Estimation of the Required Lipoprotein(a)-Lowering Therapeutic Effect Size for Reduction in Coronary Heart Disease Outcomes: A Mendelian Randomization Analysis

Abstract

Importance: Genetic and epidemiologic data suggest that lipoprotein(a) (Lp[a]) is one of the strongest genetically determined risk factors for coronary heart disease (CHD). Specific therapies to lower Lp(a) are on the horizon, but the required reduction of Lp(a) to translate into clinically relevant lowering of CHD outcomes is a matter of debate.

Objective: To estimate the required Lp(a)-lowering effect size that may be associated with a reduction of CHD outcomes compared with the effect size of low-density lipoprotein cholesterol (LDL-C)-lowering therapies.

Design, setting, and participants: Genetic epidemiologic study using a mendelian randomization analysis to estimate the required Lp(a)-lowering effect size for a clinically meaningful effect on outcomes. We used the effect estimates for Lp(a) from a genome-wide association study (GWAS) and meta-analysis on Lp(a) published in 2017 of 5 different primarily population-based studies of European ancestry. All Lp(a) measurements were performed in 1 laboratory. Genetic estimates for 27 single-nucleotide polymorphisms on Lp(a) concentrations were used. Odds ratios for these 27 single-nucleotide polymorphisms associated with CHD risk were retrieved from a subsample of the CHD Exome+ consortium.

Exposures: Genetic LPA score, plasma Lp(a) concentrations, and observations of statin therapies on CHD outcomes.

Main outcomes and measures: Coronary heart disease.

Results: The study included 13 781 individuals from the Lp(a)-GWAS-Consortium from 5 primarily population-based studies and 20 793 CHD cases and 27 540 controls from a subsample of the CHD Exome+ consortium. Four of the studies were similar in age distribution (means between 51 and 59 years), and 1 cohort was younger; mean age, 32 years. The frequency of women was similar between 51% and 55%. We estimated that the required reduction in Lp(a) effect size would be 65.7 mg/dL (95% CI, 46.3-88.3) to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67 mg/dL (to convert to millimoles per liter, multiply by 0.0259).

Conclusions and relevance: This mendelian randomization analysis estimated a required Lp(a)-lowering effect size of 65.7 mg/dL to reach the same effect as a 38.67-mg/dL lowering of LDL-C. However, this estimate is determined by the observed effect estimates of single-nucleotide polymorphisms on Lp(a) concentrations and is therefore influenced by the standardization of the Lp(a) assay used. As a consequence, calculations of the required Lp(a)-lowering potential of a drug to be clinically effective might have been overestimated in the past.

Figure 1.. Association of LPA Variants With Lipoprotein(a) (Lp[a]) Concentration and Coronary Heart Disease (CHD) Risk

Marginal genetic associations for each of the 27 evaluated single-nucleotide polymorphisms (SNPs), with Lp(a) concentrations on the x-axis (denoting absolute change in milligrams per deciliter) and CHD risk on the y-axis (log odds ratio). For direct comparison, the data from Burgess et al are illustrated in orange color and our data are given in blue color. Effect sizes refer to the minor allele and error bars give 95% confidence intervals. The lines indicate the mendelian randomization estimates from Lp(a) on CHD risk. Black arrows show the reduction of Lp(a) estimates exemplarily for 2 SNPs when taking our estimates instead of the estimates from Burgess at al. These data underline that the higher estimates of the SNPs on Lp(a) concentrations from Burgess et al result in markedly lower estimates for CHD risk per 10-mg/dL lower genetically predicted Lp(a) concentrations compared with our data. SI conversion factor: To convert cholesterol levels to millimoles per liter, multiply by 0.0259.

Figure 2.. Estimates of Coronary Heart Disease (CHD) Risk Reduction With Lowering of Lipoprotein(a) (Lp[a]) Concentration

The solid lines provide the genetically predicted lifelong reduction of CHD risk by varying amount of genetically caused Lp(a) reductions. The blue lines provide data from Burgess et al and the orange lines are based on the estimates from our study. The dashed lines give the predicted short-term trial estimates from both studies. The intersections of the horizontal and vertical dotted lines illustrate the required amount of Lp(a) lowering to reach the same effect on clinical outcomes as a 38.67 mg/dL genetically caused reduction of LDL-C (corresponds to 45% risk reduction) or therapeutic reduction of LDL-C derived from the CTT trial (corresponds to 22% risk reduction). SI conversion factor: To convert cholesterol levels to millimoles per liter, multiply by 0.0259.