General Description

Azilsartan is a prodrug and the newest approved angiotensin II receptor blocker (ARB) used for treating hypertension. It is converted to its active form quickly when administered orally. Azilsartan is a potent and highly selective AT1 receptor antagonist, binding tightly and dissociating slowly from AT1 receptors. This allows for sustained inhibitory effects on angiotensin II (AII). It also exhibits inverse agonism against AT1 receptors, offering potential organ protective effects. Preclinical research suggests that Azilsartan may have metabolic benefits beyond its antihypertensive effects. It has shown positive effects on diabetic nephropathy, insulin sensitivity, atherosclerotic pathways, and adipocyte differentiation. Further studies are needed to fully understand these effects and their clinical implications.

Figure 1. Tablet of azilsartan

Pharmacology

Azilsartan is a prodrug and the newest approved angiotensin II receptor blocker (ARB) for treating hypertension. When administered orally, it is quickly converted to its active form, azilsartan, which reaches peak plasma concentration within 1.5 to 3 hours. It has an estimated bioavailability of 60% and an elimination half-life of 11 hours. Azilsartan undergoes metabolism primarily in the liver through cytochrome P450 enzymes, mainly CYP2C9, as well as CYP2B6 and CYP2C8, resulting in the formation of inactive metabolites. The kidney primarily eliminates these metabolites, with a clearance rate of 2.3 mL/min. Compared to other ARBs, azilsartan is a potent and highly selective AT1 receptor antagonist that binds tightly and dissociates slowly from AT1 receptors. This means that even after washout, it remains substantially bound to the receptors, resulting in sustained inhibitory effects on angiotensin II (AII). In fact, the inhibitory effects of azilsartan on AII were reduced by only 25% after washout, while other ARBs like olmesartan, telmisartan, and valsartan showed greater reductions. Furthermore, azilsartan exhibited persistent inhibitory effects on IP1 accumulation and AII-induced vasoconstriction, even after washout, unlike olmesartan and valsartan. It selectively inhibited AII-induced vasoconstriction but not vasoconstriction induced by other substances. Additionally, it was found to have inverse agonism against AT1 receptors, which may offer organ protective effects. In a small study of hemodialysis patients, azilsartan showed stronger suppression of the sympathetic nervous system compared to other ARBs, resulting in a more prominent antihypertensive effect. This sympatho-inhibition is a general characteristic of ARBs and can be measured by plasma noradrenaline levels. Overall, the unique pharmacological profile of azilsartan, including its tight binding to receptors, sustained inhibitory effects, and inverse agonism, suggests that it may have potent and long-lasting antihypertensive effects with potential organ protective benefits. ¹

Preclinical Research and Metabolic Effects

Preclinical research on Azilsartan has shown promising metabolic effects beyond its primary use for hypertension. Accumulating evidence suggests that Angiotensin II receptor blockers (ARBs), including Azilsartan, can slow the progression of diabetic nephropathy independent of their blood pressure-lowering effects. Some ARBs may be more effective than others in reducing proteinuria in diabetic nephropathy patients. Additionally, specific ARBs have pleiotropic effects, meaning they have cellular actions beyond blocking AT1 receptors, which may confer favorable cardiometabolic effects. Various preclinical studies have demonstrated the beneficial effects of Azilsartan in pro-atherosclerotic pathways, insulin sensitivity, and adipocyte differentiation. Azilsartan has shown to block the activation of mitogen-activated protein kinases (MAPK) in vascular smooth muscle cells and exert anti-proliferative effects in vascular cells. It has also been found to stimulate favorable adipocyte differentiation and promote the expression of genes related to metabolic regulation. Animal studies have consistently shown that Azilsartan can improve insulin sensitivity, particularly in obese animals and models with type II diabetes. It has been reported to regulate 11β-HSD1 activity, reduce TNF-a production, and enhance the expression of PPARγ, C/EBP, and aP2. Azilsartan has also demonstrated positive effects on glucose transport, insulin signaling, and AMPKα expression. Furthermore, Azilsartan has shown efficacy in reducing diabetic kidney damage, improving glycemic status, vascular homeostasis, and reducing oxidative stress and inflammation. It has been found to have superior antihypertensive, insulin-sensitizing, and anti-proteinuric effects compared to other ARBs. Azilsartan has also been shown to restore endothelial function, normalize eNOS function, and reduce inflammation and oxidative stress in diabetic mice. Although the exact metabolic pathways activated by Azilsartan are not fully understood, it has been linked to the activation of PPARγ and protection against oxidative stress in various tissues. Azilsartan has shown greater insulin sensitivity improvement compared to other ARBs at similar doses. In conclusion, preclinical research suggests that Azilsartan offers metabolic benefits beyond its primary use for hypertension. It has demonstrated positive effects on diabetic nephropathy, insulin sensitivity, atherosclerotic pathways, and adipocyte differentiation. Further studies are needed to fully understand the underlying mechanisms of these effects and their clinical implications. ²

Reference

1. Angeli F, Verdecchia P, Pascucci C, Poltronieri C, Reboldi G. Pharmacokinetic evaluation and clinical utility of azilsartan medoxomil for the treatment of hypertension. Expert Opin Drug Metab Toxicol. 2013;9(3):379-385.

2. Georgiopoulos G, Katsi V, Oikonomou D, et al. Azilsartan as a Potent Antihypertensive Drug with Possible Pleiotropic Cardiometabolic Effects: A Review Study. Front Pharmacol. 2016;7:235.