Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes: an overview of the data from the epidemiological studies within the IMI DIRECT Consortium

Background and aims: Understanding the aetiology, clinical presentation and prognosis of type 2 diabetes (T2D) and optimizing its treatment might be facilitated by biomarkers that help predict a person9s susceptibility to the risk factors that cause diabetes or its complications, or response to treatment. The IMI DIRECT (Diabetes Research on Patient Stratification) Study is a European Union (EU) Innovative Medicines Initiative (IMI) project that seeks to test these hypotheses in two recently established epidemiological cohorts. Here, we describe the characteristics of these cohortsat baseline and at the first main follow-up examination (18-months). Materials and methods: From a sampling-frameof 24,682 European-ancestry adults in whom detailed health information was available, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm and enrolled into a prospective cohortstudy (n=2127) undertaken at four study centres across Europe ( Cohort1: prediabetes). We also recruited people from clinical registries with recently diagnosed T2D (n=789) into a second cohortstudy ( Cohort2: diabetes). The two cohortswere studied in parallel with matched protocols. Endogenous insulin secretion and insulin sensitivity were modelled from frequently sampled 75g oral glucose tolerance (OGTT) in Cohort1 and with mixed-meal tolerance tests (MMTT) in Cohort2. Additional metabolic biochemistry was determined using blood samples taken when fasted and during the tolerance tests. Body composition was assessed using MRI and lifestyle measures through self-report and objective methods. Results: Using ADA-2011 glycaemic categories, 33% (n=693) of Cohort1 ( prediabetes) had normal glucose regulation (NGR), and 67% (n=1419) had impaired glucose regulation (IGR). 76% of the cohortwas male, age=62(6.2) years; BMI=28.4(4.0) kg/m2; fasting glucose=5.7(0.6)mmol/l; 2-hr glucose=5.9(1.6) mmol/l [mean(SD)]. At follow-up, 18.5(1.4) months after baseline, fasting glucose=5.8(0.6)mmol/l; 2-hr OGTT glucose=6.1(1.7) mmol/l [mean(SD)]. In Cohort2 (diabetes): 65% (n=508) were lifestyle treated (LS) and 35% (n=271) were lifestyle + metformin treated (LS+MET). 58% of the cohortwas male, age=62(8.1) years; BMI=31(5.0)kg/m2; fasting glucose=7.2(1.4)mmol/l; 2-hr glucose=8.6(2.8)mmol/l [mean(SD)]. At follow-up, 18.2(0.6) months after baseline, fasting glucose=7.8(1.8)mmol/l; 2-hr MMTT glucose=9.5(3.3) mmol/l [mean(SD)]. Conclusion: The epidemiological IMI DIRECT cohortsare the most intensely characterised prospective studies of glycaemic deterioration to date. Data from these cohortshelp illustrate the heterogeneous characteristics of people at risk of or with T2D, highlighting the rationale for biomarker stratification of the disease - the primary objective of the DIRECT consortium.