High Serum High-density Lipoprotein Cholesterol Levels Research Articles

The associations between serum high-density lipoprotein cholesterol levels and malignant behavior in pancreatic neuroendocrine neoplasms

BackgroundThe role of serum high-density lipoprotein cholesterol (HDL-c) in tumorigenesis are observed in several endocrine-related cancers. However, its role in pancreatic neuroendocrine neoplasms (PNENs) has not been understood. In the current study, the relationship between HDL-c levels and malignant behavior in PNENs was explored.MethodsOne hundred ninety-seven patients with histopathology confirmed PNENs were included. PNENs were divided into three grades (G1, G2 and G3) as 2017 WHO classification based on ki67 index and mitosis count. The demographic data, clinical information, tumor morphological and pathological features (organs invasion, lymph node metastasis, vascular invasion and perineural invasion), and serum tumor biomarkers were collected. The relationships between HDL-c levels and malignant behaviors in PNENs were analyzed using logistic regression analysis. Models were also developed for the identification of high grade PNENs.ResultsThe levels of serum HDL-c in G2/G3 tumor were significantly lower than that in G1 tumor (P = 0.031). However, no such difference was found between G3 and G1/G2. The proportions of low HDL-c (≤ 0.9 mmol/L) were higher in high-grade PNENs (G2/G3 or G3) than those in low-grade (G1 or G1/G2) (29.0 vs 15.2%, P = 0.032; 37.0 vs 20.5%, P = 0.023). The risk of G2/G3 tumors in patients with high serum HDL-c levels was decreased (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.12–0.99). Similarly, the risk of G3 PNENs increased in patients with low HDL-c levels (OR = 2.51, 95%CI:1.12–5.60). HDL-c level was also associated with a high ki67 index (> 55%) (OR = 0.10, 95%CI: 0.02–0.51) and neuroendocrine carcinoma G3 (OR = 0.21, 95%CI: 0.06–0.80). The area under the curve (AUC) of HDL-c + tumor size + age was 0.85 (95% CI: 0.79–0.91) in identifying G2/G3 PNENs, and HDL-c (> 0.9 mmol/L) + tumor size + age had an AUC of 0.77 (95% CI: 0.70–0.84) in identifying G3 PNENs. HDL-c level was associated with lymph node metastasis (OR = 0.24, 95%CI:0.08–0.99).ConclusionSerum HDL-c levels were significantly associated with malignant behaviors in PNENs, in particular to tumor grade and lymph node metastasis.

A systematic review and meta-analysis of the serum lipid profile in prediction of diabetic neuropathy

