BMI-residualized data uncovers a cluster of people with type 2 diabetes and increased serum ferritin protected from cardiovascular disease

Abstract

Background: Understanding the relationship between serum ferritin levels and cardiovascular outcomes in type 2 diabetes is crucial for improving risk stratification and guiding therapeutic interventions aimed at preventing major adverse cardiovascular events (MACE). This study aimed to identify distinct clusters of individuals with type 2 diabetes who have varying risks of MACE using a data-driven clustering approach.

Methods: This retrospective cohort study analyzed data from 49,506 individuals within a multicenter, population-based primary care registry in Catalonia, Spain. Individuals diagnosed with type 2 diabetes at age 35 or older were recruited between January 2010 and December 2021 and followed for at least 10 years. Biomarkers associated with cardiovascular risk-including serum glucose, HbA1c, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, blood pressure, serum ferritin, leukocyte, and monocyte counts-were examined. Clustering analysis was applied to identify patient subgroups, and Cox proportional hazards models were used to assess associations with cerebrovascular events, coronary events, and composite MACE.

Results: Five distinct clusters were identified, characterized by differences in serum glucose, HbA1c, lipid profiles, blood pressure, and serum ferritin levels. Individuals with discordantly high serum ferritin levels relative to their body mass index (BMI) exhibited a lower risk of adverse cardiovascular outcomes. In men, hazard ratios (HR) were 0.68 (95% confidence interval [CI]: 0.53-0.87) for cerebrovascular events, 0.65 (95% CI 0.49-0.88) for coronary events, and 0.68 (95% CI 0.56-0.83) for MACE. In women, HRs were 0.81 (95% CI 0.67-0.92) for cerebrovascular events, 0.73 (95% CI 0.57-0.95) for coronary events, and 0.79 (95% CI 0.67-0.92) for MACE.

Conclusions: Individuals with type 2 diabetes who exhibit higher-than-expected serum ferritin levels relative to their BMI may have a lower risk of cardiovascular events. These findings suggest that ferritin may play a more complex role in cardiovascular risk than previously assumed and highlight the potential for refined risk stratification strategies in type 2 diabetes management.

Keywords: BMI; Cardiovascular diseases(s) (CVD); Ferritin; Obesity; Type 2 diabetes mellitus.

Fig. 1

Concordant and discordant profiles discovered in the SIDIAP. A Two-dimensional UMAP projection, representing the distribution of profiles in the dataset. The UMAP is colour-coded based on identified clusters. The left panel corresponds to men, while the right panel corresponds to women. B Profile centres for each identified cluster. The distinctive patterns in the profile centres provide a detailed insight into the characteristics defining each cluster. BC: Baseline concordant profile Tg, cLDL: LDL cholesterol, cHDL: HDL cholesterol, DBP: Diastolic blood pressure, SBP: Systolic blood pressure

Fig. 2

Disease-free survival comparison between the identified clusters. Kaplan–Meier curve for overall disease-free survival in the identified clusters for the three cardiovascular studied outcomes—cerebrovascular, coronary, and MACE events—stratified by sex. BC: Baseline concordant profile Tg, cLDL: LDL cholesterol, cHDL: HDL cholesterol, DBP: Diastolic blood pressure, SBP: Systolic blood pressure.

Fig. 3

Sex-stratified Hazard ratios for cardiovascular outcomes across the identified clusters. The figure shows hazard ratios (HR) for the three cardiovascular studied outcomes—cerebrovascular, coronary, and MACE events—stratified by sex