Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

Perez-Gomez, María Vanessa; Sanchez-Niño, María Dolores; Sanz, Ana B.; Martín-Cleary, Catalina; Ruíz-Ortega, Marta; Egido, Jesús; Navarro‐González, Juan F.; Ortíz, Alberto; Fernández-Fernández, Beatriz

doi:10.3390/jcm4061325

Cited by 54 publications

(30 citation statements)

References 102 publications

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“…Despite side effects, results of clinical trials continue to show therapeutic benefits of MR antagonists in a growing list of conditions 2, 96, 116, 117 , clearly indicating the need for better MR antagonists 59, 75, 118–120 . The Dialysis Outcomes Heart Failure Aldactone Study and others have been demonstrated their utility in stemming the progression of chronic kidney disease 121–123 . Another is the dramatic discovery that central serous chorioretinopathy, a rapidly progressing and heretofore untreatable cause of permanent destruction of the retina, is reversed by spironolactone and eplerenone 124, 125 .…”

Section: The First Generation Antagonistsmentioning

confidence: 99%

“…Two in early stages of clinical testing in patients with hypertension and diabetic nephropathy is MT-3995 (Mitsubishi) and SC-3150 (Daiichi-Sankyo) 123, 140, 155 . Phase II clinical trials have been completed for LY2623091 (Eli Lilly) was compared to a placebo and spironolactone in patients with primary hypertension (NCT02194465) and to eplerenone, but not a placebo, in men and women with chronic renal disease (NCT01427972).…”

Section: Other Potential Mr Antagonistsmentioning

confidence: 99%

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Third-generation Mineralocorticoid Receptor Antagonists

Gómez-Sánchez

2016

Journal of Cardiovascular Pharmacology

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The first mineralocorticoid receptor (MR) antagonist, spironolactone, was developed almost 60 years ago to treat primary aldosteronism and pathological edema. Its use waned in part due to its lack of selectivity. Subsequently knowledge of the scope of MR function was expanded along with clinical evidence of the therapeutic importance of MR antagonists to prevent the ravages of inappropriate MR activation. Forty-two years elapsed between the first and MR-selective second generation of MR antagonists. Fifteen years later, despite serious shortcomings of the existing antagonists, a third generation antagonist has yet to be marketed. Progress has been slowed by the lack of appreciation of the large variety of cell types that express the MR and its diverse cell-type-specific actions, as well as its uniquely complex interactions actions at the molecular level. New MR antagonists should preferentially target the inflammatory and fibrotic effects of MR and perhaps its excitatory effects on sympathetic nervous system, but not the renal tubular epithelium or neurons of the cortex and hippocampus. This review briefly describes efforts to develop a third generation MR antagonist and why fourth generation antagonists and selective agonists based on structural determinants of tissue and ligand-specific MR activation should be contemplated.

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Section: The First Generation Antagonistsmentioning

confidence: 99%

Section: Other Potential Mr Antagonistsmentioning

confidence: 99%

Third-generation Mineralocorticoid Receptor Antagonists

Gómez-Sánchez

2016

Journal of Cardiovascular Pharmacology

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“…Unfortunately, RAAS inhibitor trials have also produced some disappointing results, including the failure of primary prevention studies (The Renin Angiotensin System Study [RASS]), and serious side effects observed with dual RAAS blockade 2 . The lack of complete protection against the development of complications with traditional RAAS inhibitors underscores the need for new therapeutic strategies.…”

Section: Renal Protective Therapies Targeting Neurohormonal Activationmentioning

confidence: 99%

“…Unfortunately, recent renal protection trials have either failed, demonstrated harm or reported effects that are far below expectations based on data from experimental models. For example, within the last 5 years, trials with early renin-angiotensin-aldosterone system (RAAS) blockade in patients with type 1 (T1D) and type 2 diabetes (T2D), with dual RAAS blockade, protein kinase C-beta inhibition, endothelin receptor antagonists and the anti-oxidant bardoxolone have reported disappointing results 2 . Accordingly, this review will summarize promising novel therapies that may slow the progression of DN by targeting pathogenic mechanisms such as neurohormonal activation, tubuloglomerular feedback and renal inflammation/fibrosis.…”

Section: Introductionmentioning

confidence: 99%

New and old agents in the management of diabetic nephropathy

Bjornstad

Pun

Cherney

2016

Current Opinion in Nephrology and Hypertension

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Diabetic nephropathy (DN) is a long-standing complication of diabetes mellitus and is responsible for more than 40% of end stage renal disease cases in developed countries. Unfortunately, conventional renin-angiotensin-aldosterone system (RAAS) inhibitor medications only partially protect against the development and progression of DN. Moreover, RAAS inhibitors have failed as primary prevention therapy in type 1 diabetes. Thus, agents targeting alternative pathogenic mechanisms leading to DN have been intensively investigated. Promising emerging agents have targeted neurohormonal activation (alternative components of the RAAS and neprilysin inhibition), tubuloglomerular feedback mechanisms (sodium glucose co-transporter 2 inhibition and incretin-based therapy) and renal inflammation/fibrosis. The aim of this article is to review available evidence demonstrating the potential of these agents to protect and prevent progression of DN.

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“…It inhibits the production of thromboxane A2 and is used as anti-platelet agent instead of aspirin [190] . Experimental studies showed Sarpogrelate effect on mesangial type Ⅳ collagen production, on albuminuria in DKD, on antibody-mediated glomerular injury and on nephrotoxin-induced kidney fibrosis [191] . A clinical trial showed a significant decrease of urine albumin excretion in diabetic kidney disease after addition of Sarpogrelate [192] .…”

Section: Sharaf El Din Uaa Et Al Stop Chronic Kidney Disease Progrementioning

confidence: 99%

Stop chronic kidney disease progression: Time is approaching

Din¹,

Salem²,

Abdulazim³

2016

WJN

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Progression of chronic kidney disease (CKD) is inevitable. However, the last decade has witnessed tremendous achievements in this field. Today we are optimistic; the dream of withholding this progression is about to be realistic. The recent discoveries in the field of CKD management involved most of the individual diseases leading the patients to end-stage renal disease. Most of these advances involved patients suffering diabetic kidney disease, chronic glomerulonephritis, polycystic kidney disease, renal amyloidosis and chronic tubulointerstitial disease. The chronic systemic inflammatory status and increased oxidative stress were also investigated. This inflammatory status influences the antisenescence Klotho gene expression. The role of Klotho in CKD progression together with its therapeutic value are explored. The role of gut as a major source of inflammation, the pathogenesis of intestinal mucosal barrier damage, the role of intestinal alkaline phosphatase and the dietary and therapeutic implications add a novel therapeutic tool to delay CKD progression.

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Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

Cited by 54 publications

References 102 publications

Third-generation Mineralocorticoid Receptor Antagonists

Third-generation Mineralocorticoid Receptor Antagonists

New and old agents in the management of diabetic nephropathy

Stop chronic kidney disease progression: Time is approaching

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