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Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease.

ABSTRACT: Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) and statins may not be protective in advanced CKD. The reasons for the limited efficacy of statins in advanced CKD are unclear, but statins may increase plasma levels of the highly atherogenic molecule lipoprotein(a), also termed Lp(a), as well as PCSK9 (protein convertase subtilisin/kexin type 9) levels. Lp(a) has also been linked to calcific aortic stenosis, which is common in CKD. Moreover, circulating Lp(a) levels increase in nephrotic syndrome with declining renal function and are highest in patients on peritoneal dialysis. Thus, the recent publication of the Phase 2 randomized controlled trial of pelacarsen [also termed AKCEA-APO(a)-LRx and TQJ230], a hepatocyte-directed antisense oligonucleotide targeting the LPA gene messenger RNA, in persons with CVD should be good news for nephrologists. Pelacarsen safely and dose-dependently decreased Lp(a) levels by 35-80% and a Phase 3 trial [Lp(a)HORIZON, NCT04023552] is planned to run from 2020 to 2024. Unfortunately, patients with estimated glomerular filtration rate <60?mL/min or urinary albumin:creatinine ratio >100?mg/g were excluded from Phase 2 trials and those with 'significant kidney disease' will be excluded from the Phase 3 trial. Optimized exclusion criteria for Lp(a)HORIZON would provide insights into the role of Lp(a) in CVD in CKD patients.

SUBMITTER: Fernandez-Prado R

PROVIDER: S-EPMC7577764 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease.

Fernandez-Prado Raul R Perez-Gomez Maria Vanessa MV Ortiz Alberto A

Clinical kidney journal 20200211 5

Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular disease (CVD) and statins may not be protective in advanced CKD. The reasons for the limited efficacy of statins in advanced CKD are unclear, but statins may increase plasma levels of the highly atherogenic molecule lipoprotein(a), also termed Lp(a), as well as PCSK9 (protein convertase subtilisin/kexin type 9) levels. Lp(a) has also been linked to calcific aortic stenosis, which is common in CKD. Moreover, circulat ...[more]

PMID: 33123354

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Project description:Background and objectivesThe Systolic Blood Pressure Intervention Trial (SPRINT) demonstrated that intensive BP lowering reduced the risk of cardiovascular disease, but increased eGFR decline. Serum parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF23) concentrations are elevated in CKD and are associated with cardiovascular disease. We evaluated whether intact PTH or intact FGF23 concentrations modify the effects of intensive BP control on cardiovascular events, heart failure, and all-cause mortality in SPRINT participants with CKD.Design, setting, participants, & measurementsWe measured PTH and FGF23 in 2486 SPRINT participants with eGFR<60 ml/min per 1.73 m2 at baseline. Cox models were used to evaluate whether serum PTH and FGF23 concentrations were associated with cardiovascular events, heart failure, and all-cause mortality, and whether PTH and FGF23 modified the effects of intensive BP control.ResultsThe mean age of this subcohort was 73 years, 60% were men, and mean eGFR was 46±11 ml/min per 1.73 m2. Median PTH was 48 (interquartile range [IQR], 35-67) pg/ml and FGF23 was 66 (IQR, 52-88) pg/ml. There were 261 composite cardiovascular events, 102 heart failure events, and 179 deaths within the subcohort. The adjusted hazard ratio (HR) per doubling of PTH concentration for cardiovascular events, heart failure, and all-cause mortality were 1.29 (95% confidence interval [95% CI], 1.06 to 1.57), 1.32 (95% CI, 0.96 to 1.83), and 1.04 (95% CI, 0.82 to 1.31), respectively. There were significant interactions between PTH and BP arm for both the cardiovascular (P-interaction=0.01) and heart failure (P-interaction=0.004) end points. Participants with a PTH above the median experienced attenuated benefits of intensive BP control on cardiovascular events (adjusted HR, 1.02; 95% CI, 0.72 to 1.42) compared with participants with a PTH below the median (adjusted HR, 0.67; 95% CI, 0.45 to 1.00). FGF23 was not independently associated with any outcome and did not modify the effects of the intervention.ConclusionsSPRINT participants with CKD and a high serum PTH received less cardiovascular protection from intensive BP therapy than participants with a lower serum PTH.

Dataset Information

Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease.

Publications

Pelacarsen for lowering lipoprotein(a): implications for patients with chronic kidney disease.

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