Changes In High-density Lipoprotein Cholesterol Levels Research Articles

High-density lipoprotein cholesterol trajectory and new-onset metabolic dysfunction-associated fatty liver disease incidence: a longitudinal study

BackgroundAlthough high-density lipoprotein cholesterol (HDL-C) exerts a significant influence on the development of metabolic dysfunction-associated fatty liver disease (MAFLD), the association of dynamic changes in HDL-C levels with the risk of MAFLD remains unclear. Thus, the aim of the current study was to explore the association between the changing trajectories of HDL-C and new-onset MAFLD. The findings of this study may provide a theoretical basis for future personalized intervention and prevention targeting MAFLD.MethodsA total of 1507 participants who met the inclusion criteria were recruited from a community-based physical examination population in Nanjing, China from 2017 to 2021. Group-based trajectory models were constructed to determine the heterogeneous HDL-C trajectories. The incidence of MAFLD in each group in 2022 was followed up, and the Cox proportional hazards regression model was applied to investigate the associations between different HDL-C trajectories and the risk of new-onset MAFLD.ResultsThe incidences of MAFLD in the low-stable, moderate-stable, moderate-high-stable, and high-stable groups of HDL-C trajectory were 26.5%, 13.8%, 7.2% and 2.6%, respectively. The incidence rate of MAFLD in the order of the above trajectory groups exhibited a decreasing trend (χ2 = 72.55, Ptrend<0.001). After adjusting for confounders, the risk of MAFLD onset in HDL-C low-stable group was still 5.421 times (95%CI: 1.303–22.554, P = 0.020) higher than that in the high-stable group. Subgroup analyses of the combined (moderate high-stable and high-stable groups combined), moderate-stable and low-stable groups showed that sex, age, and overweight/obesity did not affect the association between HDL-C trajectory and MAFLD risk.ConclusionsPersistently low HDL-C level is a risk factor for the onset of MAFLD. Long-term monitoring of HDL-C levels and timely intervention for those experiencing persistent declines are crucial for early prevention of MAFLD.

Weight loss benefits on HDL cholesterol persist even after weight regaining.

Obesity-related comorbidities may relapse in patients with weight regain after bariatric surgery. However, HDL cholesterol (HDLc) levels increase after surgery and seem to remain stable despite a gradual increase in BMI. The aim of this study is to analyze the effects of weight regain after bariatric surgery on HDL cholesterol. This is a retrospective, observational, cohort study in patients who underwent bariatric surgery in the Hospital de la Santa Creu i Sant Pau (Barcelona) between 2007 and 2015. Patients without at least 5 years of follow-up after surgery, under fibrate treatment, and those who required revisional surgery were excluded from the analysis. Data were collected at baseline, 3 and 6 months after surgery, and then annually until 5 years post-surgery. One hundred fifty patients were analyzed. 93.3% of patients reached > 20% of total weight loss after surgery. At 5th year, 37% of patients had regained > 15% of nadir weight, 60% had regained > 10%, and 22% had regained < 5% of nadir weight. No differences were found in HDLc levels between the different groups of weight regain, nor in the % of change in HDLc levels between nadir weight and 5 years, or in the proportion of patients with normal HDLc concentrations either. HDLc remains stable regardless of weight regain after bariatric surgery.

A population-based cohort study of longitudinal change of high-density lipoprotein cholesterol impact on gastrointestinal cancer risk

High-density Lipoprotein Cholesterol (HDL-C) levels have been associated with cancer. In this observational population-based cohort study using data from the Korean National Health Insurance Service system, we investigate the impact of longitudinal changes in HDL-C levels on gastrointestinal cancer risk. Individuals who underwent health examinations in 2010 and 2014 were followed-up through 2021. Among 3.131 million, 40696 gastric, 35707 colorectal, 21309 liver, 11532 pancreatic, 4225 gallbladder, and 7051 biliary cancers are newly detected. The persistent low HDL-C group increases the risk of gastric, liver, and biliary cancer comparing to persistent normal HDL-C group. HDL-C change from normal to low level increases the risk for gastric, colorectal, liver, pancreatic, gallbladder, and biliary cancers. Effects of HDL-C change on the gastrointestinal cancer risk are also modified by sex and smoking status. HDL-C changes affect the gastric and gallbladder cancer risk in age ≥60 years and the pancreatic and biliary cancer risk in age <60 years. Here, we show persistently low HDL-C and normal-to-low HDL-C change increase gastrointestinal cancer risk with discrepancies by sex, smoking status, and age.

