Combined Hyperlipidemia Research Articles

The Emerging Potential of Apolipoprotein C-III Inhibition for ASCVD Prevention: A State-of-the-Art Review.

Multiple agents are being developed that inhibit apolipoprotein (apo) C-III. This state-of-the-art review examines their potential for atherosclerotic cardiovascular disease (ASCVD) risk reduction. Apo C-III, an apolipoprotein on the surface of triglyceride-rich lipoproteins (TRLs), impairs clearance of TRLs through both lipoprotein lipase dependent and independent pathways, thereby resulting in increased concentrations of triglycerides. Apo C-III has also been shown to have pro-atherogenic effects when bound to high-density lipoprotein (HDL) particles. Classical and genetic epidemiology studies provide support for the concept that apo C-III is associated with an increased risk of ASCVD events. Drug efficacy of agents that silence APOC3 mRNA has been studied in populations with varying hypertriglyceridemia severity, including those with familial chylomicronemia syndrome, multifactorial chylomicronemia syndrome/severe hypertriglyceridemia, and mixed hyperlipidemia. Randomized controlled trials have reported significant reductions in TG and non-HDL cholesterol levels among these patients treated with APOC3 inhibitors. Upcoming clinical outcomes trials seek to establish a role for APOC3 inhibitors to reduce risk of ASCVD.

Lipoprotein(a) and cardiovascular prognosis of familial dyslipidemias: data from a 10-year follow-up study

Abstract Background Familial dyslipidemias, such as heterozygous familial hypercholesterolemia (FH) and familial combined hyperlipidemia (FCH) are associated with premature cardiovascular (CV) disease. On the other hand, increased lipoprotein(a) [Lp(a)] is considered as the most prevalent monogenic lipid disorder in the general population. Purpose This study aimed to longitudinally follow up two specific populations with familial dyslipidemias associated with increased CV risk, namely FH and FCH, and compare them with reference to their CV prognosis, investigating in parallel the effect of Lp(a) levels. Methods 433 patients with FH (34% males, mean age 44.2±12.8 years) and 476 patients with FCH (57% males, mean age 49.0±11.1 years) from the outpatient lipid clinic of our hospital, without history of CV disease, who fulfilled the FH and FCH criteria, respectively, participated in the study. Participants were evaluated for a mean follow-up period of 9.6±7.6 years, with at least one annual visit. Venous blood samples were obtained at baseline in all patients for the determination of lipid profile and levels of Lp(a). All subjects were on lipid-lowering medication during the follow-up period. The endpoint of our study was the composite of major CV events (coronary artery disease events and stroke). Results The incidence of the composite endpoint of major CV events during the follow-up period in the total population was 6.5%, while it was greater in patients with FH compared to patients with FCH (8.1% vs 5.5%, p=0.03). Regarding CV risk factors, FCH compared to FH patients had greater prevalence of baseline hypertension (36% vs 9.7%, p<0.001) and diabetes (11% vs 2%, p<0.001), whereas FH patients had greater Lp(a) levels (37.4±40.3 vs 29.7±34.6 mg/dl, p<0.01). Multiple Cox regression analysis revealed that FH patients had greater CV risk compared to FCH patients (HR 2.17, 95% CI 1.10-4.26, p=0.02). Moreover, in FH patients, increased baseline Lp(a) levels (≥30mg/dl) were an independent predictor of major adverse CV events (HR 2.37 95% CI 1.41-4.90, p=0.02), whereas in FCH patients increased Lp(a) was not an independent predictor. In FCH patients the presence of diabetes at baseline was a strong independent prognosticator of adverse CV events (HR 3.56 95% CI 1.19-11.33, p=0.03), after adjustment for confounding factors. Conclusions FH patients have greater CV risk compared to FCH patients. In FH patients, the presence of increased Lp(a) doubles the CV risk, beyond low density lipoprotein cholesterol levels. On the other hand, in FCH patients the presence of diabetes triples the CV risk, whereas Lp(a) does not convey an independent prognostic value.