Whether the lipid profile in diabetic patients is associated with diabetic neuropathy (DN) development remains ambiguous, as does the predictive value of serum lipid levels in the risk of DN. Here, we performed the first meta-analysis designed to investigate the relationship between DN and the serum levels of triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL), and low-density lipoprotein cholesterol (LDL). Candidate studies were comprehensively identified by searching PubMed, Embase, Cochrane Library and Web of Science databases up to May 2020. Observational methodological meta-analysis was conducted to assess the relationships of TG, TC, HDL, and LDL levels with DN. Changes in blood lipids were used to estimate the effect size. The results were pooled using a random-effects or fixed-effects model. Potential sources of heterogeneity were explored by subgroup analysis. Various outcomes were included, and statistical analyses were performed using STATA (Version 12.0). Mean differences (MDs) and odds ratios (ORs) with 95% confidence intervals (CIs) were estimated. The Newcastle–Ottawa Scale (NOS) was applied to assess the methodological quality. I2 statistics were calculated to evaluate statistical heterogeneity. Funnel plots were utilized to test for publication bias. A sensitivity analysis was performed by omitting each study one by one. Thirty-nine clinical trials containing 32,668 patients were included in the meta-analysis. The results demonstrated that DN patients showed higher TG and lower HDL levels (MD = 0.34, 95% CI: 0.20–0.48 for TG; MD = -0.05, 95% CI: -0.08–-0.02, I2 = 81.3% for HDL) than controls. Subgroup analysis showed that patients with type 1 diabetes mellitus (T1DM) neuropathy had elevated TG levels in their serum (MD = 0.25, 95% CI: 0.16–0.35,I2 = 64.4% for T1DM). However, only patients with T1DM neuropathy had reduced serum HDL levels, and there was no significant difference in serum HDL levels between patients with T2DM neuropathy and controls (MD = -0.07, 95% CI: -0.10–-0.03, I2 = 12.4% for T1DM; MD = -0.02, 95% CI: -0.07–0.03, I2 = 80.2% for T2DM). TC and LDL levels were not significantly different between DN patients and controls (MD = -0.03, 95% CI: -0.14–0.09, I2 = 82.9% for TC; MD = -0.00, 95% CI: -0.08–0.08, I2 = 78.9% for LDL). In addition, compared with mild or painless DN patients, those with moderate or severe pain DN pain had significantly reduced serum TC and LDL levels (MD = -0.31, 95% CI: -0.49–-0.13, I2 = 0% for TC; MD = -0.19, 95% CI: -0.32–-0.08, I2 = 0% for LDL). TG levels and HDL levels did not vary considerably between patients with mild or painless DN and those with moderate or severe DN pain patients (MD = 0.12, 95% CI: -0.28–0.51, I2 = 83.2% for TG; MD = -0.07, 95% CI:-0.14–0.01, I2 = 58.8% for HDL). Furthermore, people with higher TG and LDL levels had higher risk of DN (OR = 1.36, 95% CI: 1.20–1.54, I2 = 86.1% for TG and OR = 1.10, 95% CI: 1.02–1.19, I2 = 17.8% for LDL). Conversely, high serum HDL levels reduced the risk of DN (OR = 0.85, 95% CI: 0.75–0.96, I2 = 72.6%), while TC levels made no significant difference with the risk of DN (OR = 1.02, 95% CI: 1.00–1.04, I2 = 84.7%). This meta-analysis indicated that serum lipid profile changes are among the biological characteristics of DN. Lipid levels should be explored as routine laboratory markers for predicting the risk of DN, as they will help clinicians choose appropriate therapies, and thus optimize the use of available resources.

Serum lipid profiles of young Japanese women with iron deficiency without anemia

PurposeWe aimed to evaluate the association between iron deficiency without anemia (IDNA) and serum lipid profiles in young women of around 20 years of age. MethodsThis study included non-anemic (hemoglobin ≥ 12 g/dL) female volunteers aged 18 to 22 years who were not taking mineral/vitamin supplements and living in the metropolitan area of Tokyo, Japan. These volunteers were classified into two groups based on their sFer (serum ferritin) levels: normal group (sFer ≥ 20 ng/mL, n = 36) and IDNA group (sFer < 20 ng/mL, n = 29). Venous blood samples were obtained from the antecubital veins of these volunteers after 10–12-h fasting to measure the hematological and biochemical parameters, including lipid levels and iron status. The results of each group were compared using Student’s t-test or the Mann–Whitney U test (for inhomogeneous variance). ResultsThe serum cholesterol levels varied depending on the iron status in the women. Serum high-density lipoprotein cholesterol (HDL-C) levels in the IDNA group were significantly higher (P = 0.006) than that in the normal group. However, the levels of total cholesterol (T-CHO), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-C) were not significantly different between the groups. Serum LDL-C levels were positively and significantly correlated with sFer levels in the IDNA group (Kendall’s rank correlation 0.264, P = 0.044), but not in the normal group. The sFer level was not correlated with serum HDL-C in both groups. The reason for the high serum HDL-C levels in young women with IDNA is not yet clear. Compared to the normal group, the frequency of eating bread containing bran was significantly higher (P = 0.031) and that for yogurt was significantly lower (P = 0.040) in the IDNA group. The proportion of the women who were susceptible to infection, which was measured using the Cornell Medical Index, was significantly higher in the IDNA group than in the normal group. Among those susceptible to infection, the serum HDL-C level of the volunteers in the IDNA group was significantly higher than that of the volunteers in the normal group (P = 0.024). ConclusionsOur findings suggest that lipid parameters may be associated with IDNA and susceptibility to infection. Further research is needed to elucidate the mechanisms underlying the changes in the serum cholesterol levels in individuals with IDNA and the clinical significance of these findings.

