Identification of Two Novel Subgroups in Patients with Diabetes Mellitus and Their Association with Clinical Outcomes: A Two-Step Cluster Analysis

Background:   The present study aims to observe whether distinct subphenotypes of patients with type 2 diabetes mellitus (T2DM) in European classification exist in Chinese populations and further establish the novel subphenotypes by adjusted cluster analysis, which are more suitable for Chinese populations.   Methods: The research retrospectively analyzed 5414 patients with T2DM from National Clinical Research Center for Metabolic Diseases Diabetes Center, China, and the two-step cluster analysis was performed. Firstly, we confirmed the European classification in Chinese populations by six parameters. Further, triglyceride, high-density lipoprotein cholesterol, uric acid etc. were included to refine the cluster analysis, and the Cox regression was used to evaluate the risk of diabetic complications. Findings:  Only three clusters were replicated in our cohort according to Emma Ahlqvists' European classification. When other variables were added into the cluster analysis, seven subgroups were identified including five clusters of European classification and two novel subgroups, which were uric acid related diabetes (UARD) and Untypical. Compared to Untypical, cases with severe insulin resistant diabetes showed higher risk of diabetic peripheral neuropathy, hypertension and chronic kidney disease, and UARD subgroup showed higher risk of coronary heart disease and end stage renal disease. Patients with severe insulin-deficient diabetes showed higher risk of diabetic foot than that of Untypical. No significant difference was observed in the prevalence of cancer in each subgroup. Interpretation:  Seven subgroups of T2DM were identified in Chinese populations with distinct characteristics and disparate clinical outcomes. This aetiology-based stratification may contribute to the diagnosis and management of T2DM.   Funding Statement:  The National Basic Research Program of China (2016YFC1305501 and 2018YFC1314002). Declaration of Interests: No potential conflicts of interest relevant to this article were reported. Ethics Approval Statement:  This study was approved by the Hunan Research Ethics Committees in the Second Xiangya Hospital of Central South University, China.