Baseline Low-density Lipoprotein Cholesterol Concentrations Research Articles

Degree of serum LDL cholesterol reduction by simvastatin and ezetimibe is dependent on baseline LDL cholesterol concentration but not on baseline values and changes of cholesterol synthesis and absorption parameters.

We questioned whether the baseline status of low-density lipoprotein cholesterol (LDL-C), cholesterol synthesis and absorption, and the changes in these parameters determine the change in serum LDL-C under statin or ezetimibe treatment or under combination treatment. 37 mildly hypercholesterolemic healthy male subjects were studied under placebo, simvastatin (20mg/d), ezetimibe (10mg/d), and combination treatment. We correlated the change of LDL-C (ΔLDL-C) under treatment with the placebo end values of LDL-C (baseline), whole-body cholesterol synthesis, and hepatic cholesterol synthesis (serum lathosterol to cholesterol ratio) as well as fractional absorption rate (FAR) of cholesterol and serum campesterol to cholesterol ratio. The change in serum LDL-C was also correlated with the changes in synthesis and absorption parameters. ΔLDL-C was highly negatively related to baseline LDL-C under ezetimibe (p<0.0001), simvastatin (p<0.0001), and combination treatment (p<0.0001). Under combination treatment, LDL-C lowering appears possible from baseline values of 10 mg/dL upwards, while ΔLDL-C was independent of the baseline value (-50 to -60%). ΔLDL-C was positively associated with placebo FAR under ezetimibe (p=0.0106) and combination treatment (p=0.0457). No associations were found between ΔLDL-C and baseline values for synthesis nor between ΔLDL-C and changes in synthesis and absorption surrogate markers. Under ezetimibe, simvastatin, and combination treatment, ΔLDL-C is predominantly dependent on the baseline LDL-C concentration. We hypothesize that the concentration gradient between serum LDL-C and hepatic cellular cholesterol determines the efficiency of serum LDL-C lowering. Combination treatment is the preferred treatment.

Prognostic impact of lipoprotein(a) in patients undergoing percutaneous coronary intervention modified by low density lipoprotein cholesterol

BackgroundIt is well established that lipoprotein(a)[Lp(a)] and low-density lipoprotein cholesterol (LDL-C) play a vital role in atherosclerosis. We investigated the prevalence and prognostic implications of increased Lp(a) in patients undergoing percutaneous coronary intervention (PCI) according to different LDL-C concentrations. MethodsA total of 9,190 patients with CAD after PCI were consecutively enrolled in the study and subsequently divided into three groups according to baseline LDL-C at cut-off of 70 and 100 mg/dl. Increased Lp(a) was defined as > 30 mg/dl. The primary endpoint was all-cause death. Second endpoint was cardiac death. Cox regression, Kaplan-Meier and Sensitivity analysis were performed. ResultsDuring an average of 5.0 y of follow-up, 354 (3.9 %) patients experienced all-cause death with 213(2.3 %) of whom from cardiac death. Increased Lp(a) was present in 25.7 %, 34.2 %, and 40.6 % across the LDL-C < 70, 70–100 and≧100 mg/dl groups, respectively. After multivariate adjustment, Lp(a) elevation remained significantly associated with 5-y all-cause death (adjusted HR, 1.243; 95 % CI 1.001–1.544; p = 0.048) in the total cohort and only in those with LDL-C ≥ 100 mg/dl (adjusted HR, 1.642; 95 % CI 1.139–2.367; p = 0.008) when analyzed within each LDL-C category. Consistently with the results of associations between Lp(a) and cardiac death (adjusted HR, 1.534; 95 % CI 1.164–2.021; p = 0.002 for total cohort and adjusted HR, 2.404; 95 % CI 1.439–3.872; p < 0.001 for LDL-C ≥ 100 mg/dl). And this relationship holds after adjusting for LDL-Ccorr additionally. These findings are confirmed again in sensitivity analyses that excluded patients with Lp(a) concentrations in the top or the bottom 5 %. ConclusionsWe confirmed that increased Lp(a) was associated with increased risk of long-term outcomes, and such an association was modified by the baseline LDL-C concentrations. Screening of high Lp(a) in individuals with elevations of LDL-C may enables risk stratification for poor prognosis.

Changes in Impaired Fasting Glucose and Borderline High Low-Density Lipoprotein-Cholesterol Status Alter the Risk of Cardiovascular Disease: A 9-Year Prospective Cohort Study.