Cardiorespiratory fitness and metabolic risk in Chinese population: evidence from a prospective cohort study

BackgroundStudies on the association between estimated cardiorespiratory fitness (CRF) and changes in metabolic risk in the Chinese population are limited. This study aims to examine the associations between CRF and changes in metabolic risk.Subjects and methodsWe included 4,862 and 2,700 participants recruited from 28 provinces in the China Health and Retirement Longitudinal Study (CHARLS) in the baseline (Wave 1) and follow-up (Wave 4) analyses, respectively. CRF was calculated using sex-specific longitudinal non-exercise equations. Metabolic indicators included systolic blood pressure (SBP), diastolic blood pressure (DBP), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and fasting plasma glucose (FPG) levels. The metabolic score was calculated as the number of changes in the above metabolic indicators above the 75th percentile of the distribution of changes (equal to or below the 25th percentile for HDL-C).ResultsIn the baseline analysis, CRF was negatively associated with SBP, DBP, TG, and FPG, and positively correlated with HDL-C after adjusting for age, smoking status, and drinking status (all P < 0.0001) in both males and females. In the follow-up analysis, higher baseline CRF was significantly related to a decrease in SBP, DBP, TG, FPG, and metabolic score (all P < 0.0005), and increased HDL-C (P < 0.0001) after further adjustment for corresponding baseline metabolic indicators. The associations remained significant after stratification by sex, except for the changes in HDL-C levels in females. Furthermore, improved CRF was associated with favorable changes in DBP, TG, HDL-C, FPG, and metabolic scores in all populations and males. Significant associations between changes in CRF and DBP, TG, and FPG levels were found in females.ConclusionHigher baseline CRF and improved CRF were associated with favorable changes in metabolic indicators.

Association Between Apolipoprotein C-3 SstⅠ Polymorphism and Serum Lipids in Patients With Gestational Diabetes Mellitus

To investigate the apolipoprotein C-3 (APOC3) gene Sst Ⅰ polymorphism and its relationship with changes in serum lipids in patients with gestational diabetes mellitus (GDM). A total of 630 pregnant women with GDM and 1027 normal pregnant controls were covered in the study. The genotype and allele frequencies of APOC3 Sst Ⅰ polymorphism were analyzed by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP). Total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and glucose (Glu) were measured by enzymatic methods. Plasma insulin (INS) was measured by chemiluminescence. Apolipoproteins A 1 (apoA1) and B (apoB) levels were measured by turbidimetric immunoassay. The allele frequencies of S1 and S2 of the APOC3 polymorphism at the SstⅠ locus were 0.704 and 0.296 in the GDM group and 0.721 and 0.279 in the control group, respectively. There was no significant difference in genotype frequency and allele frequency of APOC3 Sst Ⅰ polymorphism between the GDM and the control groups ( P>0.05). In the GDM group, those with S2S2 and S1S2 genotypes had higher plasma HDL-C levels and lower atherogenic index (AI) values than those with S1S1 genotype did, with the differences being statistically significant (all P<0.05). GDM patients were then divided into obesity and non-obesity subgroups. Further subgroup analysis showed that the association of APOC3 genotype with changes in HDL-C levels was observed only in obese GDM patients, while the association of APOC3 genotype with changes in AI values was observed in both obese and nonobese patients. In addition, in obese GDM patients, those with S2S2 genotype had significantly higher plasma TG levels than those with S1S1 and S1S2 genotypes did ( P<0.05 and P<0.01, respectively). In non-obese GDM patients, those with S2S2 genotype had significantly lower apoB/apoA1 ratio than S2S2 carriers did ( P<0.05). No genotype-related effect on lipid and apolipoprotein variations was evident in the normal controls. APOC3 Sst Ⅰ polymorphism in GDM patients is associated with HDL-C and TG levels as well as AI value and apoB/apoA1 ratio. The changes in lipid levels and apolipoprotein ratio showed BMI-dependent features. However, association between polymorphism at the locus and the development of GDM was not observed.

