Approximately half of all deaths in people with type 2 diabetes are caused by heart disease. The life expectancy of people with type 2 diabetes at high cardiovascular (CV) risk is reduced by approximately 12 years. Therefore, addressing the burden of CV disease is fundamental to the management of diabetes.
In the last 12 months, we have seen results from three trials showing a reduction in CV events from agents in three different classes of antidiabetes medication, possibly heralding the start of a new paradigm with respect to the choice of second- and third-line antidiabetes therapies. The first was empagliflozin, a sodium–glucose cotransporter 2 inhibitor, in the EMPA-REG OUTCOME trial. This agent reduced CV mortality by 38% and all-cause mortality by 32% compared with placebo in people with type 2 diabetes at high CV risk (Zinman et al, 2015).
In the second study, IRIS (Insulin Resistance Intervention After Stroke), pioglitazone reduced the rate of recurrent stroke or myocardial infarction in people with insulin resistance by 24% compared to placebo (Kernan et al, 2016). It also reduced the risk of progression to diabetes in this population, as shown in the article summarised on the facing page.
The third study, LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results – A Long Term Evaluation), is summarised alongside. In this CV safety trial, the glucagon-like peptide-1 receptor agonist liraglutide reduced the rates of major CV events in people with type 2 diabetes at high CV risk by 13% compared with standard care.
These positive CV outcomes are very encouraging and clearly have important implications for the treatment of people with type 2 diabetes. However, research is still at an early stage. The studies raise a number of questions. In the EMPA-REG OUTCOME trial, the mechanism behind the reduction in CV mortality is still not completely clear. Furthermore, in all three studies, the generalisability of the results to other patient groups at lower CV risk is not yet known. And particularly in the case of empagliflozin and liraglutide, it is not known whether these positive results are a class effect or particular to the agents in the trials.
While it is too early to speculate on the future impact of these trials, they may well result in a significant change in how type 2 diabetes is treated. At this time, there is still universal agreement that, for most people, metformin remains the drug of choice for first-line therapy. The options for second- and third-line treatment have expanded considerably in the last decade and we have been encouraged to individualise choice of such medication taking into account many factors, including patients’ attitudes and expected adherence, risks associated with hypoglycaemia, duration of diabetes, life expectancy, important comorbidities, established vascular complications and support systems (Inzucchi et al, 2015).
With these new studies demonstrating improved CV outcomes, possible or probable CV benefit beyond any effect related to improved glycaemia is likely to become an additional consideration in the choice of therapy beyond metformin. For high-risk patients, it is quite likely that this consideration will become the most important when choosing one medication or class over the alternatives. And given that the benefits seen with empagliflozin are probably linked to haemodynamic changes while the benefits from liraglutide are more related to modified progression of atherosclerotic disease, combining these two agents in high-risk patients may have even greater synergistic benefits in improving CV outcomes. As further studies are completed, the implication of these three studies will become clearer.
To read the article summaries, please download the PDF
Attempts to achieve remission, or at least a substantial improvement in glycaemic control, should be the initial focus at type 2 diabetes diagnosis.
9 May 2024