Combination therapy with GalNAc-siRNA drugs targeting both PCSK9 and APOC3 resulted in enhanced lipid lowering in mice

Abstract Introduction Aggressive lowering of both atherogenic low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) could reduce residual atherosclerotic cardiovascular disease (ASCVD) risk. Drugs targeting PCSK9 or APOC3 have shown good lipid-lowering effects in clinic. Here, we have developed GalNAc-conjugated siRNAs, RBD7022 targeting PCSK9 and RBD5044 targeting APOC3, as novel therapeutic agents to lower LDL-C and triglyceride (TG) plasma levels respectively. Each drug shows potent and durable effect in silencing its own target. However, it is unknown whether the combined therapy with siRNA drugs targeting both PCSK9 and APOC3 will generate enhanced effects in lipid lowering. Purpose To investigate the effects of fixed-dose combination of RBD7022 and RBD5044 on LDL-C, TG and total cholesterol (TC). Methods RBD7022 and RBD5044 completely match the human PCSK9 and APOC3 transcripts respectively. RBD7022 has 2 nucleotide mismatches with mouse pcsk9, but still shows silencing activity in mice, while RBD5044 has no activity due to 5 mismatches with mouse apoc3. Therefore, humanized APOC3 transgenic mice were used in this study, which had serious hypertriglyceridemia with relatively high cholesterol and TG levels. They were randomized into 8 groups with treatment of RBD7022 (1 mg/kg or 3 mg/kg), RBD5044 (3 mg/kg or 6 mg/kg), or 3 different dose combinations of RBD7022 and RBD5044, as well as PBS control. All animals were administrated once on Day 1. Plasma was collected to quantify lipid biomarkers. Results RBD7022 showed a robust effect on LDL-C reduction, with inhibition rates of 45% in 3 mg/kg and 43% in 6 mg/kg, indicating 3 mg/kg was a saturated dose for RBD7022 in LDL-C lowering. RBD5044 showed a dose-dependent effect on LDL-C reduction, with inhibition rate of 52% at 1 mg/kg and 59% at 3 mg/kg. Interestingly, significantly enhanced LDL-C reduction was observed in the combination groups, with 67% reduction in LDL-C at RBD5044 1 mg/kg plus RBD7022 3 mg/kg, 73% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 3 mg/kg and 78% reduction in LDL-C at RBD5044 3 mg/kg plus RBD7022 6 mg/kg, showing dose-dependent effects (Figure 1A). Enhanced TC reduction was also found in combination at RBD5044 3 mg/kg plus RBD7022 6 mg/kg compared with RBD5044 or RBD7022 alone. RBD5044 showed a dose dependent effect on TG reduction with inhibition rates of 56% at 1 mg/kg and 83% at 3 mg/kg. RBD7022 treatment alone did not show significant effect on TG reduction. No added effects of RBD7022 on TG levels was found in the combination with RBD5044, indicating the TG lowering was induced by RBD5044. Conclusions The combination of RBD7022 targeting PCSK9 and RBD5044 targeting APOC3 simultaneously reduce LDL-C and TC levels. The combination of RBD7022 and RBD5044 could be a better therapeutic option to further reduce LDL-C, particularly for mixed hyperlipidemia patients and other high-risk individuals with both high LDL-C and high TG levels.Figure 1

Comparison of Atorvastatin Alone and its Combination with Ezetimibe among Mixed Hyperlipidemic Patients

Background: Lowering the lipid levels remains the basis of recent medical therapy for preventing cardiovascular events. Statin treatment to attain target low-density lipoprotein cholesterol (LDL-C) levels is still associated with residual risk. Objective: To compare the efficacy of Atorvastatin and Atorvastatin combined with Ezetimibe among mixed hyperlipidemic patients. Methodology: This was a prospective interventional study among the 58 diagnosed mixed hyperlipidemic patients in the outpatient department (OPD) of the Department of Cardiology at the Sylhet MAG Osmani Medical College Hospital during February to November, 2023. Patients were divided into two groups. Group I had a combination of Atorvastatin 10mg and Ezetimibe 10mg, whereas Group II took Tab. Atorvastatin 20mg once daily at night for 12 weeks. Results: After 12 weeks of treatment, a comparison of lipid profile changes between the combination therapy group and the Atorvastatin group revealed a significant reduction (p<0.05) in total cholesterol (35.7% vs. 30.1%), triglycerides (30.6% vs. 16%), and LDL-C (47.5% vs. 40.1%). In the combination therapy group, ALT levels increased by 4.6%, compared to a 3.8% increase with Atorvastatin treatment alone. Combination therapy led to a 2.07% elevation in CK levels, while the Atorvastatin treatment group showed a 1.9% increase in CK values. The differences in HDL-C, ALT, and CK levels between the two groups were not statistically significant (p>0.05). Conclusion: The study revealed that combination therapy of Atorvastatin with Ezetimibe is more effective in reducing LDL-C, TG, and total cholesterol in patients with mixed hyperlipidemia compared to Atorvastatin alone. Journal of Monno Medical College June, 2024; 10 (1):23-29

