Validation of Nutritional Approaches to Modulate Cardiovascular and Diabetic Risk Factors in Patients with Hypertriglyceridemia or Prediabetes-The MoKaRi II Randomized Controlled Study.

Hypertriglyceridemia and diabetes mellitus type 2 are among the most important metabolic diseases globally. Diet plays a vital role in the development and progression of both clinical pictures. For the 10-week randomized, controlled, intervention study, 67 subjects with elevated plasma triglyceride (TG) concentrations (≥1.7 mmol/L) and 69 subjects with elevated fasting glucose concentrations (≥5.6 < 7.0 mmol/L) were recruited. The intervention groups received specially developed, individualized menu plans and regular counseling sessions to lower (A) TG or (B) fasting glucose and glycated hemoglobin A1c as well as other cardiovascular and diabetic risk factors. The hypertriglyceridemia intervention group was further supplemented with fish oil (3.5 g/d eicosapentaenoic acid + docosahexaenoic acid). The two control groups maintained a typical Western diet. Blood samples were taken every 2 weeks, and anthropometric data were collected. A follow-up examination was conducted after another 10 weeks. In both intervention groups, there were comparable significant reductions in blood lipids, glucose metabolism, and anthropometric parameters. These results were, with a few exceptions, significantly more pronounced in the intervention groups than in the corresponding control groups (comparison of percentage change from baseline). In particular, body weight was reduced by 7.4% (6.4 kg) and 7.5% (5.9 kg), low-density lipoprotein cholesterol concentrations by 19.8% (0.8 mmol/L) and 13.0% (0.5 mmol/L), TG concentrations by 18.2% (0.3 mmol/L) and 13.0% (0.2 mmol/L), and homeostatic model assessment for insulin resistance by 31.8% (1.1) and 26.4% (0.9) (p < 0.05) in the hypertriglyceridemia and prediabetes intervention groups, respectively. Some of these changes were maintained until follow-up. In patients with elevated TG or fasting glucose, implementing individualized menu plans in combination with regular counseling sessions over 10 weeks led to a significant improvement in cardiovascular and diabetic risk factors.

Assessment of triglyceride clearance of haemoperfusion from three cases of hypertriglyceridaemia-induced acute pancreatitis: a case series.

Rapid reduction of plasma triglycerides (TG) is believed to improve the outcome of pancreatitis in the context of hypertriglyceridaemia (HTG)-induced acute pancreatitis (HTG-AP). Previous studies have suggested that haemoperfusion (HP) with the Jafron cartridge series could be effective for reducing TG concentrations in patients with HTG-AP. However, the clearance capacity (CC) for TG removal has not been reported. This case series reports on data from three patients with HTG-AP who underwent HP with HA230 or HA330 cartridges. Blood samples were collected from both before and after the cartridge circuit every 30 min and the CC was calculated. Twelve pairs of blood samples were collected for each type of HP cartridge. The mean ± SD CC of the HA230 cartridge for TG removal in this case series was 0.009781 ± 1.117235 ml/min (95% confidence interval [CI], -0.7000762, 0.7196384 ml). The mean ± SD CC of the HA330 cartridge for TG removal in this case series was 0.344914 ± 1.412183 ml/min (95% CI, -0.5523448, 1.2421721 ml). Based on the findings of this small case series, special caution is advised when considering the use of the HA230 and HA330 cartridges for reducing blood TG concentration pending further conclusive evidence from larger studies.

Association of admission serum triglyceride levels with intensive care unit hospitalization rates in acute pancreatitis patients: A retrospective study.

Acute pancreatitis (AP) is a complex and unpredictable condition, of which hypertriglyceridemia (HTG) is the third most prevalent cause. This study aimed to conduct a retrospective analysis of clinical data from hospitalized AP patients to uncover a potential correlation between triglyceride (TG) levels and the necessity for intensive care unit (ICU) admission. This retrospective cohort study utilized the Medical Information Mart for Intensive Care IV 2.2 (MIMIC-IV) critical care dataset, incorporating data from 698 patients with hypertriglyceridemic acute pancreatitis (HTG-AP). The analysis employed the RCS model along with univariate and multivariate logistic regression methods to affirm the association between triglyceride levels and ICU admission. Subgroup analysis was performed to investigate specific populations. The study included 698 patients with AP, 42.41% of whom experienced HTG during hospitalization. RCS analysis revealed a linear association between TG levels and risk of ICU admission (p for nonlinear = .219, p for overall = .009). Multivariate logistic regression analysis indicated an increased risk of ICU admission in the TG range of 1.7-5.65 mmol/L (aOR = 1.83, 95% CI 1.12-2.99, P = .015) and TG >11.3 mmol/L (aOR = 5.69, 95% CI 2.36-13.74, P < .001) compared to the normal group. Similar results were observed across the various subgroups. As triglyceride levels increased, there was a corresponding increase in ICU admissions. Patients within the 1.7 to 5.65 mmol/L and > 11.3 mmol/L triglyceride groups exhibited higher rates of ICU admissions. Moreover, we observed a higher risk of ICU hospitalization even with mild TG elevation.

