis history (51.5%), diabetes (47%), and hypertension (55%), vs the no AP group ( P values < .05). Patients in the AP group had higher baseline mean TG levels (2148, SD ± 1578) vs the no AP group (1559, SD ± 861), P value < .0001. Over 50% of the patients were prescribed their index therapy by a primary care provider. Predictive factors associated with the development of AP included younger age, alcohol use, and prior history of any pancreatitis, hypertension, renal disease stage 4, and other prescriber specialty. From parameters estimates, for each 100 mg/dL unit of increase in the TG level above 1000 mg/dL, there was a 3 percent increase in risk of developing AP. Conclusions Patients with severe HTG are at a higher risk of developing AP. A number of comorbidities, risk factors, and baseline TG levels are associated with an increased incidence of AP. Patients with severe HTG are underdiagnosed, undertreated and are nonadherent to their index lipid therapy. There is a need to better define optimal approaches to treating severe HTG so as to reduce the incidence of AP. Economic studies are also needed to evaluate the burden of AP on various health care systems. [ABSTRACT FROM AUTHOR]

Background Familial hypercholesterolemia (FH) is an autosomal dominant dyslipidemia characterized by defective low-density lipoprotein (LDL) clearance. The aim of this study was to compare Friedewald-estimated LDL cholesterol (LDL-C) to biologic LDL-C in individuals screening positive for FH and then further characterize FH phenotypes. Methods We studied 1,320,581 individuals from the Very Large Database of Lipids, referred from 2009 to 2011 for Vertical Auto Profile ultracentrifugation testing. Friedewald LDL-C was defined as the cholesterol content of LDL-C, intermediate-density lipoprotein cholesterol, and lipoprotein(a) cholesterol (Lp(a)-C), with LDL-C representing biologic LDL-C. Using Friedewald LDL-C, we phenotypically categorized patients by the National Lipid Association guideline age-based screening thresholds for FH. In those meeting criteria, we categorized patients using population percentile-equivalent biologic LDL-C cutpoints and explored Lp(a)-C and remnant lipoprotein cholesterol (RLP-C) levels. Results Overall, 3829 patients met phenotypic criteria for FH by Friedewald LDL-C screening (FH+). Of those screening FH+, 78.8% were above and 21.2% were below the population percentile-equivalent biologic LDL-C. The mean difference in Friedewald biologic LDL-C percentiles was −0.01 (standard deviation, 0.17) for those above, and 1.92 (standard deviation, 9.16) for those below, respectively. Over 1 of 3 were found to have an elevated Lp(a)-C and over 50% had RLP-C greater than 95th percentile of the entire VLDL population. Conclusions Of those who screened FH+, Friedewald and biologic LDL-C levels were closely correlated. Large proportions of the FH+ group had excess levels of Lp(a)-C and RLP-C. Future studies are warranted to study these mixed phenotypic groups and determine the role for further risk stratification and treatment algorithms. [ABSTRACT FROM AUTHOR]

Background Nonalcoholic fatty liver disease (NAFLD) is associated with increased cardiometabolic risk. Although dyslipidemia represents a key factor in this disease, its impact on serum levels of distinct lipoprotein subfractions is largely unknown. Objective To assess the full low-density lipoprotein (LDL) and high-density lipoprotein (HDL) profiles in patients with NAFLD. Methods Seven LDL and 10 HDL subfractions were assessed by gel electrophoresis (Lipoprint, Quantimetrix Corporation, USA) in men with biopsy proven NAFLD (simple steatosis [n = 17, age, 34 ± 7 years] and nonalcoholic steatohepatitis [NASH; n = 24, age, 32 ± 6 years]). Exclusion criteria included robust alcohol consumption, infection with hepatitis B or C virus, body mass index ≥40 kg/m 2 , diabetes mellitus, and hypertension. Results Compared with simple steatosis, NASH patients had similar body mass index, homeostasis model assessment of insulin resistance index and plasma lipids, with increased levels of both aspartate aminotransferase and alanine transaminase. NASH subjects had lower levels of larger LDL1 (10 ± 4 vs 13 ± 4%, P = .010) and increased smaller LDL3 and LDL4 particles (9 ± 5 vs 5 ± 5%, P = .017 and 3 ± 3 vs 1 ± 2%, P = .012, respectively). No changes were found in the HDL subclass profile. By multiple regression analysis, we found that NASH was associated only with increased levels of LDL3 ( P = .0470). Conclusions The increased levels of small, dense LDL3 and LDL4 in NASH may help to at least partly explain the increased risk for atherosclerosis and cardiovascular diseases in these patients. [ABSTRACT FROM AUTHOR]

Niacin is a lipid-modifying therapy with proven efficacy for reducing cardiovascular events as monotherapy and when used in combination with other lipid-modifying medications impacts rates of atherosclerotic disease progression. Large outcome trials using niacin against a background of statin therapy with optimal control of atherogenic lipoprotein burden in serum were unable to demonstrate incremental benefit of niacin beyond statin therapy. We address 2 key questions: (1) Can the results from randomized clinical trials performed in stable ischemic heart disease populations (AIM-HIGH and HPS2-THRIVE) be applied to patients who sustain an acute coronary syndrome or myocardial infarction? (2) Are patients with very low baseline levels of high-density lipoprotein cholesterol (<30 mg/dL) at particularly high risk for subsequent cardiac events? [ABSTRACT FROM AUTHOR]

