The interplay between glycaemia and cardiovascular disease

Numerous large clinical trials of cardiovascular risk lowering agents have been conducted in the hope of reducing the excess cardiovascular risk found in patients with diabetes mellitus. However, the relationship between glucose and cardiovascular disease remains complex and various areas require further study. Even in patients with diabetes, an individual’s cardiovascular risk is highly variable depending on other clinical characteristics, the assumption that glucose is a continuous risk factor has often been based on weak evidence from relatively short studies, the effect of commonly used cardiovascular risk lowering agents often has unexpected effects on new-onset diabetes and statins have not yet been studied in detail, and whether glucose-lowering therapies actually reduce cardiovascular risk has remained a contentious issue despite the conduct of large clinical trials. Furthermore, the realisation that the combination of diabetes and chronic heart failure, a common complication of coronary disease, carries a particularly poor prognosis suggests that prediction of diabetes in this population may be clinically valuable. Aims: I aimed to address the following different, though related, questions regarding glucose and cardiovascular disease: 1. Are anticipated cardiovascular event rates in diabetes endpoint trials actually achieved? Is it possible to easily identify patients with diabetes that are at particular risk of events (information that is crucial to investigators who wish to design clinical trials)? 2. Is fasting glucose concentration independently and convincingly associated with increased risk of cardiovascular events in those without diabetes? 3. Do statins, the most commonly prescribed medications worldwide, have any influence on the risk of developing diabetes? 4. If statins do indeed affect new-onset diabetes, is there any evidence of a dose-dependent effect? 5. How effectively can clinicians predict the development of diabetes in chronic heart failure using commonly recorded clinical information? 6. Does intensive glucose-lowering therapy reduce the risk of cardiovascular events in patients with diabetes? Methods: To address these questions three approaches were used, namely (i) systematic review of previously published data from large cardiovascular endpoint trials conducted in patients with diabetes; (ii) analyses of existing datasets from two large clinical trials; (iii) meta-analyses of published and unpublished data from large clinical trials. Results and interpretation: 1. In a systematic review of 29 trials with 116,790 patients with diabetes, it was apparent that the majority of large cardiovascular endpoint trials conducted in patients with diabetes vastly overestimated the likely cardiovascular event rates in initial power calculations. Introduction of (i) previous history of cardiovascular disease and/or (ii) presence of proteinuria, as binary trial inclusion criteria, provides a simple and effective way to identify patients at high risk, something that is sought after for appropriate clinical trial power calculations. 2. In a population of 6,447 men without diabetes at baseline, impaired fasting glycaemia was not associated with increased risk of cardiovascular events over 15 years. Similarly, when baseline fasting glucose values