Association of changes in lipid levels with changes in vitamin D levels in a real-world setting

In clinical trials, vitamin D supplementation has been reported to reduce serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) but not high-density lipoprotein cholesterol (HDL-C). In this cohort study we evaluated the association between changes in vitamin D (25-hydroxyvitamin D) and changes in lipid levels in a real-world setting. Changes in lipid levels over a 1-year period were evaluated among individuals whose vitamin D levels increased (group 1) or decreased (group 2) by ≥ 10 ng/mL in year 2018 versus 2017 (cohort 1; n = 5580), in 2019 versus 2018 (cohort 2, n = 6057), or in 2020 versus 2019 (cohort 3, n = 7249). In each cohort, levels of TC, LDL-C, and TG decreased in group 1 and increased in group 2. Between-group differences in average changes in the 3 cohorts ranged from 10.71 to 12.02 mg/dL for TC, from 7.42 to 8.95 mg/dL for LDL-C, and from 21.59 to 28.09 mg/dL for TG. These differences were significant after adjusting for age, sex, race, education, body mass index, blood pressure, smoking status, geographical location, and baseline levels of vitamin D and lipids (P < 0.001). Changes in vitamin D levels were not significantly associated with changes in HDL-C levels.

Is residential greenness associated with dyslipidemia and lipid levels in Chinese rural-dwelling adults? The Henan rural cohort study.

Scarce epidemiologic research examined the associations between residential greenness and dyslipidemia or lipid levels in low/middle-income countries. Baseline statistics (2015-2017) of 39,259 rural-dwelling adults were obtained from a Chinese longitudinal study. The blood lipid level was measured utilizing an enzymatic assay method. According to the 2016 Chinese guidelines on dyslipidemia (revision), patients with dyslipidemia were defined. Participants' exposure to residential greenness was characterized by the satellite-based normalized difference vegetation index (NDVI). Mixed effects logistic regression and mixed effects linear regression were performed to assess the associations of residential greenness with dyslipidemia and lipid levels. The median (interquartile range, IQR) of 3-year average NDVI1000-m was 0.521 (0.089) units. Each IQR increase in NDVI1000-m was significantly linked with increased odds of hyperbetalipoproteinemia (OR = 1.33, 95%CI 1.21-1.46). The same increment in NDVI1000-m was associated with lower total cholesterol (TC) levels and increased low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) levels. For instance, the %changes in HDL-C levels was 0.71% (95%CI 0.17%-1.26%). The above relationships were partially mediated by reducing air pollution and lowering body mass index (BMI). Interaction effect analysis observed the greenness-lipid association was stronger in males than females (i.e., NDVI1000-m-TC association). Long-term exposure to residential greenness was associated with odds of dyslipidemia and lipid levels in Chinese rural-dwelling adults, particularly among males. Considering the cross-sectional study design, more longitudinal studies are needed to identify the causal associations.

Decreased Triglyceride and Increased Serum Lipoprotein Lipase Levels Are Correlated to Increased High-Density Lipoprotein-Cholesterol Levels after Laparoscopic Sleeve Gastrectomy

Introduction: Laparoscopic sleeve gastrectomy (LSG) significantly increases high-density lipoprotein cholesterol (HDL-C) and lipoprotein lipase (LPL) in pre-heparin serum (pre-heparin LPL levels). LPL is a regulator of serum triglyceride (TG) and HDL-C production; this may be the mechanism for HDL-C increase after LSG. This study aimed to elucidate the mechanism of increase in HDL-C levels by examining the relationship between changes in serum HDL-C levels and LPL after LSG. Methods: We retrospectively reviewed 104 obese patients, who underwent LSG and were followed up for 12 months. We analyzed the relationship between changes in serum HDL-C levels and various clinical parameters after LSG. Results: A significant decrease was observed in the patients’ BMI and serum TG levels after LSG. Conversely, HDL-C levels and pre-heparin LPL levels were significantly increased after LSG. Simple linear regression showed that changes in HDL-C levels were significantly correlated with total weight loss percentage, change in TG levels, abdominal fat areas, and pre-heparin LPL levels. Additionally, the multiple regression model revealed that a decrease in TG levels and an increase in pre-heparin LPL levels were correlated with increased HDL-C levels after LSG. Discussion/Conclusion: These results show that a decrease in TG levels and an increase in LPL are mechanisms for increased HDL-C levels after LSG.

