Relationship of hyperglycaemic and glycaemic fluctuations to major adverse cardiovascular events in type 2 Diabetes Mellitus
Authors: Borg B , Galea J , Xuereb R G , Fava S , Magri C J 
Published: May 2023

Abstract

Funding Acknowledgements
Type of funding sources: Public Institution(s). Main funding source(s): Dean's funds of the University of Malta Medical School.

Background
Type 2 diabetes mellitus (T2DM) is a known major risk factor for cardiovascular disease. Nonetheless, tight glycaemic control has not convincingly shown to lead to improved cardiovascular outcomes in clinical trials. This could be due to the fact that the vast majority of trials did not assess the effect of hypoglycaemia and glucose fluctuations in their study population. The aim of this study was thus to investigate the effects of hyperglycaemia, hypoglycaemia and glucose variability in subjects with T2DM at a median follow-up of 6.4 years.

Methods
Subjects with T2DM of less than 10 years duration, and on stable anti-glycaemic treatment were recruited. At baselines, all participants underwent 72-hour continuous glucose monitoring, as well as parameters assessment. Moreover, risk factor bloods, including an HbA1c level, were taken. Patients were consequently followed up at 6.4 years (median: 2338 days, IQR: 2116-2446 days) and MACE (major adverse cardiovascular events) was assessed. This comprised a composite of all-cause mortality, non-fatal myocardial infarction (both ST-elevation myocardial infarction and non-ST elevation myocardial infarction), revascularisation (both percutaneous and coronary artery bypass grafting), non-fatal stroke and hospitilisation for heart failure. The incidence of MACE was assessed from electronic database available at the local public hospital that caters for the entire Maltese population. Univariate analysis was performed using Mann-Whitney U test for non-parametric variables and independent samples t-test for parametric variables. Variables with a p value &lt;0.1 were consequently put in the multivariate Cox regression model to assess for independent predictors of MACE. Statistical analysis was performed using SPSS version 24.0 for Windows.
Findings: The study population comprised 122 subjects with T2DM (89 males: 32 females). The mean age was 62.6 years and the mean DM duration was 3.7 years at baseline. At follow-up, 19 participants exhibited MACE. Variables with a p value of &lt;0.1 in univariate analysis comprised fructosamine, HbA1c, mean systolic blood pressure measurements as well as duration of BG (blood glucose) &lt;3.9 mmol/L and standard deviation of BG (an indicator of intra-individual blood glucose variability; the latter two were derived from 72-hour continuous glucose monitoring). Following adjustment for both age and gender, HbA1c (OR: 1.9, 95% CI: 1.32-2.73, p= 0.001) levels at baseline as well as standard deviation of BG (OR: 1.93, 95% CI: 1.68-3.16, p= 0.009) were shown to be independent predictors of MACE.
Interpretation: This study demonstrates that cardiovascular disease in subjects with T2DM of relatively short duration is not only influenced by poor glycaemic control but also by fluctuations in glucose levels, as evidenced by measurements obtained from continuous glucose monitoring obtained at baseline.