AACE MENA 2025-Indications for SGLT2I and Incretin-Based Therapy Beyond Diabetes: Overview and Future Outlook

Indications for SGLT2I and Incretin-Based Therapy Beyond Diabetes: Overview and Future Outlook

Video Transcription

Video Summary

Dr. Ralph DeFronzo presents an advanced understanding of type 2 diabetes pathophysiology, highlighting the "ominous octet"—eight key mechanisms contributing to the disease—including insulin resistance in liver, muscle, and fat, beta-cell failure, alpha-cell glucagon overproduction, kidney glucose reabsorption, and brain regulation of obesity-related behaviors. He argues that effective treatment must target multiple pathways rather than just lowering glucose, critiquing common first-line use of metformin and sulfonylureas as inadequate long-term. <br /><br />DeFronzo extensively discusses two pivotal drug classes: GLP-1 receptor agonists and SGLT2 inhibitors. GLP-1 receptor agonists (e.g., semaglutide, tirzepatide) improve insulin secretion, inhibit glucagon, promote weight loss, cardiovascular, renal, and liver benefits, and now are recommended as first-line therapy by the ADA. However, weight regain and muscle loss post-treatment are concerns. <br /><br />SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) lower blood glucose by promoting renal glucose excretion, reducing cardiovascular events and heart failure, improving kidney outcomes, and offering safety and ease of use. The combination of GLP-1 receptor agonists and SGLT2 inhibitors shows additive benefits in glycemic control and cardiovascular mortality reduction.<br /><br />He also highlights pioglitazone, despite weight gain side effects, as a beneficial drug improving insulin sensitivity and cardiovascular outcomes. The optimal treatment algorithm involves early combination therapy with GLP-1 receptor agonists, SGLT2 inhibitors, and pioglitazone to comprehensively address the multifactorial disease process.

Keywords

type 2 diabetes pathophysiology

ominous octet

insulin resistance

GLP-1 receptor agonists

SGLT2 inhibitors

pioglitazone

combination therapy