Preoperative serum high-density lipoprotein cholesterol as a predictor of poor survival in patients with clear cell renal cell cancer.

Numerous studies have suggested that dyslipidemia is closely related to various cancers and the high-density lipoprotein cholesterol (HDL-C) levels are associated with the outcome of cancer patients. However, the predictive value of HDL-C in patients with renal cell carcinoma remains unclear. Our study aims to explore the relationship between the levels of serum HDL-C and the prognosis of renal cell carcinoma. A total of 308 patients diagnosed with clear cell renal cell carcinoma (CCRCC) who received surgical treatment were retrospectively enrolled in our study. The necessary clinical data of each enrolled patient were collected and the Kaplan-Meier method and the Cox proportional hazards regression model were used to calculate the overall survival and cancer-specific survival. Kaplan-Meier and univariate analysis showed that a lower preoperative serum HDL-C level was a risk factor of CCRCC patients. Multivariate analyses demonstrated that a higher serum HDL-C level was closely associated with better overall survival (hazard ratio = 0.32; 95% confidence interval (0.13, 0.78); P=0.013) and cancer-specific survival (hazard ratio =0.42; 95% confidence interval (0.15, 0.99); P=0.048). Our findings suggest that an increased serum level of HDL-C might predict better overall survival and cancer-specific survival in patients with CCRCC.

The association between peroxisome proliferator-activated receptor Δ rs3777744, rs3798343, and rs6922548 and coronary artery disease.

Objective: The aim of the present study is to investigate the association between the single nucleotide polymorphism (SNP) sites of peroxisome proliferator-activated receptor Δ (PPARD) and the risk of coronary artery disease (CAD). To this end, a prospective observational single-center study of the clinical data from 880 subjects in a Chinese population was conducted. Methods: A total of 880 subjects, including 609 CAD patients and 271 control subjects, were selected for the present study. All inpatients had 4 ml of venous blood drawn after 12 h of fasting, and then clinical tests were conducted to obtain the biochemical parameters. CAD patients and Controls were distinguished by coronary angiography. Statistical analysis was conducted with SPSS software (ver 16.0). Results: A significant association between the G-alleles of PPARD rs3777744 and rs3798343 and a decreased risk for CAD was found. Moreover, we found an interaction between high fasting high-density lipoprotein cholesterol (HDL-C) serum levels, low serum glucose levels and their genotypes, ultimately decreasing the risk of CAD. Haplotype analysis was conducted on the three SNP sites, rs3777744 and rs3798343 to form a block [r2 = 0.79, D′ = 0.99). The A-C haplotypes were associated with an increased risk of CAD (odds ratio (OR), 95% confidence interval (CI): 1.321 (1.060–1.647), P=0.013], and the G-G haplotypes were associated with a decreased risk [OR, 95% CI: 0.714 (0.567–0.849), P=0.004]. Conclusions: Our study indicates a significant association between the G-alleles of PPARD rs3777744 and rs3798343 and a decreased CAD risk. In addition, genotypes interact with high serum HDL-C levels and low serum glucose levels, resulting in decreased prevalence of CAD.

Association of apolipoprotein A1 and A5 polymorphisms with stroke subtypes in Han Chinese people in Taiwan