Abstract P291: Effects of a Multidisciplinary Lifestyle Intervention on HDL Cholesterol Efflux Capacities in Adolescents With Obesity

Studies have suggested that a reduced HDL cholesterol efflux capacities (CECs) may be associated with an increased risk of coronary heart disease. However, only few studies have evaluated the impact of a lifestyle modification program on HDL-CEC in adolescents with obesity. The objective of this study was to determine if a 16-week lifestyle modification program would improve HDL-CECs in adolescents with obesity. Twenty-nine adolescents with obesity (16 boys and 13 girls) from 11 to 16 years of age (14.0 ± 1.6 years) were selected to participate in this study. The aim of the lifestyle modification program was to improve eating habits and physical activity levels. During the study, each adolescent was followed by a multidisciplinary team and trained three sessions per week for 16 weeks. The exercise program focused on endurance type activities and all training sessions were supervised and performed in groups. Anthropometric data, metabolic variables and HDL-CECs were measured at baseline and at the end of the intervention. HDL-CECs were measured using ( 3 H)cholesterol-labeled J774 macrophages and HepG2 hepatocytes. Body mass index (33.6 to 32.7 kg/m 2 , p&lt;0.0001) and waist circumference (102.4 to 100.5 cm, p=0.001) were significantly reduced after the 16-week intervention program. We also found a significant decrease in triglyceride concentrations (1.28 to 1.04 mmol/L, p=0.02) as well as in total cholesterol/HDL cholesterol ratio (4.42 to 3.91, p=0.0007) whereas HDL cholesterol levels increased (1.03 to 1.14 mmol/L, p=0.002). J774-HDL-CECs and HepG2-HDL-CECs were not significantly modified after the intervention. In order to further explore the impact of intervention-induced changes in HDL cholesterol levels on exercise-induced changes in HDL-CECs, adolescents were divided into two groups according to their changes in HDL cholesterol levels during the study (low or high intervention-induced changes in HDL cholesterol levels). Adolescents with low HDL cholesterol levels intervention-induced changes did not show an increased in HepG2-HDL-CECs. However, a significant improvement in HepG2-HDL-CEC after the intervention was observed among adolescents characterized by the highest intervention-induced changes in HDL cholesterol levels (p=0.03). Intervention-induced changes in HDL cholesterol levels were also significantly associated with changes in HepG2-HDL-CEC (r=0.55; p=0.002). No association was found between changes in HDL cholesterol levels and changes in J774-HDL-CECs. In conclusion, we found that a structured lifestyle modification program leads to significant improvements in cardiometabolic risk profile and in HepG2-HDL-CEC in obese adolescents.

Changes in High-Density Lipoprotein Cholesterol and Risks of Cardiovascular Events: A Post Hoc Analysis from the PICASSO Trial

Background and purposeWhether pharmacologically altered high-density lipoprotein cholesterol (HDL-C) affects the risk of cardiovascular events is unknown. Recently, we have reported the Prevention of Cardiovascular Events in Asian Patients with Ischaemic Stroke at High Risk of Cerebral Haemorrhage (PICASSO) trial that demonstrated the non-inferiority of cilostazol to aspirin and superiority of probucol to non-probucol for cardiovascular prevention in ischemic stroke patients (clinicaltrials.gov: NCT01013532). We aimed to determine whether on-treatment HDL-C changes by cilostazol and probucol influence the treatment effect of each study medication during the PICASSO study. MethodsOf the 1,534 randomized patients, 1,373 (89.5%) with baseline cholesterol parameters were analyzed. Efficacy endpoint was the composite of stroke, myocardial infarction, and cardiovascular death. Cox proportional hazards regression analysis examined an interaction between the treatment effect and changes in HDL-C levels from randomization to 1 month for each study arm. ResultsOne-month post-randomization mean HDL-C level was significantly higher in the cilostazol group than in the aspirin group (1.08 mmol/L vs. 1.00 mmol/L, P<0.001). The mean HDL-C level was significantly lower in the probucol group than in the non-probucol group (0.86 mmol/L vs. 1.22 mmol/L, P<0.001). These trends persisted throughout the study. In both study arms, no significant interaction was observed between HDL-C changes and the assigned treatment regarding the risk of the efficacy endpoint. ConclusionsDespite significant HDL-C changes, the effects of cilostazol and probucol treatment on the risk of cardiovascular events were insignificant. Pharmacologically altered HDL-C levels may not be reliable prognostic markers for cardiovascular risk.

