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

  • Carlo Bruno GiordaEmail author
  • Giovanni Cioffi
  • Donata Lucci
  • Elisa Nada
  • Federica Ognibeni
  • Costantino Mancusi
  • Roberto Latini
  • Aldo P. Maggioni
  • on behalf of DYDA 2 Investigators



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).


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.


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.


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 Identifier: NCT02851745.


Dipeptidyl peptidase-4 inhibition Linagliptin Type 2 diabetes Glycemic control Concentric geometry Left ventricular dysfunction 


Authors’ 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.


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.

Compliance with Ethical Standards

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.


  1. 1.
    Swoboda PP, Plein S. Heart failure in diabetic patients. Eur Heart J. 2018;39:1755–7.CrossRefGoogle Scholar
  2. 2.
    De Simone G, Devereux RB, Chinali M, et al. Diabetes and incident heart failure in hypertensive and normotensive participants of the strong heart study. J Hypertens. 2010;28:353–60.CrossRefGoogle Scholar
  3. 3.
    Cioffi G, Giorda CB, Chinali M, di Lenarda A, Faggiano P, Lucci D, et al. DYDA investigators. Analysis of midwall shortening reveals high prevalence of left ventricular myocardial dysfunction in patients with diabetes mellitus: the DYDA study. Eur J Prev Cardiol. 2012;19:935–43.CrossRefGoogle Scholar
  4. 4.
    Giorda CB, Cioffi G, de Simone G, di Lenarda A, Faggiano P, Latini R, et al. DYDA investigators. Predictors of early-stage left ventricular dysfunction in type 2 diabetes: results of DYDA study. Eur J Cardiovasc Prev Rehabil. 2011;18:415–23.CrossRefGoogle Scholar
  5. 5.
    Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes on cardiac structure and function. The Strong Heart Study Circulation. 2000;101:2271–6.Google Scholar
  6. 6.
    Ernande L, Rietzschel ER, Bergerot C, de Buyzere ML, Schnell F, Groisne L, et al. Impaired myocardial radial function in asymptomatic patients with type 2 diabetes mellitus: a speckle-tracking imaging study. J Am Soc Echocardiogr. 2010;23:1266–72.CrossRefGoogle Scholar
  7. 7.
    Koh YS, Jung HO, Park MW, Baek JY, Yoon SG, Kim PJ, et al. Comparison of left ventricular hypertrophy, fibrosis and dysfunction according to various disease mechanisms such as hypertension, diabetes mellitus and chronic renal failure. J Cardiovasc Ultrasound. 2009;17:127–34.CrossRefGoogle Scholar
  8. 8.
    de Simone G, Devereux RB. Rationale of echocardiographic assessment of left ventricular wall stress and midwall mechanics in hypertensive heart disease. Eur J Echocardiogr. 2002;3:192–8.CrossRefGoogle Scholar
  9. 9.
    Aurigemma GP, Gottdiener JS, Shemanski L, Gardin J, Kitzman D. Predictive value of systolic and diastolic function for incident congestive heart failure in the elderly: the cardiovascular health study. J Am Coll Cardiol. 2001;37:1042–8.CrossRefGoogle Scholar
  10. 10.
    de Simone G, Devereux RB, Koren MJ, Mensah GA, Casale PN, Laragh JH. Midwall left ventricular mechanics. An independent predictor of cardiovascular risk in arterial hypertension. Circulation. 1996;93:259–65.CrossRefGoogle Scholar
  11. 11.
    Borlaug BA, Lam CS, Roger VL, Rodeheffer RJ, Redfield MM. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol. 2009;54:410–8.CrossRefGoogle Scholar
  12. 12.
    Cioffi G, Rossi A, Targher G, Zoppini G, de Simone G, Devereux RB, et al. Usefulness of subclinical left ventricular midwall dysfunction to predict cardiovascular mortality in patients with type 2 diabetes mellitus. Am J Cardiol. 2014;113:1409–14.CrossRefGoogle Scholar
  13. 13.
    Liu JH, Chen Y, Yuen M. Incremental prognostic value of global longitudinal strain in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2016;3:15–22.Google Scholar
  14. 14.
    Shigeta T, Aoyama M, Bando YK, Monji A, Mitsui T, Takatsu M, et al. Dipeptidyl peptidase-4 modulates left ventricular dysfunction in chronic heart failure via angiogenesis-dependent and -independent actions. Circulation. 2012;126:1838–51.CrossRefGoogle Scholar
