Novel avenues for treating diabetic nephropathy: new investigational drugs

ABSTRACT

Introduction: At present, treatment of diabetic kidney disease (DKD) is still mainly based on drugs acting on glycemic and blood pressure control, as there is no validated therapy able to halt the progression of renal failure. Because of the high incidence of DKD, due to the increase of diabetes mellitus in general population, new therapeutic strategies are needed.

Areas covered: We analysed ongoing and already completed clinical trials, from clinicaltrials.gov and PubMed, dealing with new therapies for DKD.

Expert opinion: Among the drugs currently being explored, the most promising molecules are those that interfere with glucose-dependent pathways, in particular polyol, protein kinase, hexosamine and AGEs metabolic pathways, and impaired renal vascular regulation. One of the recent goals achieved by molecular biology is the development of monoclonal antibodies able to interfere with extracellular matrix accumulation and fibrosis. Other interesting therapies are under investigation and further studies with a greater number of patients will establish a better approach for diabetic nephropathy.

KEYWORDS:

• Diabetic kidney disease
• proteinuria
• therapy
• inflammation
• fibrosis
• oxidative stress

Article highlights

• DKD is one of the most important complications of diabetes

• At present, therapy is essentially supportive; however, recent findings on the pathophysiology of the disease have stimulated the research on new therapeutic strategies, using old and new drugs, in order to halt DKD progression

• The drugs under evaluation act on several different pathophysiological mechanisms responsible for renal injury

• Molecules active on RAAS, such as ACE inhibitors (ACE-I) and angiotensin receptor blockers (ARB), are used to reduce albuminuria in DKD. Other drugs active on RAAS, such as mRAs, reduce renal expression of markers of inflammation and oxidative stress.

• The most promising molecules are those that interfere with inflammatory and hemodynamic pathways. Atrasentan was showed to decrease albuminuria, systolic and diastolic blood pressure, although this drug caused significant increase in weight as a result of fluid retention. EMPA-REG study demonstrated that SGLT2 inhibitors are able to decrease cardiovascular morbidity and mortality in patients with type 2 diabetes. Recently, empagliflozin was able to slow the progression of renal disease, causing a decrease in albuminuria and a lower risk of end stage renal disease compared to placebo [142].

• Other therapeutic strategies are currently under investigation but further and larger studies are needed to establish the best therapy for DKD.

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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.

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Funding

This paper was not funded.