Lessons learned from early-stage clinical trials for diabetic nephropathy

ABSTRACT

Introduction

The evolution of treatment for diabetic nephropathy illustrates how basic biochemistry and physiology have led to new agents such as SGLT2 inhibitors and mineralocorticoid blockers. Conversely, clinical studies performed with these agents have suggested new concepts for investigational drug development. We reviewed currently available treatments for diabetic nephropathy and then analyzed early clinical trials of new agents to assess the potential for future treatment modalities.

Areas Covered

We searched ClinicalTrials.gov for new agents under study for diabetic nephropathy in the past decade. Once we have identified investigation trials of new agents, we then used search engines and Pubmed.gov to find publications providing insight on these drugs. Current treatments have shown benefit in both cardiac and renal disease. In our review, we found 51 trials and 43 pharmaceuticals in a number of drug classes: mineralocorticoid blockers, anti-inflammatory, anti-fibrosis, nitric oxide stimulatory, and podocyte protection, and endothelin inhibitors.

Expert opinion

It is difficult to predict which early phase treatments will advance to confirmatory clinical trials. Current agents are thought to improve hemodynamic function. However, the coincident benefit of both myocardial function and the glomerulus argues for primary effects at the subcellular level, and we follow the evolution of agents which modify fundamental cellular processes.

KEYWORDS:

• Nephropathy
• chronic kidney disease
• SGLT2 inhibitors
• mineralocorticoid receptor agonists
• glomerular filtration rate

Article highlights

• There are currently five drug classes indicated to treat diabetic nephropathy:(1) The angiotensin converting enzyme inhibitors (2) The angiotensin receptor blockers (3) the SGLT2 inhibitors (4) The GLP-1 receptor agonists (5) the mineralocorticoid receptor blockers

• The currently used agents have dual benefit in treating cardiovascular and renal disease.

• These agents all have favorable hemodynamic effects, but their benefits on cardiac and renal disease may also relate to fundamental basic biochemical pathways.

• We reviewed the agents in early phase development over the past decade for the treatment of diabetic nephropathy.

• There are a number of agents targeting inflammation, fibrosis, oxidative damage, and protection of podocytes.

• It will be interesting to follow the further development of these early phase investigational studies.

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

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

Additional information

Funding

This paper was supported by the Association of Diabetes Investigators and the Rose Salter Medical Research Foundation.