  15. 15.
    Li JW, Chen YD, Liu YQ, Wang JD, Chen WR, Zhang YQ, et al. Plasma dipeptidyl-peptidase-4 activity is associated with left ventricular systolic function in patients with ST-segment elevation myocardial infarction. Sci Rep. 2017;7:6097.CrossRefGoogle Scholar
  16. 16.
    Scheen AJ. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes. Postgrad Med. 2013;125:7–20.CrossRefGoogle Scholar
  17. 17.
    Green JB, Bethel MA, Armstrong PW, TECOS Study Group, et al. Effect of Sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.CrossRefGoogle Scholar
  18. 18.
    Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. SAVOR-TIMI 53 steering committee and investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.CrossRefGoogle Scholar
  19. 19.
    Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. CARMELINA investigators. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321:69–79.CrossRefGoogle Scholar
  20. 20.
    Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2014;24:689–97.CrossRefGoogle Scholar
  21. 21.
    Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258–67.CrossRefGoogle Scholar
  22. 22.
    Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA, et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65–74.CrossRefGoogle Scholar
  23. 23.
    Aroor AR, Sowers JR, Bender SB, Nistala R, Garro M, Mugerfeld I, et al. Dipeptidylpeptidase inhibition is associated with improvement in blood pressure and diastolic function in insulin-resistant male Zucker obese rats. Endocrinology. 2013;154:2501–13.CrossRefGoogle Scholar
  24. 24.
    Cioffi G, Viapiana O, Ognibeni F, Dalbeni A, Gatti D, Adami S, et al. Prevalence and factors related to left ventricular systolic dysfunction in asymptomatic patients with rheumatoid arthritis. A prospective tissue Doppler echocardiography study. Herz. 2015;40:989–96.CrossRefGoogle Scholar
  25. 25.
    Grant RP. Notes on the muscular architecture of the left ventricle. Circulation. 1965;32:301–8.CrossRefGoogle Scholar
  26. 26.
    de Simone G, Ganau A, Roman MJ, Devereux RB. Relation of left ventricular longitudinal and circumferential shortening to ejection fraction in the presence or in the absence of mild hypertension. J Hypertens. 1997;15:1011–7.CrossRefGoogle Scholar
  27. 27.
    Shimizu G, Hirota Y, Kita Y, Kawamura K, Saito T, Gaasch WH. Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy. Circulation. 1991;83:1676–84.CrossRefGoogle Scholar
  28. 28.
    de Simone G, Devereux RB, Roman MJ, Ganau A, Saba PS, Alderman MH, et al. Assessment of left ventricular function by the midwall fractional shortening/end-systolic stress relation in human hypertension. J Am Coll Cardiol. 1994;23:1444–51.CrossRefGoogle Scholar
  29. 29.
    Rossi MC, Candido R, Ceriello A, Cimino A, di Bartolo P, Giorda C, et al. Trends over 8 years in quality of diabetes care: results of the AMD annals continuous quality improvement initiative. Acta Diabetol. 2015;52:557–71.CrossRefGoogle Scholar
  30. 30.
    Davies MJ, D'Alessio DA, Fradkin J, et al. Management of Hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of diabetes (EASD). Diabetes Care. 2018;41:2669–701.CrossRefGoogle Scholar
  31. 31.
    McMurray JJV, Ponikowski P, Bolli GB, et al. VIVIDD trial committees and investigators. Effects of Vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail. 2018;6:8–17.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Carlo Bruno Giorda
    • 1
    Email author
  • Giovanni Cioffi
    • 2
  • Donata Lucci
    • 3
  • Elisa Nada
    • 1
  • Federica Ognibeni
    • 2
  • Costantino Mancusi
    • 4
  • Roberto Latini
    • 5
  • Aldo P. Maggioni
    • 3
  • on behalf of DYDA 2 Investigators
  1. 1.Metabolism and Diabetes UnitASL TORINO 5, Regione PiemonteChieriItaly
  2. 2.Division of Rheumatology, Department of MedicineUniversity and Azienda Ospedaliera Universitaria Integrata of VeronaVeronaItaly
  3. 3.ANMCO Research CenterHeart Care FoundationFlorenceItaly
  4. 4.Hypertension Research CenterFederico II UniversityNaplesItaly
  5. 5.Department of Cardiovascular ResearchIstituto di Ricerche Farmacologiche “Mario Negri” IRCCSMilanItaly

Personalised recommendations