Circulating prekallikrein levels are correlated with lipid levels in the chinese population: a cross-sectional study.

BACKGROUND: Recent evidence has revealed that circulating coagulation factor prekallikrein (PK), an important part of the kallikrein-kinin system, regulates cholesterol metabolism, but the association between serum PK and lipid levels is unclear. METHODS: This cross-sectional study included 256 subjects (aged from 1 month to 90 years) who underwent physical examinations at the First People's Hospital of Huaihua, China. After overnight fasting, serum was collected for PK and lipid testing. Spearman correlation analysis and multivariable logistic regression analysis were used to analyze the association of PK level with lipid levels and the likelihood risk of hyperlipidemia. The possible threshold value of PK was calculated according to the receiver operating characteristic (ROC) curve. RESULTS: The median serum PK level was 280.9 µg/mL (IQR 168.0, 377.0), and this level changed with age but not sex. The serum PK level was positively correlated with the serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. A nonlinear relationship was observed between serum PK and high-density lipoprotein cholesterol (HDL-C) levels. The serum PK level was positively correlated with HDL-C when its level was lower than 240 µg/mL and negatively correlated with HDL-C when its level was higher than 240 µg/mL. The regression analysis demonstrated that an elevated serum PK level was significantly associated with the likelihood risk of hypercholesterolemia and hypertriglyceridemia. The ROC curve showed that the possible threshold values of serum PK for hypercholesterolemia and hypertriglyceridemia occurrences were 344.9 µg/mL and 305.7 µg/mL, respectively. CONCLUSIONS: Elevated serum PK levels were significantly associated with the likelihood of hypercholesterolemia and hypertriglyceridemia, and the possible threshold values of PK levels were 344.9 µg/mL and 305.70 µg/mL, respectively, suggesting that higher PK levels may be a risk factor for cardiovascular diseases.

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk.

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.).

Lipoprotein Lipase: Is It a Magic Target for the Treatment of Hypertriglyceridemia.

High levels of triglycerides (TG) and triglyceride-rich lipoproteins (TGRLs) confer a residual risk of cardiovascular disease after optimal low-density lipoprotein cholesterol (LDL-C)-lowering therapy. Consensus has been made that LDL-C is a non-arguable primary target for lipid lowering treatment, but the optimization of TGRL for reducing the remnant risk of cardiovascular diseases is urged. Omega-3 fatty acids and fibrates are used to reduce TG levels, but many patients still have high TG and TGRL levels combined with low high-density lipoprotein concentration that need to be ideally treated. Lipoprotein lipase (LPL) is a key regulator for TGs that hydrolyzes TGs to glycerol and free fatty acids in lipoprotein particles for lipid storage and consumption in peripheral organs. A deeper understanding of human genetics has enabled the identification of proteins regulating the LPL activity, which include the apolipoproteins and angiopoietin-like families. Novel therapeutic approach such as antisense oligonucleotides and monoclonal antibodies that regulate TGs have been developed in recent decades. In this article, we focus on the biology of LPL and its modulators and review recent clinical application, including genetic studies and clinical trials of novel therapeutics. Optimization of LPL activity to lower TG levels could eventually reduce incident atherosclerotic cardiovascular disease in conjunction with successful LDL-C reduction.

Association of Serum Apolipoprotein A5 Concentration with Nonalcoholic Fatty Liver Disease in Ningbo, China.

Nonalcoholic fatty liver disease (NAFLD) is a common chronic disease characterized by the excessive accumulation of hepatocyte fat and steatosis in the absence of alcohol or any other clear contributing factors to liver injury. NAFLD has been confirmed to be closely associated with obesity, insulin resistance, and dyslipidemia. Genetic polymorphism studies have shown the relations between the apolipoprotein A5 gene (APOA5) and NAFLD. However, the association between the serum ApoA5 level and NAFLD remains unclear. Between September 2018 and August 2019, adults who attended the hospital-based health checkup center were enrolled in this study. Anthropometric examination, laboratory investigations on fasting blood, and abdominal ultrasonography were performed. The serum ApoA5 level was determined by enzyme-linked immunosorbent assay. A total of 517 eligible participants (317 females and 200 males) were involved in this study, with a mean age of 54.7 ± 16.7 years. The mean ApoA5 concentration was 28.8 ± 4.7 µg/ml, among which the males had higher concentration levels than females (29.3 ± 4.5 vs. 28.5 ± 4.7 µg/mL, P=0.04). Serum ApoA5 level was not significantly correlated with NAFLD or metabolic profiles. However, the prevalence rate of hypertriglyceridemia (triglyceride ≥ 1.7 mmol/L) showed a significant inverted "U"-shaped trend in individuals with the serum ApoA5 level of quartile one to quartile four after adjusting the confounding factors. Moreover, individuals with higher serum ApoA5 levels were also more likely to suffer from hyperglycemia. The ApoA5 levels and the prevalence of hypertriglyceridemia are in an inverted "U-shaped" correlation, but there is no significant difference between ApoA5 levels, NAFLD, and metabolic syndrome.

