Sodium‐glucose cotransporter‐2 inhibitors and non‐steroidal mineralocorticoid receptor antagonists: Ushering in a new era of nephroprotection beyond renin‐angiotensin system blockade

Abstract Diabetic kidney disease develops in about 40% of patients with diabetes and is the commonest cause of chronic kidney disease worldwide. Patients with chronic kidney disease, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular death. The use of renin-angiotensin system blockers to reduce the incidence of kidney failure in patients with diabetic kidney disease dates back to studies that are now 20 or more years old. During the last few years sodium-glucose co-transporter-2 inhibitors have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with renin-angiotensin system blockers and sodium-glucose co-transporter-2 inhibitors, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of cardiovascular death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists reduce albuminuria and surrogate markers of cardiovascular disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In The FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) study comparing the actions of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo, finerenone reduced the progression of diabetic kidney disease and the incidence of cardiovascular events with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of mineralocorticoid receptor antagonists, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic chronic kidney disease.

Download Full-text

Cardiovascular Protection With Sodium-Glucose Cotransporter-2 Inhibitors and Mineralocorticoid Receptor Antagonists in Chronic Kidney Disease

Hypertension ◽

10.1161/hypertensionaha.121.17005 ◽

2021 ◽

Vol 77 (5) ◽

pp. 1442-1455

Author(s):

Pantelis Sarafidis ◽

Christodoulos E. Papadopoulos ◽

Vasilios Kamperidis ◽

George Giannakoulas ◽

Michael Doumas

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Cardiovascular Events ◽

Mineralocorticoid Receptor ◽

Mineralocorticoid Receptor Antagonists ◽

Receptor Antagonists ◽

Cardiovascular Protection ◽

Sodium Glucose Cotransporter

Chronic kidney disease (CKD) and cardiovascular disease are intimately linked. They share major risk factors, including age, hypertension, and diabetes, and common pathogenetic mechanisms. Furthermore, reduced renal function and kidney injury documented with albuminuria are independent risk factors for cardiovascular events and mortality. In major renal outcome trials and subsequent meta-analyses in patients with CKD, ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin II receptor blockers) were shown to effectively retard CKD progression but not to significantly reduce cardiovascular events or mortality. Thus, a high residual risk for cardiovascular disease progression under standard-of-care treatment is still present for patients with CKD. In contrast to the above, several outcome trials with SGLT-2 (sodium-glucose cotransporter-2) inhibitors and MRAs (mineralocorticoid receptor antagonists) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article discusses existing evidence on the effects of SGLT-2 inhibitors and MRAs on cardiovascular outcomes in patients with CKD that open new roads in cardiovascular protection of this heavily burdened population.

Download Full-text

Combined Blockade of the Renin Angiotensin System with ACE Inhibitors and AT1 Receptor Antagonists

Angiotensin Vol. II - Handbook of Experimental Pharmacology ◽

10.1007/978-3-642-18497-0_20 ◽

2004 ◽

pp. 485-516

Author(s):

M. Azizi ◽

J. Ménard

Keyword(s):

Ace Inhibitors ◽

Renin Angiotensin System ◽

At1 Receptor ◽

Receptor Antagonists ◽

Angiotensin System ◽

Renin Angiotensin ◽

At1 Receptor Antagonists

Download Full-text

Molecular, Cellular, and Clinical Evidence That Sodium‐Glucose Cotransporter 2 Inhibitors Act as Neurohormonal Antagonists When Used for the Treatment of Chronic Heart Failure

Journal of the American Heart Association ◽

10.1161/jaha.120.016270 ◽

2020 ◽

Vol 9 (16) ◽

Cited By ~ 2

Author(s):

Milton Packer

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Mineralocorticoid Receptor ◽

