Impact of Liraglutide on Cardiac Function and Structure in Young Adults With Type 2 Diabetes: an Open-label, Randomised Active-comparator Trial

T2DM in the young

T2DM has traditionally been associated with older age, with type 1 diabetes (T1DM) being the dominant form in younger populations. This traditional profile has dramatically altered over the last couple of decades; the sharp rise in levels of obesity and sedentary lifestyles witnessed in younger age groups in developed countries has resulted in up to a 10 fold increase in the prevalence of T2DM in younger adults and youth [7]. Whereas T2DM was once a rarity in those under 40 years, we have recently shown that T2DM now represents up to 20% of all registered diabetes cases across centres in Leicester and Sheffield in this age group [8]. More worryingly, sub-analysis of the Leicester arm of the international ADDITION study [9], a large population-based screening study that included a small cohort under 40 years of age (n = 445), and an on-going NPRI-MRC study in younger high risk adults, suggest the prevalence of undiagnosed T2DM in those under 40 years is between 2 to 4% depending on the diagnostic criteria used and over 5% in those with a family history or obesity (unreported observations). The focus of health care policy and research has lagged behind this substantive shift in the profile of T2DM towards younger populations. For example, the NHS health checks programme is targeted at those over 40 years of age while previous self-management, lifestyle and pharmaceutical interventions which have been used to inform NICE guidance have been conducted in groups aged between 50 and 70 years.

Clinical Burden of T2DM in the young

The onset of T2DM in younger adults and youth represents an extreme phenotype that magnifies the disease profile observed in older adults. For example, those diagnosed with T2DM under 40 years are more likely to be classified with Class II or Class III obesity (≥35 kg/m2), have a multigenerational family history of T2DM, lead a sedentary lifestyle and be of minority ethnic origin [7]. Of particular concern is that the onset of T2DM in younger adults is associated with dramatic elevations in the risk of cardiovascular disease, particularly coronary heart disease. For example, the risk of any macrovascular complication in younger adults with T2DM compared to controls has been shown to be twice as high compared to other T2DM patients (HR 7.9 vs. 3.8, respectively)[10]. Myocardial infarction (MI) was found to be the most common macrovascular outcome; the hazard of developing an MI in younger adults with T2DM was 14-fold higher than in control subjects [10]. In contrast, older adults with T2DM had less than four times the risk of developing an MI compared with control subjects. Others have reported that the mortality rate in young people with T2DM was as high as 9% over a 9 year period [11]. Younger people with T2DM therefore have higher complication rates than their peers with Type 1 diabetes, despite a shorter duration of diabetes, highlighting the aggressive nature of the disease.

Our group has recently completed a Medical Research Council (MRC) funded study aimed at elucidating the biochemical and cardiac abnormalities associated with T2DM in younger adults (18 to 40 years). The study recruited 20 young adults (18 to 40 years) with diagnosed T2DM and 20 age-matched metabolically healthy obese and lean controls (paper under preparation). Cardiac structure and function were assessed by state-of-the-art tagged cardiac MRI imaging. The most striking finding from this study was evidence of greater diastolic dysfunction in T2DM compared to both the obese and lean controls. Specifically, peak end diastolic strain rate, a highly sensitive measure of left ventricular (LV) diastolic function, had an average value of 1.27 s-1 in the T2DM cohort (the lower limit of normal ranges has been defined as 1.3 s-1) which was 20% lower than the obese controls and 30% lower than the lean controls. This finding is consistent with a larger study that used echocardiography to assess cardiac function and structure in over 150 adolescents and younger adults with T2DM compared to obese and lean controls; this study reported that diastolic dysfunction was reduced from lean to obese and from obese to T2DM. These studies therefore suggest that pre-clinical diastolic dysfunction is already manifest in younger adults with T2DM, despite their relatively young age and short duration of type 2 diabetes. This finding is highly clinically relevant and suggests that the high risk of cardiovascular disease observed in T2DM is predominantly characterised by diastolic dysfunction predisposing these patients to heart failure, in advance of overt systolic compromise [12,13]. For example, 50% of all cases of chronic heart failure have preserved ejection fraction [12,13]. Therefore therapeutic strategies that target both glycaemic control and diastolic cardiac function would be highly desirable in younger adults with T2DM.