Effectiveness of a Novel ω-3 Krill Oil Agent in Patients With Severe Hypertriglyceridemia: A Randomized Clinical Trial.

Importance: Intense interest exists in novel ω-3 formulations with high bioavailability to reduce blood triglyceride (TG) levels. Objective: To determine the phase 3 efficacy and safety of a naturally derived krill oil with eicosapentaenoic acid and docosahexaenoic acid as both phospholipid esters (PLs) and free fatty acids (FFAs) (ω-3-PL/FFA [CaPre]), measured by fasting TG levels and other lipid parameters in severe hypertriglyceridemia. Design, Setting, and Participants: This study pooled the results of 2 identical randomized, double-blind, placebo-controlled trials. TRILOGY 1 (Study of CaPre in Lowering Very High Triglycerides) enrolled participants at 71 US centers from January 23, 2018, to November 20, 2019; TRILOGY 2 enrolled participants at 93 US, Canadian, and Mexican centers from April 6, 2018, to January 9, 2020. Patients with fasting TG levels from 500 to 1500 mg/dL, with or without stable treatment with statins, fibrates, or other agents to lower cholesterol levels, were eligible to participate. Interventions: Randomization (2.5:1.0) to ω-3-PL/FFA, 4 g/d, vs placebo (cornstarch) for 26 weeks. Main Outcomes and Measures: The primary outcome was the mean percentage of change in TG levels at 12 weeks; persistence at 26 weeks was the key secondary outcome. Other prespecified secondary outcomes were effects on levels of non-high-density lipoprotein cholesterol (non-HDL-C), very-low-density lipoprotein cholesterol (VLDL-C), HDL-C, and low-density lipoprotein cholesterol (LDL-C); safety and tolerability; and TG level changes in prespecified subgroups. Results: A total of 520 patients were randomized, with a mean (SD) age of 54.9 (11.2) years (339 men [65.2%]), mean (SD) body mass index of 31.5 (5.1), and baseline mean (SD) TG level of 701 (222) mg/dL. Two hundred fifty-six patients (49.2%) were of Hispanic or Latino ethnicity; 275 (52.9%) had diabetes; and 248 (47.7%) were receiving statins. In the intention-to-treat analysis, TG levels were reduced by 26.0% (95% CI, 20.5%-31.5%) in the ω-3-PL/FFA group and 15.1% (95% CI, 6.6%-23.5%) in the placebo group at 12 weeks (mean treatment difference, -10.9% [95% CI, -20.4% to -1.5%]; P = .02), with reductions persisting at 26 weeks (mean treatment difference, -12.7% [95% CI, -23.1% to -2.4%]; P = .02). Compared with placebo, ω-3-PL/FFA had no significant effect at 12 weeks on mean treatment differences for non-HDL-C (-3.2% [95% CI, -8.0% to 1.6%]; P = .18), VLDL-C (-3.8% [95% CI, -12.2% to 4.7%]; P = .38), HDL-C (0.7% [95% CI, -3.7% to 5.1%]; P = .77), or LDL-C (4.5% [95% CI, -5.9% to 14.8%]; P = .40) levels; corresponding differences at 26 weeks were -5.8% (95% CI, -11.3% to -0.3%; P = .04) for non-HDL-C levels, -9.1% (95% CI, -21.5% to 3.2%; P = .15) for VLDL-C levels, 1.9% (95% CI, -4.8% to 8.6%; P = .57) for HDL-C levels, and 6.3% (95% CI, -12.4% to 25.0%; P = .51) for LDL-C levels. Effects on the primary end point did not vary significantly by age, sex, race and ethnicity, country, qualifying TG level, diabetes, or fibrate use but tended to be larger among patients taking statins or cholesterol absorption inhibitors at baseline (mean treatment difference, -19.5% [95% CI, -34.5% to -4.6%]; P = .08 for interaction) and with lower (less than median) baseline blood eicosapentaenoic acid plus docosahexaenoic acid levels (-19.5% [95% CI, -33.8% to -5.3%]; P = .08 for interaction). ω-3-PL/FFA was well tolerated, with a safety profile similar to that of placebo. Conclusions and Relevance: This study found that ω-3 -PL/FFA, a novel krill oil-derived ω-3 formulation, reduced TG levels and was safe and well tolerated in patients with severe hypertriglyceridemia. Trial Registration: ClinicalTrials.gov Identifiers: NCT03398005 and NCT03361501.