All current guidelines use the 10-year risk of a cardiovascular event to select subjects for statin primary preventive therapy. Benefit from therapy is stated to be determined by risk with the result that statin primary preventive therapy is initiated only when the risk of a cardiovascular event over the next decade exceeds a specified level. Thus all current guidelines are based primarily on the Risk-Benefit paradigm of primary prevention. The recent American Heart Association/American College of Cardiology guidelines differ from others in basing selection for statin therapy virtually exclusively on risk except for those few subjects with markedly elevated levels of low-density lipoprotein cholesterol (LDL-C). The Causal Exposure paradigm differs from the Risk-Benefit paradigm in that the objective of therapy is to prevent the anatomic disease within arterial walls that produces cardiovascular risk. Moreover, the anatomic disease and, therefore, the cardiovascular risk, is a function of the injurious action of the causal factors of vascular disease, such as blood pressure and LDL, on the arterial wall over long periods. In this article, we explain the strengths and weaknesses of both paradigms to provide a more secure framework to compare the strengths and weaknesses in the different cholesterol guidelines with particular emphasis on the evidence that the cardiovascular risk and the benefit from statin therapy is related to the level of LDL. [ABSTRACT FROM AUTHOR]

Nothing to disclose. Novartis Pharmaceuticals Corporation, East Hanover, NJ. Most patients with atherosclerotic cardiovascular disease (ASCVD) have elevated low-density lipoprotein cholesterol (LDL-C). Compared to placebo, inclisiran has been shown to be safe, tolerable, and effective at reducing LDL-C in patients with ASCVD. It is unknown whether an inclisiran first strategy compared to usual care (allowing for changes in lipid-lowering therapy to mimic routine clinical decision-making) can improve LDL-C control in patients with ASCVD when inclisiran is added to statin therapy. Describe the rationale and design of the ongoing VICTORION-INITIATE (NCT04929249) trial. VICTORION-INITIATE is a phase 3, randomized, 2-arm, parallel-group, open-label, U.S.-based trial assessing the efficacy of an inclisiran first strategy vs usual care to treat ASCVD. Patients in the inclisiran arm will receive both inclisiran and maximally tolerated statin therapy immediately upon failure to reach LDL-C less than 70 mg/dL with statins alone. Patients in the usual care arm will continue to receive maximally tolerated statin therapy and may receive other non-statin therapies per usual care. Sites were selected based on geography, population, and lipid management practices. The trial will enroll ∼444 patients (aged greater than or equal to 18 years) with established ASCVD and elevated LDL-C (greater than or equal to 70 mg/dL) or non-high-density lipoprotein cholesterol (greater than or equal to 100 mg/dL) despite receiving maximally tolerated statin therapy, fasting triglycerides less than 500 mg/dL, and an estimated glomerular filtration rate greater than 30 mL/min. The study has 6 planned visits over 330 days from screening to completion. Primary outcomes are percent change from baseline in LDL-C and proportion of patients discontinuing statins during the 330-day trial. Key secondary outcomes include the proportion of patients achieving prespecified LDL-C targets, proportion of patients achieving greater than or equal to 50% LDL-C reductions, absolute and time-averaged changes in LDL-C, changes in other lipids, changes in and adherence to ongoing lipid-lowering therapy, visit-to-visit variability in LDL-C, and inclisiran safety and tolerability. VICTORION-INITIATE is ongoing and planned to complete in early 2023. This trial aims to determine the efficacy of adding inclisiran first when maximally tolerated statin therapy fails to achieve LDL-C less than 70 mg/dL in those with ASCVD. [ABSTRACT FROM AUTHOR]

PPT has received honorarium for consultancy from Amarin, AstraZeneca, Kowa, Merck, Novo-Nordisk, and Resverlogix. Esperion Therapeutics, Inc. Patients with renal impairment and elevated levels of low-density lipoprotein cholesterol (LDL-C) are at very high risk for cardiovascular disease. Statins are safe and effective in this population but are often underutilized and underdosed; additional non-statin therapies to lower LDL-C are needed. Bempedoic acid (BA) is an ATP citrate lyase inhibitor that lowers LDL-C. To evaluate the safety and efficacy of BA in patients with Stage 2 or Stage 3a+b renal impairment. Data were pooled from four phase 3 studies in which patients were randomized 2:1 to BA or placebo (PBO) for 12 to 52 weeks. All studies permitted stable background lipid-lowering therapy: in 2 studies, patients received background moderate- to high-intensity statin, and in 2 studies, patients had a history of statin intolerance and received low-dose or no statin. Patients were grouped by baseline estimated glomerular filtration rate (eGFR [mL/min/1.73m2]) into the following renal function subgroups: Stage 1 (≥90), Stage 2 (60-89) or Stage 3a+b (30-59). A total of 3,619 (2,422 BA; 1,197 PBO) patients were included in the analysis. Baseline Stage 2 or Stage 3a+b renal impairment was present in 63% and 15% of patients in each treatment arm, respectively; 22% of the patients had Stage 1 renal function at baseline. LDL-C lowering of BA was similar across renal function subgroups with significant reductions at week 12 from baseline in each subgroup: Stage 1-20.8%, Stage 2 -18.8% and Stage 3a+b -21.1% (P <.0001 vs PBO for each; interaction P =.4442). Significant reductions in ApoB levels were also observed with BA treatment compared with PBO regardless of renal function (P <.0001). The overall pattern of adverse events was consistent across the renal function subgroups; any differences appeared to be driven by overall BA vs PBO differences rather than by renal function at baseline. Creatinine levels were generally consistent within each renal function subgroup in both arms with arm means varying by < 7% at each assessed time point through 52 weeks. BA was generally well-tolerated among patients with Stage 2 or Stage 3a+b renal impairment and significantly lowered LDL-C regardless of renal function status. [ABSTRACT FROM AUTHOR]