Familial hypercholesterolaemia with high triglycerides: A diagnostic challenge.

Combined or mixed hyperlipidaemia is characterised by hypercholesterolaemia together with high triglyceride concentrations. It is found in approximately 1 in 100 people in the United Kingdom. Most cases are secondary to an underlying condition such as the metabolic syndrome, diabetes mellitus (especially poorly controlled) or individuals with a high alcohol intake. Mixed hyperlipidaemia is also a feature of some primary hyperlipidaemia conditions such familial combined hyperlipidaemia (FCH) or type III hyperlipidaemia (dysbetalipoproteinaemia). One differential diagnosis for mixed hyperlipidaemia that can easily be overlooked is a patient with an underlying diagnosis of familial hypercholesterolaemia (FH) who also has a hypertriglyceridaemia due to any other cause. Those patients may have very high total and low-density lipoprotein cholesterol concentrations (LDL-C) with a moderately elevated triglyceride concentration. In this article, we report 4 cases of familial hypercholesterolaemia, confirmed by genetic testing, in patients initially presenting with hypertriglyceridaemia in addition to high total cholesterol and LDL-C. This article discusses the diagnostic challenges associated with this presentation and highlights the key role of directly measuring LDL-C to aid diagnosis in these specific situations.

Recaticimab Monotherapy for Nonfamilial Hypercholesterolemia and Mixed Hyperlipemia: The Phase 3 REMAIN-1 Randomized Trial

BackgroundMonoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have been used to reduce the level of low-density lipoprotein cholesterol (LDL-C), but require either biweekly or monthly dosing frequency. Recaticimab is a new humanized monoclonal antibody selectively targeting PCSK9, with long-acting characteristic. ObjectivesThe purpose of this study was to assess the efficacy and safety of recaticimab monotherapy in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk, and to explore different dosing strategies to provide patients with flexible administration options. MethodsThis was a randomized, double-blind, placebo-controlled, phase 3 study conducted at 59 sites in China. Patients with fasting LDL-C ≥2.6 to <4.9 mmol/L, fasting triglyceride ≤5.6 mmol/L, and 10-year ASCVD risk score <10% were randomly assigned (2:2:2:1:1:1) to receive subcutaneous injections of recaticimab at 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg every 12 weeks (Q12W), or matching placebo, on background lipid-lowering diet. Primary endpoint was percentage change in LDL-C from baseline to week 12 for 150 mg Q4W and 450 mg Q12W and to week 16 for 300 mg Q8W. ResultsA total of 703 patients underwent randomization and received recaticimab (n = 157, 156, and 155 for 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W, respectively) or placebo (n = 78, 79, and 78, respectively). Compared with placebo, recaticimab further reduced LDL-C by 49.6% (95% CI: 44.2%-54.9%) at 150 mg Q4W, 52.8% (95% CI: 48.3%-57.2%) at 300 mg Q8W, and 45.0% (95% CI: 41.0%-49.0%) at 450 mg Q12W (P < 0.0001 for all comparisons). Safety with recaticimab was comparable to placebo. After 12 or 16 weeks of treatment, patients who received recaticimab continued treatment until week 24, whereas those allocated to placebo were switched to recaticimab treatment with the same dosing strategy. Both 24-week recaticimab and 12- or 8-week recaticimab switched from placebo were effective. With 24 weeks of recaticimab treatment, the most common treatment-related adverse event was injection site reaction (n = 23 [4.9%]). ConclusionsRecaticimab monotherapy yielded significant LDL-C reductions and showed comparable safety vs placebo in patients with nonfamilial hypercholesterolemia and mixed hyperlipemia at low-to-moderate ASCVD risk, even with an infrequent dosing interval up to Q12W.

