pf-04971729 and Fibrosis

To conduct a post hoc analysis to explore indices of hepatic steatosis/fibrosis and cardiorenal outcomes in the VERTIS CV study.. Patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease were randomized to ertugliflozin or placebo. Liver steatosis and fibrosis were assessed post hoc using the hepatic steatosis index (HSI) and fibrosis-4 (FIB-4) index to explore associations with cardiorenal outcomes (ertugliflozin and placebo data pooled, intention-to-treat analysis set). Cardiorenal outcomes (major adverse CV events [MACE]; hospitalization for heart failure [HHF]/CV death; CV death; HHF; and a composite kidney outcome) were stratified by baseline HSI and FIB-4 quartiles (Q1-Q4). Change in liver indices and enzymes over time were assessed (for ertugliflozin vs. placebo).. In VERTIS CV, higher FIB-4 score was associated with CV events. HSI correlated with HHF. Neither measure was associated with the composite kidney outcome. Ertugliflozin was associated with a reduction in liver enzymes and HSI.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Fatty Liver; Fibrosis; Glucose; Heart Failure; Humans; Middle Aged; Sodium; Sodium-Glucose Transporter 2 Inhibitors

To investigate cardiac signalling pathways connecting substrate utilization with left ventricular remodelling in a murine pressure overload model.. Cardiac hypertrophy was induced by transverse aortic constriction surgery in 20-week-old C57BL/6J mice treated with or without the sodium-glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin (225 mg kg. Ertugliflozin improved left ventricular function and reduced myocardial fibrosis. This occurred simultaneously with a fasting-like response characterized by improved glucose tolerance and increased ketone body concentrations. While cardiac insulin signalling was reduced in response to SGLT2 inhibition, AMP-activated protein kinase (AMPK) signalling was increased with induction of the fatty acid transporter cluster of differentiation 36 and phosphorylation of acetyl-CoA carboxylase (ACC). Further, enzymes responsible for ketone body catabolism (β-hydroxybutyrate dehydrogenase, succinyl-CoA:3-oxoacid-CoA transferase and acetyl-CoA acetyltransferase 1) were induced by SGLT2 inhibition. Ertugliflozin led to more cardiac abundance of fatty acids, tricarboxylic acid cycle metabolites and ATP. Downstream mechanistic target of rapamycin (mTOR) pathway, relevant for protein synthesis, cardiac hypertrophy and adverse cardiac remodelling, was reduced by SGLT2 inhibition, with alleviation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) providing a potential mechanism for abundant reduced left ventricular apoptosis and fibrosis.. SGLT2 inhibition reduced left ventricular fibrosis in a murine model of cardiac hypertrophy. Mechanistically, this was associated with reduced cardiac insulin and increased AMPK signalling as a potential mechanism for less cardiac mTOR activation with alleviation of downstream ER stress, UPR and apoptosis.

Topics: Acetyl-CoA C-Acetyltransferase; Acetyl-CoA Carboxylase; Adenosine Triphosphate; AMP-Activated Protein Kinases; Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cardiomegaly; Coenzyme A-Transferases; Endoplasmic Reticulum Stress; Fatty Acids; Fibrosis; Glucose; Hydroxybutyrate Dehydrogenase; Insulins; Keto Acids; Ketones; Mice; Mice, Inbred C57BL; Myocytes, Cardiac; Sirolimus; Sodium; Sodium-Glucose Transporter 2; Sodium-Glucose Transporter 2 Inhibitors; TOR Serine-Threonine Kinases