bay-94-8862 and Obesity

In the present review, we will discuss the evidence and the mechanisms underlying the complex interplay between obesity, mineralocorticoid receptor activation, and cardiovascular dysfunction with special emphasis on the pathogenesis of cardiovascular disease (CVD) in obese and insulin-resistant females.. Since the initial isolation of aldosterone in 1953 and the cloning of the mineralocorticoid receptor (MR) decades later, our understanding has expanded tremendously regarding their involvement in the pathogenesis of CVD. Recent results from both pre-clinical and clinical studies support a close correlation between increase adiposity and enhanced aldosterone production (MR activation). Importantly, insulin resistance and obese females are more prone to the deleterious cardiovascular effects of MR activation, and enhanced MR activation in females has emerged as an important causative event in the genesis of a more severe CVD in diabetic women. Different clinical trials have been completed examining the effect of MR blockade in subjects with CVD. Despite its important beneficial mortality impact, side effects are frequent and a newer MR antagonist, finerenone, with less risk of hyperkalemia is currently being tested in large clinical trials.

Topics: Animals; Cardiovascular Diseases; Female; Humans; Insulin Resistance; Mineralocorticoid Receptor Antagonists; Naphthyridines; Obesity; Receptors, Mineralocorticoid

To assess the effect of finerenone on the risk of cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes, with and without obesity.. A post hoc analysis of the prespecified pooled FIDELITY dataset assessed the association between waist circumference (WC), composite cardiovascular and kidney outcomes, and the effects of finerenone. Participants were stratified by WC risk groups (representing visceral obesity) as low-risk or high-very high-risk (H-/VH-risk).. Of 12 986 patients analysed, 90.8% occupied the H-/VH-risk WC group. Incidence of the composite cardiovascular outcome was similar between finerenone and placebo in the low-risk WC group (hazard ratio [HR] 1.03; 95% confidence interval [CI], 0.72-1.47); finerenone reduced the risk in the H-/VH-risk WC group (HR 0.85; 95% CI, 0.77-0.93). For the kidney outcome, the risk was similar in the low-risk WC group (HR 0.98; 95% CI, 0.66-1.46) and reduced within the H-/VH-risk WC group (HR 0.75; 95% CI, 0.65-0.87) with finerenone versus placebo. There was no significant heterogeneity between the low-risk and H-/VH-risk WC groups for cardiovascular and kidney composite outcomes (P interaction = .26 and .34, respectively). The apparent greater benefit of finerenone on cardiorenal outcomes but lack of significant heterogeneity observed in H-/VH-risk WC patients may be because of the small size of the low-risk group. Adverse events were consistent across WC groups.. In FIDELITY, benefits of finerenone in lowering the risk of cardiovascular and kidney outcomes were not significantly modified by patient obesity.

Topics: Diabetes Mellitus, Type 2; Humans; Kidney; Obesity; Renal Insufficiency, Chronic

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Topics: Aminoquinolines; Animals; Blood Pressure; Diabetes Mellitus, Type 2; Epithelial Sodium Channels; Gene Expression; Immediate-Early Proteins; Kidney; Male; Mice; Naphthyridines; Obesity; Protein Serine-Threonine Kinases; Pyrimidines; rac1 GTP-Binding Protein; Receptors, Mineralocorticoid; Signal Transduction; Sodium Chloride, Dietary