Glycemic Index, Glycemic Load and Dyslipidemia in Adolescents from Chiapas, Mexico.

Cardiovascular disease risk throughout the life course is increased by abnormal blood lipid levels in youth. The dietary glycemic index (GI) and glycemic load (GL) during adolescence might be related to abnormal blood lipids. This study aimed to analyze the association between dietary GI, GL and dyslipidemia in adolescents from two marginalized regions of Chiapas, Mexico. A cross-sectional study was conducted with 213 adolescents. Food intake was assessed using 24 h recalls. The association between dyslipidemia and dietary GI or GL was tested by using logistic regression models. Low HDL-c was the most prevalent risk factor (47.4%), followed by hypertriglyceridemia (25.4%). In this population, overall dietary GI was not associated with dyslipidemia. A high dietary GL was associated with 2.39 higher odds of low HDL-c (95% CI: 1.21-4.74) when compared to low GL. Female adolescents with high dietary GL had 3.20 higher odds of hypertriglyceridemia (95% CI: 1.03-9.88), whereas no association was found for males. No associations were observed between overall dietary GL and total cholesterol or LDL-c. In adolescents from urban and rural communities in Chiapas, a high dietary GL was associated with a detrimental effect on HDL-c. In female adolescents, high GL was associated with hypertriglyceridemia.

Prediction of severe hypertriglyceridemia-associated acute pancreatitis using a nomogram based on CT findings and blood biomarkers.

Hypertriglyceridemia is a common cause of acute pancreatitis (AP). Fatty liver, a manifestation of metabolic syndrome, is related to the severity of AP. The present study aimed to construct an accurate predictive model for severe AP (SAP) by combining the fatty liver infiltration on a computerized tomography (CT) scan with a series of blood biomarkers in patients with hypertriglyceridemia-associated AP (HTG-AP). A total of 213 patients diagnosed with HTG-AP were included in the present retrospective study. Clinical information and imageological findings were retrospectively analyzed. The model was constructed from independent risk factors using univariate analysis, the least absolute shrinkage and selection operator method. Subsequently, the data from the training group of 111 patients with HTG-AP was analyzed using logistic regression analysis. The efficacy of the model was verified using an external validation group of 102 patients through the receiver operating characteristic curve (ROC). Independent predictors, including serum calcium, C-reactive protein, lactate dehydrogenase and liver-to-spleen CT attenuation ratio (L/S ratio), were incorporated into the nomogram model for SAP in HTG-AP. The model achieved a sensitivity of 91.3% and a specificity of 88.6% in the training group. Compared with the Ranson model, the established nomogram model exhibited a better discriminative ability in the training group [area under the curve (AUC): 0.957] and external validation group (AUC: 0.930), as well as better calibration and clinical benefits. The present study demonstrates that the constructed nomogram based on CT findings and blood biomarkers is useful for the accurate prediction of SAP in HTG-AP.

Olezarsen, Acute Pancreatitis, and Familial Chylomicronemia Syndrome.