Clinical application of centrifugal-membrane hybrid plasmapheresis in the treatment of hyperlipidemia.

This study aimed to clarify the clinical application of centrifugal-membrane hybrid plasmapheresis (CMHP) in the treatment of hyperlipidemia. A retrospective study was conducted on 48 patients who were diagnosed with hyperlipidemia and had received CMHP treatment. Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were monitored, and adverse reactions to the treatment were observed. Forty-eight patients with hyperlipidemia received CMHP over 59 sessions. The average age of the 48 patients with hyperlipidemia, including 32 males (66.67%) and 16 females (33.33%), was 44.23 ± 12.02 years. Twenty-nine outpatients (60.42%) and 19 inpatients (39.58%) were included. Hypertriglyceridemia was diagnosed in 16 cases (33.33%), mixed hyperlipidemia in 31 cases (64.58%), and hypercholesterolemia in one case (2.08%). The pretreatment blood lipid concentrations were significantly different after the 59 CMHP treatments (p < .001). The concentrations of TC, TG, HDL-C, and LDL-C decreased significantly after the treatment, and the median ratios of reduction were 67.06% (range: 58.97%-71.87%), 63.33% (range: 55.20%-74.86%), 45.87% (range: 35.86%-52.95%), and 66.09% (range: 44.37%-73.94%), respectively. Three adverse reactions (5.08%) were recorded. No differences were detected in therapeutic parameters, effects, or adverse reactions between the two blood cell separators, there was no difference in Lipoprotein apheresis efficacy. This preliminary study demonstrated the clinical application of CMHP in patients in the treatment of hyperlipidemia. However, further studies are needed applying CMHP with hyperlipidemia.

Safety and Efficacy of the Novel RNA Interference Therapies for Hypertriglyceridemia and Mixed Hyperlipidemia Management: A Systematic Review and Meta-analysis

BackgroundNo meta-analysis has holistically analyzed and summarized the safety and therapeutic efficacy of the newer RNA interference (RNAi) therapies, olezarsen, plozasiran, and zodasiran, in managing conditions associated with hypertriglyceridemia (HTG). MethodsRandomized controlled trials (RCTs) involving patients with HTG or mixed hyperlipidemia (MHL) receiving either olezarsen, plozasiran, or zodasiran in the intervention arm and a placebo in the control arm were searched through electronic databases. The primary outcome was the safety profile of the drugs studied; secondary outcomes included the percent change from baseline (CFB) in the lipid levels, including triglyceride (TG). ResultsSix RCTs with 334 participants were evaluated. Olezarsen, plozasiran, and zodasiran were well-tolerated with no higher risk of serious adverse events or injection-site reactions. After 24 weeks, plozasiran increased alanine aminotransferase and HbA1c more than placebo, although the difference was insignificant at 48 weeks. Plozasiran and zodasiran had little effect on hyperglycemia worsening. Olezarsen increased the likelihood of mild platelet count decreases without clinical harm. At their longest clinical trial follow-up, the highest doses of olezarsen, plozasiran, and zodasiran lowered TG by 55.2%, 50.57%, and 51.2% of baseline levels. All three drugs decreased non-HDL-C and remnant cholesterol. Olezarsen and plozasiran lowered ApoC-III and increased HDL-C, whereas zodasiran reduced HDL-C. Zodasiran decreased LDL-C, whereas olezarsen and plozasiran had no effects on LDL-C. Plozasiran and zodasiran lowered apolipoprotein B, but not olezarsen. ConclusionThe newer RNA interference (RNAi) therapies appear safe and have excellent TG-lowering efficacy in patients with HTG and MHL.

The association between lipoprotein(a) and nonalcoholic fatty liver disease in patients with familial combined hyperlipidemia

The association between lipoprotein(a) and nonalcoholic fatty liver disease in patients with familial combined hyperlipidemia

Interaction Between Primary Hyperlipidemias and Type 2 Diabetes: Therapeutic Implications.

