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Cardiovascular impact of new drugs (GLP-1 and gliflozins): the ABCD position statement

The glucose intolerance of diabetes aggravates atherosclerosis indirectly through its effect on lipids and endothelial function. The cardiovascular (CV) impact of this metabolic disturbance is seen in the worsening of atherosclerotic vascular disease predominantly manifest as progression of coronary and cerebrovascular disease. The microvascular changes induced by prolonged glucose intolerance lead to ultrastructural changes in the glomerular basement membrane and renal mesangium which alters intrarenal haemodynamics, which may become evident initially as proteinuria and later lead to a decline in glomerular filtration rate. As the kidney plays a central role in blood pressure control, these changes have far-reaching CV consequences in patients with diabetes. Despite this, glucose lowering has been shown to have only a modest impact on CV outcomes in diabetes. The new antidiabetic medications have been studied in clinical trials designed to assure safety as grounded in the FDA guidance of 2008. Whilst a direct comparison of results from these trials is not possible in view of heterogeneity in trial design, the individual CV outcome measures have broadly re-defined their role in terms of equivalence (non-inferiority) and/or benefit (superiority). The composite endpoint of CV death, non-fatal myocardial infarction and non-fatal stroke (major adverse cardiovascular events, MACE) may be perceived as surrogate markers for atherosclerotic cardiovascular disease (ASCVD). This has been universally accepted as the primary endpoint in these cardiovascular outcome trials (CVOTs) and has been helpful in understanding the possible CV impact these drugs may have on patients with diabetes. The dipeptidyl peptidase 4 (DPP-IV) inhibitors (sitagliptin, alogliptin, saxagliptin, linagliptin), two sodium-glucose co-transporter 2 (SGLT2) inhibitors (dapagliflozin and ertugliflozin) and two glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1 RA) drugs (lixisenatide and extended-release exenatide) have demonstrated non-inferiority on MACE outcomes with comparators – that is, they have assured CV safety when used in conjunction with other glucose-lowering treatment to improve glycaemic control. Four GLP-1 agonists (liraglutide, albiglutide, semaglutide and dula- glutide) and two SGLT2 inhibitors (empagliflozin and canagliflozin) have demonstrated CV benefit on MACE outcomes; such demonstration of superiority may be seen as evidence for benefit. The SGLT2 inhibitors canagliflozin, empagliflozin, dapagliflozin and ertugliflozin have all demonstrated a significant benefit in reducing the risk of hospitalisation due to heart failure (HHF) as a secondary/ exploratory outcome measure in their CVOTs. Further confirmation of benefit in heart failure independent of the presence of glucose intolerance has been demonstrated with dapagliflozin and empagliflozin in heart failure patients with or without diabetes. However, a comparable benefit in heart failure has not so far been seen in studies with the DPP-IV inhibitors or GLP-1 receptor agonists. Albiglutide is not available in the UK and may have little relevance to the practising clinician other than through the information it contributes about the possible mechanisms of action of GLP-1 RA medications.