Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk

Exploring Avenues for Raising HDL Cholesterol

Pitavastatin is a 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitor used to treat hypercholesterolemia. The goal of this study was to compare the efficacy and safety of pitavastatin versus those of simvastatin in Korean patients with hypercholesterolemia. This was an 8-week, multicenter, prospective, randomized, open-label, Phase III clinical trial. Male and female Korean patients with hypercholesterolemia who were between the ages of 20 and 75 years and who had a fasting triglyceride level <600 mg/dL and a low-density lipoprotein (LDL) cholesterol level >130 mg/dL after a 4-week dietary lead-in period were eligible for entry. Eligible patients were randomized into 2 groups in a 1:1 ratio. Patients received pitavastatin 2 mg once daily or simvastatin 20 mg once daily for 8 weeks. The medication was administered initially for 4 weeks, and an additional 4 weeks of study medication was prescribed at week 4. The final visit was conducted 8 weeks after randomization. Of the 104 patients randomized to treatment, 95 patients (59 women; 36 men) completed the study (49 in the pitavastatin group [mean age, 59.9 years] and 46 in the simvastatin group [mean age, 56.4 years]). No significant difference was found between groups with respect to patient age, sex, or body mass index. There was no significant difference in the percent decrease in LDL cholesterol levels (mean [SD], 38.2% [11.6%] decrease for the pitavastatin group vs 39.4% [12.9%] decrease for the simvastatin group [P = 0.648]). Also, there were no significant differences between the 2 study groups in the percent changes in total cholesterol, triglyceride, or high-density lipoprotein (HDL) cholesterol levels from baseline to study end. No significant difference was observed for the proportion of patients who achieved the LDL cholesterol goal of the National Cholesterol Education Program Adult Treatment Panel III: 93.9% (46/49) of patients in the pitavastatin group and 91.3% (42/46) of patients in the simvastatin group (P = 0.709) met the target level. At least 1 clinical adverse event and at least 1 adverse drug reaction were observed in 25.0% (13/52) and 11.5% (6/52), respectively, of patients in the pitavastatin group, and 37.3% (19/51) and 23.5% (12/51), respectively, in the simvastatin group; this difference was not statistically significant. The most common adverse event was an elevation in creatine kinase levels >2 times the upper limit of normal in 3.8% of pitavastatin-treated patients and 9.8% of simvastatin-treated patients (P = 0.269). There were no serious adverse drug reactions observed in either group. The HMG-CoA reductase inhibitor pitavastatin was found to be noninferior to simvastatin in terms of reducing LDL cholesterol, total cholesterol, and triglyceride levels, and increasing HDL cholesterol levels, in Korean patients with hypercholesterolemia after 8 weeks of treatment.

High-density lipoprotein cholesterol (HDL-C) is a strong and independent predictor of major cardiovascular events in a wide range of patients. The relationship between HDL-C cholesterol and cardiovascular risk appears to be linear, continuous, negative and independent of other risk factors such as blood pressure, smoking and BMI. In addition, the inverse relationship between HDL-C and cardiovascular events does not depend on low-density lipoprotein cholesterol (LDL-C) levels, so a substantial residual cardiovascular risk is maintained also in individuals with LDL-C levels below the target recommended by scientific guidelines. Furthermore, a strong relationship among HDL-C levels, progression of atherosclerosis and risk of cardiovascular diseases has been also demonstrated. Treatments that increase HDL-C levels have been shown to be effective in reducing incidence of cardiovascular diseases both in primary and secondary prevention settings. However, proof that increasing HDL-C levels by pharmacological treatment is able to confer a reduction in major cardiovascular outcomes independent of changes in LDL-C or triglycerides levels is not completely defined. Among currently available compounds, statins do not seems to have a sufficient effect on HDL-C profile. Studies on fibrates have shown inconclusive results. Although niacin has been demonstrated to reduce the incidence of major cardiovascular events paralleling the regression of atherosclerosis, significant side-effects still limit its use. The potential benefit of cholesterol ester transfer protein inhibition is still under investigation. The combination therapy of fibrates with statins is also controversial. Thus, despite the potentially favorable effect of raising HDL-C levels, the available guidelines still do not consider HDL-C levels as a specific target for therapy. Further studies are needed to assess the role of new compounds to raise HDL-C levels or modify HDL composition and functionality.