BackgroundWe aimed to characterize the relationships of the changes in impaired fasting glucose (IFG) and borderline high low-density lipoprotein-cholesterol (LDL-C) status with cardiovascular disease (CVD).MethodsA total of 36,537 participants who did not have previous CVD, diabetes mellitus, or high LDL-C (≥ 4.1 mmol/L), nor were taking lipid-lowering drugs were recruited from the Kailuan study. The participants were allocated to six groups according to their baseline and follow-up fasting blood glucose (FBG) and LDL-C concentrations: (1) both were normal; (2) both normal at baseline, one abnormality subsequently; (3) both normal at baseline, both abnormal subsequently; (4) at least one abnormality that became normal; (5) at least one abnormality at baseline, a single abnormality subsequently; and (6) at least one abnormality, two abnormalities subsequently. The outcomes were CVD and subtypes of CVD (myocardial infarction and stroke). Multiple Cox regression models were used to calculate adjusted hazard ratio (HR) and confidence interval (95% CI).ResultsDuring a median follow-up period of 9.00 years, 1,753 participants experienced a CVD event. After adjustment for covariates, participants with IFG in combination with a borderline high LDL-C status at baseline and follow-up had higher risks of CVD (HR: 1.52; 95% CI: 1.04–2.23 and HR: 1.38, 95% CI: 1.13–1.70, respectively) compared with those with normal fasting blood glucose and LDL-C. Compared with participants that remained normal, those who changed from normality to having two abnormalities were at a higher risk of CVD (HR: 1.26; 95% CI: 0.98–1.61), as were those who changed from at least one abnormality to two abnormalities (HR: 1.48, 95% CI: 1.02–2.15).ConclusionChanges in IFG and borderline high LDL-C status alter the risk of CVD and its subtype, implying that it is important to focus on such individuals for the prevention and control of CVD.

Paradoxical Association Between Baseline Apolipoprotein B and Prognosis in Coronary Artery Disease: A 36,460 Chinese Cohort Study.

BackgroundApolipoprotein B (ApoB) and low-density lipoprotein cholesterol (LDL-C) were identified targets for blood lipid management among coronary artery disease (CAD) patients. However, previous studies reported an inverse correlation between baseline LDL-C concentration and clinical outcomes. This study aims to explore the definite association between baseline ApoB and long-term prognosis.MethodsA total of 36,460 CAD patients admitted to Guangdong Provincial People's Hospital were enrolled and categorized into two groups: high ApoB (≥65 mg/dL) group and low ApoB (<65 mg/dL) group. The association between baseline ApoB and long-term all-cause mortality was evaluated by the Kaplan-Meier method, Cox regression analyses and restricted cubic splines.ResultsThe overall mortality was 12.49% (n = 4,554) over a median follow-up period of 5.01 years. Patients with low baseline ApoB levels were paradoxically more likely to get a worse prognosis. There was no obvious difference in risk of long-term all-cause mortality when only adjusted for age, gender, and comorbidity (aHR: 1.07, 95% CI: 0.99–1.16). When CONUT and total bilirubin were adjusted, the risk of long-term all-cause mortality would reduce in the low-ApoB (<65 mg/dL) group (aHR: 0.86, 95% CI: 0.78–0.96). In the fully covariable-adjusted model, patients in the ApoB <65 mg/d group had a 10.00% lower risk of long-term all-cause mortality comparing to patients with ApoB ≥65 mg/dL (aHR: 0.90; 95% CI:0.81–0.99).ConclusionThis study found a paradoxical association between baseline ApoB and long-term all-cause mortality. Malnutrition and bilirubin mainly mediate the ApoB paradox. Increased ApoB concentration remained linearly associated with an increased risk of long-term all-cause mortality.

Association between baseline ldl-c and prognosis among patients with coronary artery disease and advanced kidney disease