One of the most difficult and confusing issues for clinical lipidologists and physicians in general has been the management of low concentrations of high-density lipoprotein cholesterol. We know this to be a very powerful predictor of risk in scores of community-based and clinical trial cohorts. Raising this number in many patients would seem to provide a great therapeutic opportunity, but so far this concept has been very difficult to prove. I have been joined for this discussion by a cardiovascular epidemiologist, Dr. Rachel Mackey, from the University of Pittsburgh and two clinical lipidologists who have studied and written in depth about this problem. These are Dr. Benjamin Ansell from the University of California in Los Angeles and Dr. Peter Toth from Johns Hopkins University School of Medicine. Our objective in this discussion is to give primary care clinicians our thoughts about the recent research findings and the implications of these data on the best clinical practice. [ABSTRACT FROM AUTHOR]

Background and Objectives: Dyslipidemia is a modifiable major risk factor for coronary heart disease. The objective of this study was to determine the prevalence of dyslipidemia among Turkish adults and its associations with other cardiovascular risk factors. Methods: This study included 4309 people ages 20 to 83 years old from 7 provinces of Turkey. People from the city centers, districts, and villages were selected by a stratified sampling method. Weight, height, and waist and hip circumferences were measured. Blood samples were obtained to determine glucose, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG); these parameters were measured with an autoanalyzer. Dyslipidemia was defined according to National Cholesterol Education Program Adult Treatment Panel III diagnostic criteria. Results: Of 4309 subjects, 43% had high TC, 41.5% had low HDL-C, 36.2% had high LDL-C, and 35.7% had high TG. Of these measures, at least 1 lipid abnormality was diagnosed in 78.7% of men and 80.4% of women. The prevalence of high TC, LDL-C, and TG increased with age, with the highest prevalence in the 46-to-65-year-old age group. The mean values (mg/dL) of TC, LDL-C, HDL-C, and TG were 194.2 ± 47.7, 117.7 ± 41.1, 50.3 ± 16.3, and 145.4 ± 96.3, respectively. Dyslipidemia was positively associated with age, body mass index, waist circumference, fasting blood glucose, and blood pressure, and negatively associated with altitude. Conclusions: The high prevalence of dyslipidemia in Turkey is an important public health problem. Enhanced public health preventive measures should be implemented to better diagnose and comprehensively treat dyslipidemia in Turkey. [Copyright &y& Elsevier]

Abstract: Familial hypercholesterolemia (FH) is a dominantly inherited disorder present from birth that markedly elevates plasma low-density lipoprotein cholesterol and causes premature coronary heart disease. There are at least 20 million people with FH worldwide, but the majority remains undetected, and current treatment is often suboptimal. To address this major gap in coronary prevention we present, from an international perspective, consensus-based guidance on the care of FH. The guidance was generated from seminars and workshops held at an international symposium. The recommendations focus on the detection, diagnosis, assessment, and management of FH in adults and children and set guidelines for clinical purposes. They also refer to best practice for cascade screening and risk notifying and testing families for FH, including use of genetic testing. Guidance on treatment is based on risk stratification, management of noncholesterol risk factors, and the safe and effective use of low-density lipoprotein–lowering therapies. Recommendations are given on lipoprotein apheresis. The use of emerging therapies for FH is also foreshadowed. This international guidance acknowledges evidence gaps but aims to make the best use of contemporary practice and technology to achieve the best outcomes for the care of FH. It should accordingly be used to inform clinical judgment and be adjusted for country-specific and local healthcare needs and resources. [Copyright &y& Elsevier]

Background: Statin combination therapy and statin uptitration have been shown to be efficacious in low-density lipoprotein cholesterol (LDL-C) lowering and are recommended for patients with high-risk coronary heart disease (CHD) who do not reach guideline-endorsed LDL-C goals on statin monotherapy. Objective: This analysis evaluated treatment practice patterns and LDL-C lowering for patients with CHD/CHD risk equivalent on statin monotherapy in a real-world practice setting in the United States. Methods: In this retrospective, observational study, patients with CHD/CHD risk equivalent on statin therapy were identified during 2004 to 2008 in a US managed care database. Prescribing patterns and effect of switching from statin monotherapy to combination ezetimibe/simvastatin therapy vs uptitration to higher statin dose/potency level and no change from initial statin potency on LDL-C lowering were assessed. Percentage of change from baseline in LDL-C levels and odds ratios for LDL-C goal attainment were estimated with analyses of covariance and logistic regression. Results: Of 27,919 eligible patients on statin therapy, 2671 (9.6%) switched to ezetimibe/simvastatin therapy, 11,035 (39.5%) uptitrated statins, and 14,213 (50.9%) remained on the same statin monotherapy. LDL-C reduction from baseline and attainment of LDL-C <100 and <70 mg/dL were substantially greater for patients who switched to ezetimibe/simvastatin therapy (−24.0%, 81.2%, and 35.2%, respectively) than for patients who titrated (−9.6%, 68.0%, and 18.4%, respectively) or remained on initial statin therapy (4.9%, 72.2%, and 23.7%, respectively). The odds ratios for attainment of LDL-C <100 and <70 mg/dL were also higher for patients who switched than for patients who uptitrated and had no therapy change than for patients who titrated vs no therapy change. Similarly, among a subgroup of patients not at LDL-C <100 mg/dL on baseline therapy, attainment of LDL-C <100 and <70 mg/dL was greater for patients who switched than for statin uptitration vs no change, as well as for patients who uptritrated statins vs no therapy change. Conclusion: In this study, LDL-C lowering and goal attainment rates improved substantially for patients with high-risk CHD on statin monotherapy who switched to combination ezetimibe/statin or uptitrated their statin therapies; however, approximately one-third of these patients still did not attain the optional recommended LDL-C goal of <70 mg/dL. Moreover, these higher efficacy lipid-lowering therapies were infrequently prescribed, indicating the need for further assessment of barriers to LDL-C goal attainment in actual practice settings. [Copyright &y& Elsevier]

