Cardiovascular outcome trials of glucose-lowering medications: an update

Three further cardiovascular (CV) outcome studies of glucose-lowering drugs (linagliptin, albiglutide and dapagliflozin) have recently been published, adding to the twelve earlier within-class studies. The linagliptin study (CARMELINA) recruited people with renal disease as well as prior CV events and confirms the overall CV safety (and other safety) of the dipeptidylpeptidase-4 (DPP4) inhibitors, with no heart failure risk associated with this agent. However, taken together with the findings from two previous studies of DPP4 inhibitors (sitagliptin and saxagliptin), the three DPP4 inhibitor CV outcome trials (CVOTs) have highlighted a safety signal regarding risk of pancreatitis. Like CARMELINA, the albiglutide study (Harmony Outcome) had a very high CV event rate. Despite being a short duration study, albiglutide showed strong superiority for reduction in the major adverse CV events (MACE) composite in people with extant cardiovascular disease (CVD), in line with the earlier studies on the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide. Positive effects can be detected for all these medications from before 12 months and continue for the whole study duration. No new safety issues for albiglutide are identified and the lack of a pancreatitis or a pancreatic cancer signal for this class is now clear. For the sodium–glucose cotransporter-2 (SGLT2) inhibitor class, the DECLARE-TIMI 58 study (of dapagliflozin) clearly indicates strong protection for heart failure in those with CVD, and probably in those with no prior CVD. There is also strong protection against renal decline with dapagliflozin, with similar risk estimates in DECLARE as previously reported for empagliflozin and canagliflozin. However, findings for MACE outcomes with dapagliflozin are not concordant with the empagliflozin and canagliflozin studies, and are not convincingly superior across class and for the longer term. Care is required when prescribing the SGLT2 inhibitor class of medications to people with foot vascular issues or prior amputation, and to insulin users in regard of ketoacidosis. In summary, taking into account the findings from these new studies, it is suggested that a GLP-1RA should be offered to all people with CVD and type 2 diabetes, and SGLT2 inhibitors should be prescribed for those at high risk of heart failure or with progressive decline in eGFR. DPP4 inhibitors are a safe choice within the glucose-lowering stepped algorithm.