👤 Helina Kassahun

Mendelian randomization studies suggest a causal effect of lipoprotein(a) (Lp(a)) on atherosclerotic cardiovascular disease. Noncardiovascular effects (eg, diabetes risk) are inadequately investigated. In this noninterventional phenome-wide association study designed to better understand the potential causal role of Lp(a), direct causal phenotypic effects of exposure to Lp(a) were estimated. Also, the association between LPA null allele rs41272114 with type 2 diabetes was assessed, and ancestry-specific Lp(a) thresholds were determined. In the UK Biobank (n = 425,677 adults, 55% female), we studied 1,456 phenotypes spanning 18 classes using 4 ancestry-specific polygenic risk scores and false discovery rate multiple testing correction. Network deconvolution Mendelian randomization was leveraged to separate direct from indirect (ie, associations via mediating variables) causal phenotypic effects and account for confounding, reverse causation, and bidirectionality. Lp(a) was significantly associated with 80 phenotypes across 7 classes. Higher Lp(a) exposure had significant direct causal effects, independent of low-density lipoprotein cholesterol, on coronary artery disease (OR: 1.36; 95% CI: 1.21-1.54) and glycated hemoglobin (HbA1c; β = 0.099; 95% CI: 0.051-0.15) only. Very low Lp(a) exposure was not associated with type 2 diabetes (OR: 0.92; 95% CI: 0.64-1.31) or HbA1c (β = -0.016; 95% CI: -0.062 to 0.030). Among European and African ancestries, 86 (77th percentile) and 93 (59th percentile) nmol/L optimally discriminated myocardial infarction risk, respectively. Increasing Lp(a) exposure had direct, independent causal effects on coronary artery disease and HbA1c only; very low Lp(a) exposure is suggested to not be causally associated with type 2 diabetes. The optimal European and African ancestry threshold to stratify cardiovascular risk is comparable, and below 125/105 nmol/L in current U.S./European medical professional society guidelines. Show less

Lipoprotein(a) (Lp[a]) is thought to be the major carrier of oxidized phospholipids (OxPL). OxPL are believed to be a potent driver of inflammation and atherosclerosis. Olpasiran, a small interfering RNA, blocks Lp(a) production by inducing degradation of apolipoprotein(a) messenger RNA. Olpasiran's effects on OxPL and systemic markers of inflammation are not well described. To assess the effects of olpasiran on OxPL, high-sensitivity interleukin 6 (hs-IL-6), and hs-C-reactive protein (hs-CRP) in the OCEAN(a)-DOSE randomized clinical trial. OCEAN(a)-DOSE was an international, multicenter, placebo-controlled, phase 2, dose-finding randomized clinical trial conducted between July 2020 and November 2022. A total of 281 patients with atherosclerotic cardiovascular disease and Lp(a) levels greater than 150 nmol/L were included. Participants were randomized to receive 1 of 4 active subcutaneous doses of olpasiran vs placebo: (1) 10 mg, administered every 12 weeks (Q12W); (2) 75 mg, Q12W; (3) 225 mg, Q12W; or (4) 225 mg, administered every 24 weeks (Q24W). OxPL on apolipoprotein B (OxPL-apoB), hs-CRP, and hs-IL-6 were assessed at baseline, week 36, and week 48 in 272 patients. The primary outcome was placebo-adjusted change in OxPL-apoB from baseline to week 36. Among 272 participants, median (IQR) age was 62 years (56-69), and 86 participants (31.6%) were female. Baseline median (IQR) Lp(a) concentration was 260.3 nmol/L (198.1-352.4) and median (IQR) OxPL-apoB concentration was 26.5 nmol/L (19.7-33.9). The placebo-adjusted mean percentage change in OxPL-apoB from baseline to week 36 was -51.6% (95% CI, -64.9% to -38.2%) for the 10-mg Q12W dose, -89.7% (95% CI, -103.0% to -76.4%) for the 75-mg Q12W dose, -92.3% (95% CI, -105.6% to -78.9%) for the 225-mg Q12W dose, and -93.7% (95% CI, -107.1% to -80.3%) for the Q24W dose (P < .001 for all). These effects were maintained to week 48 (-50.8%, -100.2%, -104.7%, and -85.8%, respectively; P < .001 for all). There was a strong correlation between percentage reduction in Lp(a) and OxPL-apoB for patients treated with olpasiran (r = 0.79; P < .001). Olpasiran did not significantly impact hs-CRP or hs-IL-6 compared with placebo to weeks 36 or 48 (P > .05). In the OCEAN(a)-DOSE multicenter randomized clinical trial, olpasiran led to a significant and sustained reduction in OxPL-apoB but no significant effects on hs-CRP or hs-IL-6. Show less