Abstract: For >4 decades it has been recognized that elevated serum levels of high-density lipoprotein cholesterol (HDL-C) are associated with reduced risk of cardiovascular disease (CVD) and its sequelae. Many prospective observational studies performed around the world have confirmed an inverse relationship between HDL-C and cardiovascular risk in people irrespective of sex, race, or ethnicity. Consequently, it was assumed that, by extension, raising HDL-C through lifestyle modification and pharmacologic intervention would reduce risk of CVD. Animal studies are consistent with this assumption. Lipid treatment guidelines around the world promoted the recognition of HDL-C as a therapeutic target, especially in high-risk patients. Some post hoc analyses from randomized controlled trials also suggest that raising HDL-C beneficially affects the risk of CVD. However, a number of recent randomized studies putatively designed to test the “HDL hypothesis” have failed to show benefit. The results of these trials have caused many clinicians to question whether HDL-C is a legitimate therapeutic target. In response to the many questions and uncertainties raised by the results of these trials, the National Lipid Association convened an expert panel to evaluate the current status of HDL-C as a therapeutic target; to review the current state of knowledge of HDL particle structure, composition, and function; and to identify the salient questions yet to be answered about the role of HDL in either preventing or contributing to atherosclerotic disease. The expert panel's conclusions and clinical recommendations are summarized herein. The panel concludes that, although low HDL-C identifies patients at elevated risk, and much investigation suggests that HDL may play a variety of antiatherogenic roles, HDL-C is not a therapeutic target at the present time. Risk stratified atherogenic lipoprotein burden (low-density lipoprotein cholesterol and non–HDL-C) should remain the primary and secondary targets of therapy in patients at risk, as described by established guidelines. The National Lipid Association emphasizes that rigorous research into the biology and clinical significance of low HDL-C should continue. The development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue. On the basis of an enormous amount of basic scientific and clinical investigation, a considerable number of reasons support the need to continue to investigate the therapeutic effect of modulating HDL structure and function. [Copyright &y& Elsevier]

Abstract: The term “fat” may refer to lipids as well as the cells and tissue that store lipid (ie, adipocytes and adipose tissue). “Lipid” is derived from “lipos,” which refers to animal fat or vegetable oil. Adiposity refers to body fat and is derived from “adipo,” referring to fat. Adipocytes and adipose tissue store the greatest amount of body lipids, including triglycerides and free cholesterol. Adipocytes and adipose tissue are active from an endocrine and immune standpoint. Adipocyte hypertrophy and excessive adipose tissue accumulation can promote pathogenic adipocyte and adipose tissue effects (adiposopathy), resulting in abnormal levels of circulating lipids, with dyslipidemia being a major atherosclerotic coronary heart disease risk factor. It is therefore incumbent upon lipidologists to be among the most knowledgeable in the understanding of the relationship between excessive body fat and dyslipidemia. On September 16, 2012, the National Lipid Association held a Consensus Conference with the goal of better defining the effect of adiposity on lipoproteins, how the pathos of excessive body fat (adiposopathy) contributes to dyslipidemia, and how therapies such as appropriate nutrition, increased physical activity, weight-management drugs, and bariatric surgery might be expected to impact dyslipidemia. It is hoped that the information derived from these proceedings will promote a greater appreciation among clinicians of the impact of excess adiposity and its treatment on dyslipidemia and prompt more research on the effects of interventions for improving dyslipidemia and reducing cardiovascular disease risk in overweight and obese patients. [Copyright &y& Elsevier]

Abstract: There is little known about the relative predictive value of different lipoprotein(a) [Lp(a)] assays in clinical use, although each has been shown to predict similar incremental risk over conventional clinical and lipid risk factors. Thus, we examined the classification behavior of two commonly used Lp(a) assays and their associations with other lipid parameters. Serum lipid and Lp(a) concentrations were measured in 144 primary and secondary prevention patients. Lp(a) cholesterol [Lp(a)-C] was measured with the Vertical Auto Profile (upper limit of normal, 10 mg/dL). Lp(a) particle concentrations [Lp(a)-P] were measured with an isoform-independent molar assay (upper limit of normal, 70 nmol/L). The subjects were divided into the following four groups on the basis of their Lp(a)-C and Lp(a)-P levels: normal Lp(a)-P and Lp(a)-C; high Lp(a)-P and normal Lp(a)-C; normal Lp(a)-P and high Lp(a)-C; and high Lp(a)-P and Lp(a)-C. The proportion of subjects with values above the upper limit of normal was similar with both assays (P = .15). However, the Lp(a)-C and Lp(a)-P assays discordantly classified 23% of the study’s subjects. In addition, the four Lp(a)-defined groups displayed differences in their relationships with other lipoproteins. The two groups with elevated Lp(a)-C showed significant associations with higher high-density lipoprotein cholesterol, apolipoprotein AI, and high-density lipoprotein cholesterol/apolipoprotein AI ratios. Triglycerides were also noted to be above normal in discordant and normal within concordant Lp(a) groups. Finally, the amount of cholesterol per Lp(a) particle [Lp(a)-C/Lp(a)-P] varied widely across the four groups. These findings suggest that the four Lp(a)-defined groups are physiologically discrete. Further investigation is warranted to assess which parameters among Lp(a)-P, Lp(a)-C, and Lp(a)-C/Lp(a)-P can be used to more accurately characterize Lp(a)-associated cardiovascular risk. [Copyright &y& Elsevier]