BACKGROUND: Familial chylomicronemia syndrome is a genetic disorder associated with severe hypertriglyceridemia and severe acute pancreatitis. Olezarsen reduces the plasma triglyceride level by reducing hepatic synthesis of apolipoprotein C-III. METHODS: In a phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with genetically identified familial chylomicronemia syndrome to receive olezarsen at a dose of 80 mg or 50 mg or placebo subcutaneously every 4 weeks for 49 weeks. There were two primary end points: the difference between the 80-mg olezarsen group and the placebo group in the percent change in the fasting triglyceride level from baseline to 6 months, and (to be assessed if the first was significant) the difference between the 50-mg olezarsen group and the placebo group. Secondary end points included the mean percent change from baseline in the apolipoprotein C-III level and an independently adjudicated episode of acute pancreatitis. RESULTS: A total of 66 patients underwent randomization; 22 were assigned to the 80-mg olezarsen group, 21 to the 50-mg olezarsen group, and 23 to the placebo group. At baseline, the mean (±SD) triglyceride level among the patients was 2630±1315 mg per deciliter, and 71% had a history of acute pancreatitis within the previous 10 years. Triglyceride levels at 6 months were significantly reduced with the 80-mg dose of olezarsen as compared with placebo (-43.5 percentage points; 95% confidence interval [CI], -69.1 to -17.9; P<0.001) but not with the 50-mg dose (-22.4 percentage points; 95% CI, -47.2 to 2.5; P = 0.08). The difference in the mean percent change in the apolipoprotein C-III level from baseline to 6 months in the 80-mg group as compared with the placebo group was -73.7 percentage points (95% CI, -94.6 to -52.8) and between the 50-mg group as compared with the placebo group was -65.5 percentage points (95% CI, -82.6 to -48.3). By 53 weeks, 11 episodes of acute pancreatitis had occurred in the placebo group, and 1 episode had occurred in each olezarsen group (rate ratio [pooled olezarsen groups vs. placebo], 0.12; 95% CI, 0.02 to 0.66). Adverse events of moderate severity that were considered by a trial investigator at the site to be related to the trial drug or placebo occurred in 4 patients in the 80-mg olezarsen group. CONCLUSIONS: In patients with familial chylomicronemia syndrome, olezarsen may represent a new therapy to reduce plasma triglyceride levels. (Funded by Ionis Pharmaceuticals; Balance ClinicalTrials.gov number, NCT04568434.).

Olezarsen for Hypertriglyceridemia in Patients at High Cardiovascular Risk.

BACKGROUND: Reducing the levels of triglycerides and triglyceride-rich lipoproteins remains an unmet clinical need. Olezarsen is an antisense oligonucleotide targeting messenger RNA for apolipoprotein C-III (APOC3), a genetically validated target for triglyceride lowering. METHODS: In this phase 2b, randomized, controlled trial, we assigned adults either with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) in a 1:1 ratio to either a 50-mg or 80-mg cohort. Patients were then assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the percent change in the triglyceride level from baseline to 6 months, reported as the difference between each olezarsen group and placebo. Key secondary outcomes were changes in levels of APOC3, apolipoprotein B, non-high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein (LDL) cholesterol. RESULTS: A total of 154 patients underwent randomization at 24 sites in North America. The median age of the patients was 62 years, and the median triglyceride level was 241.5 mg per deciliter. The 50-mg and 80-mg doses of olezarsen reduced triglyceride levels by 49.3 percentage points and 53.1 percentage points, respectively, as compared with placebo (P<0.001 for both comparisons). As compared with placebo, each dose of olezarsen also significantly reduced the levels of APOC3, apolipoprotein B, and non-HDL cholesterol, with no significant change in the LDL cholesterol level. The risks of adverse events and serious adverse events were similar in the three groups. Clinically meaningful hepatic, renal, or platelet abnormalities were uncommon, with similar risks in the three groups. CONCLUSIONS: In patients with predominantly moderate hypertriglyceridemia at elevated cardiovascular risk, olezarsen significantly reduced levels of triglycerides, apolipoprotein B, and non-HDL cholesterol, with no major safety concerns identified. (Funded by Ionis Pharmaceuticals; Bridge-TIMI 73a ClinicalTrials.gov number, NCT05355402.).

Acute pancreatitis risk in multifactorial chylomicronemia syndrome depends on the molecular cause of severe hypertriglyceridemia.

