Common Drug Pipelines for the Treatment of Diabetic Nephropathy and Hepatopathy: Can We Kill Two Birds with One Stone?

Abstract

Type 2 diabetes (T2D) is associated with diabetic nephropathy as well as nonalcoholic steatohepatitis (NASH), which can be called "diabetic hepatopathy or diabetic liver disease". NASH, a severe form of nonalcoholic fatty disease (NAFLD), can sometimes progress to cirrhosis, hepatocellular carcinoma and hepatic failure. T2D patients are at higher risk for liver-related mortality compared with the nondiabetic population. NAFLD is closely associated with chronic kidney disease (CKD) or diabetic nephropathy according to cross-sectional and longitudinal studies. Simultaneous kidney liver transplantation (SKLT) is dramatically increasing in the United States, because NASH-related cirrhosis often complicates end-stage renal disease. Growing evidence suggests that NAFLD and CKD share common pathogenetic mechanisms and potential therapeutic targets. Glucagon-like peptide 1 (GLP-1) receptor agonists and sodium-glucose cotransporter 2 (SGLT2) inhibitors are expected to ameliorate NASH and diabetic nephropathy/CKD. There are no approved therapies for NASH, but a variety of drug pipelines are now under development. Several agents of them can also ameliorate diabetic nephropathy/CKD, including peroxisome proliferator-activated receptors agonists, apoptosis signaling kinase 1 inhibitor, nuclear factor-erythroid-2-related factor 2 activator, C-C chemokine receptor types 2/5 antagonist and nonsteroidal mineral corticoid receptor antagonist. This review focuses on common drug pipelines in the treatment of diabetic nephropathy and hepatopathy.

Keywords: chronic kidney disease; diabetic hepatopathy; diabetic nephropathy; glucagon-like peptide 1; peroxisome proliferator-activated receptor; sodium–glucose cotransporter 2.

Figure 1

Potential mechanisms linking nonalcoholic steatohepatitis (NASH)/nonalcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD)/diabetic nephropathy. NEFA: nonesterified fatty acid, ROS: reactive oxygen species, RAAS: renin–angiotensin–aldosterone, CRP: C-reactive protein, TNFα: tumor necrosis factor α, TGFβ: transforming growth factorβ, FGF-21: fibroblast growth factor-21, PAI-1: plasminogen activator inhibitor-1, T2D: type 2 diabetes, PNPLA3: patatin-like phospholipase domain-containing protein-3, SNP: single nucleoside polymorphism. * NASH Clinical Research Network. # National Kidney Foundation.