Cardiovascular and metabolic outcomes associated with insulin use in type 2 diabetes: evidence from insulin users in the UK primary care

Abstract

In clinical use, insulin improves glycaemic control at the cost, typically, of weight gain and more hypoglycaemia – both being risk factors for cardiovascular (CV) disease mortality. The issue of the effect of exogenous insulin on CV disease meanwhile has been debated for a long time. Data on the CV outcomes associated with insulin-treated diabetes in both randomised trials and observational studies have largely been inconsistent. Thus, a balance of the positives and the negatives of insulin therapy needs to be taken into account when prescribing insulin in routine clinical practice, particularly in the context of the progressive nature of diabetes, its requirement for combination glucose-lowering therapy and the availability of novel glucose lowering agents. So, in a cohort of only insulin-users in ‘real-world’ condition, this thesis aims to explore the association between insulin use and CV and metabolic outcomes. Firstly, a systematic review and meta-analysis of clinical trials that compared only insulin vs other non-insulin glucose-lowering therapies (GLTs) within the past decade was performed and the risk of CV events and important metabolic outcomes were compared between both treatment groups. Then, data from RCTs were compared with ‘real-world’ data (using the UK Primary Care database – The Health improvement Network (THIN)) in terms of clinical outcomes between insulin regimens. Thirdly, using THIN database, retrospective cohort studies were conducted to explore the CV outcomes associated with insulin as regards to the use of newer GLTs, concurrent use of other medications, target HbA1c outcome levels and baseline metabolic profile of insulin-users. Logistic, linear, and Cox regression models; and propensity-score matching models were fitted to explore these associations. Finally, a comparative cross-sectional study was conducted to explore clinical outcomes between the insulin users in a representative UK population database (THIN) vs the local Derbyshire integrated Diabetes service database. A meta-analysis of RCTs first provided insight that allayed fears on the CV concerns on insulin use. It showed no difference in the risk of death and adverse CV events between insulin and non-insulin GLTs. Although insulin was associated with better glycaemic control, similar proportions of both insulin and non-insulin users attained their target HbA1c. The increase in the risks of hypoglycaemia and weight-gain seen in insulin users did not translate to adverse CV events. Furthermore, although RCTs provide superior evidence from which clinical guidelines are built, they do not mirror what happens in ‘real-world’. The discrepancies in glycaemic control (which is lower in real-world) and weight (higher in RCTs) were highlighted. Thus, caution is needed in the extrapolation of RCT-derived estimates of clinical outcomes when formulating guidelines for routine clinical practice. Given the observed discrepancies between weight and HbA1c outcomes between real world and RCT, I investigated the CV and metabolic effects of insulin therapy in the context of baseline weight and insulin-induced weight gain. I observed that in a background of obesity, the use of insulin did not lead to poorer glycaemic control beyond 24 months, instead, patients who were obese experienced a significant reduction in weight and BMI. In the morbidly obese, the risk of composite adverse CV outcomes was, however, increased by 30%. Also, insulin-induced weight-gain was associated with significant reductions in HbA1c and no adverse CV outcomes and mortality. When compared with newer GLTs like the glucagon-like peptide receptor agonists (GLP-1RA), insulin was associated with greater weight-gain and a higher risk of composite CV events and mortality; but in combination with GLP1-RA, it showed both a decrease in the risk of CV event and a reduction in weight. In the elderly insulin users with multiple comorbidities and longer duration of diabetes, extreme HbA1c targets were associated with increased mortality – representing a U-shaped relationship between mortality and HbA1c targets. Furthermore, background statin use among insulin users did not worsen glycaemic control in the long term, but was associated with reduction in composite adverse CV events and mortality independent of the statin type. Finally, the Derby model of integrated diabetes service appeared to confer better clinical outcomes compared with the UK population in terms of the achievement of the combined National Institute for Health and Care Excellence (NICE) targets of HbA1c (<7.5%), blood pressure (<140/80) and total cholesterol (<4mmol/L). This research highlights the important central role insulin plays in the management of T2D; and adds to the growing evidence on its safety and benefits among the high risk groups – the elderly, obese and those with longer duration of diabetes. It also highlights the benefits of the combination of insulin with newer novel GLTs; and concomitant use of other medications which modify CV risk factors. Above all, it recommends individualised treatment approach with full consideration of individual’s metabolic profile and other social factors. Further trials focusing on insulin therapy combinations with newer GLTs will be invaluable in providing more water-tight evidence in insulin use