Novel therapeutic agents for the treatment of diabetic kidney disease

ABSTRACT

Introduction

Diabetic kidney disease (DKD) involves multifaceted pathophysiology which increases the risk of cardiorenal events and mortality. Conventional therapy is limited to renin-angiotensin aldosterone system inhibition and management of hyperglycemia and hypertension. Recent clinical trials have demonstrated promising nephroprotective effects of antihyperglycemic agents thus modifying guideline treatment recommendations for type 2 diabetic patients with chronic kidney disease.

Areas of covered

Relevant studies and clinical trials were searched via PubMed and clinicaltrials.gov through August 2020. Authors offer an update on clinical evidence regarding nephroprotective effects and side effects of sodium-glucose-cotransporter-2 (SGLT2) inhibitors, glucagon-like-peptide-1 (GLP1) agonists and dipeptidylpeptidase-4 (DPP4) inhibitors. They discuss the potential benefits of novel therapy targeting DKD pathogenic processes including inflammation, oxidative stress, fibrosis, and vasoconstriction shown in early phases of clinical trials and offer an opinion on key challenges and directions for future progress.

Expert opinion

SGLT2 inhibitors are the most promising agents for DKD and improving cardiorenal outcomes. Mineralocorticoid-receptor antagonists and janus kinase inhibitors are also promising investigational therapies that target oxidative stress, nitric oxide synthesis, and inflammation. Novel therapeutic targets and the identification of clinically useful biomarkers may provide future therapies that detect early stages of DKD enabling a slower kidney function decline.

KEYWORDS:

• Renal disease
• diabetic kidney disease
• novel drugs
• investigational agents
• albuminuria
• glomerular filtration rate

Article Highlights

• Research to delineate the diabetic kidney disease (DKD) pathways and to expand treatment options has grown exponentially over the past two decades.

• Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown significant reduction of incident macroalbuminuria and delaying of glomerular filtration rate decline whilst renal benefits of glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors are mainly derived from albuminuria reduction. SGLT2 inhibitors and GLP-1 agonists have emerged as second-line therapy for type 2 diabetic patients with chronic kidney disease.

• The exact nephroprotective mechanisms of SGLT2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors are still to be elucidated in ongoing mechanistic and clinical trials but appear to be independent of their hypoglycemic effects.

• Numerous novel agents targeting multifaceted pathogenic pathways of DKD have exhibited promising preclinical outcomes and are currently undergoing various phases of clinical trials to establish their efficacy and safety as potential DKD treatment options. These include avosentan (endothelin receptor antagonist), allopurinol (uric acid lowering agent), finerenone (nonsteroidal mineralocorticoid receptor antagonist), selonsertib (apoptosis signal-regulating kinase 1 inhibitor), baricitinib (janus kinase 1/2 inhibitor), ASP8232 (vascular adhesion protein 1 inhibitor), DM199 (recombinant kallikrein), GFB-024 (cannabinoid receptor 1 monoclonal antibody), and VAR 200/400 (podocyte cholesterol accumulation remover).

• Novel drug therapy targets include reducing proinflammatory mediators, increasing nitric oxide production and decreasing podocyte cholesterol accumulation. Development of clinically useful biomarkers to identify early kidney damage are needed for clinical practice and research.

• Evidence suggests the cardiovascular and renal related drug therapy benefits may be attributed to decreased oxidative stress, inflammation, and sodium retention resulting in less cellular damage and glomerular hyperfiltration.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One peer reviewer has received consulting fees and research funding from AstraZeneca for being a National Lead Investigator and site investigator for the DAPA-CKD study. They have also received consulting fees from NovoNordisk for serving as a renal outcomes adjudicator.

Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Supplementary material

Supplemental data for this article can be accessed here.