Abstract Background Lower low-density lipoprotein cholesterol (LDL-C) is significantly associated with improved prognosis in patients with coronary artery disease (CAD). However, LDL-C reduction does not decrease all-cause mortality among CAD patients when renal function impairs. There are currently no studies examining the association of low baseline LDL-C concentration (&amp;lt;1.8 mmol/L) with mortality among patients with CAD and advanced kidney disease (AKD). We aimed to evaluate prognostic value of low baseline LDL-C level for all-cause death in these patients. Methods In this observational study, 803 CAD patients complicated with AKD (eGFR &amp;lt;30 mL/min/1.73 m 2) were enrolled between January 2008 to December 2018. Patients were divided into two groups (LDL-C &amp;lt;1.8 mmol/L, n=138; LDL-C ≥1.8 mmol/L, n=665). We used Kaplan-Meier methods and Cox regression analyses to assess the association between baseline low LDL-C levels and long-term all-cause mortality. Results Among 803 participants (mean age 67.4 years; 68.5% male), there were 315 incidents of all-cause death during a median follow-up of 2.7 years. Kaplan–Meier analysis showed that low LDL-C levels were associated with worse prognosis. After adjusting for full 24 confounders (e.g., age, diabetes, heart failure, and dialysis, etc.), multivariate Cox regression analysis revealed that lower LDL-C level (&amp;lt;1.8mmol/L) was significantly associated with higher risk of all-cause death (adjusted HR, 1.38; 95% CI, 1.01–1.89). Conclusions Our data demonstrated that among patients with CAD and AKD, a lower baseline LDLC level (&amp;lt;1.8mmol/L) did not present a higher survival rate but was related to a worse prognosis, suggesting a cautiousness of too low LDL-C levels among patients with CAD and AKD. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This study was supported by the National Natural Science Foundation of China (Grant No. 81670339 and Grant No. 81970311), Cardiovascular Research Foundation Project of the Chinese Medical Doctor Association (SCRFCMDA201216) and Beijing Lisheng Cardiovascular Health Foundation (LHJJ20141751).

Dianas terapéuticas en el tratamiento de las dislipemias: de las estatinas a los inhibidores de PCSK9. Necesidades no cubiertas

The use of low-density lipoprotein cholesterol (LDLc)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statins represent the cornerstone of lipid-lowering treatment and substantially decreases cardiovascular morbidity and mortality. However, there are still unmet clinical needs in the management of dyslipidaemia. Indeed, it is difficult to achieve LDLc targets in many patients, particularly in those at high/very high cardiovascular risk and in those with very high baseline LDLc concentrations. Moreover, a considerable proportion of patients are unable to tolerate maximum statin doses, mostly due to muscle-related adverse effects. In the present narrative review, a summary is presented on the current knowledge on the effects of the different cholesterol-lowering drugs, including those recently approved by European and American regulatory agencies, on lipid profile, and on cardiovascular risk. Since difficult-to-treat patients may benefit from new combination therapies as a result of the emergence of new drugs with clinical evidence, updates of the clinical guidelines would be recommended.

Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES.

Lowering of atherogenic lipoproteins, including low-density lipoprotein cholesterol (LDL-C), reduces the risk of ischemic stroke. However, concerns have been raised about very low LDL-C levels and a potential increased risk of hemorrhagic stroke. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, despite intensive statin therapy, targeting LDL-C levels of 25 to 50 mg/dL and avoiding sustained LDL-C <15 mg/dL. This prespecified analysis was designed to assess the effect of alirocumab on ischemic and hemorrhagic stroke. We hypothesized that for patients treated with alirocumab there would be a reduction in risk of ischemic stroke without increasing hemorrhagic stroke, irrespective of baseline LDL-C and of history of cerebrovascular disease. Patients were randomized to alirocumab or placebo 1 to 12 months after acute coronary syndrome. The risk of nonfatal or fatal ischemic or hemorrhagic stroke was evaluated, stratified by baseline LDL-C concentration and history of cerebrovascular disease. A potential association of very low achieved LDL-C with alirocumab treatment at month 4 and subsequent hemorrhagic stroke was assessed. Median follow-up was 2.8 years. In total, 263 ischemic and 33 hemorrhagic strokes occurred. Alirocumab reduced the risk of any stroke (HR, 0.72 [95% CI, 0.57-0.91]) and ischemic stroke (HR, 0.73 [95% CI, 0.57-0.93]) without increasing hemorrhagic stroke (HR, 0.83 [95% CI, 0.42-1.65]). In total, 7164 (37.9%), 6128 (32.4%), and 5629 (29.7%) patients had a baseline LDL-C of <80, 80 to 100, and >100 mg/dL, respectively. The treatment effect on stroke appeared numerically greater for patients with higher baseline LDL-C, but there was no formal evidence of heterogeneity (Pinteraction=0.31). The effect of alirocumab on stroke was similar among 944 patients (5.0%) with a history of previous cerebrovascular disease and among those without a history of cerebrovascular disease (Pinteraction=0.37). There was no apparent adverse relation between lower achieved LDL-C and incidence of hemorrhagic stroke in the alirocumab group. In patients with recent acute coronary syndrome and dyslipidemia despite intensive statin therapy, alirocumab decreased the risk of stroke, irrespective of baseline LDL-C and history of cerebrovascular disease, over a median follow-up of 2.8 years. Furthermore, risk of hemorrhagic stroke did not depend on achieved LDL-C levels within the alirocumab group. URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402.