There is a gap of knowledge about the clinical and pathophysiological implications resulting from the interaction between primary hyperlipidemias and type 2 diabetes (T2D). Most of the existing evidence comes from sub-analyses of cohorts; scant information derives from randomized clinical trials. The expected clinical implications of T2D in patients with primary hyperlipidemias is an escalation of their already high cardiovascular risk. There is a need to accurately identify patients with this dual burden and to adequately prescribe lipid-lowering therapies, with the current advancements in newer therapeutic options. This review provides an update on the interactions of primary hyperlipidemias, such as familial combined hyperlipidemia, familial hypercholesterolemia, multifactorial chylomicronemia, lipoprotein (a), and type 2 diabetes.

Evaluation of biochemical algorithms to screen dysbetalipoproteinemia in ε2ε2 and rare APOE variants carriers.

Dysbetalipoproteinemia (DBL) is a combined dyslipidemia associated with an increased risk of atherosclerotic cardiovascular diseases mostly occurring in ε2ε2 subjects and infrequently in subjects with rare APOE variants. Several algorithms have been proposed to screen DBL. In this work, we compared the diagnostic performances of nine algorithms including a new one. Patients were divided into 3 groups according to their APOE genotype: ε2ε2 ("ε2ε2", n=49), carriers of rare variants ("APOEmut", n=20) and non-carriers of ε2ε2 nor APOE rare variant ("controls", n=115). The algorithms compared were those from Fredrickson, Sniderman, Boot, Paquette, De Graaf, Sampson, eSampson, Bea and ours, the "Hospices Civils de Lyon (HCL) algorithm". Our gold standard was the presence of a ε2ε2 genotype or of a rare variant associated with triglycerides (TG) >1.7 mmol/L. A replication in the UK Biobank and a robustness analysis were performed by considering only subjects with both TGand low-density lipoprotein-cholesterol (LDLc) >90th percentile. Total cholesterol (TC)/ApoB and NHDLC/ApoB are the best ratios to suspect DBL. In ε2ε2, according to their likelihood ratios (LR), the most clinically efficient algorithms were the HCL, Sniderman and De Graaf's. In APOEmut, Sniderman's algorithm exhibited the lowest negative LR (0.07) whereas the HCL's exhibited the highest positive LR (29). In both cohorts, the HCL algorithm had the best LR. We proposed a powerful algorithm based onApoB concentration and the routine lipid profile, whichperforms remarkably well in detecting ε2ε2 or APOE variant-related DBL. Additional studies are needed to further evaluate algorithms performances in DBL carriers of infrequent APOE variants.

Dyslipidaemia in women with polycystic ovary syndrome referred to a teaching hospital in Cape Town, South Africa.

The polycystic ovary syndrome (PCOS) imparts health risks including dyslipidaemia, diabetes and cardiovascular disease that are amenable to lifestyle adjustment and/or medication. We describe dyslipidaemia in women referred to a gynaecological endocrine clinic. Clinical data and endocrine and lipoprotein investigations comprising fasting triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDLC) and calculated low density lipoprotein cholesterol (LDLC) were studied along with electrophoresis patterns of apolipoprotein B-containing lipoproteins. The 1721 participants comprised black, mixed ancestry, white and Indian individuals (9.8%, 83.2%, 5.8% and 1.2%, respectively). The mean ± standard deviation of the age, body mass index (BMI) and waist/hip ratio were 26.0 ± 5.9 years, 32.3 ± 8.3 kg/m2 and waist/hip ratio 0.88 ± 0.11, respectively. Overweight status (BMI 26-30 kg/m2) and obesity (BMI >30 kg/m2) involved 272 (15.8%) and 1010 (58.7%) individuals, respectively. Morbid obesity (BMI >40 kg/m2) was present in 309 (17.9%) individuals. The TG, TC, HDLC and LDLC concentrations were 1.22 ± 0.86, 4.77 ± 1.02, 1.3 ± 0.36, 2.94 ± 0.94 mmol/L, respectively. LDL hypercholesterolaemia occurred in 753 (43.7%) and exceeded 5 mmol/L in 39 (2.3%) women. Low HDLC (<0.9 mmol/L) affected 122 (7%), hypertriglyceridaemia (>1.7 mmol/L) affected 265 (15.4%) and exceeded 2.5 mmol/L in 91 (5.3%) women. Mixed hyperlipidaemia (TG >1.7, TC >5.0 mmol/L) occurred in 176 (10.2%). Electrophoresis revealed small LDL particles in 79 (4.6%) and dysbetalipoproteinaemia in 13 (0.76%) of the cohort. Small LDL associated with obesity, blood pressure, TG and glucose concentration and higher androgenic state. Many women with PCOS had unfavourable lipoprotein results: mostly moderate changes in TG, HDLC and LDLC. Small LDL is not rare, may aid risk assessment and is best determined directly. Incidental monogenic disorders of lipoprotein metabolism included dysbetalipoproteinaemia, familial hypercholesterolaemia and severe hypertriglyceridaemia. Dyslipidaemia in PCOS requires more careful diagnosis, individualised management and research.