Studies have shown that phosphatidylinositol (PI) can stimulate reverse cholesterol transport by enhancing the flux of cholesterol into HDL and by promoting the transport of high density lipoprotein-cholesterol (HDL-C) to the liver and bile. The goal of this study was to determine the safety and therapeutic value of PI after oral administration to normolipidemic human subjects. We performed a randomized 2 week study in 16 normolipidemic subjects. Subjects received either 2.8 or 5.6 g of PI, with or without food. PI was well tolerated by all subjects. PI significantly affected the levels of HDL-C and triglyceride in the plasma of subjects receiving PI with food. The lower dose showed a 13% increase in HDL-C, whereas the high dose showed an increase of 18% over the 2 week period. Both low- and high-dose groups showed significant increases in plasma apolipoprotein A-I. The high dose of PI also decreased plasma triglycerides by 36% in the fed subjects. These data suggest that after only 2 weeks, PI may have a comparable therapeutic value to niacin, with negligible side effects.

BackgroundLittle is known about the interactions of apolipoprotein (Apo) A5 gene polymorphisms and alcohol consumption on serum lipid profiles. The present study was undertaken to detect the interactions of ApoA5–1131T>C, c.553G>T and c.457G>A polymorphisms and alcohol consumption on serum lipid levels.Methodology/Principal FindingsA total of 516 nondrinkers and 514 drinkers were randomly selected from our previous stratified randomized cluster samples. Genotyping was performed by polymerase chain reaction and restriction fragment length polymorphism. The levels of serum total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), ApoA1 and ApoB were higher in drinkers than in nondrinkers (P<0.05–0.001). The genotypic and allelic frequencies of three loci were not different between the two groups. The interactions between –1131T>C genotypes and alcohol consumption on ApoB levels (P<0.05) and the ApoA1/ApoB ratio (P<0.01), between c.553G>T genotypes and alcohol consumption on low-density lipoprotein cholesterol (LDL-C) levels (P<0.05) and the ApoA1/ApoB ratio (P<0.05), and between c.457G>A genotypes and alcohol consumption on TG levels (P<0.001) were detected by factorial regression analysis after controlling for potential confounders. Four haplotypes (T-G-G, C-G-G, T-A-G and C-G-T) had frequencies ranging from 0.06 to 0.87. Three haplotypes (C-G-G, T-A-G, and C-G-T) were significantly associated with serum lipid parameters. The –1131T>C genotypes were correlated with TG, and c.553G>T and c.457G>A genotypes were associated with HDL-C levels in nondrinkers (P<0.05 for all). For drinkers, the –1131T>C genotypes were correlated with TC, TG, LDL-C, ApoB levels and the ApoA1/ApoB ratio (P<0.01 for all); c.553G>T genotypes were correlated with TC, TG, HDL-C and LDL-C levels (P<0.05–0.01); and c.457G>A genotypes were associated with TG, LDL-C, ApoA1 and ApoB levels (P<0.05–0.01).ConclusionsThe differences in some serum lipid parameters between the drinkers and nondrinkers might partly result from different interactions of the ApoA5 gene polymorphisms and alcohol consumption.

