The Novel Phosphate and Bile Acid Sequestrant Polymer SAR442357 Delays Disease Progression in a Rat Model of Diabetic Nephropathy

• Published in: The Journal of pharmacology and experimental therapeutics 2021-02, Vol.376 (2), p.190-203
• Main Authors: Castañeda, Tamara R., Méndez, María, Davison, Ian, Elvert, Ralf, Schwahn, Uwe, Boldina, Galina, Rocher, Corinne, Scherer, Petra, Singh, Kuldeep, Bangari, Dinesh S., Falkenhahn, Mechthilde, Kannt, Aimo, Konkar, Anish, Larsen, Philip J., Arbeeny, Cynthia, Dhal, Pradeep K., Hübschle, Thomas
• Format: Article
• Language: English
• Subjects: Animals; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - therapeutic use; Bile Acids and Salts - metabolism; Cholesterol - metabolism; Diabetic Nephropathies - drug therapy; Hydrogels - chemical synthesis; Hydrogels - therapeutic use; Hypertension - drug therapy; Hypoglycemic Agents - chemical synthesis; Hypoglycemic Agents - therapeutic use; Liver - metabolism; Phosphates - metabolism; Polyamines - chemistry; Rats; Rats, Zucker
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.120.000285

As a gut-restricted, nonabsorbed therapy, polymeric bile acid sequestrants (BAS) play an important role in managing hyperlipidemia and hyperglycemia. Similarly, nonabsorbable sequestrants of dietary phosphate have been used for the management of hyperphosphatemia in end-stage renal disease. To evaluate the potential utility of such polymer sequestrants to treat type 2 diabetes (T2D) and its associated renal and cardiovascular complications, we synthesized a novel polymeric sequestrant, SAR442357, possessing optimized bile acid (BA) and phosphate sequestration characteristics. Long-term treatment of T2D obese cZucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) with SAR442357 resulted in enhanced sequestration of BAs and phosphate in the gut, improved glycemic control, lowering of serum cholesterol, and attenuation of diabetic kidney disease (DKD) progression. In comparison, colesevelam, a BAS with poor phosphate binding properties, did not prevent DKD progression, whereas losartan, an angiotensin II receptor blocker that is widely used to treat DKD, showed no effect on hyperglycemia. Analysis of hepatic gene expression levels of the animals treated with SAR442357 revealed upregulation of genes responsible for the biosynthesis of cholesterol and BAs, providing clear evidence of target engagement and mode of action of the new sequestrant. Additional hepatic gene expression pathway changes were indicative of an interruption of the enterohepatic BA cycle. Histopathological analysis of ZSF1 rat kidneys treated with SAR442357 further supported its nephroprotective properties. Collectively, these findings reveal the pharmacological benefit of simultaneous sequestration of BAs and phosphate in treating T2D and its associated comorbidities and cardiovascular complications. A new nonabsorbed polymeric sequestrant with optimum phosphate and bile salt sequestration properties was developed as a treatment option for DKD. The new polymeric sequestrant offered combined pharmacological benefits including glucose regulation, lipid lowering, and attenuation of DKD progression in a single therapeutic agent.