The Effect of High Carbohydrate-to-fat Intake Ratios on Hypo-HDL-cholesterolemia Risk and HDL-cholesterol Levels over a 12-year Follow-up

Considering the strong correlation between carbohydrate and fat intake, we defined and assessed the association of the carbohydrate-to-fat ratio with the high-density lipoprotein cholesterol (HDL-c) level using 12-year follow-up data from the community-based cohort of the Korean Genome Epidemiology Study. We evaluated the long-term changes in HDL-c levels according to quartiles of carbohydrate-to-fat ratio using a mixed model. We also assessed the effect of the carbohydrate-to-fat ratio on the prevalence and incidence of hypo-HDL-cholesterolemia. Of 6,627 subjects, the prevalence of undiagnosed hypo-HDL-cholesterolemia at baseline was 35.3% (n = 2,339). Among the disease-free subjects, 56.8% developed hypo-HDL-cholesterolemia (incidence = 92/1,000 person-years). The prevalence and incidence of hypo-HDL-cholesterolemia were higher in females than in males. The highest carbohydrate-to-fat ratio quartile, which was characterized by high and low intake of carbohydrate and fat, was consistently associated with a lower HDL-c level during the 12-year follow up. Moreover, those in the highest quartile had a 1.14-fold greater risk of incident hypo-HDL-cholesterolemia than those in the lowest quartile, with a significant dose-response relationship. We found that high and low intake of carbohydrate and fat, respectively, was consistently associated with a low HDL-c level over a prolonged period. More research is needed to promote appropriate intake of macronutrients.

Cholesteryl Ester Transfer Protein Influences High-Density Lipoprotein Levels and Survival in Sepsis.

High-density lipoprotein (HDL) cholesterol (HDL-C) levels decline during sepsis, and lower levels are associated with worse survival. However, the genetic mechanisms underlying changes in HDL-C during sepsis, and whether the relationship with survival is causative, are largely unknown. We hypothesized that variation in genes involved in HDL metabolism would contribute to changes in HDL-C levels and clinical outcomes during sepsis. We performed targeted resequencing of HDL-related genes in 200 patients admitted to an emergency department with sepsis (Early Infection cohort). We examined the association of genetic variants with HDL-C levels, 28-day survival, 90-day survival, organ dysfunction, and need for vasopressor or ventilatory support. Candidate variants were further assessed in the VASST (Vasopressin versus Norepinephrine Infusion in Patients with Septic Shock Trial) cohort (n = 632) and St. Paul's Hospital Intensive Care Unit 2 (SPHICU2) cohort (n = 203). We identified a rare missense variant in CETP (cholesteryl ester transfer protein gene; rs1800777-A) that was associated with significant reductions in HDL-C levels during sepsis. Carriers of the A allele (n = 10) had decreased survival, more organ failure, and greater need for organ support compared with noncarriers. We replicated this finding in the VASST and SPHICU2 cohorts, in which carriers of rs1800777-A (n = 35 and n = 12, respectively) had significantly reduced 28-day survival. Mendelian randomization was consistent with genetically reduced HDL levels being a causal factor for decreased sepsis survival. Our results identify CETP as a critical regulator of HDL levels and clinical outcomes during sepsis. These data point toward a critical role for HDL in sepsis.

