👤 Klaus G Parhofer

Lipoprotein apheresis (LA) is the only approved treatment for patients with elevated lipoprotein(a) [Lp(a)]. The Lp(a)FRONTIERS APHERESIS trial investigated whether pelacarsen reduces the need for LA in patients from Germany with elevated Lp(a) and established cardiovascular disease (CVD). Adult patients with Lp(a) levels >60 mg/dl who had undergone ≥35 LA sessions in the prior year were randomized to receive pelacarsen 80 mg or placebo every 4 weeks for 52 weeks. Weekly LA sessions were performed if the Lp(a) measurement from the prior visit was >60 mg/dL. The primary endpoint was the rate of performed LA sessions normalized to the weekly LA schedule (the number of actual LA sessions divided by the number of planned LA sessions during the 52-week period). Secondary endpoints were time to LA avoidance (for ≥24 consecutive weeks) and total LA avoidance from week 12 to week 52. Fifty-one patients were randomized (mean age 61.7 years, mean Lp(a) at baseline 85.4 mg/dL, and mean 44.0 LA sessions in the past 12 months), with 25 of 26 (96.2%) in the pelacarsen arm and 23 of 25 (92.0%) in the placebo arm completing the study. Baseline characteristics were generally balanced between treatment arms. Pelacarsen reduced the mean rates of LA (0.16 vs 0.93 in placebo, odds ratio 0.006, 95% confidence interval [CI] 0.003, 0.013; P < .0001) and substantially increased the hazard of achieving LA avoidance (hazard ratio: 88.3; P = .0014; median time to achieve LA avoidance: 6.1 weeks) and total LA avoidance (odds ratio: 163.2; P = .0005). The placebo-adjusted Lp(a) change from baseline at week 52 was -72% (95% CI: -79%, -61%; P < .0001). Treatment emergent adverse events were similar between arms, except for mostly mild injection site erythema (pelacarsen 38.5%; placebo 0%). Pelacarsen is a highly effective and well-tolerated Lp(a)-targeted therapy that substantially reduces the need for LA in patients with elevated Lp(a) and established CVD. NCT05305664. Show less

Blood lipids are causally involved in the pathogenesis of atherosclerosis, but their role in cerebral small vessel disease remains largely elusive. Here, we explored associations of genetic determinants of blood lipid levels, lipoprotein particle components, and targets for lipid-modifying drugs with small vessel disease phenotypes. We selected genetic instruments for blood levels of high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides, for cholesterol and triglycerides components of size-defined lipoprotein particles, and for lipid-modifying drug targets based on published genome-wide association studies (up to 617 303 individuals). Applying two-sample Mendelian randomization approaches we investigated associations with ischaemic and haemorrhagic manifestations of small vessel disease [small vessel stroke: 11 710 cases, 287 067 controls; white matter hyperintensities (WMH): 10 597 individuals; intracerebral haemorrhage: 1545 cases, 1481 controls]. We applied the inverse-variance weighted method and multivariable Mendelian randomization as our main analytical approaches. Genetic predisposition to higher HDL-C levels was associated with lower risk of small vessel stroke [odds ratio (OR) per standard deviation = 0.85, 95% confidence interval (CI) = 0.78-0.92] and lower WMH volume (β = -0.07, 95% CI = -0.12 to -0.02), which in multivariable Mendelian randomization remained stable after adjustments for LDL-C and triglycerides. In analyses of lipoprotein particle components by size, we found these effects to be specific for cholesterol concentration in medium-sized high-density lipoprotein, and not large or extra-large high-density lipoprotein particles. Association estimates for intracerebral haemorrhage were negatively correlated with those for small vessel stroke and WMH volume across all lipid traits and lipoprotein particle components. HDL-C raising genetic variants in the gene locus of the target of CETP inhibitors were associated with lower risk of small vessel stroke (OR: 0.82, 95% CI = 0.75-0.89) and lower WMH volume (β = -0.08, 95% CI = -0.13 to -0.02), but a higher risk of intracerebral haemorrhage (OR: 1.64, 95% CI = 1.26-2.13). Genetic predisposition to higher HDL-C, specifically to cholesterol in medium-sized high-density lipoprotein particles, is associated with both a lower risk of small vessel stroke and lower WMH volume. These analyses indicate that HDL-C raising strategies could be considered for the prevention of ischaemic small vessel disease but the net benefit of such an approach would need to be tested in a randomized controlled trial. Show less

ApoA-IV, an apolipoprotein (apo) with antioxidant, antiatherogenic, and antiinflammatory properties, was recently demonstrated to inhibit dextran sulfate sodium (DSS)-induced experimental colitis in mice. We therefore hypothesized that apoA-IV may be associated with disease activity in patients with inflammatory bowel disease (IBD). We addressed this question by testing for associations between apoA-IV genotypes, apoA-IV plasma levels, inflammatory parameters, and clinical disease activity in 206 patients with Crohn's disease (CD), 95 subjects with ulcerative colitis (UC), and 157 healthy controls. In CD patients, apoA-IV plasma levels were inversely associated with C-reactive protein (CRP) (P = 0.005) and disease activity (P = 0.01) in univariate analysis. In multiple logistic regression analysis, apoA-IV levels were identified as an independent predictor of elevated CRP (odds ratio [OR] 0.956, 95% confidence interval [CI]: 0.916-0.998, P = 0.04) and active disease (OR 0.957, 95% CI: 0.918-0.998, P = 0.04). In UC patients the apoA-IV gene variant 360 His (P = 0.03) but not apoA-IV levels (P = 0.15) were associated with increased disease activity in univariate analysis. This association, however, was lost in multiple logistic regression analysis (OR 3.435, 95% CI 0.995-11.853, P = 0.05). To our knowledge, this is the first study to demonstrate an association of apoA-IV with disease activity in patients with CD. Further studies are needed to define the relationship of apoA-IV to IBD. Show less