Diabetes and vascular disease: epidemiology and management options
General practitioners from about 20 European countries travelled to Barcelona to attend the Annual EPCCS CV Summit for Primary Care. In addition to the lively discussions and interaction between primary care physicians of different corners of Europe, an important objective of this summit is to produce guidance documents specifically aimed at primary care. Sessions were set up in such a way that not only the current evidence on a subject was reviewed, but that specific considerations for primary care were discussed and challenges and gaps in the evidence were identified. These sessions focused on diabetes and vascular care, managing lipids, hypertension and heart failure. Based on the sessions, EPCCS guidance documents will be written.
Dr. Xavier Cos (Universitat Autonoma de Barcelona) gave an update on type 2 diabetes (T2DM). Diabetes is a progressive disease, starting with prediabetes, and with accumulation of complications over time. Diabetes is associated with risk of a range of CV diseases and is recognized as a CV mortality risk factor.
Studies have evaluated the effect of lowering HbA1c to lower the risk of diabetes complications. Mixed results have been demonstrated on tight and rapid HbA1c control. Finding a good risk-benefit balance is important when choosing the intensity of the HbA1c-lowering strategy. Early glycaemic control is key to long-term reduction in complications, which is known as the legacy effect. A good legacy effect was shown in the UK Prospective Diabetes Study, in which early, strict glycaemic control reduced the long-term risk of microvascular and macrovascular complications. A bad legacy effect can occur when glycaemic control is achieved late in the disease, after a long period of poor control; then the long-term risk of macrovascular complications is not improved.
Regardless, controlling HbA1c is not enough. Many factors contribute to increased CV risk in T2DM, among which hyper-insulinaemia in the pancreas and in skeletal muscle, hyperglycaemia leading to advanced glycation end-products, hypertension, lipidaemia, thrombosis, and nowadays inflammation and the microbiome can be added to the list of processes involved. Consequently, therapy for T2DM ideally targets all or most of these processes. An ideal drug for T2DM should also be safe, efficacious and well-tolerated, provide durable control, have a low risk of hypoglycaemia, is weight neutral or induce weight loss, and should reduce complications in the long term.
In the past, safety of new antidiabetic agents became a topic of concern, when rosiglitazone was found to be associated with a significant increase in the risk of myocardial infarction and CV death. Consequently, the CV safety of new therapy now needs to be demonstrated (as issued by the American FDA), which has led to several CV outcomes studies that were designed to demonstrate non-inferiority, rather than superiority.
Some CV outcomes studies have, however, demonstrated a significant CV benefit with new T2DM treatment, namely with the SGLT2 inhibitors empagliflozin and canagliflozin and the GLP-1 receptor agonists liraglutide and semaglutide. Other agents were neutral with regard to CV outcomes (lixisenatide, exenatide) or studies are ongoing (dulaglutide, albiglutide, dapagliflozin, ertugliflozin).
Data suggest that certain T2DM patient groups may benefit more of the observed effects; for instance the effect of canagliflozin on the risk of CV death or hospitalised heart failure (HF) seemed greater in those with a history of HF at baseline. Dr. Cos summarised the currently known trial data according to a traffic light system, indicating whether the CV impact associated with an antidiabetic drug is harmful, neutral or beneficial, or unknown. Based on the current evidence, he concluded that in T2DM patients with established CVD, it is clear that these subjects should receive metformin therapy, combined with additional therapy with demonstrated CVD benefit. In those with a seemingly low CVD risk, treatment on top of metformin should be chosen based on the best benefit-risk-ratio, both considering the short and long term. Various options are available, but certainties on their effects are scarce in these subjects, also because of the lack of head-to-head comparison studies. He showed a flow chart of the new Standard of Medical Care in Diabetes 2018 of the American Diabetes Association as an example of how to manage T2DM patients. The guidance is based on HbA1c, and the choice for additional therapy, next to lifestyle management and metformin, should depend on the characteristics of the individual patient. The Canadian Diabetes guideline 2016 follows a similar logic.
He pointed out the different risk clusters among patients with adult-onset diabetes that have been described very recently in Lancet Diabetes Endocrinology. These clusters are based on six variables, and may help in choosing the right therapy, based on associated risks of specific outcomes in each cluster.
We will compose an EPCCS Guidance Document for Primary Care about management of T2DM, based on this session (presentation and discussion) during the EPCSS CV Summit 2018 in Barcelona.