Triglyceride/low-density-lipoprotein cholesterol ratio is the most valuable predictor for increased small, dense LDL in type 2 diabetes patients.

BACKGROUND: Small, dense low-density lipoprotein (sd-LDL) increases in type 2 diabetes patients and causes arteriosclerosis. Non-high-density-lipoprotein cholesterol (non-HDL-C) is thought to be useful for predicting arteriosclerosis and sd-LDL elevation; however, there are no data about whether the triglyceride /low-density-lipoprotein cholesterol (TG/LDL-C) ratio is a valuable predictor for sd-LDL. METHODS: A total of 110 type 2 diabetes patients with hypertriglyceridemia were analyzed. No patients were treated with fibrates, but 47 patients were treated with statins. LDL-C was measured by the direct method. LDL-migration index (LDL-MI) using electrophoresis (polyacrylamide gel, PAG) was calculated, and a value ≥0.400 was determined to indicate an increase in sd-LDL. Simple regression analyses were carried out between LDL-MI and lipid markers. Receiver operating characteristic curves of lipid markers for predicting high LDL-MI were applied to determine the area under the curve (AUC), sensitivity, specificity, and cut-off point. RESULTS: LDL-MI correlated negatively with LDL-C (P = 0.0027) and PAG LDL fraction (P < 0.0001) and correlated positively with TGs, non-HDL-C, TG/LDL-C ratio, TG/HDL-C ratio, and non-HDL-C/HDL-C ratio among all study patients. Similar results were obtained for patients analyzed according to statin treatment. The AUCs (95% confidence interval) were 0.945 (0.884-1.000) for TG/LDL-C ratio and 0.614 (0.463-0.765) for non-HDL-C in patients without statins (P = 0.0002). The AUCs were 0.697 (0.507-0.887) for TG/LDL-C and 0.682 (0.500-0.863) for non-HDL-C in patients treated with statins. The optimal cut-off point for TG/LDL-C ratio for increased LDL-MI was 1.1 (molar ratio) regardless of statin treatment. The sensitivity and specificity of the TG/LDL-C ratio (90.0 and 93.9%, respectively) were higher than those of non-HDL-C (56.7 and 78.8%, respectively) in patients without statins. CONCLUSIONS: The TG/LDL-C ratio is a reliable surrogate lipid marker of sd-LDL and superior to non-HDL-C in type 2 diabetes patients not treated with statins.

Rapid reduction in triglyceride levels by therapeutic plasma exchange in patients with hypertriglyceridemic pancreatitis.

OBJECTIVE: To investigate the effect of therapeutic plasma exchange (TPE) on lowering triglyceride (TG) levels in patients with hypertriglyceridemic pancreatitis (HLAP). METHODS: The TG-lowering in patients with HLAP was compared between the TPE group and conservative treatment group (non-TPE). The primary outcome was TG reduction to less than 500 mg/dL within 48 hours. RESULTS: The primary outcome was significantly correlated with TPE (univariate analysis odds ratio [OR] 2.74; 95% confidence interval [CI] 1.30-5.79, P = .008; multivariate analysis OR 3.03; 95% CI 1.28-7.19, P = .012). At 24 and 48 hours, conservative treatment resulted in a 48.24% and 70.44% reduction in TG, while TPE resulted in a 70.91% and 76.39% reduction in TG, respectively. A more rapid decrease of in TGs in a short period was clearly associated with TPE (P < .001 for interaction). After 72 hours, the TGs decreased by approximately 77% in both groups, with no significant difference (P = .563). There was no difference between groups in clinical outcomes over the acute time period or over the longer term. CONCLUSIONS: In patients with HLAP, TPE resulted in a short-term and rapid reduction in plasma TG concentrations, with no significant advantage over non-TPE after 72 hours.

Validating the NIH LDL-C equation in a specialized lipid cohort: Does it add up?