Background and purposesStroke is a leading cause of death and serious disability worldwide. Now, evidences indicate that dyslipidemia may play an important role in stroke. APOA1 and APOA5 involve in lipid metabolism. In this study, we investigated the association of APOA1 rs670 and APOA5 rs662799 with different stroke subtypes in the Han Chinese population of Taiwan. MethodsA total of 1751 participants, including 459 control subjects, 606 large artery atherosclerosis (LAA), 339 small vessel occlusion (SVO), and 347 hypertensive intracranial hemorrhage (HICH), were enrolled. The presence of rs670 and rs662799 was analyzed through polymerase chain react ion and matrix-assisted laser desorption/ionization–time-of-flight–mass spectrometry. ResultsNotably, the frequency of the rs662799 C allele was significantly lower in the SVO patients than in the controls (24.36% vs. 29.74%, P = 0.024). The frequencies of heterozygote TC [odd ratio (OR) = 0.732, 95% confidence interval (CI) = 0.544–0.984, P = 0.038] and TC + CC (OR = 0.719, 95% CI = 0.542–0.953, P = 0.022) genotypes were significantly lower in the SVO patients than in the controls. In addition, triglyceride levels in individuals carrying the rs662799 TC + CC genotype were significantly higher than in those carrying the TT genotype, especially in older age, female, and body mass index (BMI) ≥ 25 groups. On the contrary, the low-density lipoprotein-cholesterol (LDL-C) was significantly lower in rs662799 TC + CC genotype than TT genotype. The BMI was significantly lower in subjects with rs662799 TC + CC genotype than those with TT genotype, especially in older age and female. High-density lipoprotein-cholesterol (HDL-C) levels were higher in individuals carrying the rs670 GG genotype than in those carrying the AG + AA genotype, especially in BMI < 25 group. Logistic regression analysis showed that the rs662799 C allele (TC + CC) was an independent protective factor for SVO after adjustment for conventional risk factors (OR = 0.709, 95% CI = 0.526–0.956; P = 0.024). ConclusionGG genotype of rs670 is correlated with high serum HDL-C levels, whereas TC + CC genotype of rs662799 is associated with high serum triglyceride and low LDL and BMI levels. In addition, the rs662799 C allele (TC + CC) is an independent protective factor for SVO in the Han Chinese population in Taiwan.

Usefulness of High-Density Lipoprotein Cholesterol to Predict Survival in Pulmonary Arterial Hypertension

It has been suggested that lipoprotein abnormalities may contribute to the pulmonary arteriolar dysfunction observed in pulmonary arterial hypertension (PAH). High-density lipoprotein cholesterol (HDL) has vasodilatory, anti-inflammatory, and endothelial protective properties. We hypothesized that a higher serum HDL level may be advantageous for survival in PAH and that the serum HDL level at diagnosis would be an independent predictor of survival in PAH and be additive to previously validated predictors of survival. This study included all patients with PAH seen at the Mayo Clinic Pulmonary Hypertension Clinic from January 1, 1995, to December 31, 2009, who had a baseline HDL measurement. Mortality was analyzed over 5years using the Kaplan-Meier method. Univariate and multivariable Cox proportional hazards ratios were calculated to evaluate the relation between baseline HDL level and survival. HDL levels were available for 227 patients. Higher HDL levels were associated with significantly lower mortality. Patients with an HDL >54mg/dl at diagnosis had a 5-year survival of 59%. By comparison those with an HDL <34mg/dl had a 5-year survival of 30%. On multivariate analysis, higher HDL was associated with an age-adjusted risk ratio for death of 0.78 (CI 0.67 to 0.91; p <0.01) per 10mg/dl increase. In conclusion, HDL was an independent predictor of survival in PAH.

The Relationship between Very High Levels of Serum High-Density Lipoprotein Cholesterol and Cause-Specific Mortality in a 20-Year Follow-Up Study of Japanese General Population.

