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Effect of vildagliptin versus glibenclamide on endothelial function and arterial stiffness in patients with type 2 diabetes and hypertension: a randomized controlled trial

  • Luciana Neves Cosenso-Martin
  • Luiz Tadeu Giollo-Júnior
  • Letícia Aparecida Barufi Fernandes
  • Cláudia Bernardi Cesarino
  • Marcelo Arruda Nakazone
  • Maurício de Nassau Machado
  • Juan Carlos Yugar-Toledo
  • José Fernando Vilela-Martin
Original Article

Abstract

Aims

Several trials have reported that dipeptidyl peptidase-4 (DPP-4) inhibitors, used to treat type 2 diabetes (T2DM), improve endothelial function. The current study investigated the effects of vildagliptin, a DPP-4 inhibitor, compared to glibenclamide on endothelial function, arterial stiffness, and blood pressure in patients with T2DM and hypertension.

Methods

Patients aged over 35 years with T2DM and hypertension, but without cardiovascular disease, were randomly allocated to treatment with vildagliptin (n = 25) or glibenclamide (n = 25). Both groups took metformin. Endothelial function was evaluated by peripheral artery tonometry (Endo-PAT 2000) to calculate the reactive hyperemia index (RHI) and arterial stiffness. Primary outcome was change in the RHI after 12 weeks of treatment. Twenty-four-hour non-invasive ambulatory blood pressure monitoring was performed using a Mobil-O-Graph® 24-h PWA monitor. Arterial stiffness was assessed using the augmentation index corrected for 75 bpm (AIx75), pulse wave velocity (PWV) and central systolic blood pressure (cSBP).

Results

There were no changes in the RHI in the vildagliptin group (before 2.35 ± 0.59; after 2.24 ± 0.60; p value = NS) or in the glibenclamide group (before 2.36 ± 0.52; after 2.34 ± 0.50; p value = NS), with no differences between groups (p value = NS). There was also no difference between vildagliptin and glibenclamide treatment in respect to AIx75 (p value = NS), cSBP (p value = NS) or PWV (p value = NS).

Conclusions

Vildagliptin and glibenclamide similarly do not change the endothelial function and arterial stiffness after 12 weeks of treatment in diabetic and hypertensive patients without cardiovascular disease. Thus, vildagliptin has a neutral effect on vascular function.

Trial registration

ClinicalTrials.gov: NCT02145611, registered on 11 Jun 2013.

Keywords

Arterial stiffness Diabetes Hypertension Endothelial function DPP-4 inhibitor 

Abbreviations

ABPM

Ambulatory blood pressure monitoring

AIx

Augmentation index

BMI

Body mass index

BP

Blood pressure

CAD

Coronary artery disease

cSBP

Central systolic blood pressure

CVD

Cardiovascular disease

DBP

Diastolic BP

DPP-4

Dipeptidyl peptidase-4

eGFR

Estimated glomerular filtration ratio

Endo-PAT 2000

Peripheral artery tonometry

FMD

Flow-mediated vasodilatation

GLP-1

Glucagon-like peptide-1

HbA1c

Glycated hemoglobin

HDLc

High-density lipoprotein cholesterol

LDLc

Low-density lipoprotein cholesterol

MBP

Mean BP

PP

Pulse pressure

PWV

Pulse wave velocity

RHI

Reactive hyperemia index

SBP

Systolic BP

SD

Standard deviation

T2DM

Type 2 diabetes

TC

Total cholesterol

TG

Triglycerides

Notes

Acknowledgements

The authors would like to thank the patients and staff who are participating in this clinical trial. We thank the reviewer David Hewitt for correcting both the English spelling and grammar and Lilian Castiglioni for the statistical analysis.

Author contributions

LNC-M and JFV-M contributed to the concept and design of this ongoing study. MAN and MNM take responsibility for the integrity of the data and accuracy of data analysis. LNC-M, LTG, LABF, CBC, JCY-T and JFV-M helped with the literature search. All authors read and approved the final manuscript. LNC-M and JFV-M wrote the manuscript.

Funding

This study was sponsored by Novartis. However, Novartis did not have any influence on the study design, methods, data management or analysis.

Compliance with ethical standards

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.

Ethics approval and consent to participate

The study protocol (no. 11665513.7.00005415) was approved by the Research Ethics Committee of State Medical School at Sao Jose do Rio Preto (FAMERP) and the study was conducted in accordance with the principles of the Helsinki Declaration.

Consent for publications

Not applicable.

Conflict of interest

Jose F Vilela-Martin has received research grants from Novartis. The other authors do not have a conflict of interest.

