Abstract
Type 2 diabetes is associated with a variety of cardiovascular (CV) risk factors and a higher risk of cardiovascular disease with poorer outcomes compared to the non-diabetes population. Amongst the plethora of abnormalities that can be identified there is a classical dyslipidaemia characterized by raised triglyceride and low HDL cholesterol. Lipid lowering has been pivotal in reducing cardiovascular outcomes in diabetes with statin therapy reducing CV risk by around 30% in diabetes and non-diabetes subjects. Whilst elevated LDL cholesterol does not specifically associate with diabetes, patients with diabetes have increased residual risk despite best management and it remains unclear whether there is a lower level of LDL at which maximal benefit occurs. The IMPROVE-IT trial added ezetimibe to maximal statin therapy causing a further small lowering in LDL-C which was associated with further reductions in CV mortality over statin therapy alone (1). These results further raised the question of what level of LDL-C we should be aiming for in our patients as there didn’t appear to be a cut off point for cardiovascular risk.
The identification and characterization of proprotein convertase subtilisin-kexin type 9 (PCSK9) and its role in LDL metabolism (2) have dramatically altered the landscape in this field. The description of missense mutations in PCSK9 that led to increased cholesterol and loss of function mutations that reduced cholesterol was followed by population studies demonstrating that certain mutations were associated with both reduced LDL-C and CV risk (3). More recently we have seen the development of pharmaceuticals (PCSK9 inhibitors) that markedly lower LDL-C to a level that was previously unimaginable with standard therapies.
In March this year, we saw the first prospective study of a PCSK9 inhibitor reported in the New England Journal of Medicine (4). This study recruited more than 27,000 subjects with atherosclerotic CV disease and an LDL level >1.8 mmol/L (70mg/dl) on statin therapy who were randomized to a PCSK9 inhibitor or placebo and followed up for a median time of 2.2 years. The use of a PCSK9 inhibitor was associated with a staggering 59% reduction in LDL to 0.78 mmol/L (30mg/dl), a change that was sustained over the duration of the study. The PCSK9 treated subjects compared to placebo experienced a significant reduction in the primary (composite of CV death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization) and secondary (CV death, myocardial infarction or stroke) endpoints. The authors described significant reductions in myocardial infarction (27%), coronary revascularization (22%) and in ischaemic stroke or transient ischaemic event (23%), however there was no difference in CV death due to myocardial infarction.
This brings us back again to lipid management in diabetes for which no data has been provided in the current trial, despite more than 10,000 individuals taking part who were designated as having diabetes. The low death rates and short follow up probably contributed to the lack of a significant change in CV mortality in this population, but it begs the question as to the possible effects of PCSK9 inhibition in high risk groups, such as diabetes patients with comorbidities. Diabetes patients continue to have a worse outcome in all presentations of CV disease and we await with interest data from the current trial in this population and new trials specifically designed to provide data on the effects of PCSK9 inhibitors in diabetes.