Effects of rosuvastatin on the immune system in healthy volunteers with normal serum cholesterol

Abstract

BACKGROUNDHMG-CoA reductase inhibitors (statins) are prescribed to millions of people. Statins are antiinflammatory independent of their cholesterol-reducing effects. To date, most reports on the immune effects of statins have assayed a narrow array of variables and have focused on cell lines, rodent models, or patient cohorts. We sought to define the effect of rosuvastatin on the "immunome" of healthy, normocholesterolemic subjects.METHODSWe conducted a prospective study of rosuvastatin (20 mg/d × 28 days) in 18 statin-naive adults with LDL cholesterol <130 mg/dL. A panel of >180 immune/biochemical/endocrinologic variables was measured at baseline and on days 14, 28, and 42 (14 days after drug withdrawal). Drug effect was evaluated using linear mixed-effects models. Potential interactions between drug and baseline high-sensitivity C-reactive protein (hsCRP) were evaluated.RESULTSA wide array of immune measures changed (nominal P < 0.05) during rosuvastatin treatment, although the changes were modest in magnitude, and few met an FDR of 0.05. Among changes noted were a concordant increase in proinflammatory cytokines (IFN-γ, IL-1β, IL-5, IL-6, and TNF-α) and peripheral blood neutrophil frequency, and a decline in activated Treg frequency. Several drug effects were significantly modified by baseline hsCRP, and some did not resolve after drug withdrawal. Among other unexpected rosuvastatin effects were changes in erythrocyte indices, glucose-regulatory hormones, CD8+ T cells, and haptoglobin.CONCLUSIONRosuvastatin induces modest changes in immunologic and metabolic measures in normocholesterolemic subjects, with several effects dependent on baseline CRP. Future, larger studies are warranted to validate these changes and their physiological significance.TRIAL REGISTRATIONClinicalTrials.gov NCT01200836.FUNDINGThis research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES102005), and the trans-NIH Center for Human Immunology.

Keywords: Cellular immune response; Cholesterol; Clinical Trials; Cytokines; Immunology.

Figure 1. Study design for evaluating the effect of rosuvastatin initiation and discontinuation on the human immunome.

Figure 2. Effect of rosuvastatin on serum lipids.

Serum total cholesterol (A), LDL-C (B), HDL-C (C), and triglycerides (D) were measured in study participants at the indicated trial time points (baseline [day 0], rosuvastatin treatment [days 14 and 28], and 14 days after rosuvastatin discontinuation [day 42]). Data for subjects with low versus high CRP at baseline are plotted separately. Boxes depict IQR around the median. The upper whisker extends from the hinge to the largest value no further than 1.5 * IQR from the hinge; the lower whisker extends from the hinge to the smallest value at most 1.5 * IQR of the hinge. Outlying points are plotted individually. Nominal P values for rosuvastatin treatment and discontinuation were determined for the overall study group by linear regression (also listed in Table 2 and Table 3).

Figure 3. Effect of rosuvastatin on immune measures.

Immune measures were plotted in study participants at the indicated trial time points (baseline [day 0], rosuvastatin treatment [days 14 and 28], and 14 days after rosuvastatin discontinuation [day 42]). Data for subjects with low versus high CRP at baseline are plotted separately. Boxes depict IQR around the median. Upper whisker extends from the hinge to the largest value no further than 1.5 * IQR from the hinge; lower whisker extends from the hinge to smallest value at most 1.5 * IQR of the hinge. Outlying points are plotted individually. Nominal P values for the overall study group were determined by linear regression. P values in A–G are for rosuvastatin treatment compared with day 0 (Table 2); in H–J, for rosuvastatin treatment in interaction with CRP (Supplemental Table 3); and in K and L, for rosuvastatin discontinuation (Table 3).

Figure 4. Effect of rosuvastatin on endocrine measures.

Levels of glucagon (A), GLP-1 (B), insulin (C), and C-peptide (D) in study subjects during the rosuvastatin time course. Subjects with low versus high CRP at baseline are plotted separately. The upper whisker extends from the hinge to the largest value no further than 1.5 * IQR from the hinge; the lower whisker extends from the hinge to the smallest value at most 1.5 * IQR of the hinge. Outlying points are plotted individually. Nominal P values for rosuvastatin treatment and discontinuation were determined for the overall study group by linear regression (also listed in Table 2 and Table 3).