P645Low levels of low density lipoprotein cholesterol and cardiovascular, cancer and all-cause mortality outcomes

Abstract Aims The effect of low concentrations of low density lipoprotein-cholesterol (LDL-C) on cardiovascular disease (CVD) cancer and all-cause mortality is still controversial. In a large, young, well characterized, relatively healthy occupational cohort (Kangbuk Samsung health study, KSHS), we tested associations between low levels of LDL-C concentration, and CVD, cancer and all- cause mortality. To validate these associations, we analyzed data from another cohort (Korean genome and epidemiology study, KoGES). Methods and results 347,971 subjects in KSHS (mean age 39.6 years, 57.4% men) were studied over a mean follow up of 5.64±3.27 years. All subjects treated with any lipid lowering therapy were excluded. After excluding the data from subjects who died during the first 3 years of follow up, five groups were defined according to baseline LDL-C concentration (&lt;70, 70–99, 100–129, 130–159, ≥160 mg/dL). Hazard ratios (HR and 95% CIs) for all-cause mortality, CVD and cancer mortality were estimated using Cox proportional hazards models. In the KoGES validation cohort, 182,943 subjects (mean age 53.1 years, 34.6% men) were studied over a mean follow up of 8.57±2.59 years with same methods. 2,028 deaths (897 from cancer and 282 from CVD) occurred during follow-up in KSHS. The lowest LDL-C group (LDL&lt;70 mg/dL) had a higher risk of all-cause mortality (HR 1.95, 1.55–2.47), CVD mortality (HR 2.02, 1.11–3.64) and cancer mortality (HR 2.06, 1.46–2.90) compared to the reference group (LDL 120–139 mg/dL). This association was more prominent in men than in women. In the validation cohort, 2,338 deaths (1,823 from cancer and 199 from CVD) occurred during follow-up. The lowest LDL-C group (LDL&lt;70 mg/dL) had a higher risk of all-cause mortality (HR 1.81, 1.44–2.28). Men in the lowest LDL-C group had a higher risk of CVD mortality (HR 3.15, 1.21–8.21) and cancer mortality (1.34, 0.99–1.82) in the KoGES cohort. Conclusions Low levels of LDL-C concentration are strongly and independently associated with increased risk of cancer, CVD and all-cause mortality especially in men.

Low Levels of Low-Density Lipoprotein Cholesterol and Mortality Outcomes in Non-Statin Users.

We aimed to test the association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular disease (CVD), cancer, and all-cause mortality in non-statin users. A total of 347,971 subjects in Kangbuk Samsung Health Study (KSHS.57.4% men, mean follow up: 5.64 ± 3.27 years) were tested. To validate these associations, we analyzed data from another cohort (Korean genome and epidemiology study, KoGES, 182,943 subjects). All subjects treated with any lipid-lowering therapy and who died during the first 3 years of follow up were excluded. Five groups were defined according to baseline LDL-C concentration (<70, 70–99, 100–129, 130–159, ≥160 mg/dL). A total of 2028 deaths occurred during follow-up in KSHS. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.95, 1.55–2.47), CVD mortality (HR 2.02, 1.11–3.64), and cancer mortality (HR 2.06, 1.46–2.90) compared to the reference group (LDL 120–139 mg/dL). In the validation cohort, 2338 deaths occurred during follow-up. The lowest LDL-C group (LDL < 70 mg/dL) had a higher risk of all-cause mortality (HR 1.81, 1.44–2.28) compared to the reference group. Low levels of LDL-C concentration are strongly and independently associated with increased risk of cancer, CVD, and all-cause mortality. These findings suggest that more attention is needed for subjects with no statin-induced decrease in LDL-C concentrations.

Persistent Safety and Efficacy of Evolocumab in Patients with Statin Intolerance: a Subset Analysis of the OSLER Open-Label Extension Studies.

