Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating condition associated with approximately 30% mortality and 20% severe disability among survivors. Delayed cerebral ischemia due to cerebral vasospasm and hydrocephalus significantly contribute to poor neurological outcomes. Currently, reliable biomarkers for early prediction of these complications remain lacking. In this study, 63 patients with a mean age of 59.7 ± 11.53 years were enrolled. Functional outcomes were assessed by the modified Rankin Scale (mRS). Cerebrospinal fluid (CSF) samples were obtained through lumbar drainage (LD) or external ventricular drainage (EVD) and analyzed by ELISA. The predictive value of biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis. Elevated Apolipoprotein C-III (ApoC3) levels in CSF of aSAH patients were observed. Furthermore, increased ApoC3 concentrations were significantly associated with poor prognosis and an elevated risk of severe complications. At an optimal cutoff value of 4,463 ng/mL, patients with high ApoC3 levels exhibited significantly worse 3-month functional outcomes and a higher incidence of delayed cerebral ischemia and hydrocephalus. Monitoring ApoC3 levels in CSF may be beneficial for predicting complications such as delayed cerebral ischemia and hydrocephalus in patients with aSAH.

Hypertriglyceridemia is a well-recognized contributor to residual atherosclerotic cardiovascular disease risk and a predisposing factor for acute pancreatitis. Despite the availability of pharmacologic agents and lifestyle interventions, patients with severe and refractory hypertriglyceridemia often fail to achieve adequate control. Recent advances in the molecular understanding of triglyceride metabolism have driven the development of targeted therapies that selectively modulate key regulatory pathways. This study sought to provide an overview of triglyceride regulation, the atherogenic role of remnant lipoproteins, and clinical evidence of emerging triglyceride-lowering therapies. Lipoprotein metabolism is regulated by a complex network of regulatory proteins that include lipoprotein lipase (LPL), apolipoproteins such as apolipoprotein C-III (ApoC-III), and angiopoietin-like proteins (ANGPTLs). Targeting these proteins in the metabolic cascade has shown promising results in reducing triglyceride levels. Emerging therapies such as antisense oligonucleotides (ASOs) and small interfering RNA (siRNA) directed against ApoC-III (volanesorsen, olezarsen, and plozasiran), inhibitors of ANGPTL3 (evinacumab and zodasiran), and fibroblast growth factor 21 (FGF-21) analogs (pegozafermin) have demonstrated substantial triglyceride-lowering efficacy. These agents have achieved reductions in triglyceride levels of up to 80% in clinical trials. Additionally, preliminary evidence suggests that these agents may also reduce the incidence of acute pancreatitis and improve cardiometabolic risk profiles, although dedicated trials are still needed to confirm these outcomes. The therapeutic landscape for hypertriglyceridemia is rapidly evolving. Integrating these novel agents into clinical practice will require individualized treatment plans, sustained lifestyle modification, and careful safety monitoring.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by hepatic triglyceride accumulation in the setting of obesity and insulin resistance. Although apolipoprotein C-III (APOC3) is a well-established regulator of plasma triglyceride metabolism, its hepatocyte-intrinsic role in intracellular lipid accumulation remains unclear. In this study, we investigated whether APOC3 contributes to hepatocellular triglyceride synthesis during early metabolic dysfunction. In 6-week-old db/db mice, early hepatic lipid accumulation was observed without detectable fibrosis. Transcriptomic profiling identified APOC3 as an upregulated gene associated with lipid metabolic pathways, and its hepatic upregulation was confirmed at both mRNA and protein levels. Gain- and loss-of-function experiments in HepG2 cells demonstrated that APOC3 overexpression significantly increased intracellular triglyceride content, whereas APOC3 knockdown reduced triglyceride accumulation. Mechanistically, APOC3 selectively regulated diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triglyceride synthesis, without significantly affecting major lipogenic transcription factors. Furthermore, under de novo lipogenesis-inducing conditions triggered by the liver X receptor agonist T0901317 and insulin, APOC3 markedly amplified DGAT2 expression and triglyceride accumulation. Collectively, these findings suggest a hepatocyte-intrinsic role for APOC3 in promoting triglyceride accumulation through DGAT2-dependent mechanisms. The APOC3-DGAT2 axis may represent a relevant pathway contributing to hepatic lipid accumulation in metabolic liver disease.

