👤 Saeid Mirzai

The prognostic value of jointly assessing lipoprotein(a) [Lp(a)] and high-sensitivity C-reactive protein (hsCRP) in primary prevention among individuals without standard modifiable risk factors (SMuRFs) remains unclear. We analyzed 50,450 UK Biobank participants free of cardiovascular disease at baseline who were SMuRF-less, defined as absence of current smoking, obesity, hypertension, dyslipidemia, and diabetes. Elevated Lp(a) and hsCRP were defined using cohort-specific 75th percentile cutoffs and established clinical thresholds. Incident atherosclerotic cardiovascular disease (ASCVD), defined as nonfatal myocardial infarction, nonfatal ischemic stroke, or cardiovascular death, was ascertained. Associations were evaluated using Fine-Gray competing-risk regression models to estimate subdistribution hazard ratios (sHRs) with 95% confidence intervals (CI), accounting for competing non-cardiovascular death. Over 15 years of follow-up, 1,104 (2.2%) incident ASCVD events occurred. Using cohort-specific cutoffs, elevated hsCRP was associated with higher ASCVD risk (sHR 1.35, 95% CI 1.16-1.57), while elevated Lp(a) showed a more modest association (sHR 1.24, 95% CI 1.06-1.45). In joint analyses, isolated elevations of hsCRP or Lp(a) were each associated with increased risk, with the highest risk observed among individuals with concurrent elevations (sHR 1.64, 95% CI 1.28-2.09), without evidence of interaction. Similar patterns were observed using clinical cutoffs (Lp(a) ≥125 nmol/L; hsCRP ≥2.0 mg/L), with concurrent elevation conferring the greatest risk (sHR 1.74, 95% CI 1.17-2.59). In SMuRF-less individuals, Lp(a) and hsCRP independently predict ASCVD risk. These findings suggest that combined assessment of Lp(a) and hsCRP may provide complementary information for risk characterization among SMuRF-less adults in primary prevention. Show less

Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride-glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log-transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as <125 or ≥125 nmol/L; high IR was TyG ≥75th cohort percentile. Participants were stratified into 4 joint Lp(a)/IR groups using low Lp(a)/low IR as reference. Among 328 031 participants (mean age 56.4 years; 54.7% women), 26 865 CVD events occurred over 14.6 years median follow-up (interquartile range 13.7-15.4). Per 1-SD increase, aHRs were 1.08 (95% CI, 1.06-1.09) for log-Lp(a) and 1.06 (95% CI, 1.04-1.07) for TyG, each adjusted for the other. The Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)-associated risk in the context of primary CVD prevention setting. Show less

Numerous studies have established lipoprotein(a) [Lp(a)] as an independent and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). As such Lp(a) has become the focus of targeted drug therapy development with the goal of reducing Lp(a) serum concentrations and improving outcomes. This review aims to inform readers on the investigational agents currently in clinical trials and highlight key differences including dosing intervals and routes of administration that may facilitate uptake and retention of a particular potential medication in certain patient populations. Five investigational agents are currently undergoing various stages of clinical trials for the treatment of elevated Lp(a). Three potential therapies are small interfering RNA (siRNA) molecules and a fourth is an antisense oligonucleotide (ASO) all of which are subcutaneously injected. A fifth agent is a small molecule inhibitor that is orally administered. A sixth agent, a cholesteryl ester transfer protein (CETP) inhibitor that is primarily being studied for LDL-C reduction has shown promise for reducing Lp(a). A seventh agent based on gene-editing is currently in the developmental stage. Results have revealed notable reductions in Lp(a) with favorable tolerability and safety. Phase 3 trials will be crucial in determining the viability of lowering Lp(a) with such therapies and improving cardiovascular outcomes. Promising results indicate the potential in the near future to have medications primarily for lowering Lp(a) which has thus far eluded targeted drug therapy. As such advances stand to benefit large segments of the population living with and at risk for ASCVD, future research is vital to validate safety and efficacy in the long-term as well to understand how to optimize uptake and retention among patients with diverse circumstances. Show less