Colesevelam is a bile acid sequestrant that differs structurally from traditional bile acid sequestrants, allowing it to bind bile acids with greater affinity. Studies have shown that colesevelam significantly reduces low-density lipoprotein cholesterol (LDL-C) levels and, in some cases, significantly increases high-density lipoprotein cholesterol (HDL-C) levels in adults with primary hypercholesterolemia. To investigate the safety and efficacy of colesevelam in adults with primary hypercholesterolemia. This multicenter, open-label, titration-based extension study enrolled subjects who completed one of three multicenter, randomized, double-blind, placebo-controlled phase II studies with colesevelam. This study consisted of a 4-week washout/dietary stabilization period, a 50-week open-label treatment period, and a 2-week follow-up period. Ten clinical centers within the US. Males and females 18 years of age or older who had completed a previous short-term (4- or 6-week) phase II clinical study with colesevelam. At week 0 (following a 4-week washout of all lipid-lowering medication), subjects initiated treatment with colesevelam at a dosage of 1.5 g/day. Colesevelam was uptitrated to a maximum dosage of 3.75 g/day as necessary to achieve a 15-30% reduction from baseline in LDL-C level. At week 12, an HMG-CoA reductase inhibitor (statin) or niacin (nicotinic acid) could be added if colesevelam 3.75 g/day was not sufficient to result in a 15-30% reduction from baseline in LDL-C level. The primary efficacy measure was the change in LDL-C level from baseline to week 50 across all treatment regimens. Secondary efficacy parameters included the change and percent change in total cholesterol, HDL-C, and triglyceride levels from baseline to week 50. There were three cohorts analyzed: (i) colesevelam monotherapy (included all subjects who received colesevelam monotherapy, regardless of dose); (ii) all treatment regimens (included all subjects who received colesevelam monotherapy or colesevelam plus low-dose statin or niacin therapy); and (iii) combination therapy (included only subjects who received colesevelam plus low-dose statin therapy). Two additional cohorts were also evaluated: (iv) maximum-dose colesevelam monotherapy (included only subjects who received colesevelam 3.75 g/day monotherapy); and (v) all maximum-dose colesevelam treatment regimens (included all subjects who received colesevelam 3.75 g/day, either as monotherapy or in combination with low-dose statin or niacin therapy). In total, 272 subjects were screened, 260 enrolled, and 186 completed the study. In total, 255 subjects were included in the intent-to-treat population. The maximum dosage of colesevelam (3.75 g/day) was taken by 50% of subjects (n = 94/188) at week 50; only 38 subjects received low-dose statin or niacin by study end. At week 50, LDL-C levels were significantly (p < 0.001) reduced from baseline across all treatment regimens (by 29.6 mg/dL [from 185.8 to 156.2 mg/dL; 15.0%]). Colesevelam also significantly reduced total cholesterol levels and significantly increased HDL-C and triglyceride levels across all treatment regimens (p < 0.001 for all). Drug-related adverse events were reported by 36.2% of subjects across all treatment regimens (and by 47.4% of subjects who received colesevelam plus low-dose statin or niacin therapy). In this study, colesevelam was found to be safe and effective for the management of LDL-C levels in adults with primary hypercholesterolemia.

BackgroundGlobally, the most common malignancy in women today is breast cancer. Numerous factors affect the incidence of breast cancer; therefore, we examined the connections involving age, body mass index (BMI), serum lipid levels, and breast cancer risk in women.MethodsThis was a cross-sectional analytical study. 382 female patients with a breast cancer diagnosis in this study, and 11842 healthy, age-matched females who were selected from physical examination centers in the same period. Univariate analysis was conducted first, after which factors with statistically significant differences were used to construct a multi-factor binary logistic regression equation. We explored associations across different ages, BMI, triglyceride (TG), and high-density lipoprotein-cholesterol (HDL-C) levels, and breast cancer risk.ResultsAge, BMI, TG, and HDL-C were the risk factors that showed the most significant association with breast cancer. Age, BMI, low-density lipoprotein-cholesterol (LDL-C) and TG levels in the breast cancer group were higher than those in the control group, but HDL-C and total cholesterol (TC) levels were lower. As BMI and TG levels increased, the risk of developing breast cancer increased, and, as HDL-C levels decreased, the risk of developing breast cancer increased. Women aged ≥ 40 years old had an increased breast cancer risk. There were no significant variations in TC and LDL-C levels between groups.ConclusionsIn this study, a lower risk of breast cancer was linked to high HDL-C levels, while a higher risk of breast cancer was linked to high BMI and TG levels. Women aged ≥ 40 years old had an increased breast cancer risk.