Background: Recent trends suggest a decreased use of ezetimibe/simvastatin combination and coadministered ezetimibe plus statin therapies. Objective: This analysis evaluated changes in prescription patterns for ezetimibe/simvastatin, ezetimibe plus statins, and statin therapies and expected effects on low-density lipoprotein cholesterol (LDL-C) lowering during 2007 to 2008. Methods: Prescription pattern changes were assessed by the use of patient-level data from the IMS Health Longitudinal Rx database during two time periods, July 14, 2007 to January 13, 2008 (n = 8,813,674) and January 14, 2008 to July 13, 2008 (n = 9,131,030), 6 months before and after reporting of the results of The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression trial (ENHANCE) trial on January 14, 2008. Expected LDL-C reductions were estimated using data from previous controlled clinical trials. Results: During 6 months post-ENHANCE, greater proportions of patients were switched from ezetimibe/simvastatin and ezetimibe plus statins to other lipid-lowering therapies by health care providers than 6 months pre-ENHANCE (21.1% vs 6.0% and 46.9% vs 38.5%, differences: −15.06% [95% confidence interval −15.14%, −14.97%] and −8.43% [95% confidence interval −8.70%, −8.17%], respectively). Greater proportions of these patients switched to statin monotherapy in the later than earlier period. Prescription patterns were similar for statins during both time periods, although fewer patients switched to ezetimibe/simvastatin and ezetimibe plus statin therapies post-ENHANCE. In both time periods, greater proportions of patients on ezetimibe/simvastatin and ezetimibe plus statins switched to less-than-equivalent LDL-C lowering efficacy doses of statins than those on statin therapy. On the basis of previous clinical data for these therapies, smaller LDL-C reductions would be expected in patients who switched from ezetimibe/simvastatin and ezetimibe plus statins to statins, despite a trend toward switching to greater statin doses in the later time period. Conclusions: More patients switched from ezetimibe/simvastatin and ezetimibe plus statin to statin monotherapy 6 months after the reporting of the ENHANCE trial, the majority of which were prescribed less potent, LDL-C–lowering therapies. On the basis of the known LDL-C lowering efficacies for these therapies, such changes would be expected to increase LDL-C levels in these patients and may reduce the proportion of patients who achieve guideline-recommended LDL-C goals. [Copyright &y& Elsevier]

Abstract: Lipoprotein(a) [Lp(a)] is a complex lipoprotein consisting of a low-density lipoprotein (LDL)-like ApoB100-containing core particle covalently bound to apo(a), a large functionally complex glycoprotein. The mechanisms of Lp(a) metabolism and its interactions with cell-surface lipoprotein receptors are incompletely understood. In this study, we investigated the relationship of Lp(a) to other lipoproteins at high and normal levels of serum triglycerides (TGs). We measured serum lipid and Lp(a) particle concentrations in 148 unselected primary- and secondary-prevention patients. Subjects with TG > 200 mg/dL were classified as having high TG in accordance with National Cholesterol Education Program Adult Treatment Panel III guidelines. Our analysis revealed mean TG levels of 100 and 270 mg/dL in the normal and high TG groups, respectively. Lp(a)-C, Lp(a)-P, and Lp(a) cholesterol content per particle [Lp(a)-C/Lp(a)-P] did not differ between groups. At normal TG levels, stepwise multiple linear regression revealed that Lp(a)-P correlated with Lp(a)-C (P < 10−6), ApoAI (P = .0001), the high-density lipoprotein cholesterol subfraction ratio (HDL2-C/HDL3-C; P = .002), and dense very-low-density lipoprotein cholesterol (VLDL3-C; P = .04), overall model R = 0.74. At high TG levels, Lp(a)-P very strongly correlated primarily with HDL2-C/HDL3-C and TG-related variables with minimal dependence on Lp(a)-C (P = .09), overall model R = 0.96. These findings provide evidence of shared metabolic mechanisms for Lp(a), HDL, TG, and very low-density lipoprotein at high serum TG. Future studies are needed to elucidate common mechanisms, enzymes, and receptors involved in Lp(a) and HDL/TG metabolism with a focus on how these mechanisms are modified in the setting of hypertriglyceridemia. [Copyright &y& Elsevier]

Background: Because a significant percentage of patients who require high-dose statin therapy for dyslipidemia experience treatment-related muscle symptoms and an inconsistent clinical response, alternative or adjunctive approaches to the management of dyslipidemia are needed. One alternative approach, antisense therapy, may offer an effective and well-tolerated option for patients not satisfactorily responsive to or intolerant to standard pharmacologic dyslipidemia therapies. Objective: This review provides an overview of antisense technology and its potential role in the management of dyslipidemia. Methods: Source material was obtained primarily from the published literature identified through a search of the PubMed database. Results: Antisense technology is an evolving approach to therapy that has gone through a series of refinements to enhance molecular stability, potency, and tolerability. Mipomersen is an antisense molecule capable of producing clinically meaningful reductions in low-density lipoprotein cholesterol in patients with severe familial hypercholesterolemia. Further long-term clinical studies are required to more clearly quantify its impact on risk for cardiovascular events and establish whether it increases risk for hepatosteatosis. Conclusion: Antisense therapy represents a potentially effective and well-tolerated emerging treatment modality for numerous diseases. In the treatment of hypercholesterolemia, the antisense therapy mipomersen may provide a possible treatment option for patients with treatment-resistant dyslipidemia. [ABSTRACT FROM AUTHOR]

Abstract: The National Cholesterol Education Program Adult Treatment Panel guidelines have established low-density lipoprotein cholesterol (LDL-C) treatment goals, and secondary non-high-density lipoprotein (HDL)-C treatment goals for persons with hypertriglyceridemia. The use of lipid-lowering therapies, particularly statins, to achieve these goals has reduced cardiovascular disease (CVD) morbidity and mortality; however, significant residual risk for events remains. This, combined with the rising prevalence of obesity, which has shifted the risk profile of the population toward patients in whom LDL-C is less predictive of CVD events (metabolic syndrome, low HDL-C, elevated triglycerides), has increased interest in the clinical use of inflammatory and lipid biomarker assessments. Furthermore, the cost effectiveness of pharmacological intervention for both the initiation of therapy and the intensification of therapy has been enhanced by the availability of a variety of generic statins. This report describes the consensus view of an expert panel convened by the National Lipid Association to evaluate the use of selected biomarkers [C-reactive protein, lipoprotein-associated phospholipase A2, apolipoprotein B, LDL particle concentration, lipoprotein(a), and LDL and HDL subfractions] to improve risk assessment, or to adjust therapy. These panel recommendations are intended to provide practical advice to clinicians who wrestle with the challenges of identifying the patients who are most likely to benefit from therapy, or intensification of therapy, to provide the optimum protection from CV risk. [Copyright &y& Elsevier]