BACKGROUND: Guideline recommendations for the management of lipids in patients at risk for cardiovascular disease is largely based on low-density lipoprotein cholesterol (LDL-C) concentration. LDL-C is commonly calculated by the Friedewald equation, which has many limitations. The National Institutes of Health (NIH) equation better estimates LDL-C, particularly in patients with hypertriglyceridemia and/or low LDL-C. We validated the NIH LDL-C equation at the first Canadian clinical laboratory to implement this equation. METHODS: A total of 3161 lipid ultracentrifugation results from a specialized lipid cohort of 2836 patients were included. LDL-C was calculated using the NIH and Friedewald equations and compared to LDL-C measured by ultracentrifugation. We determined the accuracy of these equations at treatment thresholds and developed NIH equation restriction criteria to ensure only accurate results are reported. RESULTS: Ultracentrifugation LDL-C more strongly correlated with NIH-calculated LDL-C (r2 = 0.889) than Friedewald-calculated LDL-C (r2 = 0.807) and resulted in fewer non-sensical negative LDL-C values. The correlation for NIH-calculated LDL-C improved to r2 = 0.975 after applying our restriction criteria. The NIH equation showed equivalent or superior concordance with ultracentrifugation at treatment thresholds. The LDL-C mean absolute difference increased with increasing TG and decreasing LDL-C concentrations, although the NIH equation was more robust under both conditions. CONCLUSIONS: We validated the NIH equation against ultracentrifugation in a cohort with a wide lipid concentration range, which supported its superiority over the Friedewald equation. We recommend clinical implementing the NIH equation for all patients except those with type III hyperlipoproteinemia or TG > 9.04 mmol/L, with an LDL-C lower reporting limit of <0.50 mmol/L.

Higher fasting triglyceride predicts higher risks of diabetes mortality in US adults.

BACKGROUND: It is unknown whether higher triglyceride results in higher mortality from diabetes, i.e., diabetes mortality. This study aimed to investigate the association of fasting triglyceride with diabetes mortality. METHODS: This study included 26,582 US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. Diabetes mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglyceride for diabetes mortality. RESULTS: Higher levels of fasting triglyceride were associated with higher levels of glucose, glycated hemoglobin, insulin, and homeostatic model assessment for insulin resistance at baseline. A 1-natural-log-unit increase in triglyceride (e.g., from 70 to 190 mg/dL) was associated with a 115% higher multivariate-adjusted risk of diabetes diagnosis (odds ratio, 2.15; 95% CI, 2.00-2.33). During 319,758 person-years of follow-up with a mean follow-up of 12.0 years, 582 diabetes deaths were documented. Compared with people with triglyceride in the lowest quintile, people with triglyceride in the highest quintile had an 85% higher risk of diabetes mortality (HR, 1.85; 95% CI, 1.25-2.73). A 1-natural-log-unit increase in triglyceride was associated with a 40% higher multivariate-adjusted risk of diabetes mortality. The positive association between triglyceride and diabetes mortality was also presented in sub-cohorts of participants with or without diabetes. CONCLUSIONS: This study demonstrated that higher fasting triglyceride was associated with a higher diabetes mortality risk.

Association between thyroid hormone and components of metabolic syndrome in euthyroid Korean adults: A population-based study.

ABSTRACT: Thyroid dysfunction increases the prevalence of metabolic syndrome. However, the link between thyroid hormones and metabolic syndrome remains debatable, and the effect of sex on their relationship is not completely understood. To elucidate the relationship of thyroid hormones with metabolic syndrome and its components according to sex in euthyroid individuals in South Korea. Adult participants who underwent thyroid tests at our institution between January 2015 and December 2018 and had thyroid-stimulating hormone (TSH; 0.270-4.200 µIU/mL) and free thyroxine (FT4; 0.93-1.70 ng/dL) levels in the normal range were included. After correcting for age and body mass index, multiple linear regression was performed to assess the association of TSH and FT4 with metabolic syndrome and its components, and logistic regression was performed to estimate the risk of developing metabolic syndrome and its components according to different thyroid hormone quartiles. We included 12,478 men and 7,575 women in this study. The prevalence of metabolic syndrome was 9.68%. In men, TSH was positively associated with blood pressure and triglycerides, and the odds ratio for high blood pressure and hypertriglyceridemia was approximately 1.3 times higher in the fourth quartile than in the first quartile. FT4 associated positively with waist circumference, and a high odds ratio for abdominal obesity in the fourth quartile was observed in both men (odds ratio [OR], 1.239; 95% confidence interval [CI], 1.045-1.470) and women (OR, 1.302; 95% CI, 1.029-1.649). A negative association was found between FT4 and triglycerides, and concurrently, the odds ratios for hypertriglyceridemia were lower in the fourth quartile in both men (OR, 0.692; 95% CI, 0.619-0.774) and women (OR: 0.641; 95% CI: 0.512-0.803). In addition, a higher odds ratio for high blood pressure was observed in the fourth quartiles of FT4 and TSH in women. However, there was no association between TSH and FT4 levels and the onset of metabolic syndrome in either of the sexes. Serum TSH and FT4 levels were associated with different metabolic syndrome components in men and women, but there was no association with the onset of metabolic syndrome.

