Kidney Week

Abstract: PUB047

Reduction in Insulin Exposure: An Underrecognized Mechanism of Cardiorenal Benefit with GLP-1 Receptor Agonists

Session Information

• Publication Only

Category: Cardiovascular-Kidney-Metabolic Health

• 602 Cardiovascular-Kidney-Metabolic Health: Clinical

Authors

• Baskin, Stuart E., Rutgers University New Brunswick, New Brunswick, New Jersey, United States

Stuart E. Baskin, MD

• Klair, Nathaniel, University of Southern California, Los Angeles, California, United States

Nathaniel Klair, MD

• Taylor, Joseph, University of Southern California, Los Angeles, California, United States

Joseph Taylor, DO

• Li, Davey, University of Southern California, Los Angeles, California, United States

Davey Li, MD

• Sharma, Neeraj, University of Southern California, Los Angeles, California, United States

Neeraj Sharma

Background

Glucagon-like peptide-1 receptor agonist (GLP-1RA) trials have demonstrated cardiovascular and renal protective effects with reductions in major adverse cardiovascular events, albuminuria progression, and decline in kidney function. Although there are many proposed mechanisms, the exact pathways remain incompletely understood.

One hypothesis is that GLP-1RAs may exert part of their benefit through reduction of insulin exposure. Hyperinsulinemia and insulin resistance have been associated with endothelial dysfunction, oxidative stress, sympathetic activation, sodium retention, mesangial proliferation, and vascular remodeling, all of which contribute to cardiovascular and renal disease progression.

Methods

A comprehensive literature review was conducted evaluating GLP-1 receptor agonists, insulin resistance, hyperinsulinemia, cardiovascular outcomes, and renal protection. Search terms included “GLP-1 receptor agonist,” “insulin sensitivity,” “hyperinsulinemia,” “cardiovascular outcomes,” “renal outcomes,” “endothelial dysfunction,” and “insulin dose reduction.” Priority was given to landmark cardiovascular and renal outcome trials including LEADER, SUSTAIN-6, REWIND, and FLOW, as well as metabolic studies examining insulin sensitivity and insulin dose requirements with GLP-1RA therapy.

Results

Multiple studies demonstrate that GLP-1RAs improve insulin sensitivity and reduce total insulin exposure. This mechanism is supported by evidence linking hyperinsulinemia to endothelial dysfunction, vascular inflammation, oxidative stress, renal sodium retention, sympathetic nervous system activation, and glomerular hyperfiltration. Insulin also functions as a growth factor and may contribute to vascular smooth muscle proliferation and maladaptive renal remodeling.

Conclusion

GLP-1 receptor agonists provide significant cardiovascular and renal protection through complex and likely overlapping mechanisms. Emerging evidence suggests that reduction in endogenous and exogenous insulin exposure through improved insulin sensitivity may represent an important contributing pathway. This hypothesis may also help explain why GLP-1RAs provide benefits that appear disproportionate to their glucose-lowering effects alone. Further mechanistic and prospective studies are needed to clarify the extent to which reduction in insulin exposure independently mediates these favorable outcomes.