Abstract: The familial hypercholesterolemias (FH) are a group of genetic defects resulting in severe elevations of blood cholesterol levels and increased risk of premature coronary heart disease. FH is among the most commonly occurring congenital metabolic disorders. FH is a treatable disease. Aggressive lipid lowering is necessary to achieve the target LDL cholesterol reduction of at least 50% or more. Even greater target LDL cholesterol reductions may be necessary for FH patients who have other CHD risk factors. Despite the prevalence of this disease and the availability of effective treatment options, FH is both underdiagnosed and undertreated, particularly among children. Deficiencies in the diagnosis and treatment of FH indicate the need for greatly increased awareness and understanding of this disease, both on the part of the public and of healthcare practitioners. This document provides recommendations for the screening, diagnosis and treatment of FH in pediatric and adult patients developed by the National Lipid Association Expert Panel on Familial Hypercholesterolemia. This report goes beyond previously published guidelines by providing specific clinical guidance for the primary care clinician and lipid specialist with the goal of improving care of patients with FH and reducing their elevated risk for CHD. [Copyright &y& Elsevier]

Abstract: The proteosome of high-density lipoprotein particles is quite complex and consists of up to 75 different proteins and enzymes. The specific protein cargo of HDL particles regulates their functionality. In addition to their documented capacity to engage in reverse cholesterol transport, reduce oxidized lipid, and function as apoprotein donors, HDL particles can activate a variety of signaling systems in endothelial cells, smooth muscle cells, and platelets. The HDLs can deliver sphingolipids to the surface of these cell types and activate sphingosine phosphate receptors. Sphingosine phosphate receptors are coupled to numerous different intracellular signaling cascades exerting roles in vasodilatation, inflammation, cell migration and apoptosis, inhibition of platelet activation, and endothelial adhesion molecule expression, among other functions. The ability of HDL to influence such a diverse array of cellular functions lends biological plausibility to the substantial epidemiological and clinical evidence suggesting that the HDLs are unique among lipoproteins in that they are vasculoprotective and antiatherogenic. [ABSTRACT FROM AUTHOR]

Abstract: The high-density lipoproteins (HDLs) are complex, polymolecular assemblies produced by the jejunum, liver, in serum, and on the surface of macrophages. HDL cholesterol (HDL-C) levels are an independent predictor of risk for cardiovascular events in both men and women. High serum levels of this lipoprotein are associated with reduced risk for atherosclerosis and its clinical sequelae, such as myocardial infarction, ischemic stroke, and death. The molecular basis for the apparent vasculoprotection afforded by elevated HDL-C is widely attributed to the ability of HDL particles to drive reverse cholesterol transport. The proteosome (protein cargo) of HDL also appears to endow this lipoprotein with a capacity to reduce oxidized lipids, promote endothelial cell nitric oxide production, reduce adhesion molecule expression, inhibit platelet activation, stimulate endothelial proliferation and inhibit apoptosis, and reduce inflammatory mediator expression, among other functions. Recent investigation suggests that among patients with coronary artery disease, HDL can also be dysfunctional, yielding a pro-inflammatory and pro-oxidative phenotype. Numerous drugs are currently in development in an effort to devise the means by which to optimally increase serum levels of functional, antiatherogenic HDL species. These drugs exploit a diverse range of mechanisms with potential for beneficially impacting the development and progression of atherosclerotic disease. [ABSTRACT FROM AUTHOR]

Background: National clinical treatment guidelines recommend pharmacologic treatment in addition to therapeutic lifestyle modifications in patients with mixed dyslipidemia and multiple risk factors for coronary heart disease (CHD). Objectives: To evaluate real-world pharmacologic treatment of mixed dyslipidemia patients with cardiovascular disease (CVD) risk factors. Methods: Commercial health plan members in a large, United States managed-care database with complete lipid panel results (ie, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C], total cholesterol [TC], triglycerides [TG]) between January 1, 2006 and December 31, 2006 were included. Mixed dyslipidemia was defined as any two nonoptimal lipid parameters (LDL-C, HDL-C, TG) according to National Cholesterol Education Program/Adult Treatment Panel III guidelines. Subjects were observed for 182 days pre-index to determine CVD risk factors (ie, male aged 45+ years, female 55+ years, CHD history, hypertension, diabetes mellitus). Lipid treatment status 6 months pre- and post-index dates was determined using pharmacy claims for any lipid monotherapy (statin, fibrate, niacin, “other”), or combination therapy (statin + fenofibrate; statin + niacin; statin + other). Results: Lipid treatment increased post-index for all mixed dyslipidemia groups and by total number of risk factors. The increased LDL-C and low HDL-C group had the lowest treatment rates; the group with low HDL-C and elevated TG had the highest. In the latter group, when treated, primarily statin monotherapy (51%) was used post-index; only 26% received niacin or fibrate therapy targeting HDL-C or TG abnormalities. Across all mixed dyslipidemia patients, >30% with three to four CVD risk factors were not treated ≥6 months post-index. Conclusions: In real-world clinical practice, pharmacologic treatment rates increased upon assessment of multiple lipid abnormalities and by total risk factors for CHD. However, mixed dyslipidemia remained undertreated with low rates of niacin and fibrate usage. [Copyright &y& Elsevier]