There is no community-based cohort study to examine the effect of very high level of high-density lipoprotein cholesterol (HDL-C) on coronary heart disease (CHD) and other cause-specific mortality. Therefore, we investigated the relationship between HDL-C including very high level and cause-specific mortality in a 20-year cohort study of the representative sample of Japanese. We followed 7,019 individuals from the Japanese general population (2,946 men and 4,073 women). We defined HDL-C levels as follow: low (HDL-C ＜1.04 mmol/L), reference (1.04-1.55 mmol/L), high (1.56-2.06 mmol/L), very high (≥2.07 mmol/L). The multivariate adjusted hazard ratio (HR) for all-cause or cause-specific mortality was calculated using a Cox proportional hazards model adjusted for other traditional risk factors. During follow-up, we observed 1,598 deaths. No significant association was observed between HDL-C and all-cause mortality. Serum HDL-C also showed no association with stroke. In contrast, the risk for CHD among high HDL-C was lower than reference, HRs were 0.51 [95% confidence interval (CI): 0.21-1.23] in men, 0.33 (95% CI: 0.11-0.95) in women, and 0.41 (95% CI: 0.21-0.81) when men and women were combined. However, very high HDL-C did not show significant association with CHD and other cause-specific mortality. HDL-C was not associated with all-cause and stroke mortality. In contrast, high serum HDL-C levels, at least up to 2.06 mmol/L, were protective against CHD, although further high levels were not. However, sample size of cause-specific death in very high HDL-C group was not enough even in this 20-year follow-up of 7,019 Japanese; larger cohort studies should be warranted.

Association of MYLIP rs3757354 SNP and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations

BackgroundThe association of rs3757354 single nucleotide polymorphism (SNP) in the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP, also known as IDOL) gene and serum lipid levels is not well known in the general population. The present study aimed to detect the association of rs3757354 SNP and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.MethodA total of 627 subjects of Bai Ku Yao minority and 614 participants of Han nationality were randomly selected from our stratified randomized cluster samples. Genotyping of the rs3757354 SNP was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.ResultsThe levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.05-0.001). The frequency of G allele was 49.92% in Bai Ku Yao and 56.27% in Han (P < 0.05). The frequencies of AA, GA and GG genotypes were 25.52%, 49.12% and 25.36% in Bai Ku Yao, and 19.87%, 47.72% and 32.41% in Han (P < 0.05); respectively. There were no significant differences in the genotypic and allelic frequencies between males and females in both ethnic groups. The levels of HDL-C in Bai Ku Yao were different among the genotypes (P < 0.05), the G allele carriers had higher serum HDL-C levels than the G allele noncarriers. The levels TC, HDL-C and ApoAI in Han were different among the genotypes (P < 0.05 for all), the participants with GA genotype had lower serum TC, HDL-C and ApoAI levels than the participants with AA genotype. These findings were found only in females but not in males. The levels of TG and HDL-C in Bai Ku Yao were correlated with the genotypes, whereas the levels of TC in Han, and TC, LDL-C in Han females were associated with the genotypes (P < 0.05 for all). Serum lipid parameters were also correlated with age, sex, alcohol consumption, cigarette smoking, blood pressure, and body mass index in both ethnic groups (P < 0.05-0.001).ConclusionsThe present study suggests that the MYLIP rs3757354 SNP is associated with serum TC, HDL-C and ApoAI levels in the Bai Ku Yao and Han populations. But the association is different between the two ethnic groups.

The proprotein convertase subtilisin/kexin type 9 gene E670G polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

BackgroundProprotein convertase subtilisin-like kexin type 9 (PCSK9) plays a key role in regulating plasma low-density lipoprotein cholesterol (LDL-C) levels. However, the association of E670G (rs505151) polymorphism in the PCSK9 gene and serum lipid levels is inconsistent in several previous studies. The present study was undertaken to detect the association of PCSK9 E670G polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations.MethodsA total of 649 subjects of Bai Ku Yao and 646 participants of Han were randomly selected from our previous samples. Genotypes of the PCSK9 E670G polymorphism were determined via polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing.ResultsSerum levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), LDL-C, and apolipoprotein (Apo) AI were lower in Bai Ku Yao than in Han (P < 0.01 for all). The frequency of G allele was 2.00% in Bai Ku Yao and 4.80% in Han (P < 0.01). There was significant difference in the genotypic and allelic frequencies between Bai Ku Yao and Han (P < 0.01); between normal LDL-C (≤ 3.20 mmol/L) and high LDL-C subgroups (> 3.20 mmol/L, P < 0.01) in Bai Ku Yao; and between normal HDL-C (≥ 0.91 mmol/L) and low HDL-C (< 0.91 mmol/L, P < 0.05), between normal ApoAI (≥ 1.00 g/L) and low ApoAI (< 1.00 g/L, P < 0.05), or between normal ApoAI/ApoB ratio (≥ 1.00) and low ApoAI/ApoB ratio (< 1.00, P < 0.01) subgroups in Han. The G allele carriers in Han had higher serum HDL-C levels and the ratio of ApoAI to ApoB than the G allele noncarriers. The G allele carriers in Han had higher serum HDL-C and ApoAI levels than the G allele noncarriers in males (P < 0.05 for each), whereas the G allele carriers had lower serum ApoB levels and higher the ratio of ApoAI to ApoB than the G allele noncarriers in females (P < 0.05 for all). Serum HDL-C and ApoAI levels in Han were correlated with genotypes (P < 0.05) in males, and serum ApoB levels and the ratio of ApoAI to ApoB were associated with genotypes (P < 0.05) in females.ConclusionsThe PCSK9 E670G polymorphism is mainly associated with some serum lipid parameters in the Han population. The G allele carriers had higher serum HDL-C and ApoAI levels in males, and lower serum ApoB levels and higher the ApoAI/ApoB ratio in females than the G allele noncarriers.

