A novel diabetes typology: towards precision diabetology from pathogenesis to treatment

Abstract

The current classification of diabetes, based on hyperglycaemia, islet-directed antibodies and some insufficiently defined clinical features, does not reflect differences in aetiological mechanisms and in the clinical course of people with diabetes. This review discusses evidence from recent studies addressing the complexity of diabetes by proposing novel subgroups (subtypes) of diabetes. The most widely replicated and validated approach identified, in addition to severe autoimmune diabetes, four subgroups designated severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes and mild age-related diabetes subgroups. These subgroups display distinct patterns of clinical features, disease progression and onset of comorbidities and complications, with severe insulin-resistant diabetes showing the highest risk for cardiovascular, kidney and fatty liver diseases. While it has been suggested that people in these subgroups would benefit from stratified treatments, RCTs are required to assess the clinical utility of any reclassification effort. Several methodological and practical issues also need further study: the statistical approach used to define subgroups and derive recommendations for diabetes care; the stability of subgroups over time; the optimal dataset (e.g. phenotypic vs genotypic) for reclassification; the transethnic generalisability of findings; and the applicability in clinical routine care. Despite these open questions, the concept of a new classification of diabetes has already allowed researchers to gain more insight into the colourful picture of diabetes and has stimulated progress in this field so that precision diabetology may become reality in the future.

Keywords: Clustering; Complications; Diabetes subgroups; Personalised medicine; Precision medicine; Reclassification; Review.

Fig. 1

Possible future implications of precision diabetology based on the novel diabetes subgroups. Although the utility of the concept needs to be evaluated in RCTs, one may speculate on the potential implications of a new (sub)classification of diabetes for tailored diagnosis, prevention and treatment. Individuals in the different diabetes subgroups differ in their susceptibility to developing specific complications. The different (pathophysiological) phenotypes may also differ in their response to lifestyle-related and pharmacological strategies. SAID requires early introduction of insulin supplementation, whereas SIDD may also benefit from a dipeptidyl peptidase 4 inhibitor (DPP4i) or, when cost is a major issue, a sulfonylurea. SIRD and MOD would benefit from medication that induces weight loss (SGLT2i, GLP-1RA, dual agonist) or also addresses risk of CVD or nephropathy (SGLT2i, GLP-1RA). Providing that safety and efficacy have been established, new insulin sensitisers (e.g. peroxisome proliferator activator receptor agonists) or anti-inflammatory drugs could also improve targeted treatment of SIRD. On the other hand, individuals with MARD should receive treatments avoiding weight loss and sarcopenia (e.g. protein-balanced diets and moderate resistance training). PPARa, peroxisome proliferator activator receptor agonist. This figure is available as a downloadable slide