The two major goals of the treatment of hypertriglyceridemia are the prevention of cardiovascular disease and pancreatitis. Here we discuss the drugs used for the treatment of hypertriglyceridemia: (niacin, fibrates, omega-3-fatty acids, and apo CIII inhibitors. Niacin decreases total cholesterol, TGs (20-50% decrease), LDL-C, and Lp(a). Additionally, niacin decreases small dense LDL resulting in a shift to large, buoyant LDL particles. Moreover, niacin increases HDL-C. Skin flushing, insulin resistance, and other side effects have limited the use of niacin. The enthusiasm for niacin has greatly decreased with the failure of AIM-HIGH and HPS-2 Thrive to decrease cardiovascular events when niacin was added to statin therapy. The omega-3-fatty acids eicosapentaenoic acid (C20:5n-3) (EPA) and docosahexaenoic acid (C22:6n-3) (DHA) lower TGs by 10-50% but do not affect total cholesterol, HDL-C, or Lp(a). LDL-C may increase with EPA + DHA when the TG levels are markedly elevated (>500mg/dL). EPA alone does not increase LDL-C. Omega-3-fatty acids have few side effects, drug interactions, or contraindications. Numerous studies of low dose omega-3-fatty acids on cardiovascular outcomes have failed to demonstrate a benefit. However, in the JELIS, REDUCE-IT, and RESPECT-EPA trials high doses of EPA alone reduced cardiovascular events while in the STRENGTH and OMEMI trials high doses of EPA+DHA did not reduce cardiovascular events. Fibrates reduce TG levels by 25-50% and increase HDL-C by 5-20%. The effect on LDL-C is variable. If the TG levels are very high (>500mg/dL), fibrate therapy may result in an increase in LDL-C, whereas if TGs are not markedly elevated fibrates decrease LDL-C by 10-30%. Fibrates also reduce apolipoprotein B, LDL particle number, and non-HDL-C and there may be a shift from small dense LDL towards large LDL particles. Fibrates do not have any major effects on Lp(a). Monotherapy with fibrates appears to reduce cardiovascular events particularly in patients with high TG and low HDL-C levels. In contrast, in the ACCORD LIPID and PROMINENT trials the addition of fibrates to statin therapy did not reduce cardiovascular disease, which has reduced the enthusiasm for using fibrates to reduce cardiovascular disease. In patients with diabetes fibrates appear to slow the progression of microvascular disease (retinopathy, nephropathy, and amputations, ulcers, and gangrene. Antisense oligonucleotides, volanesorsen and olezarsen, inhibit the production of apolipoprotein C-III and decrease TG levels in patients with severe hypertriglyceridemia including patients with the familial chylomicronemia syndrome (FCS). Studies also suggest that apo CIII inhibitors reduce episodes of pancreatitis in patients with severe hypertriglyceridemia. Patients with FCS have also reported that apo C-III inhibitors improved symptoms and reduced interference of FCS with work/school responsibilities. Of concern has been decreases in platelet levels with 47% of patients treated with volanesorsen developing platelet counts below100 x 109/L, a side effect that is not observed with olezarsen. Thus, a number of drugs are available for the treatment of hypertriglyceridemia and may be employed when lifestyle changes are not sufficient. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

Hypertriglyceridemia (HTG) is a heterogeneous metabolic disorder driven by both genetic susceptibility and secondary factors. Most cases of severe HTG (triglyceride [TG] >10 mmol/L [>885 mg/dL]) have multifactorial chylomicronemia syndrome (MCS) while only a few have familial chylomicronemia syndrome (FCS), a rare autosomal recessive condition.

Plozasiran (Redemplo), a novel small interfering RNA (siRNA) therapeutic targeting the hepatic biosynthesis of apolipoprotein C-III (APOC3), is approved by the US FDA for treating familial chylomicronemia syndrome (FCS), a disease of rare prevalence that presents with extremely elevated levels of serum triglycerides (TG) leading to a higher risk of acute pancreatitis. Plozasiran is also in Phase 3 development to treat the broader indication of severe hypertriglyceridemia. Population pharmacodynamic (PD) analysis of plozasiran was conducted on serially measured serum APOC3 and TG levels in the FCS patients participating in the pivotal Phase 3 study by employing a cascading kinetic-PD model that described the inhibitory effect of plozasiran on the synthesis of APOC3, which in turn decreases serum TG levels. The estimated IC50 dose of plozasiran was 2.2 mg, demonstrating potent on-target pharmacological activity of plozasiran conferred by its efficient mechanism of action via RNA interference (RNAi). The model-estimated elimination half-life of plozasiran in the liver was 48 days, supporting quarterly dosing (Q3M) for patients' convenience. Body mass index (BMI) and background TG-lowering therapy were identified as the only statistically significant covariates without clinical importance, and the subcutaneous 25 mg Q3M dose is approved for all adult FCS patients, including those with Asian ethnicity, mild-to-moderate degrees of renal impairment or a mild degree of hepatic impairment. There was no evidence to suggest that the TG-lowering efficacy of plozasiran was significantly different between clinically diagnosed and genetically confirmed FCS patients, and therefore plozasiran treatment is suitable for both genetic and clinically diagnosed FCS patients.

Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder marked by severe hypertriglyceridemia and characteristic clinical manifestations, particularly acute pancreatitis. Conventional triglyceride-lowering therapy is largely ineffective. Apolipoprotein (apo) C-III has emerged as a key therapeutic target to lower triglycerides in FCS.

Schizophrenia is frequently comorbid with dyslipidemia and hyperglycemia. However, whether metabolic-modifying agents aggravate schizophrenia progression remains unclear. We perform a drug-target genetic association study in two independent Han Chinese schizophrenia cohorts (N = 2,111/292 for discovery/validation). Leveraging metabolic genome-wide association studies, we generate genetic risk scores (GRSs) for lipid-modifying and hypoglycemic targets. Those with higher APOC3 (inhibited by volanesorsen/olezarsen) GRS exhibit attenuated triglycerides and improvement in negative symptoms assessed by Positive and Negative Syndrome Scale (PANSS) (β = 1.23, 95% confidence interval [CI]: 0.30-2.16). Higher GCK (activated by dorzagliatin) GRS is associated with decreased glucose and less improvement across PANSS total (β = -1.70, 95% CI: -2.91-0.50), positive, negative, general subscales. Causal associations of GCK are replicated in independent validation. The effects of APOC3 and GCK on negative symptom recovery are robust in hyperlipidemic/diabetic subgroups. Genetically proxied proteomics analysis provides further functional validation for the identified target-outcome associations. Our findings suggest volanesorsen/olezarsen as potential adjunctive candidates; dorzagliatin warrants prudence in schizophrenia with metabolic disturbance.