Abstract
Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD) in the United States. Risk factor modification, such as tight control of blood glucose, management of hypertension and hyperlipidemia, and the use of renin–angiotensin–aldosterone system (RAAS) blockade have been proven to help delay the progression of DKD. In recent years, new therapeutics including sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), have provided additional treatment options for patients with DKD. This review discusses the various treatment options available to treat patients with diabetic kidney disease.
Highlights
Diabetes is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States and worldwide [1,2].The renin–angiotensin–aldosterone system (RAAS) blockade, with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB), was the sole treatment option for diabetic kidney disease (DKD) for about 20 years
ARB, and newer therapies such as sodium-glucose transport protein 2 (SGLT2) inhibitors, endothelin antagonists, glucagon-like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRA), along with a summary of landmark trials that support the use of these agents (Figure 1)
AMPLITUDE-O = cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes; AWARD-7 = dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease; CI = confidence interval; CKRT = continuous kidney replacement therapy; CV = cardiovascular; FLOW = effect of semaglutide versus placebo on the progression of renal impairment in subjects with type 2 diabetes and chronic kidney disease; eGFR = estimated glomerular filtration rate; ESKD = end-stage kidney disease; HR = hazard ratio; KRT = kidney replacement therapy; LEADER = liraglutide effect and action in diabetes: evaluation of cardiovascular outcome results; REWIND = dulaglutide and cardiovascular outcomes in type 2 diabetes; SUSTAIN-6 = trial to evaluate cardiovascular and other long-term outcomes with semaglutide in subjects with type 2 diabetes; UACR =
Summary
Endothelins comprise three structurally similar peptides involved in various vasoconstrictor pathways [66]. The kidney expresses endothelin receptors [67], and there is evidence of their overexpression in diabetics. The renal endothelin system has been shown to play an important role in normal renal function, and derangements of this system are involved in the initiation and progression of DKD, HTN and even glomerular nephritis [68]. Endothelin receptor antagonism has been shown to improve kidney microcirculation [69], and there has been evidence that endothelin antagonism can lower urinary protein excretion [70]. Given this evidence of potential kidney benefit, trials have been conducted to assess the benefits of endothelin antagonists in the treatment of patients with DKD (Table 5)
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