Changes in plasma lipids predict pravastatin efficacy in secondary prevention

Abstract

BACKGROUNDStatins have pleiotropic effects on lipid metabolism. The relationship between these effects and future cardiovascular events is unknown. We characterized the changes in lipids upon pravastatin treatment and defined the relationship with risk reduction for future cardiovascular events.METHODSPlasma lipids (n = 342) were measured in baseline and 1-year follow-up samples from a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study subcohort (n = 4991). The associations of changes in lipids with treatment and cardiovascular outcomes were investigated using linear and Cox regression. The effect of treatment on future cardiovascular outcomes was examined by the relative risk reduction (RRR).RESULTSPravastatin treatment was associated with changes in 206 lipids. Species containing arachidonic acid were positively associated while phosphatidylinositol species were negatively associated with pravastatin treatment. The RRR from pravastatin treatment for cardiovascular events decreased from 23.5% to 16.6% after adjustment for clinical risk factors and change in LDL-cholesterol (LDL-C) and to 3.0% after further adjustment for the change in the lipid ratio PI(36:2)/PC(38:4). Change in PI(36:2)/PC(38:4) mediated 58% of the treatment effect. Stratification of patients into quartiles of change in PI(36:2)/PC(38:4) indicated no benefit of pravastatin in the fourth quartile.CONCLUSIONThe change in PI(36:2)/PC(38:4) predicted benefit from pravastatin, independent of change in LDL-C, demonstrating its potential as a biomarker for monitoring the clinical benefit of statin treatment in secondary prevention.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry identifier ACTRN12616000535471.FUNDINGBristol-Myers Squibb; NHMRC grants 211086, 358395, and 1029754; NHMRC program grant 1149987; NHMRC fellowship 108026; and the Operational Infrastructure Support Program of the Victorian government of Australia.

Keywords: Cardiovascular disease; Cholesterol; Clinical Trials; Clinical practice; Metabolism.

Figure 1. Association of pravastatin treatment with change in the concentration of lipid species (n = 4991).

Linear regression analysis of the percentage change in each lipid species against statin treatment, adjusted for age, sex, BMI, and percentage change in cholesterol, HDL-C, and triglycerides, was performed. The β-coefficient denotes the difference in percentage changes (from baseline to follow-up) between treatment and placebo groups. DG, diacylglycerol; HexCer, monohexosylceramide; LPC, lysophosphatidylcholine; LPE, lysophosphatidylethanolamine; LPI, lysophosphatidylinositol; PC, phosphatidylcholine; PI, phosphatidylinositol.

Figure 2. Association of statin treatment with percentage difference of lipid species and classes.

(A) Percentage difference between statin-treated and untreated participants of the LIPID study (taken at the 12-month time point; n = 4991) and the ADVANCE study (taken at baseline; n = 3779). The percentage difference values were analyzed against statin treatment in a linear regression analysis, adjusted for age, sex, BMI, cholesterol, HDL-C, and triglycerides. (B) Correlation between the percentage difference between statin-treated and untreated participants in the LIPID study and ADVANCE study as analyzed via a linear regression. CE, cholesteryl ester; Cer, ceramide; COH, free cholesterol; DG, diacylglycerol; dhCer, dihydroceramide; GM3, G_M3 ganglioside; HexCer, monohexosylceramide; Hex2Cer, dihexosylceramide; Hex3Cer, trihexosylceramide; LPC, lysophosphatidylcholine; LPC(O), lysoalkylphosphatidylcholine; LPE, lysophosphatidylethanolamine; LPI, lysophosphatidylinositol; PC, phosphatidylcholine; PC(O), alkylphosphatidylcholine; PC(P), alkenylphosphatidylcholine; PE, phosphatidylethanolamine; PE(O), alkylphosphatidylethanolamine; PE(P), alkenylphosphatidylethanolamine; PG, phosphatidylglycerol; PI, phosphatidylinositol; PS, phosphatidylserine; SM, sphingomyelin; TG, triacylglycerol.

Figure 3. Association of treatment with future cardiovascular events after adjustment for changes in LDL-C and lipid concentration (n = 4991).

The base model describes the association of treatment with future cardiovascular events analyzed via Cox regression, adjusted for the Marschner covariates (age, sex, total cholesterol, HDL-C, current smoking, nature of prior acute coronary syndrome, revascularization, diabetes history, stroke history, and history of hypertension). The subsequent models incorporate change in LDL-C and change in plasma lipid species into the model with base covariates described above. The hazard ratios and relative risk reduction (RRR) are for those individuals who did not exhibit a change in the lipid species. The hazard ratios adjusted for the interaction effect between the change in lipid species and treatment depend on the magnitude of the change in lipid species. LPC, lysophosphatidylcholine; PC, phosphatidylcholine; PI, phosphatidylinositol.

Figure 4. Association of treatment with future cardiovascular events and cardiovascular death in quartiles of ΔLR, PI(36:2)/PC(38:4), in the statin treatment group (n = 4991).

The samples in each quartile of the ΔLR on statin treatment were combined with all the samples in the placebo group, and a Cox regression analysis was performed to find the hazard ratio of treatment for cardiovascular events and death with or without adjustment for change in LDL-C. Base models included the Marschner covariates (age, sex, total cholesterol, HDL-C, current smoking, nature of prior acute coronary syndrome, revascularization, diabetes history, stroke history, and history of hypertension) previously developed in the LIPID cohort. Bootstrapping (1000 iterations) was performed to determine the CIs for the RRR.