Increased serum high-density lipoprotein cholesterol level is associated with a reduction in peripheral monocyte count in normal individuals.

Monocytes and high-density lipoprotein cholesterol (HDL-C) both play important roles in the process of atherosclerosis. This retrospective study investigated whether an increase in serum HDL-C level would be followed by a reduction in monocyte count. A total of 781 participants in a health check program in 1996 who had received a second health check in 1997, 1998, or 1999 were included. Based on the change in HDL-C at the second health check, the subjects were divided into the following 3 groups: 1) increase in HDL-C of >or= 5% (n = 426); 2) change of HDL-C of < 5% (n = 162); and 3) decrease of HDL-C of >or= 5% (n = 193). The relations between the change in HDL-C and the change in monocyte count were analyzed. A significant inverse relation between the change in HDL-C level and the change in monocyte count was found among the 3 study groups by 1-way analysis of variance (p = 0.002). Subjects with increased HDL-C had significantly decreased monocyte count at the second check while subjects with decreased HDL-C had increased monocyte count. Multivariate regression analysis of data from all subjects revealed that the change of HDL-C was independently associated with a significant inverse change in monocyte count (p = 0.007). In view of the documented inflammatory nature of atherosclerosis, the inverse relation between the change of HDL-C level and the change of monocyte count may partly explain why a higher serum HDL-C level can protect arteries against atherosclerosis.

Glucocorticoid use and serum lipid levels in US adults: The third national health and nutrition examination survey

It has been generally perceived that glucocorticoids adversely affect serum lipid levels, although results of prospective studies have suggested the contrary. In this study, we sought to examine the relationship between glucocorticoid use and lipid profiles in a nationally representative sample of subjects. Using data from 15,004 participants ages 20 years and older in The Third National Health and Nutrition Examination Survey (1988-1994), we examined the relationship between glucocorticoid use and serum lipid profiles. Glucocorticoid use was determined from the household interview regarding prescription medication use. We used multivariate linear regression to adjust for age, sex, race or ethnicity, education, smoking status, body mass index, physical activity, alcohol consumption, energy fraction from protein and carbohydrates, and total energy intake. Glucocorticoid use was associated with a higher serum high-density lipoprotein (HDL) cholesterol level and a lower ratio of total cholesterol-to-HDL cholesterol among subjects ages 60 years or older (multivariate difference 9.0 mg/dl [95% confidence interval (95% CI) 3.9, 14.1] and -0.6 mg/dl [95% CI -0.9, -0.3], respectively) but not among those younger than age 60 years (multivariate difference -1.5 mg/dl [95% CI -5.4, 2.5] and 0.1 mg/dl [95% CI -0.3, 0.5], respectively). Correspondingly, glucocorticoid use was associated with a higher serum apolipoprotein A-I (Apo A-I) level and a lower Apo A-I:Apo B ratio (multivariate difference 12.1 mg/dl [95% CI 2.9, 21.3] and 0.16 mg/dl [95% CI 0.03, 0.29], respectively) only among subjects ages 60 years or older. Inhalation/intranasal glucocorticoid use was also associated with a higher serum HDL cholesterol level (multivariate difference 4.9 mg/dl [95% CI 0.3, 9.5]) only among subjects ages 60 years or older. Our results suggest that glucocorticoid use is not associated with an adverse lipid profile in the US population and may be associated with a favorable lipid profile among persons ages 60 years or older, in concordance with previous prospective studies.

