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Effects of Dipeptidyl Peptidase-4 Inhibitor Linagliptin on Left Ventricular Dysfunction in Patients with Type 2 Diabetes and Concentric Left Ventricular Geometry (the DYDA 2™ Trial). Rationale, Design, and Baseline Characteristics of the Study Population

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Abstract

Purpose

A multicentre, randomized, double-blind, placebo-controlled, parallel-group study aimed to define the potential positive effect of dipeptidyl peptidase-4 inhibition on left ventricular systolic function (LVSF) beyond glycemic control in type 2 diabetes mellitus (T2DM) (DYDA 2™ trial).

Methods

Individuals with fairly controlled T2DM and asymptomatic impaired LVSF were randomized in a 1:1 ratio to receive for 48 weeks either linagliptin 5 mg daily or placebo, in addition to their stable diabetes therapy. Eligibility criteria were age ≥ 40 years, history of T2DM with a duration of at least 6 months, HbA1c ≤ 8.0% (≤ 64 mmol/mol), no history or clinical signs/symptoms of cardiac disease, evidence at baseline echocardiography of concentric LV geometry (relative wall thickness ≥ 0.42), and impaired LVSF defined as midwall fractional shortening (MFS) ≤ 15%. The primary end-point was the modification from baseline to 48 weeks of MFS. As an exploratory analysis, significant changes in LV global longitudinal strain and global circumferential strain, measured by speckle tracking echocardiography, were also considered. Secondary objectives were changes in diastolic and/or in systolic longitudinal function as measured by tissue Doppler.

Results

A total of 188 patients were enrolled. They were predominantly males, mildly obese, with typical insulin-resistance co-morbidities such as hypertension and dyslipidemia. Mean relative wall thickness was 0.51 ± 0.09 and mean MFS 13.3% ± 2.5.

Conclusions

DYDA 2 is the first randomized, double-blind, placebo-controlled trial to explore the effect of a dipeptidyl peptidase-4 inhibitor on LVSF in T2DM patients in primary prevention regardless of glycemic control. The main characteristics of the enrolled population are reported.

Trial registration

ClinicalTrial.gov Identifier: NCT02851745.

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Funding

The sponsors of the study are the Fondazione Associazione Medici Diabetologi and Heart Care Foundation, two non-profit independent organizations, which also own the database. Database management, quality control of the data, and data analyses were under the responsibility of the ANMCO Research Centre of the Heart Care Foundation. The study was partially supported by an unrestricted grant by Boehringer Ingelheim, Italy. The Steering Committee of the study had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of data analysis.

Author information

Authors and Affiliations

  1. Metabolism and Diabetes Unit, ASL TORINO 5, Regione Piemonte, Chieri, Italy

    Carlo Bruno Giorda & Elisa Nada

  2. Division of Rheumatology, Department of Medicine, University and Azienda Ospedaliera Universitaria Integrata of Verona, Verona, Italy

    Giovanni Cioffi & Federica Ognibeni

  3. ANMCO Research Center, Heart Care Foundation, Florence, Italy

    Donata Lucci & Aldo P. Maggioni

  4. Hypertension Research Center, Federico II University, Naples, Italy

    Costantino Mancusi

  5. Department of Cardiovascular Research, Istituto di Ricerche Farmacologiche “Mario Negri” IRCCS, Milan, Italy

    Roberto Latini

Authors
  1. Carlo Bruno Giorda
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  2. Giovanni Cioffi
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  3. Donata Lucci
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  4. Elisa Nada
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  5. Federica Ognibeni
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  6. Costantino Mancusi
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  7. Roberto Latini
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  8. Aldo P. Maggioni
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Consortia

on behalf of DYDA 2 Investigators

  • Carlo Bruno Giorda
  • , Giovanni Cioffi
  • , Antonio Amico
  • , Antonino Cimino
  • , Stefano Genovese
  • , Sandro Gentile
  • , Michele Massimo Gulizia
  • , Guerrino Zuin
  • , Donata Lucci
  • , Francesca Bianchini
  • , Elisa Bianchini
  • , Martina Ceseri
  • , Lucio Gonzini
  • , Marco Gorini
  • , Andrea Lorimer
  • , Michele Miccoli
  • , Stefano Musio
  • , Giampietro Orsini
  • , Federica Ramani
  • , Aldo Pietro Maggioni
  • , Serge Masson
  • , Deborah Novelli
  • , Roberto Latini
  • , Irina Suliman
  • , Aldo Pietro Maggioni
  • , Andrea D’Amato
  • , Grazia Canciello
  • , Costantino Mancusi
  • , Giovanni de Simone
  • , G. Cioffi
  • , E. Buczkowska
  • , M. Studnicka
  • , C. B. Giorda
  • , T. Marchese
  • , L. M. T. Brero
  • , A Robusto
  • , R. Candido
  • , C. Mazzone
  • , M. Casson
  • , S. De Cosmo
  • , A. Rauseo
  • , A. Russo
  • , S. Mastroianno
  • , G. Magro
  • , L. Morena
  • , G. Falco
  • , S. Gentile
  • , G. Guarino
  • , D. Cozzolino
  • , A. Aglialoro
  • , O. Magaia
  • , C. Tenca
  • , S. Squatrito
  • , A. Tumminia
  • , D. S. Mangiameli
  • , E. L. Greco
  • , G. Fatati
  • , D. Bovelli
  • , P. Limone
  • , A. Pizzuti
  • , D. Cucinotta
  • , C. Zito
  • , M. Comaschi
  • , F. Drago
  • , S. Genovese
  •  & L. Trupiano