Relationship between Serum Angiopoietin-like Proteins 3 and 8 and Atherogenic Lipid Biomarkers in Non-Diabetic Adults Depends on Gender and Obesity.

Hypertriglyceridemia is an independent risk factor for coronary artery disease. Lipoprotein lipase (LPL) plays an essential role in the metabolism of triglyceride-rich lipoproteins (TRLs). Angiopoietin-like proteins ANGPTL3 and ANGPTL8 are shown to be important regulators of LPL activity. Increased concentrations of these proteins may reflect cardiovascular risk, and the treatment of patients with dyslipidemia with ANGPTLs inhibitors may decrease this risk. We assessed the gender-specific relationships of serum ANGPTL3 and ANGPTL8 with atherogenic lipid biomarkers and obesity in non-diabetic adults. The study comprised 238 participants aged 25-74 [122 with triglycerides (TG) <150 mg/dL (<1.7 mmol/L) and 116 with hypertriglyceridemia]. Total cholesterol, HDL-cholesterol, LDL-cholesterol, TG, C-reactive protein (CRP), glycated hemoglobin, apolipoprotein B, small dense LDL-C (sd-LDL-C), ANGPTL3, and ANGPTL8 were measured. Non-HDL-cholesterol, remnant cholesterol (remnant-C) concentrations, and body mass index (BMI) were calculated. Results: Women and men did not differ in terms of age, CRP levels, the percentage of obese subjects, and concentrations of atherogenic lipid biomarkers, except higher TG in males and higher ANGPTL3 concentrations in females. Positive correlations of both ANGPTLs with TG, remnant-C, and sdLDL-C levels were found in females. In males, only ANGPTL3 correlated positively with atherogenic biomarkers, but there were no correlations with ANGPTL8. Concentrations of ANGPTL3 were higher in obese men, whereas ANGPTL8 levels were higher in obese women. In women alone, ANGPTL8 showed very good discrimination power to identify subjects with hypertriglyceridemia (AUC = 0.83). Contrary to this, ANGPTL3 was a better discriminator of hypertriglyceridemia (AUC = 0.78) in male subjects. Regression models, adjusted for age, sex, and BMI showed a weak but significant effect of ANGPTL8 to increase the risk of hypertriglyceridemia. Conclusions: In females, ANGPTL8 is more strongly associated with TRLs metabolism, whereas in males, ANGPTL3 plays a more important role. We suggest sex differences be taken into consideration when applying new therapies with angiopoietin-like proteins inhibitors in the treatment of dyslipidemia.

Hypertriglyceridemia-associated acute pancreatitis: Response to continuous insulin infusion.

OBJECTIVE: To assess the response of serum triglycerides (TG) to continuous insulin infusion (CII) in adults with hypertriglyceridemia-associated acute pancreatitis (HTGP). METHODS: Retrospective analysis of TG response to standardized CII therapy in 77 adults admitted to intensive care with TG >1000 mg/dL and HTGP. RESULTS: Participants had initial TG 3869.0 [2713.5, 5443.5] mg/dL and were 39.3 ± 9.7 years old, 66.2% males, 58.4% Hispanic, BMI 30.2 [27.0, 34.8] kg/m2, 74.0% with diabetes mellitus (DM) and 50.6% with excess alcohol use. TG-goal, defined as ≤1,000 ± 100 mg/dL, was achieved in 95%. Among the 73 TG-goal achievers (responders), 53.4% reached TG-goal in <36 hours after CII initiation (rapid responders). When compared to slow responders taking≥36 hours, rapid responders had lower initial TG (2862.0 [1965.0, 4519.0] vs 4814.5 [3368.8, 6900.0] mg/dL), BMI (29.4 [25.9, 32.8] vs 31.9 [28.2, 38.3] kg/m2), DM prevalence (56.4 vs 94.1%), and reached TG-50% (half of respective initial TG) faster (12.0 [6.0, 17.0] vs 18.5 [13.0, 32.8] hours). Those with DM (n = 57) vs non-DM (n = 20) were obese (31.4 [28.0, 35.6] vs 27.8 [23.6, 30.3] kg/m2), took longer to reach TG-final (41.0 [25.0, 60.5] vs 14.5 [12.5, 25.5] hours) and used more daily insulin (1.7 [1.3, 2.1] vs 1.1 [0.5, 1.9] U/kg/day). Among those with DM, the rapid responders had higher daily use of insulin vs slow responders 1.9 [1.4, 2.3] vs 1.6 [1.1, 1.8] U/kg/day. All results significant. In multivariable analysis, predictors of faster TG response were absence of DM, lower BMI and initial TG. CONCLUSION: CII was effective in reaching TG-goal in 95% of patients with HTGP. Half achieved TG-goal within 36 hours. Presence of DM, higher BMI and initial TG slowed the time to reach TG-goal. These baseline parameters and rate of decline to TG-50% may be real-time indicators to initiate and adjust the CII for quicker response.

