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BackgroundHypertriglyceridemia is a major risk factor for cardiovascular disease and remains poorly managed in high-risk individuals despite existing treatments. Olezarsen, a novel antisense oligonucleotide targeting Apo C-III, has shown reduction in triglyceride levels and potentially reducing cardiovascular risk in hypertriglyceridemia patients.ObjectiveTo assess the efficacy and safety of Olezarsen in treating hypertriglyceridemia.MethodsA comprehensive search was conducted through PubMed, Cochrane, Embase, Scopus, and ClinicalTrials.gov databases from inception till July 16, 2024. This review included RCTs involving adults (18–65 years) with moderate to severe hypertriglyceridemia (TAG ≥ 200 mg/dL). The dichotomous outcomes were pooled as risk ratio (RR) and continuous outcomes represented as mean % change from baseline with 95% confidence intervals (CI) using the random-effects model. The I2 and X2 statistics were employed to evaluate interstudy heterogeneity. All the calculations were performed using RevMan 5.4 and OpenMeta. A p-value of < 0.05 was indicative of statistical significance.ResultsThis meta-analysis included 4 RCTs with 202 patients. We found a significant mean % change for -65.38% Apo-CIII levels (95% CI − 75.00 to − 55.55, p = 0.000, I2 = 99.7%), − 44.64% TAGS (95% CI − 55.635 to − 33.649, p = 0.000, I2 = 99.53%), −14.81% Apo-B (95% CI − 22.05 to − 7.57, p = 0.000, I2 = 99.39%), 38.85% HDL (95% CI 27.688 to 50.042, p = 0.000, I2 = 99.55%), and -8.84% total cholesterol (95% CI − 11.483 to − 6.203, p = 0.000, I2 = 94.92%) from baseline versus placebo. We found reduced risk of any adverse events (RR 0.96, 95% CI 0.87–1.05, p = 0.34 I2 = 0%), any serious adverse events (RR 0.94, 95% CI 0.44–2.03, p = 0.88, I2 = 34%) and hypersensitivity reaction (RR 0.65, 95% CI 0.20–2.08, p = 0.47, I2 = 12%) in Olezarsen group as compared to placebo.ConclusionOlezarsen is proved to be effective in managing hypertriglyceridemia patients with no significant adverse events. The small sample size and high heterogeneity undermine our findings and more robust studies with larger sample sizes are required to evaluate its full potential.