Evolocumab reduced low-density lipoprotein cholesterol (LDL-C) in 12-week trials in statin-intolerant patients (GAUSS-1 and GAUSS-2); however, the persistence of efficacy during longer-term treatment is unknown. This subset analysis of the open-label extension studies (OSLER-1 and OSLER-2) aimed to evaluate the safety and efficacy of evolocumab up to 2years in statin-intolerant patients. Patients who completed GAUSS-1 and GAUSS-2 were enrolled in the OSLER studies and rerandomized 2:1 to evolocumab (140mg biweekly or 420mg monthly) plus standard of care (SOC) or SOC during year 1, and thereafter, evolocumab plus SOC. A total of 382 statin-intolerant patients who completed the GAUSS-1 and GAUSS-2 parent studies were enrolled and rerandomized into the OSLER studies. After year 1, 246 (98%) patients randomized to evolocumab plus SOC and 124 (95%) on SOC during year 1 remained in the OSLER studies; after year 2, 364 (95%) remained on study. Mean parent study baseline LDL-C concentration was 4.97-5.02mmol/L (192-194mg/dL). The median percentage reduction from baseline in LDL-C was 13% for SOC and 57% for evolocumab plus SOC at year 1, and 59% for evolocumab plus SOC at year 2. The patient incidence of muscle-related adverse events during year 1 in the SOC and evolocumab plus SOC groups was 16% and 14%, respectively, and 11% for evolocumab plus SOC at year 2. No patient discontinued the study due to adverse events. Evolocumab plus SOC was persistently safe, tolerable, and efficacious for up to 2years in statin-intolerant patients.

Blood cholesterol in late-life and cognitive decline: a longitudinal study of the Chinese elderly

BackgroundPrevious studies regarding the lipid-cognition relation in older adults are limited and have generated mixed results. We thus examined whether higher blood cholesterol concentrations were associated with faster cognitive decline in a community-based longitudinal study of Chinese elderly.MethodsThe study included 1,159 Chinese adults aged over 60 years (women: 48.7%, mean age: 79.4 years), who were free of dementia, Parkinson disease and stroke at the baseline. Blood concentrations of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), were assessed at the baseline. Global cognitive functions were assessed using the Chinese Mini-Mental State Examination (MMSE) at in 2009, 2012 and 2014. Association between blood cholesterol and repeated cognitive function was analyzed with linear mixed models, adjusting for sociodemographic information, behavior and lifestyle, depression symptoms, physical examination, hypertension, and laboratory indexes.ResultsHigher baseline TC and LDL-C concentrations were significantly associated with greater cognitive decline. Adjusted mean difference in cognitive decline rate, comparing two extreme quartiles, was 0.28 points (MMSE score) per year (95% confident interval (CI): -0.54,–0.02; P-trend = 0.005) for TC and 0.42 points per year (95% CI: -0.69, -0.16; P-trend = 0.006) for LDL-C. In a subgroup analysis, the associations between all lipids and cognitive decline appeared to be more pronounced among individuals aged 100 years or older (n = 90), relative to others.ConclusionsHigher blood concentrations of TC and LDL-C in late-life were associated with faster global cognitive decline.

Population pharmacodynamic analysis of LDL-cholesterol lowering effects by statins and co-medications based on electronic medical records.

HMG-CoA reductase inhibitors are available for use in low density lipoprotein-cholesterol (LDL-C) lowering therapy. The purposes of this study were to develop a population pharmacodynamic (PPD) model to describe the time course for the LDL-C lowering effects of statins and assess the efficacy of combination therapy based on electronic medical records. Patient backgrounds, laboratory tests and prescribed drugs were collected retrospectively from electronic medical records. Patients who received atorvastatin, pitavastatin or rosuvastatin were enrolled. A physiological indirect response model was used to describe the changes observed in LDL-C concentrations. The PPD analysis was performed using nonmem 7.2.0 with the first order conditional estimation method with interaction (FOCE-INTER). An indirect response Imax model, based on the 2863 LDL-C concentrations of 378 patients, successfully and quantitatively described the time course for the LDL-C lowering effects of three statins. The combination of ezetimibe, a cholesterol absorption inhibitor, decreased the LDL synthesis rate (Kin ) by 10.9%. A simulation indicated that the combined treatment of ezetimibe with rosuvastatin (2.5 mg day(-1) ) led to superior clinical responses than those with high doses of rosuvastatin (5.0 mg day(-1) ) monotherapy, even in patients with higher baseline LDL-C concentrations prior to the treatment. A newly constructed PPD model supported previous evidence for the beneficial effects of ezetimibe combined with rosuvastatin. In addition, the established framework is expected to be applicable to other drugs without pharmacokinetic data in clinical practice.

The case for more intensive use of statins.

The case for more intensive use of statins.