Comparative Safety of Atorvastatin 80 mg Versus 10 mg Derived from Analysis of 49 Completed Trials in 14,236 Patients

The high-density lipoprotein (HDL) cholesterol level is a strong predictor of cardiovascular events in epidemiologic studies. Until recently, it has been less extensively studied as a therapeutic target. To assess the angiographic and clinical effects of a pharmacologic strategy to increase HDL cholesterol levels. Randomized, double-blind, placebo-controlled trial conducted from 1993 to 1996. Outpatient specialty clinic of a large U.S. military medical center. 143 military retirees younger than 76 years of age with low HDL cholesterol levels and angiographically evident coronary disease. Gemfibrozil, niacin, and cholestyramine or corresponding placebos, with aggressive dietary and lifestyle intervention at baseline. Change from baseline to 30 months and a composite measure of clinical events that included hospitalization for angina, myocardial infarction, transient ischemic attack and stroke, death, and cardiovascular procedures. At baseline, mean (+/-SD) lipid values were as follows: total cholesterol, 5.1 +/- 0.8 mmol/L (196 +/- 31 mg/dL); low-density lipoprotein (LDL) cholesterol, 3.3 +/- 0.7 mmol/L (128 +/- 27 mg/dL); and HDL cholesterol, 0.9 +/- 0.2 mmol/L (34 +/- 6 mg/dL). Compared with placebo, the pharmacologically treated group experienced a 20% (95% CI, 14.8% to 24.3%) decrease in total cholesterol level, a 36% (CI, 28.4% to 43.5%) increase in HDL cholesterol level, a 26% (CI, 19.1% to 33.7%) decrease in LDL cholesterol level, and a 50% (CI, 40.5% to 59.2%) reduction in triglyceride levels. Focal coronary stenosis increased by 1.4% in the placebo group but decreased by 0.8% in the drug group (difference, -2.2 percentage points [CI, -4.2 to -0.1 percentage points]). A composite cardiovascular event end point was reached in 26% of patients in the placebo group and 13% of those in the drug group (difference, 13.7 percentage points [CI, 0.9 to 26.5 percentage points]). Side effects, particularly flushing and gastrointestinal intolerance, were more common in the drug group but rarely led to withdrawal from the study. The study was small and used a composite clinical outcome. Whether improvements in angiographic findings were due to reductions in LDL cholesterol or increases in HDL cholesterol was not established. Flushing may have led to inadvertent unblinding in patients who were randomly assigned to active study drugs. A combination regimen aimed at increasing HDL cholesterol levels improves cholesterol profiles, helps prevent angiographic progression of coronary stenosis, and may prevent cardiovascular events in some people who exercise regularly and eat low-fat diets.

Hypercholesterolemia has been known to be an important factor in the development of atherosclelosis. Blood cholesterol screening and related health education in children, however, have not yet been widely practiced in Japan. From 1985 to 1990, blood samples were obtained from 5825 school children aged 6 to 14 years residing in Hisayama, Japan. The mean total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were determined. The mean TC levels ranged from 155 to 172 mg/dL for boys and from 156 to 170 mg/dL for girls, peaking at 9 years for both sexes. The TG levels also tended to increase gradually and to peak at 11 years for both sexes. The tendency for TG levels to be higher was much clearer than in US children and adolescents. The HDL-C levels were highest at 9 years of age for both sexes and the LDL-C levels also tended to peak at 9 years of age for boys and at 8 years of age for girls. Atherogenic Indices [(TC-HDL-C)/HDL-C] ranged from 1.7 to 1.9 for boys and 1.8 to 2.0 for girls. As the cholesterol level of Japanese children would be expected to rise steadily reflecting their westernized lifestyle, preventive programes on a nationwide base including health education at school environments should be emphasized.

Recently, studies have shown significant association between the rs2000999 polymorphism in the haptoglobin-encoding gene (HP) and low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels, which are important risk factors for cardiovascular diseases. However, the association of rs2000999 with serum lipids in Latin American diabetic populations is still uncharacterized. Here, we analyzed the association of rs2000999 with TC, high-density lipoprotein cholesterol (HDL-C), and LDL-C levels in 546 Mexican adults with type 2 diabetes (T2D) and in 654 controls without T2D. In this observational case-control study we included adults from 4 centers of the Mexican Social Security Institute in Mexico City recruited from 2012 to 2015. TC, HDL-C, LDL-C, triglycerides (TG), and glucose levels were measured by an enzymatic colorimetric method. The variant rs2000999 was genotyped using TaqMan real time polymerase chain reaction. The percentage of Native-American ancestry showed a negative association with the rs2000999 A allele. In contrast, the rs2000999 A allele had a strong positive association with European ancestry, and to a lesser extent, with African ancestry. Linear regression was used to estimate the association between the variant rs2000999 and lipid concentrations, using different genetic models. Under codominant and recessive models, rs2000999 was significantly associated with TC and LDL-C levels in the T2D group and in controls without T2D. In addition, the group with T2D showed a significant association between the variant and HDL-C levels. In summary, the rs2000999 A allele in Mexican population is positively associated with the percentage of European and negatively associated with Native American ancestry. Carriers of the A allele have increased levels of TC and LDL-C, independently of T2D diagnosis, and also increased concentrations of HDL-C in the T2D sample.