A Systems Approach Dissociates Fructose-Induced Liver Triglyceride from Hypertriglyceridemia and Hyperinsulinemia in Male Mice.

The metabolic syndrome (MetS), defined as the co-occurrence of disorders including obesity, dyslipidemia, insulin resistance, and hepatic steatosis, has become increasingly prevalent in the world over recent decades. Dietary and other environmental factors interacting with genetic predisposition are likely contributors to this epidemic. Among the involved dietary factors, excessive fructose consumption may be a key contributor. When fructose is consumed in large amounts, it can quickly produce many of the features of MetS both in humans and mice. The mechanisms by which fructose contributes to metabolic disease and its potential interactions with genetic factors in these processes remain uncertain. Here, we generated a small F2 genetic cohort of male mice derived from crossing fructose-sensitive and -resistant mouse strains to investigate the interrelationships between fructose-induced metabolic phenotypes and to identify hepatic transcriptional pathways that associate with these phenotypes. Our analysis indicates that the hepatic transcriptional pathways associated with fructose-induced hypertriglyceridemia and hyperinsulinemia are distinct from those that associate with fructose-mediated changes in body weight and liver triglyceride. These results suggest that multiple independent mechanisms and pathways may contribute to different aspects of fructose-induced metabolic disease.

New Therapies for Lowering Triglyceride-Rich Lipoproteins: JACC Focus Seminar 3/4.

Emerging evidence suggests that elevated concentrations of triglyceride-rich lipoprotein remnants (TRLs) derived from hepatic and intestinal sources contribute to the risk of atherosclerotic cardiovascular events. Natural selection studies support a causal role for elevated concentrations of remnant cholesterol and the pathways contributing to perturbations in metabolic pathways regulating TRLs with an increased risk of atherosclerotic cardiovascular disease events. New therapies targeting select catalytic pathways in TRL metabolism reduce atherosclerosis in experimental models, and concentrations of TRLs in patients with a vast range of triglyceride levels. Clinical trials with inhibitors of angiopoietin-like 3 protein and apolipoprotein C-III will be required to provide further guidance on the potential contribution of these emerging therapies in the paradigm of cardiovascular risk management in patients with elevated remnant cholesterol.

Clinical characteristics of cardiovascular patients with extremely low levels of high-density lipoprotein cholesterol.

BACKGROUND: Extremely low levels of high-density lipoprotein cholesterol (HDL-C) are related to high cardiovascular mortality. The underlying mechanism is not well known. This research aims to study the clinical characteristics of cardiovascular patients with extremely low levels of HDL-C. METHODS: All cardiovascular patients in a single Chinese cardiology center that were admitted from January to December 2019 were reviewed. The clinical characteristics of those with HDL-C<20 mg/dL were investigated. RESULTS: A total of 20,655 individuals were enrolled. Of these, 52.17 % were males, and the average age was 58.20 ± 12.98 years old. The prevalence of HDL-C<20 mg/dL was 0.47 % for all patients (N=98) and 1.05 % for inpatients. Of those with HDL-C<20 mg/dL, 88.8 % were inpatients, and 77.6 % were males. Their average age was 60.7 ± 15.1 years. Compared with matched patients with normal HDL-C, systemic inflammation (OR= 5.556, 95% CI 2.798-11.030), hypoalbuminemia (OR=5.714, 95% CI 2.702-12.085), hyperuricemia (OR=5.156, 95% CI 2.560-10.386), low T3 syndrome (OR=4.278, 95% CI 1.627-11.245), anemia (OR=3.577, 95% CI 1.680-7.617), diabetes (OR=3.534, 95% CI 1.693-7.376) and hypertriglyceridemia (OR=2.493, 95% CI 1.264-4.918) were identified as adverse concomitant factors of extremely low HDL-C. HDL-C levels were inversely correlated with the total risk scores in patients with HDL-C<20 mg/dL (r=-0.381, P<0.001) and more significantly correlated in patients with HDL-C<15 mg/dL (r=-0.511, P=0.004). CONCLUSIONS: Extremely low levels of HDL-C tend to occur more frequently in males, older individuals and inpatients. For cardiovascular patients, extremely low levels of HDL-C are usually due to the presence of multiple adverse factors with relatively severe conditions. This could explain the high cardiovascular mortality of individuals with extremely low levels of HDL-C.

