Characteristics of Prediabetes, predictors of progression and strategies to prevent Type 2 Diabetes Mellitus in a multiethnic population in the United Kingdom

Executive Summary: Type 2 Diabetes Mellitus (T2DM) is a chronic multi factorial disorder linked to obesity that is associated with increased morbidity and mortality. T2DM poses a major public health problem with the prevalence expecting to reach 4 million in the United Kingdom by the year 2025. Upto 50% of people may have established complications at the time of diagnosis of T2DM. However, T2DM is preceded by a latent phase of Prediabetes (PDM) which provides a window of opportunity for primary prevention. PDM is often known as impaired glucose metabolism (IGM) or impaired glucose regulation (IGR). PDM is a collective term for impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and those with combined IFG and IGT. The reported prevalence of these conditions is variable throughout the world. This thesis seeks to address key questions on identification of IGR, determine factors predicting progression to T2DM and thus propose prevention strategies in a mixed ethnic population in the UK using data from the ADDITION Leicester and ADDITION PLUS studies. ADDITION Leicester is a sub study of the multinational multi centre study-ADDITION Europe. ADDITION study is a randomised controlled trial evaluating the benefits of a multi factorial cardiovascular disease risk factor intervention in a cohort of patients with screen detected T2DM. The prevalence of PDM was 16% in the study population with IFG, IGT and combined IFG and IGT being 2.8%, 11% and 2.2% respectively. People of South Asian (SA) origin have a significantly higher adjusted prevalence of PDM compared to those of White European (WE) origin (OR: 1.57; 95% CI: 1.24 to 1.98). A risk score tailored to the local population (Leicester risk assessment score) was robust in identifying those at risk of developing T2DM and PDM as well those progressing from PDM to T2DM at 12 months. Subjects with PDM have a unique phenotype placing their cardiovascular disease (CVD) risks between T2DM and normal glucose tolerance. Novel markers of CVD such as Interleukin 6, Adiponectin, Leptin and C-reactive protein are also raised in those with PDM compared to normal. The risk of progression from PDM to T2DM at 12 months is higher for SA compared to WE (OR: 3.09, 95% CI- 1.58 to 6.02). The diabetes progression rate (cases/100 person-years) for IFG, IGT and combined IFG and IGT were 5.51, 3.13 and 14.46 respectively. The risk of progression for SA people occurs at a lower cut off for BMI and waist circumference. A meta analysis of 13,314 patients from 22 studies with PDM revealed a pooled progression rate (cases per 100 person-years) (95% CI) to be 6.29 (4.29- 9.22), 7.48 (5.00-11.18) and 7.86 (5.51- 11.20) for people with IFG, IGT and combined IFG+IGT respectively. Presence of CVD, central obesity measured both by waist circumference and BMI, triglycerides, fasting plasma glucose (FPG) and HbA1c significantly predict progression to T2DM at 12 months. Presence of metabolic syndrome with more than 2 additional criteria significantly predicts progression to T2DM. In terms of adipocytokines, TNFα is the only marker, after adjusting for confounders that is significantly associated with progression to T2DM. In terms of follow up of this cohort, we propose a two step method using FPG >6 mmol/L as a screening tool to identify people who can subsequently be screened using an OGTT, reducing the number of OGTT needed to 23.5%. Our findings suggest using a structured screening programme with a risk score used in parallel to the recommended opportunistic screening for T2DM. The need for ethnic specific cut-off for obesity has been established. Factors such as presence of metabolic syndrome, HbA1c >6%, presence of a single diabetes range glucose value and pre-existing CVD may be used in risk stratification of individuals with PDM. These factors may also be used to guide those who may benefit from Metformin in addition to established life style interventions for PDM. Our findings provide a contemporary and prospective data on the prevalence of PDM in a multi ethnic UK population and factors predicting progression from PDM to T2DM. A robust strategy using a self assessed risk score is proposed to identify those at risk of developing PDM and T2DM. A step wise ethnic specific algorithm using anthropometric measures is also recommended to enable follow up of those with PDM. These findings have important implications for public health in informing strategies to address the emerging pandemic of T2DM.