Genetic Architecture and Clinical Outcomes of Combined Lipid Disturbances.

Dyslipoproteinemia often involves simultaneous derangements of multiple lipid traits. We aimed to evaluate the phenotypic and genetic characteristics of combined lipid disturbances in a general population-based cohort. Among UK Biobank participants without prevalent coronary artery disease, we used blood lipid and apolipoprotein B concentrations to ascribe individuals into 1 of 6 reproducible and mutually exclusive dyslipoproteinemia subtypes. Incident coronary artery disease risk was estimated for each subtype using Cox proportional hazards models. Phenome-wide analyses and genome-wide association studies were performed for each subtype, followed by in silico causal gene prioritization and heritability analyses. Additionally, the prevalence of disruptive variants in causal genes for Mendelian lipid disorders was assessed using whole-exome sequence data. Among 450 636 UK Biobank participants: 63 (0.01%) had chylomicronemia; 40 005 (8.9%) had hypercholesterolemia; 94 785 (21.0%) had combined hyperlipidemia; 13 998 (3.1%) had remnant hypercholesterolemia; 110 389 (24.5%) had hypertriglyceridemia; and 49 (0.01%) had mixed hypertriglyceridemia and hypercholesterolemia. Over a median (interquartile range) follow-up of 11.1 (10.4-11.8) years, incident coronary artery disease risk varied across subtypes, with combined hyperlipidemia exhibiting the largest hazard (hazard ratio, 1.92 [95% CI, 1.84-2.01]; P=2×10-16), even when accounting for non-HDL-C (hazard ratio, 1.45 [95% CI, 1.30-1.60]; P=2.6×10-12). Genome-wide association studies revealed 250 loci significantly associated with dyslipoproteinemia subtypes, of which 72 (28.8%) were not detected in prior single lipid trait genome-wide association studies. Mendelian lipid variant carriers were rare (2.0%) among individuals with dyslipoproteinemia, but polygenic heritability was high, ranging from 23% for remnant hypercholesterolemia to 54% for combined hyperlipidemia. Simultaneous assessment of multiple lipid derangements revealed nuanced differences in coronary artery disease risk and genetic architectures across dyslipoproteinemia subtypes. These findings highlight the importance of looking beyond single lipid traits to better understand combined lipid and lipoprotein phenotypes and implications for disease risk.

Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia

BackgroundAngiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver.MethodsWe conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.ResultsA total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, −54 percentage points with 50 mg, −70 percentage points with 100 mg, and −74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, −51 percentage points, −57 percentage points, and −63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, −29 percentage points with 50 mg, −29 percentage points with 100 mg, and −36 percentage points with 200 mg; for apolipoprotein B level, −19 percentage points, −15 percentage points, and −22 percentage points, respectively; and for LDL cholesterol level, −16 percentage points, −14 percentage points, and −20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.ConclusionsIn patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.)

Plozasiran, an RNA Interference Agent Targeting APOC3, for Mixed Hyperlipidemia

BackgroundPersons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non–high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)–mediated inhibition of lipoprotein lipase.MethodsWe carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24.ResultsA total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of −49.8 percentage points (95% confidence interval [CI], −59.0 to −40.6) with the 10-mg-quarterly dose, −56.0 percentage points (95% CI, −65.1 to −46.8) with the 25-mg-quarterly dose, −62.4 percentage points (95% CI, −71.5 to −53.2) with the 50-mg-quarterly dose, and −44.2 percentage points (95% CI, −53.4 to −35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose.ConclusionsIn this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.)

