Novel Therapies for Kidney Disease in People with Diabetes

2021 ◽  
Author(s):  
Nayana Khurana ◽  
Steven James ◽  
Melinda T Coughlan ◽  
Richard J MacIsaac ◽  
Elif I Ekinci
Keyword(s):  
Kidney Disease ◽  
Mineralocorticoid Receptor ◽  
Novel Therapies ◽  
Mineralocorticoid Receptor Antagonists ◽  
Omega 3 ◽  
Receptor Antagonists ◽  
Tripterygium Wilfordii Hook F ◽  
Renal Outcomes ◽  
Sodium Glucose Cotransporter ◽  
Tripterygium Wilfordii Hook

Abstract Aim The increasing burden of diabetic kidney disease (DKD) has led to the discovery of novel therapies. This review aims to summarise the results of recent clinical trials that test the efficacy of potential therapies for DKD. Methods A systematised narrative review was performed utilising PubMed, Embase (Ovid), CINAHL and Cochrane databases (January 2010-January 2021). Trials included assessed the efficacy of specific medications using renal endpoints in adult participants with either type 1 or 2 diabetes. Results 53 trials were identified. Large, multinational and high-powered trials investigating sodium-glucose cotransporter-2 inhibitors demonstrated improved renal outcomes, even in patients with established DKD. Trials examining incretin-related therapies also showed some improvement in renal outcomes. Additionally, mineralocorticoid-receptor antagonists exhibited potential with multiple improved renal outcomes in large trials, including those involving participants with established DKD. Atrasentan, baricitinib, ASP8232, PF-04634817, CCX140-B, atorvastatin, fenofibrate, probucol, doxycycline, vitamin D, omega-3 fatty acids, silymarin, turmeric, total glucosides of paeony and tripterygium wilfordii Hook F extract were all associated with some improved renal endpoints, but with need for further exploration. While bardoxolone methyl was associated with a decrease in albuminuria, high rates of cardiovascular adverse effects curtailed further exploration into this agent. Selonsertib, allopurinol, praliciguat, palosuran, benfotiamine and diacerein were not associated with improved renal outcomes. Conclusion Trials have yielded promising results in the search for new therapies to manage DKD. Sodium-glucose cotransporter-2 inhibitors and incretin-related therapies have demonstrated benefit and were associated with improved cardiovascular outcomes. Mineralocorticoid-receptor antagonists are another class of agents with increasing evidence of benefits.

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

Hypertension ◽  
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.

scholarly journals Mineralocorticoid receptor antagonists for nephroprotection and cardioprotection in patients with diabetes mellitus and chronic kidney disease

2021 ◽  
Author(s):  
Alberto Ortiz ◽  
Charles J Ferro ◽  
Olga Balafa ◽  
Michel Burnier ◽  
Robert Ekart ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Kidney Failure ◽  
Mineralocorticoid Receptor ◽  
Diabetic Kidney Disease ◽  
Renin Angiotensin System ◽  
Cardiovascular Death ◽  
Mineralocorticoid Receptor Antagonists ◽  
Receptor Antagonists ◽  
Diabetic Kidney

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.

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

2020 ◽  
Vol 9 (16) ◽  
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.

Effects of mineralocorticoid receptor antagonists in proteinuric kidney disease

2019 ◽  
Vol 37 (12) ◽  
pp. 2307-2324 ◽  
Author(s):  
Maria-Eleni Alexandrou ◽  
Aikaterini Papagianni ◽  
Apostolos Tsapas ◽  
Charalampos Loutradis ◽  
Afroditi Boutou ◽  
...  
Keyword(s):  
Kidney Disease ◽  
Mineralocorticoid Receptor ◽  
Mineralocorticoid Receptor Antagonists ◽  
Receptor Antagonists
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