The prodrug fenofibrate, a synthetic phenoxy-isobutyric acid derivative, is rapidly hydrolyzed in vivo to form fenofibric acid, which alters plasma lipid levels by activating the peroxisome proliferator-activated receptor alpha. The micronized fenofibrate 200 mg capsule formulation, and the recently developed micronized fenofibrate 160 mg tablet formulation, are bioequivalent. Micronized fenofibrate 200 mg/day (capsules) increased high density lipoprotein cholesterol (HDL-C) levels significantly from baseline in up to 7098 patients with various dyslipidemias in noncomparative studies. Micronized fenofibrate 200 mg/day (capsules) produced significantly greater elevations in HDL-C levels than a variety of HMG-CoA reductase inhibitors in small, randomized, double-blind and nonblind studies in patients with dyslipidemia (n = 91 to 227). This formulation of fenofibrate and gemfibrozil produced similar increases in HDL-C levels in a randomized, double-blind study (n = 234). Micronized fenofibrate 160 mg once daily (tablet) increased HDL-C levels significantly from baseline by 10.6 to 14.5% in patients with type IIa or IIb dyslipidemia (n = 353) in two noncomparative studies. Additionally, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and LDL-C to HDL-C and TC to HDL-C ratios were lowered significantly from baseline. The tablet and capsule formulations of fenofibrate were both generally well tolerated in two noncomparative studies in 375 or 9884 patients. In double-blind, placebo-controlled trials in a total of 804 patients, the pooled incidences of individual adverse events were generally similar with fenofibrate and placebo.

BackgroundNon-fasting (i.e., postprandial) lipid detection is recommended in clinical practice. However, the change in blood lipids in Chinese patients with cardiovascular diseases after three daily meals has never been reported yet.MethodsSerum levels of blood lipids were measured or calculated in 77 inpatients (48 men and 29 women) at high or very high risk of atherosclerotic cardiovascular disease (ASCVD) in the fasting state and at 4 h after three meals within a day according to their diet habits.ResultsFemale patients showed significantly higher level of high-density lipoprotein cholesterol (HDL-C) than male patients, and the gender difference in other lipid parameters did not reach statistical significance at any time-point. Levels of triglyceride (TG) and remnant cholesterol (RC) increased, while that of low-density lipoprotein cholesterol (LDL-C) decreased significantly after three meals (p < 0.05). Levels of HDL-C, total cholesterol (TC), and non-high-density lipoprotein cholesterol (non-HDL-C) showed smaller changes after three meals. Percent reductions in the non-fasting LDL-C levels after lunch and supper were around 20%, which were greater than that after breakfast. The percent reductions in the non-fasting non-HDL-C levels after three meals were smaller than those in the non-fasting LDL-C levels. Patients with TG level ≥ 2.0 mmol/L (177 mg/dL) after lunch had significantly greater absolute reduction of LDL-C level than those with TG level < 2.0 mmol/L (177 mg/dL) after lunch [–0.69 mmol/L (–27 mg/dL) vs. –0.36 mmol/L (–14 mg/dL), p<0.01]. There was a significant and negative correlation between absolute change in LDL-C level and that in TG level (r = −0.32) or RC level (r = −0.67) after lunch (both p<0.01).ConclusionLDL-C level decreased significantly after three daily meals in Chinese patients at high or very high risk of ASCVD, especially when TG level reached its peak after lunch. Relatively, non-HDL-C level was more stable than LDL-C level postprandially. Therefore, when LDL-C level was measured in the non-fasting state, non-HDL-C level could be evaluated simultaneously to reduce the interference of related factors, such as postprandial hypertriglyceridemia, on detection.