Abstract: Cardiovascular disease (CVD) causes nearly one third of all deaths worldwide. Estimates of the cumulative effects of the most common cardiovascular risk factors indicate that >30% of the chronic care burden of CVD and >50% of deaths from CVD are attributable to modifiable risk factors, such as cigarette smoking, elevated low-density lipoprotein cholesterol, low levels of high-density lipoprotein cholesterol, diabetes mellitus, and hypertension. While a significant percentage of patients present with one or more of these risk factors, health care practitioners encounter great difficulty in achieving long-term patient adherence to risk-factor modification interventions. More accurate stratification of death and disability risk across age, gender, and ethnic categories—and more comprehensible quantification of the magnitude and timeframe of the impact of risk-factor modification on such risks—will likely be useful to patients and health care practitioners in the implementation of more effective strategies. There is a need to study which risk-assessment methodologies, which depictions of short- and long-term risk, and which intervention modalities will have the greatest possible impact on patients’ understanding of risk factors and risk-modification behaviors. [Copyright &y& Elsevier]

Abstract: 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) are the first-line treatment for dyslipidemia and the results of large statin trials have a significant impact on guidelines for cardiovascular disease (CVD) management, such as those set by the National Cholesterol Education Program Adult Treatment Panel. The benefit of statin therapy in CVD prevention has traditionally been demonstrated in clinical trials by the superior efficacy of statins vs placebo in lowering low-density lipoprotein cholesterol (LDL-C) and preventing hard coronary heart disease (CHD) outcomes including myocardial infarction and CHD death. However, due to earlier and improved treatment of CVD, the clinical manifestations of atherosclerosis are changing and other forms of CVD are now thought to predominate (such as revascularization and stroke). These changes in how CVD manifests in the patient population may have consequences for selection of endpoints when designing future clinical trials. Recent statin trials have also demonstrated the early and improved clinical benefit of lowering LDL-C beyond traditional goals with intensive statin therapy vs more moderate lipid-lowering therapy. This review assesses the impact of early statin trials on current CVD management guidelines, summarizes results of recent landmark statin trials, and evaluates the potential implications of these studies for future clinical trials and CVD management guidelines. [Copyright &y& Elsevier]

Elevated remnant lipoprotein cholesterol (RLP-C) levels increase cardiovascular disease risk. However, RLP-C measurement methods are not standardized, leading to variations across studies. To evaluate the effect of ezetimibe (Eze) + statins vs statin monotherapy on RLP-C using immunoseparation (IM), vertical auto profile (VAP) ultracentrifugation, and calculated RLP-C measurement methods. This post hoc analysis evaluated data pooled from 3 first-line (all-statin [simvastatin 10/20/40/80 mg] vs Eze + statin [Eze 10 mg + simvastatin]) and 2 second-line (statin [atorvastatin uptitrated to 40/80 mg] vs statin + Eze [atorvastatin 20/40 mg + Eze 10 mg]) studies. Similarity of RLP-C methods was evaluated using Pearson correlation coefficients and Bland-Altman plots. RLP-C changes and percent changes from baseline were measured by all 3 methods in first-line and VAP and calculated methods in second-line studies. Correlations between methods were generally moderate to strong for RLP-C levels, changes, and percent changes across treatment groups (r = 0.29–0.79) but with little evidence of agreement by Bland-Altman plots. Baseline RLP-C levels for Eze + statin vs all-statin groups were lower by IM (14.0 vs 14.0) compared with VAP (36.9 vs 35.9) and calculated (32.8 vs 33.3) methods. RLP-C changes (mg/dL) and percent changes from baseline were significantly greater (P <.01) with Eze + statins vs statins by VAP, calculated, and IM methods (between-treatment differences: −5.0 and −12.0, −2.0 and −5.4, and −1.5 and −12.1, respectively) in first-line, and VAP and calculated methods (between-treatment differences: −5.0 and −19.9 and −2.0 and −7.3) in second-line studies. Although the 3 methods showed little agreement, each supported Eze + statins for achieving greater RLP-C reductions vs statin monotherapy; variability of results reinforces urgent need to standardize RLP-C measurements. • Remnant lipoprotein cholesterol measurement methods showed little agreement. • Correlations between the measurement methods were generally moderate to strong. • Ezetimibe/statin showed greater remnant lipoprotein cholesterol reduction vs statin. • There is a need to standardize remnant lipoprotein cholesterol measurement methods. [ABSTRACT FROM AUTHOR]

The Martin/Hopkins low-density lipoprotein cholesterol equation (LDL-C N) was previously demonstrated as more accurate than Friedewald LDL-C estimation (LDL-C F) in a North American database not able to take race into account. We hypothesized that LDL-C N would be more accurate than LDL-C F and correlate better with LDL particle number (LDL-P) in a racially diverse Brazilian cohort. We performed a cross-sectional analysis of 4897 participants in the Brazilian Longitudinal Study of Adult Health, assessing LDL-C F and LDL-C N accuracy via overlap with ultracentrifugation-based measurement among clinical guideline LDL-C categories as well as mg/dL and percent error differences. We analyzed by triglyceride categories and correlated LDL-C estimation with LDL-P. LDL-C N demonstrated improved accuracy at 70 to <100 and <70 mg/dL (P <.001), with large errors ≥20 mg/dL about 9 times more frequent in LDL-C F at LDL-C <70 mg/dL, mainly due to underestimation. Among individuals with LDL-C <70 mg/dL and triglycerides ≥150 mg/dL, 65% vs 100% of ultracentrifugation-based low-density lipoprotein cholesterol calculation fell within appropriate categories of estimated LDL-C F and LDL-C N , respectively (P <.001). Similar results were observed when analyzed for age, sex, and race. Participants at LDL-C <70 and 70 to <100 mg/dL with discordantly elevated LDL-C N vs LDL-C F had a 58.5% and 41.5% higher LDL-P than those with concordance (P <.0001), respectively. In a diverse Brazilian cohort, LDL-C N was more accurate than LDL-C F at low LDL-C and high triglycerides. LDL-C N may avoid underestimation of LDL-C and better reflect atherogenic lipid burden in low particle size, high particle count states. • LDL-C N is superior to LDL-C F in a racially diverse Brazilian population. • LDL-C N confers accuracy benefits in those at low LDL-C and high triglycerides. • LDL-C F more frequently falsely categorizes patients into lower LDL-C categories. • LDL-C N better reflects lipid burden in low particle size/high count states. [ABSTRACT FROM AUTHOR]