Sglt2 Inhibitors ◽

Autophagic Flux ◽

Mineralocorticoid Receptor Antagonists ◽

Receptor Antagonists ◽

Cellular Effects ◽

Sodium Glucose Cotransporter ◽

Β Blockers

Abstract Sodium‐glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. Initially, these drugs were believed to have a profile similar to diuretics or hemodynamically active drugs, but they do not rapidly reduce natriuretic peptides or cardiac filling pressures, and they exert little early benefit on symptoms, exercise tolerance, quality of life, or signs of congestion. Clinically, the profile of SGLT2 inhibitors resembles that of neurohormonal antagonists, whose benefits emerge gradually during sustained therapy. In experimental models, SGLT2 inhibitors produce a characteristic pattern of cellular effects, which includes amelioration of oxidative stress, mitigation of mitochondrial dysfunction, attenuation of proinflammatory pathways, and a reduction in myocardial fibrosis. These cellular effects are similar to those produced by angiotensin converting enzyme inhibitors, β‐blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. At a molecular level, SGLT2 inhibitors induce transcriptional reprogramming of cardiomyocytes that closely mimics that seen during nutrient deprivation. This shift in signaling activates the housekeeping pathway of autophagy, which clears the cytosol of dangerous cytosolic constituents that are responsible for cellular stress, thereby ameliorating the development of cardiomyopathy. Interestingly, similar changes in cellular signaling and autophagic flux have been seen with inhibitors of the renin‐angiotensin system, β‐blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. The striking parallelism of these molecular, cellular, and clinical profiles supports the premise that SGLT2 inhibitors should be regarded as neurohormonal antagonists when prescribed for the treatment of heart failure with a reduced ejection fraction.

Download Full-text

Competing Effects of Renin Angiotensin System Blockade and Sodium-Glucose Cotransporter-2 Inhibitors on Erythropoietin Secretion in Diabetes

American Journal of Nephrology ◽

10.1159/000507272 ◽

2020 ◽

Vol 51 (5) ◽

pp. 349-356 ◽

Cited By ~ 1

Author(s):

Katerina P. Marathias ◽

Vaia A. Lambadiari ◽

Konstantinos P. Markakis ◽

Vassilios D. Vlahakos ◽

Dimitra Bacharaki ◽

...

Keyword(s):

Angiotensin Receptor Blockers ◽

Haemoglobin Concentration ◽

Renin Angiotensin System ◽

Sglt2 Inhibitors ◽

Common Finding ◽

Diabetic Patients ◽

Angiotensin System ◽

Renin Angiotensin ◽

Sodium Glucose Cotransporter ◽

Glucose Reabsorption

Background: Anaemia is a common finding in diabetes, particularly in those patients with albuminuria or renal dysfunction and is associated with impaired erythropoietin (EPO) secretion. This review focuses on mechanisms involved in the regulation of erythropoiesis in diabetic patients in an effort to elucidate the competing effects of the renin angiotensin system (RAS) blockade and sodium-glucose cotransporter-2 (SGLT2) inhibitors on haemoglobin concentration and hematocrit values. Summary: The RAS shows significant activation in diabetic subjects. Angiotensin II, its active octapeptide, causes renal tubulointerstitial hypoxia, which stimulates hypoxia-inducible factors (HIF) and increases EPO secretion and erythropoiesis. As expected, drugs that inactivate RAS, such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers (ACEi/ARB) are associated with a significant hematocrit-lowering effect and/or anaemia in various clinical conditions, including diabetes. Dual blockade by a combination of ACEi and ARB in diabetic patients achieves a better RAS inhibition, but at the same time a worse drop of haemoglobin concentration. Increased glucose reabsorption by SGLTs in diabetic subjects generates a high-glucose environment in renal tubulointerstitium, which may impair HIF-1, damage renal erythropoietin-producing cells (REPs) and decrease EPO secretion and erythropoiesis. SGLT2 inhibitors, which inhibit glucose reabsorption, may attenuate glucotoxicity in renal tubulointerstitium, allowing REPs to resume their function and increase EPO secretion. Indeed, EPO levels increase within a few weeks after initiation of therapy with all known SGLT2 inhibitors, followed by increased reticulocyte count and a gradual elevation of haemoglobin concentration and hematocrit level, which reach zenith values after 2–3 months. Key Messages: The competing effects of RAS blockade and SGLT2 inhibitors on erythropoiesis may have important clinical implications. The rise of hematocrit values by SGLT2 inhibitors given on top of RAS blockade in recent outcome trials may significantly contribute to the cardiorenal protection attained. The relative contribution of each system to erythropoiesis and outcome remains to be revealed in future studies.

Download Full-text

Angiotensin II receptor antagonists: A new approach to blockade of the renin-angiotensin system

American Heart Journal ◽

10.1016/0002-8703(94)90061-2 ◽

1994 ◽

Vol 127 (5) ◽

pp. 1388-1401 ◽

Cited By ~ 74

Author(s):

Peter M Kang ◽

Andre J Landau ◽

Robert T Eberhardt ◽

William H Frishman

Keyword(s):

Angiotensin Ii ◽

Renin Angiotensin System ◽

Angiotensin Ii Receptor ◽

Angiotensin Ii Receptor Antagonists ◽

Receptor Antagonists ◽

Angiotensin System ◽

New Approach ◽

Renin Angiotensin

Download Full-text

Salt-sensitive hypertension in chronic kidney disease: distal tubular mechanisms

AJP Renal Physiology ◽

10.1152/ajprenal.00407.2020 ◽

2020 ◽

Vol 319 (5) ◽

pp. F729-F745

Author(s):

Dominique M. Bovée ◽

Catharina A. Cuevas ◽

Robert Zietse ◽

A. H. Jan Danser ◽

Katrina M. Mirabito Colafella ◽

...