Contributions

CBG, GC, APM literature search, study design, data collection and interpretation, writing; DL data collection, analysis and interpretation; EN, FO literature search, data collection; CM, RL data management, reading and interpretation. No other persons have made substantial contributions to this manuscript. All authors approved the final version.

Corresponding author

Correspondence to Carlo Bruno Giorda.

Ethics declarations

Conflict of Interest

CBG has nothing to disclose with respect to the present manuscript. In 2018, he received fees from Boehringer Ingelheim, Italy, for data interpretation of other trials. GC, EN, RL, and CM have nothing to disclose. DL is employee of Heart Care Foundation, which conducted the study with an unresctricted grant by Boehringer Ingelheim, Italy. APM nothing to disclose with respect to the present manuscript. Personal fees for participation in study committees sponsored by Bayer, Fresenius, and Novartis.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

This article does not contain any study with animals performed by any of the authors.

Additional information

Publisher’s Note

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Appendix

Appendix

Steering Committee

Carlo Bruno Giorda (Chairman), Giovanni Cioffi (Co-Chairman), Antonio Amico, Antonino Cimino, Stefano Genovese, Sandro Gentile, Michele Massimo Gulizia, Guerrino Zuin.

Coordinating Center

Donata Lucci, Francesca Bianchini, Elisa Bianchini, Martina Ceseri, Lucio Gonzini, Marco Gorini, Andrea Lorimer, Michele Miccoli, Stefano Musio, Giampietro Orsini, Federica Ramani, Aldo Pietro Maggioni.

Biomakers Core Laboratory

Serge Masson, Deborah Novelli, Roberto Latini (Istituto Mario Negri, Milano).

ECG Core Laboratory

Irina Suliman, Aldo Pietro Maggioni (Centro Studi ANMCO, Firenze).

ECO Core Laboratory

Andrea D’Amato, Grazia Canciello, Costantino Mancusi, Giovanni de Simone (Laboratorio di Ecocardiografia CIRIAPA, Università Federico II, Napoli).

Participating Centers and Investigators

Trento, Casa di Cura Villa Bianca (G. Cioffi, E. Buczkowska, M. Studnicka); Chieri, Ospedale Maggiore (C.B. Giorda, T. Marchese, L.M.T. Brero, A Robusto); Trieste, ASUI Trieste (R. Candido, C. Mazzone, M. Casson); San Giovanni Rotondo, Ospedale Casa Sollievo della Sofferenza (S. De Cosmo, A. Rauseo, A. Russo, S. Mastroianno); Cuneo, AO Santa Croce e Carle (G. Magro, L. Morena, G. Falco); Napoli, Seconda Università (S. Gentile, G. Guarino, D. Cozzolino); Genova, Ospedale Villa Scassi (A. Aglialoro, O. Magaia, C. Tenca); Catania, Ospedale Garibaldi-Nesima (S. Squatrito, A. Tumminia, D.S. Mangiameli); Copertino, Ospedale San Giuseppe da Copertino (E.L. Greco); Terni, AO Santa Maria (G. Fatati, D. Bovelli); Torino, Ospedale Mauriziano Umberto I (P. Limone, A. Pizzuti); Messina, Policlinico G. Martino (D. Cucinotta, C. Zito); Rapallo, ICLAS (M. Comaschi, F. Drago); Sesto San Giovanni, IRCCS Policlinico Multimedica (S. Genovese, L. Trupiano).

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Giorda, C.B., Cioffi, G., Lucci, D. et al. Effects of Dipeptidyl Peptidase-4 Inhibitor Linagliptin on Left Ventricular Dysfunction in Patients with Type 2 Diabetes and Concentric Left Ventricular Geometry (the DYDA 2™ Trial). Rationale, Design, and Baseline Characteristics of the Study Population. Cardiovasc Drugs Ther 33, 547–555 (2019). https://doi.org/10.1007/s10557-019-06898-6

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  • DOI: https://doi.org/10.1007/s10557-019-06898-6

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