Association of glyoxalase I inhibition by angiotensin II receptor blockers with adverse events in diabetic patients

Angiotensin II receptor blockers (ARBs) are essential antihypertensive drugs, particularly for patients with diabetes. Glyoxalase I (GLO1) is a key enzyme in detoxifying methylglyoxal (MGO), a cytotoxic byproduct of glycolysis. Prompted by our previous work linking the phenyltetrazole moiety to GLO1 inhibition, we investigated whether ARBs inhibit human GLO1 and if this off-target effect is associated with clinical adverse events. We assessed the in vitro GLO1 inhibitory activity of seven ARBs and analyzed the Japanese Adverse Drug Event Report (JADER) database, comparing adverse event reporting between patients prescribed telmisartan, identified as the most potent human GLO1 inhibitor, and those prescribed other ARBs. All tested ARBs inhibited GLO1 activity, but telmisartan exhibited uniquely high potency against the human enzyme (IC 50 = 60.4 μM). The JADER analysis revealed that significant adverse event signals, including hepatocellular injury (reporting odds ratio (ROR) = 54.66), chronic kidney disease (ROR = 3.81), and lactic acidosis (ROR = 2.45), which were more severely or uniquely manifested in the diabetic cohort. Furthermore, telmisartan significantly promoted MGO-induced advanced glycation endproduct accumulation in HepG2 human liver cells. In conclusion, GLO1 inhibition is a novel off-target effect of several ARBs. This mechanism may contribute to a systemic toxicity profile specifically in diabetic patients susceptible to high carbonyl stress. These findings suggest that GLO1 inhibitory potential is a relevant consideration in ARB selection for high-risk patient populations.