Beyond Low-Density Lipoprotein

The metabolic syndrome and type 2 diabetes mellitus are both becoming more prevalent, and both increase the risk of cardiovascular disease. Many patients are not receiving appropriate treatment for the type of dyslipidemia that commonly occurs in these disorders--the so-called 'atherogenic lipid triad' of high serum triglyceride levels, low serum high-density lipoprotein cholesterol (HDL-C) levels, and a preponderance of small, dense, low-density lipoprotein cholesterol (LDL-C) particles. All of the processes involved in atherogenesis can be exacerbated by insulin resistance and/or the metabolic syndrome. Hypertriglyceridemia is a strong predictor of coronary heart disease. There is also an inverse relationship between serum levels of HDL-C and triglycerides in diabetic patients, with low serum HDL-C levels possibly representing an independent risk factor for cardiovascular disease. Small, dense, LDL-C particles are also highly atherogenic as they are more likely to form oxidized LDL and are less readily cleared. Insulin resistance, which is central to the metabolic syndrome and type 2 diabetes mellitus, leads to high levels of very low-density lipoprotein (VLDL), which contain a high concentration of triglycerides, resulting in high serum triglyceride levels and low serum HDL-C levels. Even though modification of the atherogenic lipid triad is probably one of the most effective methods of reducing cardiovascular risk, therapy for diabetic dyslipidemia is often directed to first lowering serum LDL-C levels with a HMG-CoA reductase inhibitor. This may leave substantial excess risk for cardiovascular disease in patients with these types of dyslipidemia. The results of recent trials evaluating HMG-CoA reductase inhibitors have been mixed, with two showing no significant effect on cardiovascular outcomes in subgroups of diabetic patients. The recent CARDS (Collaborative Atorvastatin Diabetes Study) showed that atorvastatin can reduce cardiovascular events in a trial specifically designed for a diabetic population, though the population had to have at least one other risk factor in addition to diabetes mellitus. Fibric acid derivatives, such as fenofibrate, bezafibrate and gemfibrozil, are potentially well suited to the treatment of dyslipidemia that is generally associated with type 2 diabetes mellitus and the metabolic syndrome, as they are usually more effective than HMG-CoA reductase inhibitors for normalizing serum levels of HDL-C and triglycerides. Promising results have been obtained from several trials of fibric acid derivatives including the BIP (Bezafibrate Infarction Prevention) study and the VA-HIT (Veterans Affairs Cooperative Studies Program HDL-C Intervention Trial; gemfibrozil). The FIELD (Fenofibrate Intervention and Event Lowering in Diabetes) trial, a clinical outcomes trial specifically designed to evaluate fenofibrate in a large population of patients with type 2 diabetes mellitus, many of whom have the metabolic syndrome, is underway. The FIELD trial results should shed light on the efficacy and safety of fenofibrate in reducing cardiovascular morbidity in diabetic and metabolic syndrome patients and on the safety profile of combination therapy with fenofibrate and a HMG-CoA reductase inhibitor.

Association of I27L polymorphism of hepatocyte nuclear factor-1 alpha gene with high-density lipoprotein cholesterol level.

