Thresholds of risk factors for ischemic stroke in type 2 diabetic patients with and without albuminuria—A non-linear approach

Abstract

Objectives

Multiple risk factors in type 2 diabetes may explain their high risk for ischemic stroke (IS). However, it remains unknown whether these risk factors exhibit threshold characteristics and whether these relationships are influenced by albuminuria. The study aims to investigate whether risk factors exhibit any albuminuria specific threshold for IS.

Patients and methods

This is a prospective cohort study with 6969 Chinese type 2 diabetic patients without history of stroke after a median follow-up of 5.36 years. We identified thresholds of risk factors for IS using hazard ratio plots followed by confirmation using traditional Cox regression analysis.

Results

In the non-albuminuric group (n = 4008), IS risk started to increase rapidly at a body mass index threshold of 24 kg/m². The risk of IS declined with increasing blood hemoglobin reaching a threshold value of 14 g/dl. Using these threshold values as cutoff point, body mass index ≥24 kg/m² and hemoglobin <14 g/dl were associated with 2-fold increased risk of IS in these subjects. In the albuminuric group (n = 2961). IS risk started to increase rapidly from a systolic blood pressure threshold of 135 mmHg and declined with increasing estimated glomerular filtration rate (eGFR) reaching a trough of 115 ml/min per 1.73 m². Using these values as cutoff points, patients with systolic blood pressure ≥135 mmHg and eGFR <115 ml/min per 1.73 m² had 2-fold increased risk of IS.

Conclusion

In type 2 diabetic patients, body mass index, hemoglobin, systolic blood pressure and eGFR exhibit different risk relationships and thresholds for IS contingent upon presence or absence of albuminuria.

Introduction

Type 2 diabetes is a highly heterogeneous condition with multiple risk factors and complications including stroke [1], [2]. Old age, high BP, smoking and hyperglycaemia are firmly established risk factors of stroke [3], [4], [5], [6] although the risk association between obesity and stroke remains to be clarified [7], [8], [9]. Albuminuria is a powerful predictor for cardiovascular diseases including stroke in both diabetic and non-diabetic populations [10]. There are now clinical and experimental data supporting albuminuria as a marker of endothelial dysfunction [11]. Prospective data have also shown that HbA_1c, BP and BMI are promoters of albuminuria [12]. On the other hand, albuminuria can lead to progressive increase in total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels which can increase the risk of coronary heart disease (CHD) [13]. Taken together, these data suggest that different causal factors may initiate the onset and progression of albuminuria while the latter can increase the risk of cardiovascular diseases independently or by promoting other risk factors.

In many epidemiological studies, the linear nature of these risk associations is often presumed although this has never been well demonstrated in literature. Confirming or refuting the linearity of these relationships have important therapeutic implications in light of ongoing debates on the target level to achieve and the threshold value to commence intervention. These questions cannot be easily addressed in a clinical trial whose primary objective is to examine the efficacy of a treatment, and often entails multiple exclusion criteria.

In this study, we aim to firstly, clarify whether these risk relationships exhibit non-linearity and threshold and secondly, whether these relationships are altered in the presence or absence of albuminuria.