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Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial

Abstract

Aims/hypothesis

Data analyses from Swedish individuals with newly diagnosed diabetes have suggested that diabetes could be classified into five subtypes that differ with respect to the progression of dysglycaemia and the incidence of diabetes consequences. We assessed this classification in a multiethnic cohort of participants with established and newly diagnosed diabetes, randomly allocated to insulin glargine vs standard care.

Methods

In total, 7017 participants from the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial were assigned to the five predefined diabetes subtypes (namely, severe auto-immune diabetes, severe insulin-deficient diabetes, severe insulin-resistant diabetes, mild obesity-related diabetes, mild age-related diabetes) based on the age at diabetes diagnosis, BMI, HbA1c, fasting C-peptide levels and the presence of glutamate decarboxylase antibodies at baseline. Differences between diabetes subtypes in cardiovascular and renal outcomes were investigated using Cox regression models for a median follow-up of 6.2 years. We also compared the effect of glargine vs standard care on hyperglycaemia, defined by having a mean post-randomisation HbA1c ≥6.5%, between subtypes.

Results

The five diabetes subtypes were replicated in the ORIGIN trial and exhibited similar baseline characteristics in Europeans and Latin Americans, compared with the initially described clusters in the Swedish cohort. We confirmed differences in renal outcomes, with a higher incidence of events in the severe insulin-resistant diabetes subtype compared with the mild age-related diabetes subtype (i.e., chronic kidney disease stage 3A: HR 1.49 [95% CI 1.31, 1.71]; stage 3B: HR 2.25 [1.82, 2.78]; macroalbuminuria: HR 1.56 [1.22, 1.99]). No differences were observed in the incidence of retinopathy and cardiovascular diseases after adjusting for multiple hypothesis testing. Diabetes subtypes also differed in glycaemic response to glargine, with a particular benefit of receiving glargine (vs standard care) in the severe insulin-deficient diabetes subtype compared with the mild age-related diabetes subtype, with a decreased occurrence of hyperglycaemia by 13% (OR 1.36 [1.30, 1.41] on glargine; OR 1.49 [1.43, 1.57] on standard care; p for interaction subtype × intervention = 0.001).

Conclusions/interpretation

Cluster analysis enabled the characterisation of five subtypes of diabetes in a multiethnic cohort. Both the incidence of renal outcomes and the response to insulin varied between diabetes subtypes. These findings reinforce the clinical utility of applying precision medicine to predict comorbidities and treatment responses in individuals with diabetes.

Trial registration

ORIGIN trial, ClinicalTrials.gov NCT00069784.

Graphical abstract

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Data availability

No additional data are available.

Abbreviations

ADOPT:

A Diabetes Outcome Progression Trial

ANDIS:

All New Diabetics in Scania

DEVOTE:

Trial Comparing Cardiovascular Safety of Insulin Degludec Versus Insulin Glargine in Subjects With Type 2 Diabetes at High Risk of Cardiovascular Events

LEADER:

Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results

MARD:

Mild age-related diabetes

MOD:

Mild obesity-related diabetes

ORIGIN:

Outcome Reduction with Initial Glargine Intervention

RECORD:

Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes

SAID:

Severe auto-immune diabetes

SIDD:

Severe insulin-deficient diabetes

SIRD:

Severe insulin-resistant diabetes

SUSTAIN-6:

Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes

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Acknowledgements

We are thankful to all the participants for contributing to this project.

Authors’ relationships and activities

MP declares that there are no relationships or activities that might bias, or be perceived to bias, her work. SH is an employee of Sanofi. GP has received consulting fees from Sanofi, Bristol Myers Squibb, Lexicomp and Amgen, and support for research through his institution from Sanofi. HG has received consulting fees from Sanofi, Novo Nordisk, Lilly, AstraZeneca, Boehringer Ingelheim and GlaxoSmithKline, and support for research or continuing education through his institution from Sanofi, Lilly, Takeda, Novo Nordisk, Boehringer Ingelheim and AstraZeneca.

Funding

The ORIGIN trial and biomarker project were supported by Sanofi and the Canadian Institutes of Health Research (CIHR). The biomarker project was led by ORIGIN investigators at the Population Health Research Institute (Hamilton, Canada) with the active collaboration of Sanofi scientists. Sanofi directly compensated Myriad RBM, Inc. for measurement of the biomarker panel and the Population Health Research Institute for scientific, methodological and statistical work. This project was also supported by the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 115974 (BEAt-DKD). This Joint Undertaking receives support from the European Union’s Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations, and JDRF. Genetic analysis of ORIGIN participants was supported by CIHR (award 125794 to GP). MP is supported by the E.J. Moran Campbell Internal Career Research Award from McMaster University. MFG is supported by the Swedish Heart and Lung Foundation (20160872), the Swedish Research Council (2018-02837; 2014-03352; EXODIAB 2009-1039) and the Swedish Foundation for Strategic Research (LUDC-IRC 15-0067). GP is supported by the Canada Research Chair in Genetic and Molecular Epidemiology and the CISCO Professorship in Integrated Health Biosystems. The study funder was not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.

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Authors

Contributions

SH and LG proposed validating the type 2 diabetes clusters in the ORIGIN cohort. MP, GP and HG designed the study, planned the analyses, interpreted the results and wrote the manuscript. MP and OA performed the statistical and bioinformatics analyses. SH suggested including C-peptide in the biomarker panel and coordinated the biomarker screen at Myriad RBM, Inc. (Austin, TX, USA). MFG contributed to the interpretation of the data. All authors contributed to the critical reading and revision of the manuscript. All authors have approved the submitted version of this manuscript. HG is the guarantor of this work.

Corresponding author

Correspondence to Marie Pigeyre.

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Pigeyre, M., Hess, S., Gomez, M.F. et al. Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05567-4

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Keywords

  • Clusters
  • Diabetes complications
  • Insulin glargine
  • ORIGIN
  • Personalised medicine
  • Type 2 diabetes