LPA VARIANTS, RISK OF CORONARY DISEASE, AND ESTIMATED CLINICAL BENEFIT OF LIPOPROTEIN(A) LOWERING THERAPIES: A MENDELIAN RANDOMIZATION ANALYSIS

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) by 25-35% have not provided any evidence that lowering Lp(a) reduces CHD risk. Objective: To estimate the magnitude of the change in plasma Lp(a) needed to have the same effect on CHD risk as a 1 mmol/L (38.67 mg/dL) change in LDL-C, a change in LDL-C that has been shown to produce a clinically meaningful reduction in the risk of CHD. Design: Meta-analysis of Mendelian randomization studies conducted using individual participant data from 5 studies; with external validation using summarized data from 48 studies. Setting: Population based prospective cohort and case-control studies. Participants: 20,793 CHD cases and 27,540 controls with individual participant data; 62,240 CHD cases and 127,299 controls with summarized data. Exposure: Genetic Lp(a) score and plasma Lp(a) mass concentration. Main outcomes and measures: Coronary heart disease. Results: The causal effect of Lp(a) on 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 estimated using an LDL-C genetic score was associated with a 14.5% lower CHD risk (0.855; 0.818–0.893; p=2×10-12). Thus, a 101.5 mg/dL (95% CI: 71.0–137.0) change in Lp(a) had the same effect on CHD risk as a 1 mmol/L change in LDL-C. The effect of Lp(a) on CHD risk appeared to be independent of changes in LDL-C due to genetic variants that mimic the effect of statins, PCSK9 inhibitors and ezetimibe. Conclusions and relevance: Large absolute reductions in Lp(a) of approximately 100 mg/dL may be required to a produce clinically meaningful reduction in the risk of CHD similar in magnitude to what can be achieved by lowering LDL-C by 1 mmol/L. Therefore, only people with very high plasma Lp(a) concentration are likely to derive a clinical benefit from therapies that lower Lp(a).