Evidence-Based Medicine and the Selection of Lipid-Lowering Therapy in Type 2 Diabetes

Evidence-based medicine is defined as “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients” [1]. Evidence-based medicine has changed the way in which guidelines and clinical recommendations are prepared. A premise of the strategy is to use the evidence that is most likely to be free of bias and representative of the clinical scenario that physicians will confront. The main sources are randomized controlled trials, meta-analyses, and systematic reviews. However, the end result of the process is heavily dependent on the proper definition of the population, the intervention, the comparator, and the outcome. Despite the application of strict methodological standards, the results of trials are never absolutely certain, as even the best trials have various limitations. In addition, the employment of the conclusion in populations different from those originally studied is a complex process. Furthermore, the utilization of cost-effectiveness analysis techniques requires experience, clinical judgment, and common sense. Lipid-lowering therapy is a core component in the treatment of type 2 diabetes. Within a decade, clinical guidelines have moved from recommending the achievement of lowdensity lipoprotein (LDL) cholesterol goals to the systematic use of statins for high-risk cases, regardless of the baseline LDL cholesterol concentration [2]. Evidence-based medicine has played a major role in this change. A critical analysis of the evidence supporting the selection of the LDL cholesterol treatment goals proved that LDL cholesterol thresholds were not chosen based on a randomized controlled study or a meta-analysis. Meta-analyses showed that statins reduce the incidence of cardiovascular events in patients with diabetes, and the number of patients needed to treat to prevent one event was determined mainly by the magnitude of the cardiovascular risk. Moreover, statins reduced the incidence of cardiovascular events even in subjects with LDL cholesterol concentrations below the target levels. These conclusions could not have been reached and properly supported without large-scale multicenter studies and their cumulative analysis using the principles of evidence-based medicine [3, 4]. However, additional research is needed to generate the evidence required to support recommendations applicable for the full spectrum of patients included in the term “type 2 diabetes.” Although type 2 diabetes is considered as a coronary heart disease equivalent [5], type 2 diabetes includes a wide range of incidence rates of cardiovascular events. Additional efforts are needed to support the clinical decisions applicable in young adults with type 2 diabetes or even in conditions with a high risk for developing diabetes. Earlyonset type 2 diabetes is a common variant of the disease in non-white populations; it has been under-represented in the majority of studies. Since the incidence of cardiovascular outcomes is lower in this group compared to that observed in older cases [6], the length of follow-up in the currently C. A. Aguilar-Salinas (*) : R. Mehta Departamento de Endocrinologia y Metabolismo, Instituto Nacional de Ciencias Medicas y Nutricion, Vasco de Quiroga 15, Mexico City 14000, Mexico e-mail: caguilarsalinas@yahoo.com

Polymorphisms in apolipoprotein E and apolipoprotein A-V do not influence the lipid response to rosuvastatin but are associated with baseline lipid levels in Chinese patients with hyperlipidemia

Apolipoprotein E (APOE) and APOA5 play an important role in lipid transport and metabolism. Polymorphisms in APOE and APOA5 have been reported to be associated with baseline lipid levels and lipid responses to statins in different populations. This study evaluated associations of APOE and APOA5 genotype with baseline lipid levels and response to rosuvastatin in Chinese patients with hyperlipidemia. A total of 386 patients with hyperlipidemia, including 166 with familial hypercholesterolemia (FH), with good adherence to rosuvastatin 10 mg daily, were genotyped for the APOE e2/e3/e4 and APOA5 -1131T>C polymorphisms. The lipid profile was examined before and after at least 4 weeks of therapy. In patients without FH, there was a trend that e2 carriers had lower and those e4 carriers had higher low-density lipoprotein cholesterol (LDL-C) levels than subjects with the e3/e3 genotype (P> .05). However, an opposite significant association between APOE polymorphisms and LDL-C levels was observed in patients with FH (P= .005). The APOA5 -1131C variant allele was associated with increased baseline triglycerides levels in both patients with and without FH (P < .005 for both). Neither APOE nor APOA5 polymorphisms showed a significant effect on the lipid responses to rosuvastatin. This study demonstrates different associations of APOE polymorphisms with baseline LDL-C concentrations in Chinese patients with or without FH and confirms the strong relation between the APOA5 polymorphism and baseline triglyceride levels. These findings expand our knowledge on the genetic determinants of lipids and lipid response to rosuvastatin in Chinese patients with hyperlipidemia.