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Mineralocorticoid Receptor ◽

Kidney Injury ◽

Renin Angiotensin System ◽

Distal Nephron ◽

T Helper 17 ◽

Angiotensin System ◽

Renin Angiotensin ◽

Salt Sensitive Hypertension

Chronic kidney disease (CKD) causes salt-sensitive hypertension that is often resistant to treatment and contributes to the progression of kidney injury and cardiovascular disease. A better understanding of the mechanisms contributing to salt-sensitive hypertension in CKD is essential to improve these outcomes. This review critically explores these mechanisms by focusing on how CKD affects distal nephron Na+ reabsorption. CKD causes glomerulotubular imbalance with reduced proximal Na+ reabsorption and increased distal Na+ delivery and reabsorption. Aldosterone secretion further contributes to distal Na+ reabsorption in CKD and is not only mediated by renin and K+ but also by metabolic acidosis, endothelin-1, and vasopressin. CKD also activates the intrarenal renin-angiotensin system, generating intratubular angiotensin II to promote distal Na+ reabsorption. High dietary Na+ intake in CKD contributes to Na+ retention by aldosterone-independent activation of the mineralocorticoid receptor mediated through Rac1. High dietary Na+ also produces an inflammatory response mediated by T helper 17 cells and cytokines increasing distal Na+ transport. CKD is often accompanied by proteinuria, which contains plasmin capable of activating the epithelial Na+ channel. Thus, CKD causes both local and systemic changes that together promote distal nephron Na+ reabsorption and salt-sensitive hypertension. Future studies should address remaining knowledge gaps, including the relative contribution of each mechanism, the influence of sex, differences between stages and etiologies of CKD, and the clinical relevance of experimentally identified mechanisms. Several pathways offer opportunities for intervention, including with dietary Na+ reduction, distal diuretics, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and K+ or H+ binders.

Download Full-text

Effects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes

Journal of Investigative Medicine ◽

10.1136/jim-2017-000445 ◽

2017 ◽

Vol 65 (7) ◽

pp. 1057-1061 ◽

Cited By ~ 17

Author(s):

Takuo Yoshimoto ◽

Takayuki Furuki ◽

Hiroyuki Kobori ◽

Masaaki Miyakawa ◽

Hitomi Imachi ◽

...

Keyword(s):

Blood Pressure ◽

Type 2 Diabetes ◽

Renin Angiotensin System ◽

Sglt2 Inhibitors ◽

Creatinine Ratio ◽

Angiotensin System ◽

Renin Angiotensin ◽

Urinary Angiotensinogen ◽

Sodium Glucose Cotransporter

We conducted a descriptive case study to examine the effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors on urinary angiotensinogen excretion, which represents the function of the intrarenal renin–angiotensin system, in patients with type 2 diabetes. An SGLT2 inhibitor (canagliflozin 100 mg/day, ipragliflozin 25 mg/day, dapagliflozin 5 mg/day, luseogliflozin 2.5 mg/day or tofogliflozin 20 mg/day) was administered for 1 month (n=9). ELISA kits were used to measure both urinary intact and total angiotensinogen levels. Treatment with SGLT2 inhibitors significantly decreased hemoglobin A1c, body weight, systolic blood pressure and diastolic blood pressure (8.5±1.3 to 7.5%±1.0%, 82.5±20.2 to 80.6±20.9 kg, 143±8 to 128±14 mm Hg, 78±10 to 67±9 mm Hg, p<0.05, respectively), while urinary albumin/creatinine ratio was not significantly changed (58.6±58.9 to 29.2±60.7 mg/g, p=0.16). Both total urinary angiotensinogen/creatinine ratio and intact urinary angiotensinogen/creatinine ratio tended to decrease after administration of SGLT2 inhibitors. However, these changes were not significant (p=0.19 and p=0.08, respectively). These data suggest that treatment with SGLT2 inhibitors does not activate the intrarenal renin–angiotensin system in patients with type 2 diabetes.

Download Full-text