Therapy with cholesteryl ester transfer protein (CETP) inhibitors and diabetes risk

BackgroundCholesteryl ester transfer protein (CETP) inhibitors are a class of drugs that targets the CETP enzyme to significantly increase serum high-density lipoprotein cholesterol (HDL-C) and decrease low-density lipoprotein cholesterol (LDL-C) levels. As HDL-C has potential antidiabetic properties, and the beneficial effects of CETP drugs on glucose homoeostasis have not been sufficiently studied, the aims of this study were: (1) to evaluate the effect of CETP inhibitors on the incidence of diabetes; and (2) to assess the association between CETP inhibitor-induced changes in HDL-C levels and incidence of diabetes. MethodsA meta-analysis was performed of randomized controlled clinical trials of CETP inhibitor therapy, either alone or combined with other lipid-lowering drugs, reporting data from new cases of diabetes with a minimum of 6 months of follow-up, after searching the PubMed/MEDLINE, Embase and Cochrane Controlled Trials databases. A fixed-effects meta-regression model was then applied. ResultsFour eligible trials of CETP inhibitors, involving a total of 73,479 patients, were considered for the analyses, including 960 newly diagnosed cases of diabetes in the CTEP inhibitor group vs 1086 in the placebo group. CETP inhibitor therapy was associated with a significant 12% reduction in incidence of diabetes (OR: 0.88, 95% CI: 0.81–0.96; P=0.005). Assessment of the relationship between on-treatment HDL-C and the effect of CETP inhibitors showed a statistically non-significant trend (Z=–1.13, P=0.26). ConclusionCETP inhibitors reduced the incidence of diabetes. The improvement in glucose metabolism may have been related, at least in part, to the increase in HDL-C concentration.

Endothelial lipase genetic polymorphisms and the lipid-lowering response in patients with coronary artery disease on rosuvastatin.

BackgroundEndothelial lipase (EL) plays an important role in the regulation of lipid metabolism by reducing the high density lipoprotein cholesterol (HDL-C) levels and inducing the macrophages to take up native low density lipoprotein cholesterol (LDL-C). Our purpose was to investigate the impact of EL genetic polymorphisms on the lipid-lowering effects of rosuvastatin in Chinese coronary artery disease (CAD) patients.MethodsOne hundred twenty-one unrelated CAD patients, who underwent the treatment with rosuvastatin (10mg/day) for four to eight weeks, were enrolled in this study. Before and after treatment, serum lipids levels were measured. Genotypes of EL 2037T/C and 2237 G/A polymorphisms were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.ResultsPatients with EL 2037C allele (CC + CT) had significantly lower LDL-C levels than those with TT genotype (CC + CT: 2.60 ± 0.74 mmol/l; TT: 2.90 ± 0.87 mmol/l; P = 0.047), before rosuvastatin treatment. No significant differences between baseline lipid levels and the EL 2237G/A genotypes were observed. After treatment with rosuvastatin, total cholesterol (TC), high triglyceride (TG) and LDL-C levels decreased from baseline, on average, by 23.09 % (4.59 ± 0.96 mmol/l to 3.47 ± 0.83 mmol/l), 6.36 % (2.01 ± 1.18 mmol/l to 1.68 ± 1.16 mmol/l), 32.48 % (2.77 ± 0.83 mmol/l to 1.79 ± 0.62 mmol/l), respectively (all P < 0.05) in all patients. While changes in HDL-C levels did not reach statistical significance. No significant effects of EL 2037T/C or 2237G/A polymorphism were observed on lipid-lowering effects of rosuvastatin.ConclusionsEL 2037T/C and 2237 G/A polymorphisms might not affect the lipid-owing effects of rosuvastatin in Chinese CAD patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0295-3) contains supplementary material, which is available to authorized users.

Potent peroxisome proliferator-activated receptor-α agonist treatment increases cholesterol efflux capacity in humans with the metabolic syndrome.

