The statin-iron nexus: anti-inflammatory intervention for arterial disease prevention

Abstract

Objectives: We postulated the existence of a statin-iron nexus by which statins improve cardiovascular disease outcomes at least partially by countering proinflammatory effects of excess iron stores.

Methods: Using data from a clinical trial of iron (ferritin) reduction in advanced peripheral arterial disease, the Iron and Atherosclerosis Study, we compared effects of ferritin levels versus high-density lipoprotein to low-density lipoprotein ratios (both were randomization variables) on clinical outcomes in participants receiving and not receiving statins.

Results: Statins increased high-density lipoprotein to low-density lipoprotein ratios and reduced ferritin levels by noninteracting mechanisms. Improved clinical outcomes were associated with lower ferritin levels but not with improved lipid status.

Conclusions: There are commonalities between the clinical benefits of statins and the maintenance of physiologic iron levels. Iron reduction may be a safe and low-cost alternative to statins.

FIGURE 1—

Linear regression analysis for the overall cohort (n = 1277): the Iron and Atherosclerosis Study (FeAST), Multiple US Veterans Administration Centers, 1999–2005. Note. HDL = high-density lipoprotein; LDL = low-density lipoprotein. There was no association between mean follow-up ferritin levels and mean follow-up HDL/LDL ratios (P = .89).

FIGURE 2—

Mean follow-up HDL/LDL ratio and log-relative hazard for all-cause mortality for the overall cohort (n = 1277): the Iron and Atherosclerosis Study (FeAST), Multiple US Veterans Administration Centers, 1999–2005. Note. CI = confidence interval; HDL = high-density lipoprotein; HR = hazard ratio; LDL = low-density lipoprotein. HR = 1.01 (95% CI = 0.89, 1.16; P = .84).

FIGURE 3—

Kaplan–Meier analysis for all-cause mortality in the overall cohort (n = 1277): the Iron and Atherosclerosis Study (FeAST), Multiple US Veterans Administration Centers, 1999–2005. Note. HDL = high-density lipoprotein; LDL = low-density lipoprotein. There was no difference between patients having mean follow-up HDL/LDL ratios above vs below the median of the means for the cohort (hazard ratio = 0.97; 95% confidence interval = 0.66, 1.41; P = .857).