Nut Consumption and Blood Lipid Levels

Epidemiological studies have consistently associated nut consumption with reduced risk for coronary heart disease. Subsequently, many dietary intervention trials investigated the effects of nut consumption on blood lipid levels. The objectives of this study were to estimate the effects of nut consumption on blood lipid levels and to examine whether different factors modify the effects. We pooled individual primary data from 25 nut consumption trials conducted in 7 countries among 583 men and women with normolipidemia and hypercholesterolemia who were not taking lipid-lowering medications. In a pooled analysis, we used mixed linear models to assess the effects of nut consumption and the potential interactions. With a mean daily consumption of 67 g of nuts, the following estimated mean reductions were achieved: total cholesterol concentration (10.9 mg/dL [5.1% change]), low-density lipoprotein cholesterol concentration (LDL-C) (10.2 mg/dL [7.4% change]), ratio of LDL-C to high-density lipoprotein cholesterol concentration (HDL-C) (0.22 [8.3% change]), and ratio of total cholesterol concentration to HDL-C (0.24 [5.6% change]) (P < .001 for all) (to convert all cholesterol concentrations to millimoles per liter, multiply by 0.0259). Triglyceride levels were reduced by 20.6 mg/dL (10.2%) in subjects with blood triglyceride levels of at least 150 mg/dL (P < .05) but not in those with lower levels (to convert triglyceride level to millimoles per liter, multiply by 0.0113). The effects of nut consumption were dose related, and different types of nuts had similar effects on blood lipid levels. The effects of nut consumption were significantly modified by LDL-C, body mass index, and diet type: the lipid-lowering effects of nut consumption were greatest among subjects with high baseline LDL-C and with low body mass index and among those consuming Western diets. Nut consumption improves blood lipid levels in a dose-related manner, particularly among subjects with higher LDL-C or with lower BMI.

Long-term persistence with statin treatment in a not-for-profit health maintenance organization: A population-based retrospective cohort study in Israel

Background: Although discontinuing lipid-lowering treatment can cause preventable morbidity, previously published reports have indicated considerable variability in persistence with statin use. In general, such reports have been limited by short follow-up periods and modest study populations.Objectives: The aims of this study were to assess long-term persistence with statins and to identify the sociodemographic, clinical, and pharmacotherapy-related factors associated with long-term persistence with statin treatment in first-time users in Israel.Methods: This retrospective cohort study used data from adult enrollees of a not-for-profit health maintenance organization and from death certificates in Israel. Eligible patients initiated statin treatment between 1998 and 2006. Persistence was assessed separately in patients with no indication of a cardiovascular disease (primary prevention) or coronary artery disease (secondary prevention). Treatment persistence and proportion of days covered (PDC) were measured using the interval between the date of the first prescription dispensation (index date) and the point of discontinuation.Results: Data from 229,918 patients were included (primary prevention, 136,052; secondary prevention, 93,866). The PDC was significantly higher in the secondary-prevention group compared with the primaryprevention group (59% vs 45%; P < 0.001). In both cohorts, persistence continually diminished from the index date through follow-up, with ≥75% of patients discontinuing statin therapy by 2 years. Baseline predictors of discontinuation of statin treatment included younger age, female sex, lower socioeconomic status (SES), absence of diabetes or hypertension, no concurrent use of β-blockers or angiotensin-converting enzyme inhibitors, and less health service utilization. New immigrants and patients in the primary-prevention group who had a baseline low-density lipoprotein cholesterol concentration <130 mg/dL were at increased risk for treatment discontinuation.Conclusion: In this study in these patients receiving first-time statin treatment in Israel, we found poor persistence with statins among both the primary- and secondary-prevention cohorts, especially among new immigrants and patients with low SES despite low out-of-pocket prescription costs and free access to health services.

Cost Effectiveness of Ezetimibe in Patients with Cardiovascular Disease and Statin Intolerance or Contraindications

To evaluate the cost effectiveness of long-term ezetimibe monotherapy in patients with established cardiovascular disease (CVD) who do not tolerate statins or in whom they are contraindicated. A Markov model was used to estimate the potential costs and benefits associated with ezetimibe monotherapy compared with no treatment. The benefits associated with ezetimibe treatment were informed by a systematic review of clinical evidence and a published relationship linking changes in low-density lipoprotein cholesterol (LDL-C) levels to cardiovascular events. In the absence of data from clinical outcome trials, surrogate endpoints such as changes in lipid levels were used as indicators of clinical outcomes. A meta-analysis of seven placebo-controlled trials included in the review showed that ezetimibe was associated with a statistically significant mean reduction (from baseline to endpoint) in LDL-C of 18.56% (95% CI -19.68, -17.44; p < 0.00001) compared with placebo. Using 10,000 Monte Carlo simulations, it is estimated that ezetimibe monotherapy would prevent an average of 49 nonfatal myocardial infarctions, 11 nonfatal strokes, and 37 cardiovascular deaths in a cohort of 1,000 patients aged 55 years with a baseline LDL-C concentration of 4.0 mmol/L. Events avoided provide an additional 211 quality-adjusted life-years (QALYs) over the 45 years modeled. With a mean incremental cost of pound 4,861,000 (year 2006 value), the discounted cost per QALY is pound 23,026 (Jackknife CI 22 979, 23 074). The model is reasonably robust to variations in key parameters. Incremental cost-effectiveness ratios fall below pound 20,000 per QALY for cohorts with baseline LDL-C values >4.5 mmol/L. Ezetimibe monotherapy compared with no treatment is a cost-effective alternative for individuals with a history of CVD and high LDL-C levels, who do not tolerate statins or in whom they are contraindicated.

