Battaglia M, et al. Introducing the Endotype Concept to Address the Challenge of Disease Heterogeneity in Type 1 Diabetes. Diabetes Care. 2019 Nov 21. [Epub ahead of print]

It has long been thought that the type 1 diabetes phenotype results from a single pathogenic mechanism. However, during the last two decades it has become evident that different pathogenic mechanisms can lead to the same phenotype. This also implies that therapies directed to specific pathways will only help a subgroup of people with type 1 diabetes. This line of reasoning lead to the term “endotype”, to differentiate different pathobiological mechanisms.

The authors argue that type 1 diabetes clinical trials so far have not accounted for the potential confounding effect of heterogeneity in their study designs, e.g. by stratifying for disease severity, age and genetic predisposition. Even in trials which fail to meet the primary objective(s), often a subgroup of people with type 1 diabetes responds well to the experimental treatment. For example, in a study on teplizumab (a monoclonal anti-CD3 antibody) the drug failed to meet its primary outcome, but younger participants with higher C-peptide production capacity and those from North America and Europe responded well to the drug. Also subgroups defined based on HLA and ZnT8 seemed to show different responses for this drug. In this context the term “theratype” is coined.

The authors say that

Another important point raised by the authors is that much can be learned from other diseases such as asthma, where the endotype concept has resulted in the development of drugs affecting different pathobiological pathways so that subtypes of the disease can be treated differentially. It should be noted, however, that things are more difficult for type 1 diabetes. For starters, the pancreas is not as accessible as the lung.

Three approaches for establishing different endotypes are proposed:

• Observation/hypothesis-driven approaches, e.g. development of a specific islet cell autoantibody linked to a specific genotype.
• Unsupervised/data-driven methodologies, e.g. using principal component analysis to identify subgroups of people with type 1 diabetes based on selected major traits.
• Response to therapies, i.e. following the reverse route of discovery whereby subgroups of people with type 1 diabetes responding very well or not responding are further studied to find the pathways responsible for these differences.

It could be envisaged that combinations of therapies will be developed to cover subgroups of people with type 1 diabetes.

Click here for the Pubmed abstract.