Familial combined hyperlipidemia: current status of the problem (literature review)

Among the various dyslipidemia types, familial combined hyperlipidemia (FCH) is the most common genetic disorder, which is characterized by at least two dif­ferent forms of lipid disorders: hypercholesterolemia and hypertriglyceridemia. In FCH, the risk of atherosclerotic cardiovascular diseases (CVDs), including at a young age, increases significantly. The aim was to analyze literature data on modern criteria for diagnosis, pathogenesis and data from molecular genetic studies of FCH. Future studies aimed at understanding the underlying genetic and metabolic mechanisms of FCH and developing effective treatment strategies should include larger cohort studies with greater genetic diversity, as well as inves­tigation of epigenetic and lifestyle factors.

Effect of oesophagectomy on lipid profiles in patients with oesophageal cancer combined with hyperlipidaemia: a retrospective study

BackgroundSurgery is widely regarded as a pivotal therapeutic approach for treating oesophageal cancer, and clinical observations have revealed that many oesophageal cancer patients also present with concomitant hyperlipidaemia. It is surprising that few studies have been performed to determine how blood lipid levels are affected by oesophageal cancer resection. This research was designed to assess the influence of oesophageal cancer resection on lipid profiles among individuals diagnosed with both oesophageal cancer and hyperlipidaemia.MethodsA retrospective analysis was carried out on 110 patients with hyperlipidaemia and oesophageal cancer who had undergone oesophagectomy at the 900th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army. Preoperative and postoperative serological data were collected at seven-, thirty-, sixty-day-, and one-year-long intervals. Changes in lipid levels were compared, the remission of various types of hyperlipidaemia was statistically assessed, and Pearson correlation was used to analyse the association between lipid changes and preoperative body weight. The research sought to assess the reduction in body weight and the proportion of body weight lost one year following surgery.ResultsNoteworthy decreases were observed in total cholesterol (TC), triglyceride (TG), and low-density lipoprotein (LDL) levels, with TC decreasing from 6.20 mmol/L to 5.20 mmol/L, TG decreasing from 1.40 mmol/L to 1.20 mmol/L, and LDL decreasing from 4.50 mmol/L to 3.30 mmol/L. Conversely, there was a notable increase in high-density lipoprotein (HDL) levels, which increased from 1.20 mmol/L to 1.40 mmol/L (P < 0.05) compared to the preoperative levels. Notably, the remission rates for mixed hyperlipidaemia (60.9%) and high cholesterol (60.0%) were considerably greater than those for high triglycerides (16.2%). Alterations in TC at one year postoperatively correlated with preoperative weight and weight loss (r = 0.315, -0.216); changes in TG correlated with preoperative weight, percentage of total weight loss (TWL%), and weight reduction (r = -0.295, -0.246, 0.320); and changes in LDL correlated with preoperative weight, TWL%, and weight loss (r = 0.251, 0.186, and -0.207). Changes in non-high-density lipoprotein(non-HDL) were linked to preoperative weight (r = 0.300), and changes in TG/HDL were correlated with preoperative weight and TWL% (r = -0.424, -0.251).ConclusionsOesophagectomy significantly improved lipid profiles in oesophageal cancer patients, potentially leading to a reduction in overall cardiovascular risk.

The impact of overweight on lipid phenotype in different forms of dyslipidemia: a retrospective cohort study

