Dataset Information

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

ABSTRACT:

Background

Genetic loss-of-function variants in ANGPTL3 are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.

Methods

Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non-HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3.

Results

Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58-69) years, 44% were female, the median non-HDL-C was 132.4 (interquartile range, 118.0-154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4-270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non-HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all P<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all P<0.001). The effects on LDL-C and ApoB were more modest (7.9%-16.0% and 6.0%-15.1%, respectively) and without a clear dose-response relationship' and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all P<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%).

Conclusions

Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non-HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction.

Registration

URL: https://clinicaltrials.gov; Unique identifier: NCT04516291.

SUBMITTER: Bergmark BA

PROVIDER: S-EPMC9047643 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

Bergmark Brian A BA Marston Nicholas A NA Bramson Candace R CR Curto Madelyn M Ramos Vesper V Jevne Alexandra A Kuder Julia F JF Park Jeong-Gun JG Murphy Sabina A SA Verma Subodh S Wojakowski Wojtek W Terra Steven G SG Sabatine Marc S MS Wiviott Stephen D SD

Circulation 20220403 18

<h4>Background</h4>Genetic loss-of-function variants in <i>ANGPTL3</i> are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.<h4>Methods</h4>Adults with non-high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg ...[more]

PMID: 35369705

Similar Datasets

Project description:BackgroundInclisiran is a novel, cholesterol-lowering therapy, with a long duration of effect, administered every 6 months (subcutaneously by a healthcare professional). In the ORION-10 trial in US patients with atherosclerotic cardiovascular disease (ASCVD) in addition to maximum tolerated statins, with or without ezetimibe, inclisiran demonstrated statistically significant reductions in low-density lipoprotein cholesterol (LDL-C) of up to 51%. This is the first peer-reviewed publication to investigate the price at which inclisiran is cost effective in the US.ObjectiveThe aim of this study was to determine the maximum price at which inclisiran is cost effective in addition to standard of care, in US patients with ASCVD, versus standard of care alone, at different willingness-to-pay thresholds.Design, setting and participantsA lifetime Markov model from the US health system perspective, including 15 health states, was used to evaluate the cost effectiveness of inclisiran. The following states were separated by time from a previous cardiovascular event (0-1 years, 1-2 years, 2+ years ['stable']): initial, unstable angina, myocardial infarction, and stroke. Additional states included revascularization and death (cardiovascular or non-cardiovascular causes). Baseline risk of cardivoascular events were from US database sources or published literature. Reductions in LDL-C from inclisiran were from the ORION-10 trial. LDL-C reduction was used to adjust baseline risk of cardiovascular events, based on established relationships between 1 mmol/L reduction in LDL-C and decreases in cardiovascular events, from the Cholesterol Treatment Trialists studies. The population included adults with a history of ASCVD, and LDL-C ≥ 70 mg/dL, despite maximum tolerated doses of statin therapy.InterventionsInclisiran as an adjunct to standard of care, compared with standard of care alone.Main outcomes and measuresThe threshold price of inclisiran.ResultsInclisiran as an adjunct to standard of care resulted in threshold annual inclisiran prices of $6383, $9973, and $13,563 at willingness-to-pay thresholds of $50,000, $100,000, and $150,000 per quality-adjusted life-year, respectively. Probabilistic sensitivity analysis showed that at a threshold of $100,000 per QALY, inclisiran had a 100% probability of being cost effective, with an annual price below $9000. At the publicly available price of $3250 per dose, inclisiran was found to have an incremental cost-effectiveness ratio just above the $50,000 per QALY threshold, of $51,686.Conclusions and relevanceThis study identified the price at which inclisiran is cost effective for the US health system, at generally accepted willingness-to-pay thresholds.

Project description:Administered at maximal dosages, the most common statins--atorvastatin, simvastatin and rosuvastatin--lower low-density lipoprotein cholesterol (LDLC) by an average of 37-57% in patients with primary hypercholesterolemia. We hypothesized novel genetic underpinnings for variation in LDLC levels in the context of statin therapy.Genotyping of 384 SNPs in 202 volunteers from a lipid outpatient clinic was accomplished and LDLC levels obtained from chart records. The SNPs were distributed across 222 genes representing physiological pathways such as general metabolism, cholesterol biochemistry, cardiovascular function, inflammation, neurobiology and cell proliferation. We discovered significant associations with LDLC levels for the rs34274 SNP (p < 0.0002) and for rs2241220 (p < 0.008) in the acetyl-coenzyme A carboxylase beta (ACACB) gene. When corrected for multiple testing, the false-discovery rate associated with rs34274 was 0.076 (significance threshold: 0.10) and for rs2241220 the false-discovery rate was 0.93 (not significant). The acetyl coenzyme A carboxylase beta enzyme synthesizes malonyl coenzyme A, an essential substrate for hepatic fatty acid synthesis and an inhibitor of fatty acid oxidation.The SNPs were in weak linkage disequilibrium (D = 0.302). Minor alleles at these sites demonstrate opposing influences on LDLC; the C>T substitution at rs34724 is a risk marker and the C>T substitution at rs2241220 a protective marker for LDLC levels. These SNPs hypothetically influence enzymatic activity through different mechanisms, rs34274 through the PII promoter and rs2241220 via alteration of the protein's responsiveness to allosteric influence.Physiogenomic evidence suggests a novel link between LDLC levels and the regulation of fatty acid metabolism. The findings complement previously discovered novel SNP relationships to myalgia (pain) and myositis (serum creatine kinase activity). By genotyping for myositis, myalgia and LDLC levels, a physiogenomic model may be developed to help clinicians maximize effectiveness and minimize side effects in prescribing statins.

Project description:BackgroundRobust evidence is lacking on optimal timing of statin administration and its impact on patient outcomes.ObjectiveThis study aims to evaluate among incident statin users the relationship between those prescribed evening vs. daily dosing instructions, medication adherence, and changes in low-density lipoprotein cholesterol (LDL-c).DesignThis is an observational cohort study at Sutter Health, a community-based healthcare system, 2010-2016.ParticipantsPatients were ≥ 35 years of age as of the first statin prescription (baseline), with 12 to 36 months of electronic health record activity before and after baseline. Incident use was defined as no statin prescription in 12 months prior to baseline.Main measuresDifferences in medication adherence (proportion of days covered ≥ 0.80) over 12 months from baseline and mean change in LDL-c between 12 and 24 months from baseline were measured using regression modeling, adjusting for baseline demographics and clinical, prescriber, and statin characteristics.Key resultsAmong 31,252 patients with valid statin prescriptions between 2010 and 2016, 5099 eligible incident statin users (mean age, 63 years) were identified, of whom 53% were prescribed evening and 47% daily dosing instructions. No difference in likelihood of statin adherence over 12 months was observed for evening vs. daily dosing (adjusted odds ratio [OR] 0.90; 95% CI 0.75, 1.08). No differences were observed in mean change in LDL-c (adjusted mean difference 1.42 mg/dL; 95% CI - 1.02, 3.89) or likelihood of attaining LDL-c < 70 mg/dL (adjusted OR 0.83; 95% CI 0.67, 1.04) for evening vs. daily dosing over a mean of 19 months follow-up.ConclusionsAmong incident statin users from a real-world clinical setting, those with daily and evening dosing instructions had similar adherence rates and mean changes in LDL-c. Given potential clinical equipoise for evening and daily dosing, clinicians should consider patient-tailored statin dosing instructions to reduce potentially unnecessary regimen complexity.

Dataset Information

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

Background

Methods

Results

Conclusions

Registration

Publications

Effect of Vupanorsen on Non-High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets