Statin action favors normalization of the plasma lipidome in the atherogenic mixed dyslipidemia of MetS: potential relevance to statin-associated dysglycemia

Abstract

The impact of statin treatment on the abnormal plasma lipidome of mixed dyslipidemic patients with metabolic syndrome (MetS), a group at increased risk of developing diabetes, was evaluated. Insulin-resistant hypertriglyceridemic hypertensive obese males (n = 12) displaying MetS were treated with pitavastatin (4 mg/day) for 180 days; healthy normolipidemic age-matched nonobese males (n = 12) acted as controls. Statin treatment substantially normalized triglyceride (-41%), remnant cholesterol (-55%), and LDL-cholesterol (-39%), with minor effect on HDL-cholesterol (+4%). Lipidomic analysis, normalized to nonHDL-cholesterol in order to probe statin-induced differences in molecular composition independently of reduction in plasma cholesterol, revealed increment in 132 of 138 lipid species that were subnormal at baseline and significantly shifted toward the control group on statin treatment. Increment in alkyl- and alkenylphospholipids (plasmalogens) was prominent, and consistent with significant statin-induced increase in plasma polyunsaturated fatty acid levels. Comparison of the statin-mediated lipidomic changes in MetS with the abnormal plasma lipidomic profile characteristic of prediabetes and T2D in the Australian Diabetes, Obesity, and Lifestyle Study and San Antonio Family Heart Study cohorts by hypergeometric analysis revealed a significant shift toward the lipid profile of controls, indicative of a marked trend toward a normolipidemic phenotype. Pitavastatin attenuated the abnormal plasma lipidome of MetS patients typical of prediabetes and T2D.

Trial registration: ClinicalTrials.gov NCT01595828.

Keywords: cholesterol; lipidomics; metabolic syndrome; obesity; omega-3 fatty acids; pitavastatin; plasmalogens.

Fig. 1.

Effect of pitavastatin treatment (4 mg/day) on plasma phosphatidylcholine, phosphatidylethanolamine, and diacylglycerol (DG) species (normalized to nonHDL-C) between MetS subjects pretreatment (D0) and MetS subjects posttreatment (D180). Plasma lipids were analyzed as described in the Materials and Methods and normalized to nonHDL-C. The mean percent change from MetS pretreatment (D0) to MetS posttreatment (D180) was calculated and the significance determined using a paired Student’s t-test correcting for multiple comparisons by the Benjamini-Hochberg method. A: Shows phosphatidylcholine species (light bars) and phosphatidylethanolamine species (dark bars). B: Shows diacylglycerol species. *Indicates corrected P value <0.05.

Fig. 2.

Hypergeometric analysis of the pitavastatin-mediated changes in plasma lipid species in MetS subjects in the CAPITAIN study against plasma lipid species associated with T2D/prediabetes. Plasma lipids in the AusDiab study were normalized to nonHDL-C and the association with T2D/prediabetes determined by logistic regression adjusted for age, sex, BMI, and SBP. Plasma lipids in the CAPITAIN study were normalized to nonHDL-C and the lipid species significantly altered by treatment were determined using a paired Student’s t-test. Comparison of these datasets identified 254 common lipid species. Hypergeometric tests were performed to assess the statistical significance of the overlap of the lipid set negatively associated with T2D/prediabetes [n = 57, pink circle (A)] with the lipid set that was upregulated by pitavastatin treatment [n = 97, green circle (A)]. The overlap was significant (P = 6.38 × 10⁻¹⁰). The intersection of the lipid set positively associated with T2D/prediabetes [n = 91, orange circle (B)] with the lipid set that was upregulated by statin treatment [n = 97, green circle (B)] was not significant (P = 1.0). The same analyses in the SAFHS dataset combined with the CAPITAIN dataset resulted in 303 common lipid species. The hypergeometric analyses identified a significant overlap between the lipid set negatively associated with T2D/prediabetes [pink circle (C)] and the lipid set upregulated by statin treatment [green circle (C), P = 6.47 × 10⁻¹¹]. The overlap between the lipid set positively associated with T2D/prediabetes [orange circle (D)] and the set upregulated by statin treatment [green circle (D)] was not significant (P = 1.0).

Fig. 3.

Network analysis of plasma lipids in the AusDiab cohort showing correlated changes between plasma lipids post-pitavastatin treatment. A base network was established as follows: Pearson’s linear correlation was computed between pairs of lipids on all subjects from the AusDiab cohort. Edges (dashed lines) were defined if the correlation between node pairs (lipids) was statistically significant (i.e., Benjamini-Hochberg corrected P value ≤0.05). Solid blues edges denote correlated changes between lipids post-pitavastatin treatment. All computed significant correlations were positive. Nodes were sized according to the magnitude of change (difference in mean) effected by statin treatment. Nodes were colored according to the degree of significance of the change (i.e., darker: more significant). Red (or shades of) indicates statistically significant reduction in lipid abundance resulting from statin treatment. Yellow nodes indicate a nonsignificant change in lipid abundance from statin treatment.