Phosphodiesterase Type 5 Inhibition Reduces Albuminuria in Subjects with Overt Diabetic Nephropathy

• Published in: Journal of the American Society of Nephrology Vol. 27; no. 11; pp. 3459 - 3468
• Main Authors: Scheele, Wim, Diamond, Susan, Gale, Jeremy, Clerin, Valerie, Tamimi, Nihad, Le, Vu, Walley, Rosalind, Grover-Páez, Fernando, Perros-Huguet, Christelle, Rolph, Timothy, El Nahas, Meguid
• Format: Journal Article
• Language: English
• Published: United States American Society of Nephrology 01.11.2016
• Subjects: Adult; Aged; Aged, 80 and over; Albuminuria - drug therapy; Albuminuria - enzymology; Albuminuria - etiology; Clinical Research; Diabetic Nephropathies - complications; Double-Blind Method; Female; Heterocyclic Compounds, 2-Ring - therapeutic use; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors - therapeutic use; Sulfonamides - therapeutic use; albuminuria; nitric oxide; randomized controlled trials; diabetic nephropathy
• DOI: 10.1681/ASN.2015050473
• ISSN: 1046-6673; 1533-3450

Diabetic nephropathy (DN) is the leading cause of ESRD worldwide. Reduced bioavailability or uncoupling of nitric oxide in the kidney, leading to decreased intracellular levels of the nitric oxide pathway effector molecule cyclic guanosine monophosphate (cGMP), has been implicated in the progression of DN. Preclinical studies suggest that elevating the cGMP intracellular pool through inhibition of the cGMP-hydrolyzing enzyme phosphodiesterase type 5 (PDE5) might exert renoprotective effects in DN. To test this hypothesis, the novel, highly specific, and long-acting PDE5 inhibitor, PF-00489791, was assessed in a multinational, multicenter, randomized, double-blind, placebo-controlled, parallel group trial of subjects with type 2 diabetes mellitus and overt nephropathy receiving angiotensin converting enzyme inhibitor or angiotensin receptor blocker background therapy. In total, 256 subjects with an eGFR between 25 and 60 ml/min per 1.73 m 2 and macroalbuminuria defined by a urinary albumin-to-creatinine ratio >300 mg/g, were randomly assigned 3:1, respectively, to receive PF-00489791 (20 mg) or placebo orally, once daily for 12 weeks. Using the predefined primary assessment of efficacy (Bayesian analysis with informative prior), we observed a significant reduction in urinary albumin-to-creatinine ratio of 15.7% (ratio 0.843; 95% credible interval 0.73 to 0.98) in response to the 12-week treatment with PF-00489791 compared with placebo. PF-00489791 was safe and generally well tolerated in this patient population. Most common adverse events were mild in severity and included headache and upper gastrointestinal events. In conclusion, the safety and efficacy profile of PDE5 inhibitor PF-00489791 supports further investigation as a novel therapy to improve renal outcomes in DN.