BACKGROUND AND AIMS: Multifactorial chylomicronemia syndrome (MCS) is a severe form of hypertriglyceridemia (hyperTG) associated with an increased risk of acute pancreatitis (AP). Severe hyperTG is mainly polygenic in nature, either caused by the presence of heterozygous pathogenic variants (PVs) in TG-related metabolism genes or by accumulation of common variants in hyperTG susceptibility genes. This study aims to determine if the risk of AP is similar amongst MCS patients with different molecular causes of severe hyperTG. METHODS: This study included 114 MCS patients who underwent genetic testing for PVs in TG-related metabolism genes and 16 single nucleotide polymorphisms (SNPs) in hyperTG susceptibility genes. A weighted TG-polygenic risk score (TG-PRS) was calculated. A TG-PRS score ≥ 90th percentile was used to define a high TG-PRS. RESULTS: Overall, 66.7% of patients had severe hyperTG of polygenic origin. MCS patients with only a PV and those with both a PV and high TG-PRS were more prone to have maximal TG concentration ≥ 40 mmol/L (OR 5.33 (1.55-18.36); p = 0.008 and OR 5.33 (1.28-22.25); p = 0.02), as well as higher prevalence of AP (OR 3.64 (0.89-14.92); p = 0.07 and OR 11.90 (2.54-55.85); p = 0.002) compared to MCS patients with high TG-PRS alone. CONCLUSIONS: This is the first study to show that MCS caused by a high TG-PRS and a PV is associated with higher risk of AP, similar to what is seen in the monogenic form of severe hyperTG. This suggests that determining the molecular cause of severe hyperTG could be useful to stratify the risk of pancreatitis in MCS.

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. RECENT FINDINGS: ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. SUMMARY: Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

Genetic and biochemical analysis of severe hypertriglyceridemia complicated with acute pancreatitis or with low post-heparin lipoprotein lipase mass.

Severe hypertriglyceridemia is a pathological condition caused by genetic factors alone or in combination with environmental factors, sometimes leading to acute pancreatitis (AP). In this study, exome sequencing and biochemical analyses were performed in 4 patients with hypertriglyceridemia complicated by obesity or diabetes with a history of AP or decreased post-heparin LPL mass. In a patient with a history of AP, SNP rs199953320 resulting in LMF1 nonsense mutation and APOE rs7412 causing apolipoprotein E2 were both found in heterozygous form. Three patients were homozygous for APOA5 rs2075291, and one was heterozygous. ELISA and Western blot analysis of the serum revealed the existence of apolipoprotein A-V in the lipoprotein-free fraction regardless of the presence or absence of rs2075291; furthermore, the molecular weight of apolipoprotein A-V was different depending on the class of lipoprotein or lipoprotein-free fraction. Lipidomics analysis showed increased serum levels of sphingomyelin and many classes of glycerophospholipid; however, when individual patients were compared, the degree of increase in each class of phospholipid among cases did not coincide with the increases seen in total cholesterol and triglycerides. Moreover, phosphatidylcholine, lysophosphatidylinositol, and sphingomyelin levels tended to be higher in patients who experienced AP than those who did not, suggesting that these phospholipids may contribute to the onset of AP. In summary, this study revealed a new disease-causing gene mutation in LMF1, confirmed an association between overlapping of multiple gene mutations and severe hypertriglyceridemia, and suggested that some classes of phospholipid may be involved in the pathogenesis of AP.

Impact of pemafibrate on lipid profile and insulin resistance in hypertriglyceridemic patients with coronary artery disease and metabolic syndrome.

This study examined the effects of pemafibrate, a selective peroxisome proliferator-activated receptor α agonist, on the serum biochemical parameters of male patients with coronary artery disease and metabolic syndrome (MetS). This was a post hoc analysis of a randomized, crossover study that treated hypertriglyceridemia with pemafibrate or bezafibrate for 24 weeks, followed by a crossover of another 24 weeks. Of the 60 patients enrolled in the study, 55 were male. Forty-one of 55 male patients were found to have MetS. In this sub-analysis, male patients with MetS (MetS group, n = 41) and those without MetS (non-MetS group, n = 14) were compared. The primary endpoint was a change in fasting serum triglyceride (TG) levels during pemafibrate therapy, and the secondary endpoints were changes in insulin resistance-related markers and liver function parameters. Serum TG levels significantly decreased (MetS group, from 266.6 to 148.0 mg/dL, p < 0.001; non-MetS group, from 203.9 to 97.6 mg/dL, p < 0.001); however, a percent change (%Change) was not significantly different between the groups (- 44.1% vs. - 51.6%, p = 0.084). Serum insulin levels and homeostasis model assessment of insulin resistance significantly decreased in the MetS group but not in the non-MetS group. %Change in liver enzyme levels was markedly decreased in the MetS group compared with that in the non-MetS group (alanine aminotransferase, - 25.1% vs. - 11.3%, p = 0.027; gamma-glutamyl transferase, - 45.8% vs. - 36.2%, p = 0.020). In conclusion, pemafibrate can effectively decrease TG levels in patients with MetS, and it may be a more efficient drug for improving insulin resistance and liver function in such patients.

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.