Fibrate medications weakly stimulate the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) and are currently employed clinically in patients with dyslipidaemia. The potent and selective agonist of PPAR-α LY518674 is known to substantially increase apolipoprotein A-I (apoA-I) turnover without major impact on steady-state levels of apoA-I or high-density lipoprotein-cholesterol (HDL-C). We sought to determine whether therapy with a PPAR-α agonist impacts cholesterol efflux capacity, a marker of HDL function. Cholesterol efflux capacity was measured at baseline and after 8 weeks of therapy in a randomized, placebo-controlled trial involving participants with metabolic syndrome treated with either LY518674 100 μg daily (n = 13) or placebo (n = 15). Efflux capacity assessment was quantified using a previously validated ex vivo assay that measures the ability of apolipoprotein-B depleted plasma to mobilize cholesterol from macrophages. LY518674 led to a 15.7% increase from baseline (95% CI 3.3-28.1%; P = 0.02, P vs. placebo = 0.01) in efflux capacity. The change in apoA-I production rate in the active treatment arm was strongly linked to change in cholesterol efflux capacity (r = 0.67, P = 0.01). Potent stimulation of PPAR-α leads to accelerated turnover of apoA-I and an increase in cholesterol efflux capacity in metabolic syndrome patients despite no change in HDL-C or apoA-I levels. This finding reinforces the notion that changes in HDL-C levels may poorly predict impact on functionality and thus has implications for ongoing pharmacologic efforts to enhance apoA-I metabolism.

Clinical benefit from pharmacological elevation of high-density lipoprotein cholesterol: meta-regression analysis

ContextEpidemiological evidence that the risk of coronary heart disease is inversely associated with the level of high-density lipoprotein cholesterol (HDL-C) has motivated several phase III programmes with cholesteryl ester transfer...

Relation Between Paradoxical Decrease in High-Density Lipoprotein Cholesterol Levels After Statin Therapy and Adverse Cardiovascular Events in Patients With Acute Myocardial Infarction

Statin therapy moderately increases high-density lipoprotein cholesterol (HDL-C) levels. Contrary to this expectation, a paradoxical decrease in HDL-C levels after statin therapy is seen in some patients. We evaluated 724 patients who newly started treatment with statins after acute myocardial infarction (AMI). These patients were divided into 2 groups according to change in HDL-C levels between baseline and 6 to 9 months after initial AMI (ΔHDL). In total, 620 patients had increased HDL-C levels and 104 patients had decreased HDL-C levels. Both groups achieved follow-up low-density lipoprotein cholesterol levels <100 mg/dl. Adverse cardiovascular events (a composite of all-cause death, myocardial infarction, and stroke) have more frequently occurred in the decreased HDL group compared with the increased HDL group (15.4% vs 7.1%, p = 0.01). Multivariate analysis showed that decreased HDL, onset to balloon time, and multivessel disease were the independent predictors of adverse cardiovascular events (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.08 to 3.52; HR 1.05, 95% CI 1.01 to 1.09; and HR 2.08, 95% CI 1.22 to 3.56, respectively). In conclusion, a paradoxical decrease in serum HDL-C levels after statin therapy might be an independent predictor of long-term adverse cardiovascular events in patients with AMI.

Abstract 15089: Relationship between Paradoxical Decrease in High-Density Lipoprotein Cholesterol Levels Following Statin Therapy and Severe Cardiovascular Event in Patients with Acute Myocardial Infarction

Introduction: Low levels of high-density lipoprotein-cholesterol (HDL-C) are well known as an important risk factor for cardiovascular disease. In addition to lowering low-density lipoprotein-cholesterol (LDL-C), statin therapy increase HDL-C moderately. Contrary to this expectation, we sometimes have experience to paradoxical decrease in HDL-C following statin therapy. The purpose of our study was to analyze the relation between the paradoxical HDL-C decrease following statin therapy and adverse cardiovascular event in patients with acute myocardial infarction (AMI). Methods: Total of 724 AMI patients who started statins newly after initial coronary intervention were analyzed. Change in HDL-C levels (ΔHDL) was calculated as HDL-C levels at follow-up coronary angiography minus baseline HDL-C levels. These patients were divided into two groups according toΔHDL; 620 patients with ΔHDL≥0 (increase HDL group) and 104 patients with ΔHDL&lt;0 (decrease HDL group). Severe cardiovascular events were defined as all cause death, myocardial infarction and stroke. Results: Change in lipid profile and clinical outcomes were shown in table. Event-free survival curves for severe cardiovascular events appeared in figure. Multivariate analysis showed that decrease HDL and reperfusion time per hour were the independent predictor of severe cardiovascular event (hazard ratio [HR]: 2.138; 95% confidence interval [CI]: 1.106 - 4.132 and HR: 1.070; 95% CI: 1.026 - 1.117, respectively). Conclusions: Paradoxical decrease in serum HDL-C levels following statin therapy might be an independent predictor of long-term severe cardiovascular disease in patients with AMI.