Postprandial endothelial dysfunction and CIMT after oral fat challenge in patients with type 2 diabetes mellitus with and without macrovascular disease - A preliminary study.

BACKGROUND: Very few studies have reported on association of postprandial lipids and endothelial dysfunction among patients with diabetes. Whether endothelial dysfunction particularly postprandial FMD is worse in patients with T2DM with macrovascular disease compared to those without and whether this difference is related to postprandial hypertriglyceridemia (PPHTg) is unclear. Therefore, present study was aimed to assess the relationship between PPHTg and endothelial function in patients with T2DM with and without macrovascular disease. METHOD: Endothelial dysfunction by FMD and CIMT were compared in patients with T2DM with and without macrovascular disease (n = 13 each group) and 13 age, sex and BMI matched healthy individuals after an oral fat challenge. RESULTS: There was significant postprandial deterioration of FMD 4-hr after fat challenge in patients with diabetes (P < 0.001) as well as healthy individuals (P = 0.004). Patients with diabetes with macrovascular disease had significantly lower fasting (5.7 ± 6.1% vs. 22.7 ± 10.0% and vs. 24.7 ± 5.3%) as well as postprandial (4-hr) (3.1 ± 5.0% vs. 15.3 ± 8.1% and vs. 15.4 ± 5.7%) FMD compared to other two groups. Fasting, postprandial as well as change in FMD and CIMT in patients with diabetes correlated significantly with fasting as well as postprandial triglycerides with stronger correlation in those with macrovascular disease. CONCLUSION: Study found significant endothelial dysfunction by FMD that shows substantial further deterioration postprandially following high fat meal in patients with diabetes with macrovascular disease compared to patients with diabetes without macrovascular disease and healthy individuals. Study also indicates that PPHTg is a contributor to endothelial dysfunction. However, more studies are required to corroborate these findings.

Effect of plasmapheresis versus standard treatment in preventing recurrent acute pancreatitis in Chinese patients with hypertriglyceridemia.

The present study designed to compare the effect of plasmapheresis (PPH) versus standard treatment (STD) in preventing recurrent AP in Chinese patients with severe hypertriglyceridemia. Chinese patients aged 18 to 65 years who had history of hypertriglyceridemia (>1000mg/dl) induced acute pancreatitis were assigned to plasmapheresis (up to 1.5 ml daily TG level reaches 500 mg/dl or less) or standard treatment (1:1). Standard treatment (STD) includes limited oral intake (pancreatic rest), intravenous hydration and pain management. Primary endpoint was incidence of recurrent acute pancreatitis. A total of 14% of patients in PPH group (N=50) had experienced recurrent pancreatitis as compared to 24% of patients in STD group (N=50). Also, TG clearance rate in 24 hours was substantially higher in PPH group as compared to STD. Time required to reach target TG was significantly lower in patients treated with PPH as compared to STD. Lower incidence of local complications was observed in PPH group as compared to STD. Length of stay was significantly shorter in patients of plasmapheresis group as compared to standard treatment. The results of this study recommend the use of plasmapheresis as a better alternative in preventing recurrent AP in Chinese patients with severe hypertriglyceridemia.

Hypertriglyceridemia during hospitalization independently associates with mortality in patients with COVID-19.

BACKGROUND: Alteration in blood triglyceride levels have been found in patients with coronavirus disease 2019 (COVID-19). However, the association between hypertriglyceridemia and mortality in COVID-19 patients is unknown. OBJECTIVE: To investigate the association between alteration in triglyceride level and mortality in hospitalized COVID-19 patients. METHODS: We conducted a retrospective study of 600 hospitalized patients with COVID-19 diagnosis (ICD10CM:U07.1) and/or SARS-CoV-2 positive testing results between March 1, 2020 and December 21, 2020 at a tertiary academic medical center in Milwaukee, Wisconsin. De-identified data, including demographics, medical history, and blood triglyceride levels were collected and analyzed. Of the 600 patients, 109 patients died. The triglyceride value on admission was considered the baseline and the peak was defined as the highest level reported during the entire period of hospitalization. Hypertriglyceridemia was defined as greater than 150 mg/dl. Logistic regression analyses were performed to evaluate the association between hypertriglyceridemia and mortality. RESULTS: There was no significant difference in baseline triglyceride levels between non-survivors (n = 109) and survivors (n = 491) [Median 127 vs. 113 mg/dl, p = 0.213]. However, the non-survivors had significantly higher peak triglyceride levels during hospitalization [Median 179 vs. 134 mg/dl, p < 0.001]. Importantly, hypertriglyceridemia independently associated with mortality [odds ratio=2.3 (95% CI: 1.4-3.7, p = 0.001)], after adjusting for age, gender, obesity, history of hypertension and diabetes, high CRP, high leukocyte count and glucocorticoid treatment in a multivariable logistic regression model. CONCLUSIONS: Hypertriglyceridemia during hospitalization is independently associated with 2.3 times higher mortality in COVID-19 patients. Prospective studies are needed to independently validate this retrospective analysis.

