Diabetes
Riccardo Pofi 1 , Elisa Giannetta 2 , Tiziana Feola 2 , Nicola Galea 2 , Federica Campolo 2 , Federica Barbagallo 2 , Roberto Badagliacca 3 , Biagio Barbano 4 , Federica Ciolina 5 , Giuseppe Defeudis 6 , Tiziana Filardi 2 , Franz Sesti 2 , Marianna Minnetti 2 , Carmine Dario Vizza 3 , Patrizio Pasqualetti 7 , Iacopo Carbone 5 , Marco Francone 5 , Carlo Catalano 5 , Paolo Pozzilli 6 , Andrea Lenzi 3 , Mary Anna Venneri 3 , Daniele Gianfrilli 3 & Andrea M. Isidori 3
1Department of Experimental Medicine, Sapienza University of Rome; [email protected]; 2Department of Experimental Medicine, “Sapienza” University of Rome; 3Department of Cardiovascular and Respiratory Diseases; 4Department of Translational and Precision Medicine, Sapienza University of Rome; 5Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome; 6Unit of Endocrinology and Diabetes, Department of Medicine, University Campus Bio-Medico di Roma; 7Medical Statistics and Information Technology, AFaR, Fatebenefratelli Hospital
Background: Cyclic GMP-phosphodiesterase type 5(PDE5) inhibition was shown to counteract maladaptive cardiac changes triggered by diabetes in some, but not all studies.
Objective: To assess sex differences in cardiac remodeling after PDE5 inhibition in patients with diabetic cardiomyopathy.
Methods: 20-week, double-blind, randomized, placebo-controlled trial (NCT01803828). 220 men and women (45-80 years) with long-duration (>3 years) and well-controlled T2DM (HbA1c<86 mmol/mol) were screened. 122 were selected according to echocardiographic signs of cardiac remodeling: interventricular septum ≥11 mm in men, ≥10 mm in women, or diastolic dysfunction (E/A<1 or E/e’>10 at PW and tissue Doppler). Patients were randomly assigned(1:1) to placebo(n=61) or oral tadalafil (n=61) 20 mg once daily. Primary outcome: sex-difference in cardiac torsion change, from baseline to 20 weeks. Secondary outcomes: changes in cardiovascular, metabolic, immune and renal function.
Results: At 20 weeks, the treatment-by-sex interaction documented an improvement in cardiac torsion(-3.40°,-5.96;-0.84,=0.011) and fiber shortening(-1.19%,-2.24;-0.14, P=0.027), in men but not women. Hsa-miR-199-5p, biomarker of cardiovascular remodeling, improved accordingly(-3.53copies/μLx105,-6.39;-0.67, P=0.02). In men and women, tadalafil improved albuminuria(-237.58 mg/24h,-466.12;-9.04, P=0.04), renal artery’s resistive index(-3.96%,-7.60;-0.32, P=0.03) and circulating Klotho(39.22 pg/ml,18.31;60.13, P<.001), biomarker linked to cardio-renal health. Immune cell profiling revealed low-grade chronic inflammation improvement: classic CD14++CD16- monocytes(–159 cells/μl,–245;–72, P<0.001), Tie2-expressing monocytes(19 cells/μL, 12;25, P<0.001).
Conclusions: Continuous PDE5 inhibition could represent a new treatment strategy to target cardiac and renal complications of T2DM, with a different sex- and tissue-specific response. Klotho and hsa-miR-199-5p appear as novel players for cardio-renal T2DM complications.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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