Characterization of Statin Low-Density Lipoprotein Cholesterol Dose-Response Using Electronic Health Records in a Large Population-Based Cohort

Abstract

Background: Low-density lipoprotein cholesterol (LDL-C) response to statin therapy has not been fully elucidated in real-world populations. The primary objective of this study was to characterize statin LDL-C dose-response and its heritability in a large, multiethnic population of statin users.

Methods: We determined the effect of statin dosing on lipid measures utilizing electronic health records in 33 139 statin users from the Kaiser Permanente GERA cohort (Genetic Epidemiology Research on Adult Health and Aging). The relationship between statin defined daily dose and lipid parameter response (percent change) was determined.

Results: Defined daily dose and LDL-C response was associated in a log-linear relationship (β, -6.17; SE, 0.09; P<10^-300) which remained significant after adjusting for prespecified covariates (adjusted β, -5.59; SE, 0.12; P<10^-300). Statin type, sex, age, smoking status, diabetes mellitus, and East Asian race/ethnicity were significant independent predictors of statin-induced changes in LDL-C. Based on a variance-component method within the subset of statin users who had at least 1 first-degree relative who was also a statin user (n=1036), heritability of statin LDL-C response was estimated at 11.7% (SE, 8.6%; P=0.087).

Conclusions: Using electronic health record data, we observed a statin LDL-C dose-response consistent with the rule of 6% from prior clinical trial data. Clinical and demographic predictors of statin LDL-C response exhibited highly significant but modest effects. Finally, statin-induced changes in LDL-C were not found to be strongly inherited. Ultimately, these findings demonstrate (1) the utility of electronic health records as a reliable source to generate robust phenotypes for pharmacogenomic research and (2) the potential role of statin precision medicine in lipid management.

Keywords: Hydroxymethylglutaryl-CoA Reductase Inhibitors; cholesterol, LDL; electronic health record; phenotype; precision medicine.

Figure 1:

Flow diagram of study inclusion and exclusion criteria. A “statin user” is defined as an individual who has at least two dispensing records of any statin prescription (e.g., he or she refilled the initial statin prescription; he or she was dispensed a new statin prescription after the initial statin). In order to protect patient privacy for participants >90 years of age (i.e. individuals that could be identified due to low frequency in the population), data including timing of statin initiation was not provided in this subgroup. Thus, it was not possible to determine if these participants met the criteria for inclusion. Consequently, these participants were excluded from the study. DDD, defined daily dose; EHR, electronic health records; GERA, Genetic Epidemiology Research on Adult Health and Aging; LDL-C, low-density lipoprotein cholesterol.

Figure 2:

Statin dose-response. A significant log-linear dose-response was observed in the full cohort after adjusting for pre-specified covariates (adjusted β = −5.59, SE = 0.11, P < 10⁻³⁰⁰, N = 33,139). Data presented as the median (midline), interquartile range (box), and Tukey whiskers (dotted lines) of fitted values. Outliers are not shown. DDD, defined daily dose; LDL-C, low-density lipoprotein cholesterol.

Figure 3:

Statin dose-response by statin type. A significant log-linear dose-response was observed in initiators of lovastatin (β = −5.82, SE = 0.141, P < 10⁻³⁰⁰; N = 20,853), simvastatin (β = −5.47, SE = 0.211, P = 2.9*10⁻¹⁴³; N=10.452), atorvastatin (β = −4.26, SE = 0.581, P = 3.9*10⁻¹³; N = 1,266), and pravastatin (β = −4.42, SE = 0.975, P = 7.2*10⁻⁶; N = 568) after adjusting for pre-specified covariates. Data presented as the median (midline), interquartile range (box), and Tukey whiskers (dotted lines) of fitted values. Outliers are not shown. DDD, defined daily dose; LDL-C, low-density lipoprotein cholesterol.

Figure 4:

Statin-induced triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and non-high-density lipoprotein cholesterol (non-HDL-C) changes across defined daily dose (DDD). A significant log-linear dose-response was observed for TG (β = −2.90, SE = 0.24, P = 2.0*10⁻³³), HDL-C (β = −0.41, SE = 0.10, P = 2.4*10⁻⁵), and non-HDL-C (β = −5.27, SE = 0.10, P < 1.0*10⁻³⁰⁰) lowering after adjusting for pre-specified covariates. Data presented as the median (midline), interquartile range (box), and Tukey whiskers (dotted lines) of fitted values. Outliers are not shown. Y-axis scales vary across panels.