Phytosterols dissolved in diacylglycerol oil reinforce the cholesterol-lowering effect of low-dose pravastatin treatment

Background and aims Dietary therapy using phytosterols can reinforce statin treatment; however the value of a low-dose combination of those agents remains to be investigated. Plant sterols (PS), dissolved in diacylglycerol (DAG) oil, (PS/DAG) can be effective at a relatively low dose. The objective of the present study was to examine the effect of PS/DAG oil on blood cholesterol concentrations in hypercholesterolemic outpatients on low-dose pravastatin (10 mg/day). Methods and results The patients ( n = 61) were randomly assigned to one of three groups, who consumed TAG (control), DAG or PS/DAG oil. The average intake of PS from the PS/DAG oil during the test period was significantly higher than that for TAG and DAG oils (502 vs. 49 and 38 mg/day, P < 0.05). Significant cholesterol-lowering effects from the baseline were observed in the case of the PS/DAG oil treatment alone. Changes in low-density lipoprotein (LDL) cholesterol were inversely correlated with baseline serum campesterol concentrations ( r = −0.560, P < 0.05), but not baseline LDL cholesterol concentrations. In addition, serum apolipoprotein B concentrations were reduced to a greater extent in subjects with high versus low levels of baseline campesterol (−13.2 mg/dL vs. −3.1 mg/dL, P < 0.05). Furthermore, there was a mild, but significant reduction in serum lipoprotein (a) concentration from the baseline (−5.9 mg/dL), which was correlated with the reduction in serum apolipoprotein B concentration ( r = 0.596, P < 0.05). Conclusion A low-dose combination of PS/DAG oil and pravastatin may be a useful strategy for further ameliorating blood cholesterol and lipoprotein (a) concentrations for hypercholesterolemic patients with a low response to pravastatin.

Elevation of Low-Density Lipoprotein Cholesterol Concentration with Over-the-Counter Fish Oil Supplementation

To report a case of elevated low-density lipoprotein cholesterol (LDL-C) concentration in a patient taking fish oil supplements for hypertriglyceridemia. A 63-year-old white woman had been taking 2.7 g of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily in 9 g of over-the-counter (OTC) fish oil capsules for triglyceride lowering. Prior to the adverse event, she had baseline fasting triglyceride (TG) and LDL-C concentrations of 278 mg/dL and 106 mg/dL, respectively. After 6 weeks of treatment with fish oil, fasting TG levels decreased by 47.5% (-132 mg/dL) and the LDL-C increased by 75% (+80 mg/dL). Discontinuation of therapy for 6 weeks resulted in TG returning to high concentrations (334 mg/dL; +56 mg/dL change from baseline) and LDL-C decreasing toward baseline (143 mg/dL; +37 mg/dL change from baseline). Fish oil, an omega-3 polyunsaturated fatty acid, consists of EPA and DHA. EPA and DHA are thought to inhibit the synthesis of triglycerides in the liver. Type IV dyslipidemic patients may develop increased LDL-C levels while taking fish oil to lower triglycerides due to possible down-regulation of the LDL-C receptor in hepatic cells and formation of larger LDL particles. Use of the Naranjo probability scale indicates a probable relationship between elevations in LDL-C from baseline and initiation of fish oil treatment for hypertriglyceridemia. It is unknown whether any component within this particular product could have contributed to such an unusual elevation in LDL-C. This case documents a much higher LDL-C elevation associated with OTC fish oil supplementation than has been previously identified in the literature. Healthcare providers should be advised that LDL-C levels may increase with use of OTC fish oil and should monitor patients periodically for such elevations. The significance of this increase on clinical outcomes is not known.