Sex-Specific Effects of Daily Tadalafil on Contraction Kinetics of the Diabetic Heart. The RECOGITO Randomized, Double-Blind, Placebo-Controlled Trial

Background: Cardiovascular disease is the leading cause of morbidity and mortality in type 2 diabetes (T2DM) patients. Cyclic GMP-phosphodiesterase type 5 (PDE5) inhibition was shown to counteract maladaptive cardiac changes triggered by diabetes in some studies. Our aim was to assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy (DCM). Methods: We performed a 20-week, double-blind, randomized, placebo-controlled trial. Men and women (45–80 years) with controlled T2DM and echocardiographic (ECG) signs of cardiac remodeling were randomly assigned (1:1) to placebo or tadalafil 20 mg once daily. The primary outcome was analyzing the sex-difference in cardiac torsion change, from baseline to 20 weeks. Secondary outcomes included changes in cardiovascular, metabolic, immune and renal function. Efficacy analyses included all patients who received at least one dose of treatment. Findings: Between May 2014 and July 2018, we screened 220 diabetic subjects; 122 met the inclusion criteria and were randomized to tadalafil (n=61) or placebo (n=61). At 20 weeks, the sex-by-treatment interaction documented an improvement in cardiac torsion [-3·40°(-5·96;-0·84, p =0·011)], paralleled by a consensual increase in fiber shortening, in men but not women. Biomarkers of cardiovascular remodeling , titin and hsa-miR-199-5p, improved accordingly. In both sexes, tadalafil reduced TGF-beta and improved albuminuria, renal artery’s resistive index, Klotho , and symmetric-di-methyl-arginine markers . Five months of 20 mg daily tadalafil in patients with DCM was proven safe. The most common adverse reactions were myalgia (9[14·5%]), gastric reflux (6[9·7%]), headache (4[6·4%]) and flushing (2[3·8%]); one SAE occurred in the placebo arm. Interpretation: Continuous PDE5 inhibition could represent a new treatment strategy to target cardiac and renal complications of T2DM, with a different tissue-specific response in men and women. Klotho and hsa-miR-199-5p appear as novel players linking renal disease to DCM progression. Trial Registration: NCT01803828. Funding Statement: Italian Ministry of University and Research, SIR RBSI141LY2. Declaration of Interests: Prof. Isidori reports personal fees from Takeda; non-financial support from Takeda and Ipsen; and grants from Shire and Pfizer outside the submitted work; Prof. Pozzilli reports research contracts and consulting from Eli Lilly, Sanofi, Merck, Merck Sharpt Dohme, Astra Zeneca, Medtronic, Abbott; Dr. Defeudis reports grants from Ibsa, personal fees from Abbott, grants from Novo Nordisk, grants from Kyowa Kirin , personal fees from Roche, outside the submitted work; Prof. Badagliacca reports personal fees from Bayer, personal fees from MSD, personal fees from Dompe, personal fees from GSK, personal fees from Ferrer, personal fees from United Therapeutics, personal fees from Galenica, personal fees from Janssen, outside the submitted work; all others have nothing to disclose. Ethics Approval Statement: The study was performed in the Policlinico Umberto I in Rome (Italy) and approved by the local ethical review board (3083/14), published on public registries (NCT01803828, EUDRACT 2014-000077-39), and conducted under the Declaration of Helsinki and good clinical practice.