Series: Cardiovascular outcome trials for diabetes drugs.

LEADER was a landmark cardiovascular outcome trial with the GLP-1 receptor agonist liraglutide, which demonstrated signiﬁcant reductions in major adverse cardiovascular events (MACE, a composite of cardiovascular death, non-fatal myocardial infarction and non-fatal stroke), driven by a reduction in cardiovascular deaths and accompanied by a signiﬁcant reduction in all-cause mortality. Shortly afterwards, the SUSTAIN-6 trial with once-weekly semaglutide demonstrated non-inferiority for MACE, with a nominal reduction in MACE that was driven by a reduction in the risk of non-fatal strokes. Since then, a further six cardiovascular trials have been published with GLP-1 receptor agonists, with major differences in study design and outcomes.
Four trials have been performed with once-weekly formulations. The EXSCEL trial with once-weekly exenatide showed non-inferiority for MACE, but not superiority, with a reduction in all-cause mortality which was an exploratory outcome. The Harmony Outcomes trial with albiglutide demonstrated signiﬁcant reductions in MACE, driven by reductions in fatal or non-fatal myocardial infarction. REWIND, with dulaglutide, also demonstrated signiﬁcant reductions in MACE, this time driven by reductions in strokes. The AMPLITUDE-O trial with efpeglenatide showed signiﬁcant reductions in MACE, but none of the individual components of MACE was signiﬁcantly reduced as a secondary endpoint, and in contrast to other trials there was also a signiﬁcant reduction in heart failure events. The ﬁfth trial was the PIONEER 6 trial with the oral formulation of semaglutide, and this showed non-inferiority for MACE, but not superiority, with reductions in cardiovascular deaths and all-cause mortality which were secondary outcomes. Finally, FREEDOM-CVO with a subcutaneous mini-pump of exenatide showed non-inferiority for MACE and MACE plus hospitalisation for unstable angina. A reduction in albuminuria was seen in several of these trials, but there was no deﬁnite effect on eGFR or end-stage renal disease.
Meta-analysis of the cardiovascular outcome trials with GLP-1 receptor agonists has demonstrated signiﬁcant reductions in MACE, cardiovascular death, fatal or non-fatal stroke, fatal or non-fatal myocardial infarction, and all-cause mortality. It remains unclear why updated guidance from NICE on the management of T2DM in adults fails to acknowledge these evidence-based cardiovascular beneﬁts.