Ertugliflozin

Yang J, et al. Basis of Disease, 2025, 1871(7), 167927.

Ertugliflozin was evaluated for its anti-atherosclerotic potential in nondiabetic ApoE-/- mice. Animals were fed a high-fat diet (HFD) with or without Ertugliflozin (3.075 μg/g/d) for three months. Aortic plaque burden was assessed by hematoxylin-eosin and Oil Red O staining, while macrophage infiltration was determined using MOMA2 immunohistochemistry. Ertugliflozin markedly reduced lipid accumulation and stabilized plaques. In vitro, RAW264.7 macrophages exposed to oxidized LDL (50 μg/ml) showed decreased lipid deposition upon Ertugliflozin (100 μM) treatment, confirmed by Oil Red O staining. Molecular analysis via RT-qPCR and western blot demonstrated upregulation of ABCA1 and LDLR, with concurrent suppression of CD36. Notably, the PPARγ inhibitor GW9662 attenuated these effects, confirming pathway specificity. These results underscore Ertugliflozin's experimental efficacy in modulating macrophage lipid metabolism and atherosclerotic plaque stability through PPARγ/LXRα signaling.

Yan J, et al. European Journal of Pharmacology, 2025, 1002, 177784.

This study investigated the direct vascular effects of Ertugliflozin, using rat mesenteric arteries and mouse thoracic aorta. Arterial contractility was measured with a multi-wire myograph system, revealing that Ertugliflozin induced dose-dependent vasorelaxation against phenylephrine- and K+-induced constriction. Importantly, vasodilation was shown to be mediated by vascular smooth muscle cells (VSMCs), independent of endothelium. Mechanistic experiments demonstrated that Ertugliflozin decreased intracellular ATP and ATP/ADP ratio, activating AMPK signaling. The use of Compound C, an AMPK inhibitor, abolished Ertugliflozin's vasorelaxant effect, confirming pathway involvement. Calcium imaging showed reduced cytosolic [Ca2+]i, while mitochondrial analyses indicated suppressed fission and decreased membrane potential. These experimental findings establish that Ertugliflozin directly modulates VSMC contractility through AMPK-dependent mitochondrial regulation, highlighting its therapeutic potential for hypertension management beyond glycemic control.

Dirk von Lewinski, et al. American Heart Journal, 2022, 246, 152-160.

A phase IIIb multicenter, randomized, double-blind, placebo-controlled clinical trial (ERASe) was designed to assess the efficacy of ertugliflozin in patients with reduced or midrange ejection fraction (EF) receiving implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT). A total of 402 patients across Austria are being enrolled, with inclusion criteria requiring prior ICD ± CRT implantation (>3 months) and documented ventricular tachycardia episodes (≥10 within 12 months). Participants are randomized 1:1 to oral ertugliflozin (5 mg once daily) or placebo. The primary endpoint measures total ventricular arrhythmic burden, while secondary assessments include device interventions, atrial fibrillation incidence, and heart failure biomarkers. This trial uniquely explores ertugliflozin's antiarrhythmic potential in nonpreserved EF, independent of diabetes, offering critical insights into SGLT2 inhibition as a therapeutic strategy for arrhythmia modulation.