Angiotensin pathways under therapy with empagliflozin in patients with chronic heart failure

Abstract

Aims Large outcome studies demonstrated a reduction of heart failure hospitalization or cardiovascular death in patients with chronic heart failure (CHF). The renin-angiotensin system (RAS) is a key player in fluid and sodium regulation. The classic angiotensin-converting enzyme-angiotensin II-angiotensin-1 receptor axis (Ang I-ACE-Ang II receptor axis) is predominantly angiotensin II (Ang-II) induced and promotes vasoconstriction. In contrast, the angiotensin-converting-enzyme-2angiotensin-(1-7)-Mas axis (Mas-axis) is mediated by the metabolites angiotensin-1-7 (Ang-(1-7)) and angtiotensin-1-5 (Ang-(1-5)) and exerts cardioprotective effects. Methods We previously investigated the effect of empagliflozin on the systemic haemodynamic in patients with stable CHF (NYHA II-III) in a randomized placebo-controlled clinical trial 'Analysing the Effect of Empagliflozin on Reduction of Tissue Sodium Content in Patients With Chronic Heart Failure (ELSI)'. In a post hoc analysis, we now analysed whether empagliflozin has an effect on the RAS by measuring detailed RAS profiles (LC-MS/MS-based approach) in 72 patients from ELSI. We compared RAS parameters after 1-month and 3-months treatment with empagliflozin or placebo to baseline. The secondary goal was to analyse whether the effect of empagliflozin on RAS parameters was dependent on angiotensin-receptor-blocking (ARB) or angiotensin-converting-enzyme-inhibitor (ACEI) co-medication. Results Empagliflozin medication induced a significant rise in Ang-II [68.5 pmol/L (21.3-324.2) vs. 131.5 pmol/L (34.9-564.0), P = 0.001], angiotensin-I (Ang-I) [78.7 pmol/L (21.5-236.6) vs. 125.9 pmol/L (52.6-512.9), P < 0.001], Ang-(1-7) [3.0 pmol/L (3.0-15.0) vs. 10.1 pmol/L (3.0-31.3), P = 0.006], and Ang-(1-5) [5.4 pmol/L (2.0-22.9) vs. 9.9 pmol/L (2.8-36.4), P = 0.004], which was not observed in the placebo group (baseline to 3-months treatment). A significant rise in Ang-II (206.4 pmol/L (64.2-750.6) vs. 568.2 pmol/L (164.7-1616.4), P = 0.001), Ang-(1-7) (3.0 pmol/L (3.0-14.1) vs. 15.0 pmol/L (3.0-31.3), P = 0.017), and Ang-(1-5) [12.2 pmol/L (3.8-46.6) vs. 36.4 pmol/L (11.1-90.7), P = 0.001] under empagliflozin treatment was only seen in the subgroup of patients with ARB co-medication, whereas no change of Ang-II (16.7 pmol/L (2.0-60.8) vs. 26.4 pmol/L (10.7-63.4), P = 0.469), Ang-(1-7) (6.6 pmol/L (3.0-20.7) vs. 10.5 pmol/L (3.0-50.5), P = 0.221), and Ang-(1-5) (2.7 pmol/L (2.0-8.4) vs. 2.8 pmol/L (2.0-6.9), P = 0.851) was observed in patients with empagliflozin that were on ACEI co-medication (baseline to 3-months treatment). Conclusions Our data indicate that empagliflozin might lead to an activation of both the Ang I-ACE-Ang II receptor axis and the Mas-axis pathway. Activation of the Ang I-ACE-Ang II receptor axis and the protective Mas-axis pathway after initiating treatment with empagliflozin was only seen in patients with ARB co-medication, in contrast to co-medication with ACEI.

Heart Failure With Low and Preserved Left Ventricular Ejection Fraction – are These Two Different Independent Diseases or One Disease, but at Different Stages of its Progression? How Does This Affect the Choice of Therapy and Its Effectiveness?

“…Во-вторых, фиброз миокарда, как интерстициальный при СНсФВ, так и фокальный, присущий СНнФВ, в обоих вариантах чувствителен к терапии АМКР. В-третьих, в отношении феномена ИНГЛТ2 было доказано, что препараты этого класса обладают как собственным гемодинамическим и нейрогуморальным влиянием [6,7], так и способностью прямого положительного воздействия на КМЦ, что крайне важно и в условиях миоцитарного дефицита при СНнФВ, и при микровоспалении и реактивном интерстициальном фиброзе при СНсФВ. За счет активации внутриклеточных процессов аутофагии, глифлозины добиваются устойчивости КМЦ к оксидативному стрессу и обеспечивают благоприятные условия для репарации поврежденных клеточных органелл; восстанавливая подавленные процессы митохондриального дыхания, мобилизуют утраченные в процессе заболевания энергетические ресурсы клеток сердца [8,9].…”

Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects

“…When combined with RAS blockers, this activation should not result in additional harmful effects through the Ang II-Ang II type 1 (AT 1 ) receptor axis. Some argue that dual RAS blockade/SGLT2 inhibition may yield beneficial effects through the angiotensin-(1-7) (Ang-(1-7))-Mas receptor axis [1,10,11], leading to greater blood pressure reduction [10,12,13].…”