Short-Term Effects of Extended-Release Niacin With and Without the Addition of Laropiprant on Endothelial Function in Individuals With Low HDL-C: A Randomized, Controlled Crossover Trial

BackgroundReduced plasma concentration of high-density lipoprotein cholesterol (HDL-C) is associated with vulnerability to oxidative stress and propensity to endothelial dysfunction. Niacin directly activates both GPR-109A in leukocytes and the heme oxygenase-1 pathway, promoting strong anti-inflammatory and antioxidative effects, as well as induces immediate production of prostaglandin D2, leading to endothelial vasodilation. ObjectiveThis study investigated the short-term effects of extended-release niacin (ERN) administered with or without the prostaglandin D2 receptor antagonist laropiprant on endothelial function in patients with low HDL-C. MethodsAsymptomatic men and women aged between 20 and 60 years who had plasma HDL-C levels <40 mg/dL were treated with ERN monotherapy 1 g/d or ERN/laropiprant 1 g/20 mg (ERN/LRP) in a crossover study design. The sequence of treatments was decided by simple randomization. Plasma samples and flow-mediated dilation (FMD) of the brachial artery were obtained at baseline, day 7 of treatment period 1, day 7 of washout, and day 7 of treatment period 2. ResultsEighteen patients were enrolled (mean [SD] age, 42 [17] years; 11 men). Triglyceride levels decreased by 4% and 3%, and HDL size decreased by 5.8% and 6.2%, with ERN and ERN/LRP, respectively (both, P < 0.05). There were no changes in HDL-C levels or in cholesteryl esterase transfer protein activity with either treatment. The median increases in FMD were 4.5% and 4.1% with ERN and ERN/LRP, which receded after washout. On intergroup analysis, there were no differences with respect to variation in plasma HDL-C, triglycerides, C-reactive protein, direct bilirubin, or FMD. ConclusionsIn these patients, the addition of laropiprant did not influence the effects of niacin on endothelial function. Based on these findings, short-term niacin treatment might improve endothelial function in patients with low HDL-C levels. ClinicalTrials.gov identifier: NCT01942291.

Effect of Extended-Release Niacin on Serum Lipids and on Endothelial Function in Adults With Sickle Cell Anemia and Low High-Density Lipoprotein Cholesterol Levels

Through bound apolipoprotein A-I (apoA-I), high-density lipoprotein cholesterol (HDL-C) activates endothelial nitric oxide synthase, inducing vasodilation. Because patients with sickle cell disease (SCD) have low apoA-I and endothelial dysfunction, we conducted a randomized, double-blinded, placebo-controlled trial to test whether extended-release niacin (niacin-ER) increases apoA-I-containing HDL-C and improves vascular function in SCD. Twenty-seven patients with SCD with levels of HDL-C <39 mg/dl or apoA-I <99 mg/dl were randomized to 12 weeks of niacin-ER, increased in 500-mg increments to a maximum of 1,500 mg/day, or placebo. The primary outcome was the absolute change in HDL-C level after 12 weeks, with endothelial function assessed before and at the end of treatment. Niacin-ER-treated patients trended to greater increase in HDL-C level compared with placebo treatment at 12 weeks (5.1 ± 7.7 vs 0.9 ± 3.8 mg/dl, 1-tailed p = 0.07), associated with significantly greater improvements in the ratios of low-density lipoprotein to HDL-C levels (1.24 vs 1.95, p = 0.003) and apolipoprotein B to apoA-I levels (0.46 vs 0.58, p = 0.03) compared with placebo-treated patients. No improvements were detected in 3 independent vascular physiology assays of endothelial function. Thus, the relatively small changes in HDL-C levels achieved by the dose of niacin-ER used in our study are not associated with improved vascular function in patients with SCD with initially low levels of apoA-I or HDL-C.