Dietary iron intake predicts all-cause and cardiovascular mortality in patients with diabetes

Diabetes mellitus is a significant global health concern, affecting approximately 451 million people in 2017, a number projected to rise to 693 million by 2045. Diabetes is linked to increased all-cause and cardiovascular mortality, highlighting the need to identify factors that can mitigate these risks. Iron is crucial for cellular energy metabolism, oxygen transport, and various enzymatic processes. However, both iron deficiency and excess are implicated in various diseases. Studies have suggested a link between increased iron intake and a higher risk of diabetes, with some indicating that heme iron from red meat is particularly problematic. Conversely, other studies have indicated an inverse relationship between non-heme iron and type 2 diabetes. The impact of iron intake on mortality in diabetic patients remains largely unstudied. This study aimed to explore the relationship between dietary iron intake and all-cause, cardiovascular, and cancer mortality in a large cohort of individuals with diabetes.

Previous research has explored the association between iron intake and diabetes risk. A Chinese cross-sectional survey revealed a correlation between elevated heme iron intake and increased diabetes risk, although causality remains unclear. A prospective cohort study found a positive correlation between heme iron intake (from red meat) and type 2 diabetes risk, particularly in men. Conversely, non-heme iron showed an inverse association with type 2 diabetes risk, especially in postmenopausal women. The role of iron in diabetic complications like retinopathy, kidney injury, and peripheral neuropathy has also been investigated. However, research directly linking dietary iron intake to mortality in diabetic individuals is limited. Studies have examined the association between iron status (serum iron, ferritin) and mortality in the general population, and in prediabetes, revealing complexities in the relationship, with both deficiency and excess potentially increasing mortality risk.

This study used data from the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2014. 5970 participants with diabetes were included after excluding those under 18 years of age or lacking iron intake data. Dietary iron intake was assessed using a 24-hour dietary recall with a multi-pass approach. Mortality status was determined via the National Death Index up to December 31, 2015. The primary outcome was all-cause mortality; secondary outcomes were cardiovascular disease (CVD) and cancer mortality. Baseline characteristics, including demographics, lifestyle factors, medical history, and biomedical measurements (fasting glucose, HbA1c, lipids, eGFR), were collected. Cox proportional hazards regression models, adjusted for multiple variables in three models of increasing complexity, were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Restricted cubic splines were used to analyze nonlinear associations, and subgroup analysis examined the effect of baseline serum iron levels. Statistical significance was set at p<0.05.

The average daily iron intake was 14.1 ± 7.4 mg, with 51.3% of participants being male. Over 41,425 person-years of follow-up, 1497 deaths were observed. Kaplan-Meier analysis suggested that low iron intake was associated with higher all-cause mortality in both men and women. After multivariable adjustment, iron intake between 11.1 and 14.4 mg/day was associated with the lowest risk of all-cause mortality (HR 0.83 [0.70, 0.99], p<0.05) compared to the lowest intake group (<8.3 mg/day). Analysis using restricted cubic splines revealed an L-shaped association between iron intake and all-cause mortality in men and a J-shaped association in women. The study found no significant association between iron intake and cancer mortality. There was an association between iron intake in the 14.4-18.8mg/day range and cardiovascular mortality in the univariable model but this relationship was not observed in the multivariable model.

This study's findings indicate a nonlinear association between dietary iron intake and all-cause mortality in individuals with diabetes, suggesting an optimal intake range. The observed gender difference, with higher intake potentially harmful to women but beneficial to men, requires further investigation. The lack of association with cardiovascular and cancer mortality contrasts with some previous findings, potentially reflecting differences in methodology (dietary vs. serum iron) and populations studied. The study's results are consistent with the notion that maintaining a moderate iron intake may be vital for supporting essential physiological functions, but excessive iron can lead to detrimental effects via oxidative stress and disruption of insulin secretion. The gender difference might be attributed to differences in iron storage and metabolism between sexes and the type of iron source (more red meat for higher intakes).

This study demonstrates a nonlinear relationship between dietary iron intake and all-cause mortality in diabetic adults. The findings highlight a potential optimal iron intake range of approximately 11.1-14.4 mg/day. Further research is needed to elucidate the underlying mechanisms involved in the observed gender differences and to refine recommendations for iron intake in individuals with diabetes. Consideration of other iron status markers (ferritin, transferrin saturation) and diverse iron sources are crucial in future studies.

The study relied on self-reported dietary intake and medical history, which are susceptible to recall bias. The study lacked data on serum ferritin and other iron status markers, potentially influencing the interpretation of results. The cross-sectional nature of the data limits the establishment of causal relationships. The reliance on NHANES data might not be generalizable to other populations.