総説
GLP‒1 受容体作動薬の心・腎保護作用とその想定機序
キーワード:
glucagon-like peptide‒1 receptor agonist,
Na‒H exchanger 3,
salt and water diuresis,
tubulo-glomerular feedback,
appetite loss
2022 年 53 巻 6 号 p. 249-262
詳細
2022 年 53 巻 6 号 p. 249-262
Glucagon-like peptide‒1 (GIP‒1) receptor agonists (GLP‒1 RAs) are incretin derivative hypoglycemic agents that augment endogenous insulin secretion to improve glucose metabolism in patients with diabetes. Recent clinical studies based on the guidelines of the United States Food and Drug Administration suggest that GLP‒1 RAs have cardio-renal protective effects. For example, beneficial effects on major cardio-vascular events have been observed in the LEADER, SUSTAIN‒6, REWIND, HARMONY trials. In addition, renal protective effects have been proven in the ELIXA, LEADER, SUSTAIN‒6, and REWIND trials. Despite this clinical evidence, the precise pharmacological mechanisms of the cardio-renal protective effects of GLP‒1 RAs are unclear.
Therefore, the present narrative review article assessed the assumptive mechanisms of GLP‒1 RAs. The GLP‒1 RAs act on the central and visceral vagal nervous systems to suppress appetite and reduce body weight and thereby help improve insulin resistance and decrease salt burden potentially underlying in patients with diabetes. In the kidney, GLP‒1 RAs inhibit Na reabsorption by inhibiting Na‒H exchanger 3 in the proximal tubule, which induces water and natriuresis. The GLP‒1 RAs also stimulate atrial natriuretic peptide, potentiating natriuresis, leading to a blood pressure lowering. In addition, GLP‒1 RAs improve proteinuria presumably via antioxidant, anti-inflammatory, anti-fibrotic, and anti-atherosclerotic effects. Whether GLP‒1 RAs provide glomerular protection through the Na‒H exchanger 3‒induced optimization of tubulo-glomerular feedback and the macula densa system is still a matter for debate.
In conclusion, this narrative review article provides new insights into the mechanisms of the cardio-renal protective effects of GLP‒1 RAs.
