The emergence of incretin therapy has revolutionized the management of type 2 diabetes. Before the 1980s, it was not clear that improving glucose control could prevent or delay the development of diabetes complications. It wasn’t until the incretin effect was documented in 1982 that there was a glimmer of hope that type 2 diabetes could be managed effectively.

As type 2 diabetes medications have become more effective, management goals have become more ambitious. It is no longer enough to lower A1C. The ideal type 2 diabetes medication can control glycemia with low risk of hypoglycemia and produce beneficial effects on beta cell function, weight loss, and cardiorenal function.

The ADA 2022 standard of care for type 2 diabetes recommends ≥5% weight loss for most people with the disease. Dual gastric inhibitory polypeptide (GIP) and glucagon‐like peptide‐1 (GLP‐1) agents are the most effective weight loss agents developed so far in diabetes. The SURPASS trials, which supported the approval of tirzepatide, demonstrated weight loss greater than 30% of initial body weight and A1C ≤5.7% in significant numbers of participants. Across all the SURPASS trials, 40-50% of participants achieved normoglycemia and significant weight loss without hypoglycemia.

Dual receptor agonism is both additive and complementary. GLP-1 activity reduces food intake, improves insulin secretion, reduces glucagon secretion, and delays gastric emptying. GIP activity also reduces food intake and improves beta cell function while improving insulin sensitivity and nutrient metabolism.

Dual incretin receptor agonism also brings important renal benefits and, at a minimum, carries no increased cardiovascular risk. Cardiovascular benefits are still in trial. The renal benefits alone are a dramatic improvement over existing management options.

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