Background High-density lipoprotein cholesterol (HDL-C) can be divided into subfractions, which may have variable effects in atherogenesis. The results about the association between HDL-C subfractions and risk factors for cardiovascular disease are mixed. Objective The objective of this study was to analyze the association between HDL-C subfractions and each metabolic syndrome component, homeostasis model assessment-estimated insulin resistance (HOMA-IR) and C-reactive protein (CRP). Methods Four thousand five hundred thirty-two individuals between 35 and 74 years old without previous manifest cardiovascular disease not using fibrates were enrolled. HDL-C subfractions were separated by vertical ultracentrifugation (vertical auto profile—in mg/dL) into HDL 2 -C and HDL 3 -C. HDL 2 -C/HDL 3 -C ratio, HOMA-IR, and high-sensitivity CRP were also included in the analysis. Results Mean age of participants was 51 ± 9 years, and 54.8% were women. In univariate analysis, HDL-C, HDL 2 -C, and HDL 3 -C were all inversely associated with each of the metabolic syndrome defining factors, HOMA-IR values, and serum CRP. We also observed a negative association between HDL 2 -C/HDL 3 -C ratio with the variables aforementioned even after adjusting for smoking, alcohol use, physical activity, and HDL-C levels (P <.01). Conclusion HDL-C and its subfractions (HDL 2 -C and HDL 3 -C) are inversely associated with the defining features of metabolic syndrome, insulin resistance, and systemic inflammation. In addition, the HDL 2 -C/HDL 3 -C ratio measured by vertical auto profile is significantly associated with the former factors even after comprehensive adjustment for HDL-C and other confounding variables. Graphical abstract HDL: High-density lipoprotein HDL 2 : High-density lipoprotein subfraction 2 HDL 3 : High-density lipoprotein subfraction 3 LDL: Low-density lipoprotein VLDL: Very-low-density lipoprotein TG: Triglycerides Apo A1: Apolipoprotein A1 LPL: Lipoprotein lipase HL: Hepatic lipase CE: Cholesteryl ester CETP: Cholesteryl-ester transfer protein PLTP: Phospholipid transfer protein CM: chylomicron In the metabolic syndrome setting, there is a lower apo A1 liberation from chylomicrons due to inhibition of lipoprotein lipase (1), reducing HDL formation. Also, CETP is activated (2) and leads to more significant enrichment of HDL with triglycerides, rendering this lipoprotein a better substrate for lipolysis by hepatic lipase (3 – thicker arrows), leading to the formation of smaller HDLs. Finally, there is less apoA1 production and HDL formation by hepatocytes (4). As a result, we observe less total HDL-C, HDL 2 -C, HDL 3 -C and lower values of HDL 2 -C/HDL 3 -C ratio Highlights • High-density lipoproteins cholesterol and its subfractions are inversely associated with metabolic syndrome components. • HDL 2 -C/HDL 3 -C ratio is not constant across the spectrum of HDL levels. • HDL 2 -C increases more than HDL 3 -C as total HDL-C rises. • Lower HDL 2 -C/HDL 3 -C is directly associated with each metabolic syndrome criteria. [ABSTRACT FROM AUTHOR]

Background The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial failed to demonstrate incremental clinical benefit of extended-release niacin (ERN) in 3414 statin-treated patients with established cardiovascular (CV) disease who had low baseline levels of high-density lipoprotein cholesterol (HDL-C) as compared to placebo. A previous secondary analysis suggested that ERN provided outcome benefits in ERN-treated patients with high triglycerides (TGs; >200 mg/dL) and very low HDL-C (<32 mg/dL) at baseline. The current analysis sought to ascertain how changes in TG-enriched lipoproteins and HDL subfractions impact residual risk in the comparator treatment arms. Objectives We evaluated the relationship between niacin treatment, lipoproteins and their subfractions, and CV outcomes in a non-prespecified, post hoc analysis of the AIM-HIGH trial. Methods Lipoprotein subfraction analysis was performed with zonal ultracentrifugation in 2457 AIM-HIGH participants at baseline and 1 year of treatment. Hazard ratios were estimated using Cox proportional hazards models for relationships between lipoproteins and the composite primary endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Analyses were performed for the entire cohort and in participants with TGs > 200 mg/dL and HDL-C < 32 mg/dL. Results Apoprotein B–containing lipoproteins and their subfractions decreased significantly in both treatment arms but decreased more with ERN treatment. HDL-C and its subfractions increased significantly in both treatment groups, but more so in patients treated with ERN. For the entire study population, neither apoB- nor apoA1-containing lipoprotein subfractions predicted risk at baseline or at 1 year of follow-up. In the high TG and low HDL-C subgroup treated with placebo, changes at 1 year in HDL 2 -C, total cholesterol/HDL 2 -C, and non-HDL-C/HDL 2 -C may be associated with increased CV events, whereas in the ERN treatment arm, changes at 1 year in very low–density lipoprotein cholesterol and very low–density lipoprotein subfractions, total remnant lipoproteins, and various risk ratios may be associated with increased CV events, while HDL 2 -C may be associated with reduced risk. Conclusions We provide hypothesis-generating findings that ERN may confer benefit in patients with coronary heart disease who have high TGs and low HDL by reducing serum levels of remnant lipoprotein cholesterol and increasing HDL 2 -C. [ABSTRACT FROM AUTHOR]