Association ofLPAVariants With Risk of Coronary Disease and the Implications for Lipoprotein(a)-Lowering Therapies

Abstract

IMPORTANCE Human genetic studies have indicated that plasma lipoprotein(a) (Lp[a]) is causally associated with the risk of coronary heart disease (CHD), but randomized trials of several therapies that reduce Lp(a) levels by 25% to 35% have not provided any evidence that lowering Lp(a) level reduces CHD risk.OBJECTIVE To estimate the magnitude of the change in plasma Lp(a) levels needed to have the same evidence of an association with CHD risk as a 38.67-mg/dL (ie, 1-mmol/L) change in low-density lipoprotein cholesterol (LDL-C) level, a change that has been shown to produce a clinically meaningful reduction in the risk of CHD. DESIGN, SETTING, AND PARTICIPANTSA mendelian randomization analysis was conducted using individual participant data from 5 studies and with external validation using summarized data from 48 studies. Population-based prospective cohort and case-control studies featured 20 793 individuals with CHD and 27 540 controls with individual participant data, whereas summarized data included 62 240 patients with CHD and 127 299 controls. Data were analyzed from November 2016 to March 2018.EXPOSURES Genetic LPA score and plasma Lp(a) mass concentration. MAIN OUTCOMES AND MEASURES Coronary heart disease.RESULTS Of the included study participants, 53% were men, all were of white European ancestry, and the mean age was 57.5 years. The association of genetically predicted Lp(a) with CHD risk was linearly proportional to the absolute change in Lp(a) concentration. A 10-mg/dL lower genetically predicted Lp(a) concentration was associated with a 5.8% lower CHD risk (odds ratio [OR], 0.942; 95% CI, 0.933-0.951; P = 3 × 10 −37 ), whereas a 10-mg/dL lower genetically predicted LDL-C level estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (OR, 0.855; 95% CI, 0.818-0.893; P = 2 × 10 −12 ). Thus, a 101.5-mg/dL change (95% CI, 71.0-137.0) in Lp(a) concentration had the same association with CHD risk as a 38.67-mg/dL change in LDL-C level. The association of genetically predicted Lp(a) concentration with CHD risk appeared to be independent of changes in LDL-C level owing to genetic variants that mimic the relationship of statins, PCSK9 inhibitors, and ezetimibe with CHD risk. CONCLUSIONS AND RELEVANCEThe clinical benefit of lowering Lp(a) is likely to be proportional to the absolute reduction in Lp(a) concentration. Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to produce a clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C level by 38.67 mg/dL (ie, 1 mmol/L).

Lipoprotein apheresis efficacy, challenges and outcomes: A descriptive analysis from the UK Lipoprotein Apheresis Registry, 1989–2017

“…Regarding hyper-Lp(a), a recent study suggests that the CV risk associated with an Lp(a) > 80th percentile is markedly attenuated in a primary prevention setting if the LDL cholesterol is < 2.5 mmol/l [30]. Another analysis based on Mendelian randomisation proposed that reductions in Lp(a) of 100 mg/dl are required to achieve a reduction in CV risk comparable to lowering LDL cholesterol by 1.0 mmol/l [31]. Reductions in Lp(a) of that magnitude are impossible to achieve with existing therapies which raises the question of whether it might not be more profitable in future to focus on reducing LDL-C to < 2.5 mmol/l in hyper Lp(a) patients with CV disease, accepting that this means basing a secondary prevention policy on primary prevention data.…”

Long-Term Exposure to Elevated Lipoprotein(a) Levels, Parental Lifespan and Risk of Mortality

“…16 Samples with call rate <95%, outlier heterozygosity rate, gender mismatch, non-white British ancestry, related samples (second degree or closer), samples with excess third-degree relatives (>10), or not used for relatedness calculation were excluded. Burgess et al 17 recently used a genetic risk score (GRS) of 43 single nucleotide polymorphisms (SNP) that explained approximately 60% of the variance in Lp(a) levels in four large cohorts (R 2 measure of linkage disequilibrium <0.4). The marginal effect of these SNPs on Lp(a) levels was obtained.…”

“…The marginal effect of these SNPs on Lp(a) levels was obtained. To derive an estimation of geneticallydetermined Lp(a) levels, we included 26 SNPs from the report of Burgess et al 17 that had a minor allele frequency equal or above 0.005. We also only included independent SNPs (R 2 <0.2).…”

“…To evaluate the association between genetically-determined Lp(a) levels and parental lifespan in the UK Biobank, we performed 2SMR, in which the effect of the selected SNPs on Lp(a) levels were obtained from Burgess et al 17 and the effect of the SNPs on parental lifespan were assessed in the UK Biobank. First, we separated individuals in the UK Biobank into quartiles based on wGRS distribution and performed logistic regression adjusting for age, sex and the first 10 ancestry-based principal components to document the association between genetically-elevated Lp(a) and parental lifespan.…”

Relative prognostic importance and optimal levels of risk factors for mortality and cardiovascular outcomes in type 1 diabetes mellitus

“…Thus, patients with T1DM who have not developed cardiovascular disease, specifically younger patients, might benefit from more aggressive primary cardiovascular risk prevention efforts and perhaps efforts initiated earlier in the course of disease. [18][19][20][21] This is an important clinical point because currently statins are less commonly used in patients with T1DM who are <40 years of age, 22 and some clinicians remain unconvinced of the merits of statins in the care of their patients with T1DM despite some evidence. Our observational data showed strong associations between LDL-C and long-term cardiovascular risk in patients with T1DM (in particular, MI, with risks being lower at even lower levels), which adds important support for targeting LDL-C in T1DM to prevent vascular disease.…”