Racial Differences in Iron Measures and Outcomes Observed during an Iron Reduction Trial in Peripheral Arterial Disease

Abstract

Elevated body iron (ferritin) levels may contribute to adverse health outcomes. Racial differences in iron measures and clinical outcomes were observed during an iron reduction trial in peripheral arterial disease. At entry, Black compared with White participants had higher ferritin and lower red cell measures, as well as differing ferritin and percent transferrin saturation (%TS) responses, and HDL/LDL ratios associated with statin use. Lower hematocrit levels during follow-up resulted in fewer phlebotomies, less iron unloading (ferritin reduction, p=.035) and 32% less iron removed in Black compared with White participants randomized to iron reduction. Improved primary (all-cause mortality) and secondary (death plus non-fatal myocardial infarction and stroke) outcomes among White participants correlated with lower ferritin levels (p=.005 and p=.053, respectively) and higher %TS levels (p<.001 and p=.001 respectively), associations not observed in Black participants. Variant iron homeostasis contributory to racial health disparities warrants personalized intervention strategies and race-specific clinical trial design.

Ferritin and Percent Transferrin Saturation Levels Predict Type 2 Diabetes Risk and Cardiovascular Disease Outcomes

“…Thus, normative values for the serum ferritin may range from the commonly accepted lower limit of less than about 15 ng/mL to an upper limit of about 80-100 ng/mL as observed in this study. This threshold ferritin level coincides with levels associated with increased T2D risk observed epidemiologically [13] as well as adverse outcomes observed in clinical trial data [17,21]. Fig.…”

“…The proportionate increase in ferritin and %TS values shown in Figure 3 up to ferritin levels of about 80 ng/mL and %TS levels of about 25% suggests strict physiologic correspondence or compensation of these functionally different proteins representing balance between ferritin and transferrin as they interact to maintain optimal (compensated) iron homeostasis [14] associated with minimal disease risk [13,17,21]. The curves flatten above ferritin levels of about 80 ng/mL and %TS levels above about 25% but then increase proportionately up to about 100 ng/mL of ferritin of and about 50-55%TS.…”

“…Loess curves were examined for inflections below or above which adverse clinical events were less or more likely to occur. Relevance of observed inflection points to clinical outcomes was based on outcomes from clinical trial findings [17,21,28] as well as epidemiologic studies assessing iron biomarker levels and risk of T2D and CVD [12,13,16].…”

“…We observed that higher ferritin levels correlated with mortality during a prospective randomized clinical trial of iron reduction in primarily males with cardiovascular disease (CVD, peripheral arterial disease, VACSP 410) [17] along with increased levels of inflammatory markers: TNF alpha (receptor 1), IL6 and hsCRP [18,19]. Significantly improved disease outcomes related to lower ferritin levels [17,20,21] and with increasing %TS levels in the range of 25-50%TS [21]. Mean ferritin levels in participants in CSP 410 at entry were about 122 ng/mL and iron reduction targeted ferritin levels of 60 ng/mL [17].…”

“…These epidemiologic and clinical trial associations suggested revision of normative values for ferritin and %TS levels, common measures of iron metabolism, considered indicative of the transition from low to increased disease risk. Similarities in iron biomarker levels associated with T2D risk [13,15] and adverse vascular disease outcomes [17,21] suggested that examination of graded biomarker levels during iron reduction would provide further information on quantitative relationships between these biomarkers of iron metabolism and disease risk.…”