Cardiovascular protection significantly depends on HbA1c improvement with GLP-1RAs but not with SGLT2 is in type 2 diabetes: A narrative review

Background

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2is), while developed as antihyperglycaemic medications for the treatment of type 2 diabetes, have proven to reduce major cardiovascular adverse events (MACEs) and hospitalization for heart failure (especially for SGLT2is) in dedicated cardiovascular outcome trials. The contribution of the glucose-lowering effect in the cardiovascular protection is uncertain and may differ between the two drug classes.

Methods

This narrative review compares the relative effects of glycated hemoglobin (HbA1c) reduction on the cardiovascular protection provided by GLP-1RAs and SGLT2is in placebo-controlled cardiovascular outcome trials by using the results of either post-hoc mediation analyses or meta-regression studies.

Results

Both mediation and meta-regression analyses suggest that the lower cardiovascular risk with GLP-1RAs partially but substantially tracks with their glucose-lowering effect, especially when considering the reduction in nonfatal strokes. In contrast, similar analyses fail to demonstrate any significant contribution of the glucose-lowering effect with SGLT2is, not only on MACEs but also on heart failure issues.

Conclusion

The contribution of improved glucose control in cardiovascular protection is limited, but is much greater for GLP-1RAs than for SGLT2is. Of note, such mediation or meta-regression analyses are exploratory and can only be viewed as hypothesis generating.