Effects of oral antidiabetic agents on the renin-angiotensin-aldosterone system.

Abstract

Background: The renin-angiotensin-aldosterone system (RAAS) is a vital endocrine system that plays a crucial role in maintaining homeostasis. However, excessive activation of the RAAS can contribute to the pathogenesis of certain diseases. Prolonged hyperglycemia leads to overactivation of the RAAS through the production of inflammatory factors and other mechanisms, ultimately resulting in diabetic complications. Oral antidiabetic agents are the cornerstone of diabetes treatment, and the effects of oral antidiabetic agents on the RAAS have not been clearly summarized.

Objective: To review the effects of various types of oral antidiabetic agents on the components of the RAAS.

Results: Sodium-glucose cotransporter inhibitors (SGLT2i) inhibit glucose and sodium reabsorption, which increases the flow of Na⁺ to the macula densa, thereby inhibiting tubuloglomerular feedback (TGF) and subsequently decreasing renin production. GLP-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) can directly inhibit angiotensin II (Ang II) or indirectly suppress it by modulating TGF. These agents also affect Ang II type 1 receptors (AT1R) and Ang II type 2 receptors (AT2R) to mitigate Ang II and can indirectly interact with Ang II through Na⁺/H⁺ exchanger isotope 3 (NHE3). Thiazolidinediones (TZDs), as PPAR-γ agonists, can enhance the expression of the renin gene, inhibit the production of angiotensin-converting enzyme (ACE), regulate the levels of AT1R and AT2R, and decrease aldosterone production. Metformin also inhibits the production of renin and aldosterone in patients with polycystic ovary syndrome (PCOS).

Conclusions: These oral agents, which exhibit diverse effects on the components of the RAAS, modulate the activity of these components to exert antihypertensive, anti-inflammatory, cardioprotective, and renoprotective effects, thereby offering several beneficial outcomes in the management of diabetes.