Dyslipidemia and dysglycemia are etiologically associated, but the direction, chronology, and mechanisms of the association are not fully understood. We, therefore, analyzed data from 335 healthy adults (184 black, 151 white) enrolled in the Pathobiology of Prediabetes in A Biracial Cohort study. Subjects underwent oral glucose tolerance test (OGTT) and were enrolled if they had normal fasting and 2-h plasma glucose levels. Assessments during year 1 included anthropometry, fasting lipid profile, insulin sensitivity, and insulin secretion. Thereafter, OGTT was assessed annually for 5.5 years. The primary outcome was occurrence of prediabetes (impaired fasting glucose or impaired glucose tolerance) or diabetes. During a mean follow-up of 2.62 years, 110 participants (32.8%) developed prediabetes (N = 100) or diabetes (N = 10). In multivariate logistic regression models, higher baseline low-density lipoprotein (LDL) cholesterol and triglyceride levels and lower HDL cholesterol levels significantly increased the risk of incident prediabetes. The combined relative risk (95% confidence interval [CI]) of prediabetes for participants with lower baseline HDL cholesterol (10th vs. 90th percentile), higher LDL cholesterol (90th vs. 10th percentile) and high triglycerides levels (90th vs. 10th percentile) was 4.12 (95% CI 1.61-10.56), P = 0.0032. At baseline, lipid values showed significant associations with measures of adiposity, glycemia, insulin sensitivity, and secretion. In both ethnic groups, waist circumference correlated positively with triglycerides and inversely with HDL cholesterol levels (P = 0.0004-<0.0001); fasting plasma glucose correlated positively with triglycerides and LDL cholesterol levels and inversely with HDL cholesterol levels (P = 0.006-<0.0001); insulin sensitivity correlated positively with HDL cholesterol and inversely with triglyceride levels (P < 0.0001), and insulin secretion correlated positively with triglycerides (P = 0.01) and inversely with HDL cholesterol (P < 0.0001). We conclude that a baseline lipidemic signature identifies normoglycemic individuals at high risk for future glycemic progression, via congruent associations with adiposity and glucoregulatory mechanisms. These findings suggest that early lifestyle intervention could ameliorate progressive dyslipidemia and dysglycemia.

BackgroundThis study aimed to assess the associations of serum uric acid (SUA) levels and hyperuricemia with cardiometabolic risk factors in a Chinese community-dwelling population.MethodsA large cohort of 4706 residents was enrolled in this study. Physical examinations and laboratory tests were performed following a standardized protocol. Multiple linear and logistic regression analyses were conducted with adjustment of cardiometabolic risk factors including age, sex, body mass index (BMI), blood pressure (BP), triglyceride (TG), high-density lipoprotein-cholesterol (HDL-c), low-density lipoprotein-cholesterol (LDL-c) and fasting blood glucose (FBG) levels using SPSS version 17 software.ResultsThe prevalence of hyperuricemia was 7.6 %. There were significant differences in age, BMI, BP, TG, HDL-c, LDL-c and FBG levels and the proportion of men between participants with and without hyperuricemia. Multiple linear regression analysis showed that SUA levels were positively associated with age, sex, BMI, BP, TG and LDL-c levels, but negatively associated with HDL-c and FBG levels. Multiple logistic regression analysis showed that per unit increase in age was associated with a 1.014 times higher odds of the presence of hyperuricemia. Men had a 1.858 times higher odds of the presence of hyperuricemia compared with women. Per unit increases in BMI, BP, TG and LDL-c levels were associated with 1.103, 1.016, 1.173 and 1.200 times higher odds of the presence of hyperuricemia, respectively. Per unit increases in HDL-c and FBG levels were associated with 0.616 and 0.900 times lower odds of the presence of hyperuricemia, respectively.ConclusionsIn a Chinese community-dwelling population, age, sex, BMI, BP, TG, HDL-c, LDL-c and FBG levels are cardiometabolic risk factors that are significantly associated with SUA levels, as well as the presence of hyperuricemia.