There have been seven cardiovascular outcome trials (CVOTs) exploring the impact of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on major adverse cardiovascular (CV) outcomes in people living with type 2 diabetes. Four GLP-1 RAs demonstrated CV superiority to placebo: liraglutide in LEADER, semaglutide once weekly in SUSTAIN-6, dulaglutide in REWIND and albiglutide in HARMONY OUTCOMES. The other three trials demonstrated only CV non-inferiority compared with placebo, although they did establish CV safety: exenatide once weekly in EXSCEL, lixisenatide in ELIXA and oral semaglutide in PIONEER-6.

One of the prevailing theories behind these differences in CV outcomes within the class was based on whether the GLP-1 RA molecule in question was an analogue of human GLP-1 or of exendin-4. Exendin-4 is a salivary protein from the Gila monster lizard with around 50% homology to human GLP-1.

The recently published AMPLITUDE-O trial explored the effect of a new exendin-based, once-weekly GLP-1 RA, efpeglenatide, on CV and renal outcomes in people living with type 2 diabetes at high CV risk. It should be noted that both efpeglenatide and albiglutide are currently not commercially available in the UK.

AMPLITUDE-O

In contrast to other GLP-1 RA trials, AMPLITUDE-O recruited more individuals with renal disease (around one-third had an eGFR <60 mL/min/1.73 m²) and there was also significant sodium–glucose cotransporter 2 (SGLT2) inhibitor usage at baseline (15% of participants). Individuals were followed up for a mean of 1.8 years.

There was a statistically significant 27% relative risk reduction in the primary outcome of first major adverse CV event (MACE; a composite of nonfatal myocardial infarction, nonfatal stroke, or death from CV or undetermined causes) with efpeglenatide compared to placebo. This translates into a number needed to treat (NNT) of 46 over 1.8 years to prevent one MACE episode.

Efpeglenatide was also associated with a significant 32% relative risk reduction in the prespecified secondary composite renal outcome of worsening renal function or macroalbuminuria.

Notably, the benefits of efpeglenatide were seen independently of baseline SGLT2 inhibitor use, baseline metformin use and baseline eGFR. This suggests that when using GLP-1 RAs and SGLT2 inhibitors in combination, the CV benefits may be additive.

The safety profile of efpeglenatide was reassuring. As predicted, and consistent with the GLP-1 RA class, gastrointestinal adverse effects were more common with efpeglenatide than with placebo. There was no imbalance seen in a range of prespecified safety outcomes, including pancreatic events, severe hypoglycaemia, diabetic retinopathy and acute kidney injury.

This is the first exendin-based GLP-1 RA CVOT to demonstrate statistically and clinically significant CV benefits, which dispels the prevailing theory explaining the in-class differences. Furthermore, this is the first CVOT to demonstrate robust renal benefits within the GLP-1 RA class, again independent of the established renal benefits of SGLT2 inhibitors. These renal effects may be related to the atherosclerotic benefits of GLP-1 RAs on the renal vasculature.

Overall, the AMPLITUDE-O trial cements the atherosclerotic benefits of the GLP-1 RA class and vindicates the recommendation in the 2019 update to the ADA/EASD Consensus Report (Buse et al, 2020) to preferentially consider the use of GLP-1 RAs if atherosclerotic CV disease predominates in a person living with type 2 diabetes.

Click here to read the study in full.