The serum level of high-density lipoprotein cholesterol (HDL-c), which protects against the development of atherosclerosis, is under genetic control. However, the genetic components responsible for the serum HDL-c level are yet to be determined. A recent knockout mouse study demonstrated that hepatocyte nuclear factor-1 alpha (HNF-1 alpha) is an essential transcriptional regulator of HDL-c metabolism. In this study, the association of an HNF-1 alpha gene polymorphism, isoleucine (Ile) 27 leucine (Leu), with lipid parameters, in particular with serum HDL-c level, was studied in 356 unrelated Japanese men. Though no significant difference was observed in total cholesterol and triglyceride levels among the three genotypes, the serum HDL-c level was significantly associated with the genotype (P < 0.01, trend test). Subjects with the Ile/Ile genotype had low serum HDL-c levels, and those with the Leu/Leu genotype had high serum HDL-c levels. These results demonstrate that the HNF-1 alpha gene locus is associated with serum HDL-c level and suggest that the Ile27 allele is a risk marker for atherosclerosis.

Effects of sibutramine on body weight and serum lipids: A double-blind, randomized, placebo-controlled study in 322 overweight and obese patients with dyslipidemia

Background Cardiovascular risk factors associated with obesity, including dyslipidemia, can be improved by weight loss. The main dyslipidemia associated with obesity is elevated serum triglyceride and decreased serum high-density lipoprotein cholesterol (HDL-C) levels. Methods A total of 322 obese patients (body mass index ≥27) with serum triglyceride levels ≥250 mg/dL and ≤1000 mg/dL and serum HDL-C levels ≤45 mg/dL (women) and ≤40 mg/dL (men) were placed on a step I American Heart Association diet and subsequently randomized to sibutramine 20 mg (n = 162) or placebo (n = 160) once daily for 24 weeks. Results Patients taking sibutramine had significantly greater mean weight loss than those receiving placebo (–4.9 kg vs –0.6 kg, P ≤.05). Forty-two percent of the sibutramine group lost ≥5% of baseline weight and 12% lost ≥10% compared with 8% and 3%, respectively, of the placebo group (P ≤.05). Mean decreases in serum triglyceride levels among 5% and 10% weight-loss responders in the sibutramine group were 33.4 mg/dL and 72.3 mg/dL, respectively, compared with an increase of 31.7 mg/dL among all patients receiving placebo (P ≤.05). Mean increases in serum HDL-C levels for 5% and 10% weight-loss responders in the sibutramine group were 4.9 mg/dL and 6.7 mg/dL, respectively, compared with an increase of 1.7 mg/dL among all patients in the placebo group (P ≤.05). Adverse events and discontinuation rates were similar in the sibutramine and placebo groups, although sibutramine-treated patients had mean increases in systolic and diastolic blood pressure of 2 to 3 mm Hg relative to placebo. Conclusions In overweight and obese patients with high serum triglyceride levels and low serum HDL-C levels, treatment with sibutramine was associated with significant improvements in body weight and in serum triglyceride and HDL-C levels. (Am Heart J 2001;142:489-97.)

Effects of hepatic lipase gene promoter nucleotide variations on serum HDL cholesterol concentration in the general Japanese population.

Genetic factors may play a major role in determining serum high-density lipoprotein (HDL) cholesterol (HDL-C) levels in the general population. Cholesteryl ester transfer protein (CETP) is a strong genetic factor as a determinant of HDL-C levels in Japanese, whereas hepatic lipase (HL) plays a predominant role in Caucasian populations. We investigated the effects of HL gene promoter polymorphisms on HDL-C levels in a general population of Japanese men (n = 299). An HL promoter polymorphism of -514C/T explained a considerable variance of HDL-C (2.9%), as compared with CETP mutations of D442G and IVS14 + 1G > A (3.6% and 1.9%). HL promoter variation of the -514C/C genotype, reported to have high HL activity, had significant effects on decreasing HDL-C levels (-3.8mg/dl), but -514T allele carriers had a weak effect on increasing HDL-C levels. The frequency of the -514T allele was three times higher (0.50) in the Japanese than in Caucasian populations (0.15-0.19). Thus, the higher frequency of the HL -514T allele, along with CETP gene mutations, could explain about 9% of phenotypic variability of HDL-C. These genetic attributes may be among the many factors that contribute to the relatively higher serum HDL-C levels in Japanese subjects.