PurposeDyslipidemia plays a pivotal role in increasing cardiovascular risk. In clinical practice the misleading association between altered lipid profile and obesity is common, therefore genetically inherited dyslipidemias may not completely be addressed among patients with overweight. Thus, we aim to investigate the influence of overweight and obesity on the lipid phenotype in a cohort of patients with different forms of dyslipidemia.MethodsA retrospective analysis was conducted on patients with dyslipidemia from 2015 to 2022. Patients were stratified in familial hypercholesterolemia (FH), familial combined hyperlipidemia (FCHL), non-familial hyperlipidemia or polygenic hypercholesterolemia (PH). Clinical characteristics and lipid profile were evaluated.ResultsOf the total of 798 patients, 361 were affected by non-familial hyperlipidemia (45.2%), while FCHL, FH and PH was described in 19.9%, 14.0% and 20.9% of patients, respectively. Overweight prevalence was higher in FCHL and non-familial hyperlipidemia patients than FH and PH patients. Subjects with overweight and obesity were independently associated with lower levels of high-density lipoprotein cholesterol (HDL-C) compared to patients with normal weight (52.4 and 46.0 vs 58.1, respectively; p < 0.0001); levels of triglycerides (TG) and non-HDL-C were higher in patients with overweight and obesity than patients with normal weight (257.3 and 290.9 vs 194.8, and 221.5 and 219.6 vs 210.1, p < 0.0001 and p = 0.01, respectively), while no differences were observed between patients with overweight and obesity.ConclusionWhile dyslipidemias can be influenced by various factors, an important determinant may lie in genetics, frequently acting as an underlying cause of altered lipid profiles, even in cases of overweight conditions.

Remodeling Intestinal Microbiota Alleviates Severe Combined Hyperlipidemia-Induced Nonalcoholic Steatohepatitis and Atherosclerosis in LDLR-/- Hamsters.

Combined hyperlipidemia (CHL) manifests as elevated cholesterol and triglycerides, associated with fatty liver and cardiovascular diseases. Emerging evidence underscores the crucial role of the intestinal microbiota in metabolic disorders. However, the potential therapeutic viability of remodeling the intestinal microbiota in CHL remains uncertain. In this study, CHL was induced in low-density lipoprotein receptor-deficient (LDLR-/-) hamsters through an 8-week high-fat and high-cholesterol (HFHC) diet or a 4-month high-cholesterol (HC) diet. Placebo or antibiotics were administered through separate or cohousing approaches. Analysis through 16S rDNA sequencing revealed that intermittent antibiotic treatment and the cohousing approach effectively modulated the gut microbiota community without impacting its overall abundance in LDLR-/- hamsters exhibiting severe CHL. Antibiotic treatment mitigated HFHC diet-induced obesity, hyperglycemia, and hyperlipidemia, enhancing thermogenesis and alleviating nonalcoholic steatohepatitis (NASH), concurrently reducing atherosclerotic lesions in LDLR-/- hamsters. Metabolomic analysis revealed a favorable liver lipid metabolism profile. Increased levels of microbiota-derived metabolites, notably butyrate and glycylglycine, also ameliorated NASH and atherosclerosis in HFHC diet-fed LDLR-/- hamsters. Notably, antibiotics, butyrate, and glycylglycine treatment exhibited protective effects in LDLR-/- hamsters on an HC diet, aligning with outcomes observed in the HFHC diet scenario. Our findings highlight the efficacy of remodeling gut microbiota through antibiotic treatment and cohousing in improving obesity, NASH, and atherosclerosis associated with refractory CHL. Increased levels of beneficial microbiota-derived metabolites suggest a potential avenue for microbiome-mediated therapies in addressing CHL-associated diseases.

Dyslipidemia: the association between risk and protective fac-tors in adolescence

Objective: Assessing risk and protective factors associated with dyslipidemia in adolescents. Materials and Methods: The study population comprised 77.833 schoolchildren of Montes Claros Country - MG, whereas the final sample comprised 635 adolescents (10 to 16 years old). Socio-demographic, biological, behavioral and family history variables were herein analyzed. Metabolic parameters encompassed total cholesterol (TC), triglycerides (TG), low-density lipoprotein choles-terol (LDL-C) and high-density lipoprotein cholesterol (HDL-c). Results: The female sex (p-0.008) and the age groups 10-11 / 12-13 years (p-0.008 and p-0.035) presented changes related to mixed hyperlipidemia. Overweight was associated with changes in TG (p-0.000) and with low HDL-c (p-0.000). Family history of dyslipidemia showed association (p-0.016) with undesirable LDL-c. However, sexual maturation was associated as protective factor with the development of hyper-triglyceridemia (p-0.001), and with-low HDL-c in the female sex. Conclusion: The identification of frequencies and factors presented in the current research is a potential tool to help subsidizing the elaboration and implementation of public policies addressing the adoption of preventive measures and health promotion in adolescence.