Treatment of Chinese Patients with Hypertriglyceridemia with a Pharmaceutical-Grade Preparation of Highly Purified Omega-3 Polyunsaturated Fatty Acid Ethyl Esters: Main Results of a Randomized, Double-Blind, Controlled Trial.

INTRODUCTION: The lipid-modifying potential of omega-3 polyunsaturated fatty acids in Chinese patients is under-researched. We conducted a multicenter, randomized, placebo-controlled, double-blind, parallel-group study of twice-daily treatment with OMACOR (OM3EE), a prescription-only formulation of highly purified ethyl esters of omega-3 polyunsaturated fatty acids in Chinese adult patients (≥18 years) who had elevated baseline fasting serum triglycerides (TG). METHODS: Patients were stratified according to the severity of their hypertriglyceridemia (severe HTG, with baseline TG ≥500 and <1000 mg/dL or moderate HTG, with baseline TG >200 and <500 mg/dL) or use of statins. Patients randomized to OM3EE therapy received 2 g/day for 4 weeks, then 4 g/day for 8 weeks. The primary efficacy endpoint was the percentage change in fasting serum TG between baseline and the end of treatment in patients with severe HTG. The study was concluded after a planned interim analysis demonstrated a significant TG-lowering effect of OM3EE in that contingent (p=0.0019). RESULTS: The mean TG end-of-treatment effect of OM3EE was -29.46% (standard deviation 40.60%) in the severe HTG contingent compared with +0.26% (standard deviation 54.68%) in the placebo group. Corresponding changes were -12.12% and -23.25% in the moderate HTG and combination cohorts (vs +55.45% and +6.24% in relevant placebo groups). A dose-dependent reduction in TG was evident in all patient contingents. Safety and tolerability of OM3EE were in line with previous experience. DISCUSSION: These data indicate that OMACOR therapy at a dose of 2-4 g/day is an effective treatment for Chinese patients with raised TG levels and is well tolerated.

Repetitive spikes of glucose and lipid induce senescence-like phenotypes of bone marrow stem cells through H3K27me3 demethylase-mediated epigenetic regulation.

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to endothelial repair and angiogenesis. Reduced number of circulating EPCs is associated with future cardiovascular events. We tested whether dysregulated glucose and/or triglyceride (TG) metabolism has an impact on EPC homeostasis. The analysis of metabolic factors associated with circulating EPC number in humans revealed that postprandial hyperglycemia is negatively correlated with circulating EPC number, and this correlation appears to be further enhanced in the presence of postprandial hypertriglyceridemia (hTG). We therefore examined the effect of glucose/TG spikes on bone marrow lineage-sca-1+ c-kit+ (LSK) cells in mice, because primitive EPCs reside in bone marrow LSK fraction. Repetitive glucose + lipid (GL) spikes, but not glucose (G) or lipid (L) spikes alone, induced senescence-like phenotypes of LSK cells, and this phenomenon was reversible after cessation of GL spikes. G spikes and GL spikes differentially affected transcriptional program of LSK cell metabolism and differentiation. GL spikes upregulated a histone H3K27 demethylase JMJD3, and inhibition of JMJD3 eliminated GL spikes-induced LSK cell senescence-like phenotypes. These observations suggest that postprandial glucose/TG dysmetabolism modulate transcriptional regulation in LSK cells through H3K27 demethylase-mediated epigenetic regulation, leading to senescence-like phenotypes of LSK cells, reduced number of circulating EPCs, and development of atherosclerotic cardiovascular disease.NEW & NOTEWORTHY Combination of hyperglycemia and hypertriglyceridemia is associated with increased risk of atherosclerotic cardiovascular disease. We found that 1) hypertriglyceridemia may enhance the negative impact of hyperglycemia on circulating EPC number in humans and 2) metabolic stress induced by glucose + triglyceride spikes in mice results in senescence-like phenotypes of bone marrow stem/progenitor cells via H3K27me3 demethylase-mediated epigenetic regulation. These findings have important implications for understanding the pathogenesis of atherosclerotic cardiovascular disease in patients with T2DM.