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

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Validation of the classification for type 2 diabetes into five subgroups: a report from the ORIGIN trial
Diabetologia ( IF 8.4 ) Pub Date : 2021-10-21 , DOI: 10.1007/s00125-021-05567-4
Marie Pigeyre _{1,

2,

3} , Sibylle Hess ₄ , Maria F Gomez ₅ , Olof Asplund _{6,

7} , Leif Groop _{6,

7} , Guillaume Paré _{1,

2,

8,

9} , Hertzel Gerstein _{1,

2,

3,

9}

Affiliation

Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada.
Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, Hamilton, ON, Canada.
Department of Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada.
R&D, Translational Medicine & Early Development, Biomarkers & Clinical Bioanalyses (BCB), Sanofi Aventis Deutschland GmbH, Frankfurt, Germany.
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Malmö, Sweden.
Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Skåne University Hospital, Malmö, Sweden.
Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
Department of Pathology and Molecular Medicine, McMaster University, Michael G. DeGroote School of Medicine, Hamilton, ON, Canada.
Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, ON, Canada.

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, HbA_1c, 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 HbA_1c ≥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

中文翻译：

验证将 2 型糖尿病分为五个亚组：ORIGIN 试验的报告

目标/假设

来自瑞典新诊断糖尿病患者的数据分析表明，糖尿病可分为五种亚型，这些亚型在血糖异常的进展和糖尿病后果的发生率方面有所不同。我们在一个多民族队列中评估了这一分类，该队列由已确诊和新诊断为糖尿病的参与者组成，随机分配到甘精胰岛素组和标准治疗组。

方法

总共有 7017 名来自初始甘精胰岛素干预 (ORIGIN) 试验的参与者被分配到五种预定义的糖尿病亚型（即严重的自身免疫性糖尿病、严重的胰岛素缺乏型糖尿病、严重的胰岛素抵抗性糖尿病、轻度肥胖相关糖尿病）。糖尿病、轻度年龄相关性糖尿病）基于糖尿病诊断时的年龄、BMI、HbA _1c、空腹 C 肽水平和基线时谷氨酸脱羧酶抗体的存在。使用 Cox 回归模型研究糖尿病亚型在心血管和肾脏结局方面的差异，中位随访时间为 6.2 年。我们还比较了甘精胰岛素与标准治疗对高血糖症的影响，高血糖症的定义是亚型之间的平均随机化后 HbA _1c ≥6.5%。

结果

与瑞典队列中最初描述的集群相比，在 ORIGIN 试验中复制了五种糖尿病亚型，并在欧洲人和拉丁美洲人中表现出相似的基线特征。我们证实了肾脏结局的差异，与轻度年龄相关糖尿病亚型相比，严重胰岛素抵抗糖尿病亚型的事件发生率更高（即慢性肾脏病 3A 期：HR 1.49 [95% CI 1.31, 1.71]； 3B 阶段：HR 2.25 [1.82, 2.78]；大量白蛋白尿：HR 1.56 [1.22, 1.99]）。调整多重假设检验后，视网膜病变和心血管疾病的发生率没有差异。糖尿病亚型对甘精胰岛素的血糖反应也不同，p交互亚型 × 干预 = 0.001）。