References

  1. 1.
    Benjamin EJ, Virani SS, Callaway CW, Chang AR, Cheng S, Chiuve SE et al (2018) Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation.  https://doi.org/10.1161/CIR.0000000000000558 (epub ahead of print)Google Scholar
  2. 2.
    Engelen SE, van der Graaf Y, Stam-Slob MC, Grobbee DE, Cramer MJ, Kappelle LJ et al (2017) Incidence of cardiovascular events and vascular interventions in patients with type 2 diabetes. Int J Cardiol 248:301–307CrossRefPubMedGoogle Scholar
  3. 3.
    Beckman JA, Creager MA, Libby P (2002) Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287:1420–1426CrossRefGoogle Scholar
  4. 4.
    Penny WF, Ben-Yehuda O, Kuroe K, Long J, Bond A, Bhargava V et al (2001) Improvement of coronary artery endothelial dysfunction with lipid-lowering therapy: heterogeneity of segmental response and correlation with plasma-oxidized low density lipoprotein. J Am Coll Cardiol 37:766–774CrossRefPubMedGoogle Scholar
  5. 5.
    Drucker DJ, Nauck MA (2006) The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705CrossRefPubMedGoogle Scholar
  6. 6.
    Ceriello A, Esposito K, Testa R, Bonfigli AR, Marra M, Giugliano D et al (2011) The possible protective role of glucagon-like peptide 1 on endothelium during the meal and evidence for an “endothelial resistance” to the glucagon-like peptide 1 in diabetes. Diabetes Care 34:697–702CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Druker DJ, Husain M (2008) Cardioprotective and vasodilatatory actions of glucagons-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117:2340–2350CrossRefPubMedGoogle Scholar
  8. 8.
    Gurkan E, Tarkun I, Sahin T, Cetinarslan B, Canturk Z (2014) Evaluation of exenatide versus insulin glargine for the impact on the endothelial functions and cardiovascular risk markers. Diabetes Res Clin Pract 106:567–575CrossRefPubMedGoogle Scholar
  9. 9.
    Van Poppel PC, Netea MG, Smits P, Tack CJ (2011) Vildagliptin improves endothelium-dependent vasodilatation in type 2 diabetes. Diabetes Care 34:2072–2077CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Faber R, Zander M, Pena A, Michelsen MM, Mygind ND, Prescott E (2015) Effect of glucagon-like peptide-1 analogue liraglutide on coronary microvascular function in patients with type 2 diabetes—a randomized, single-blinded, cross-over pilot study. Cardiovasc Diabetol 14:41CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Ayaori M, Iwakami N, Uto-Kondo H, Sato H, Sasaki M, Komatsu T et al (2013) Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc 2:e003277CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Cosenso-Martin LN, Giollo-Junior LT, Vilela-Martin JF (2015) DPP-4 inhibitor reduces central blood pressure in a diabetic and hypertensive patient. Medicine (Baltimore) 94:e1068CrossRefGoogle Scholar
  13. 13.
    Scirica BM, Bhatt DL, Braunwald E, Steg G, Davidson J, Hirshberg B et al, for the SAVOR-TIMI 53 Steering Committee and Investigators (2013) Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 369:1317–1326CrossRefPubMedGoogle Scholar
  14. 14.
    White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL et al, for the EXAMINE Investigators (2013) Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 369:1327–1335CrossRefPubMedGoogle Scholar
  15. 15.
    Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J et al, TECOS Study Group (2015) Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 373(3):232–242CrossRefPubMedGoogle Scholar
  16. 16.
    Balduino Mendes AB, Giollo LT Jr, de Andrade DO, Gregório ML, Yugar-Toledo JC, Vilela-Martin JF (2016) How to investigate the vascular changes in resistant hypertension. Curr Hypertens Rev 12:139–147CrossRefPubMedGoogle Scholar
  17. 17.
    Bonetti PO, Pumper GM, Higano ST, Holmes DR, Kuvin JT, Lerman A (2004) Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 44:2137–2141CrossRefPubMedGoogle Scholar
  18. 18.
    Tedesco MA, Natale F, Di Salvo G, Caputo S, Capasso M, Calabró R (2004) Effects of coexisting hypertension and type II diabetes mellitus on arterial stiffness. J Hum Hypertens 18:469–473CrossRefPubMedGoogle Scholar
  19. 19.
    Willum-Hansen T, Staessen JA, Torp-Pedersen C, Rasmussen S, Thijs L, Ibsen H et al (2006) Prognostic value of aortic pulse wave velocity as index of arterial stiffness in the general population. Circulation 113:664–670CrossRefPubMedGoogle Scholar
  20. 20.
    Vlachopoulos C, Aznaouridis K, Stefanadis C (2010) Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 55:1318–1327CrossRefPubMedGoogle Scholar
  21. 21.
    Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A, Collier D et al (2006) Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 113:1213–1225CrossRefPubMedGoogle Scholar
  22. 22.
    Cosenso-Martin LN, Giollo-Junior LT, Martinelli DD, Cesarino CB, Nakazone MA, Cipullo JP et al (2015) Twelve-week randomized study to compare the effect if vildagliptin vs. glibenclamide both added-on to metformin on endothelium function in patients with type 2 diabetes and hypertension. Diabetol Metab Syndr 7:70CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD et al (2008) Resistant hypertension: diagnosis, evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 51(6):1403–1419CrossRefPubMedGoogle Scholar
  24. 24.
    Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ (2000) The influence of heart rate on augmentation index and central arterial pressure in human. J Physiol 525:263–270CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of diet in renal disease study group. Ann Intern Med 130:461–470CrossRefPubMedGoogle Scholar
  26. 26.
    Evans M, Schweizer A, Foley JE (2016) Blood pressure and fasting lipid changes after 24 weeks’ treatment with vildagliptin: a pooled analysis in> 2,000 previously drug-naïve patients with type 2 diabetes mellitus. Vasc Health Risk Man 12:337–340CrossRefGoogle Scholar
  27. 27.
    Kubota Y, Miyamoto M, Takagi G, Ikeda T, Kirinoki-Ichikawa S, Tanaka K et al (2012) The dipeptidyl peptidase-4 inhibitor sitagliptin improves vascular endothelial function in type 2 diabetes. J Korean Med Sci 27:1364–1370CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Maruhashi T, Higashi Y, Kihara Y, Yamada H, Sata M, Ueda S et al (2016) Long-term effect of sitagliptin on endothelial function in type 2 diabetes: a sub-analysis of the PROLOGUE study. Cardiovasc Diabetol 15:134CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Nomoto H, Miyoshi H, Furumoto T, Oba K, Tsutsui H, Inoue A et al (2016) A randomized controlled trial comparing the effects of sitagliptin and glimepiride on endothelial function and metabolic parameters: Sapporo Athero-Incretin Study 1 (SAIS1). PLoS One 11(10):e0164255CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Baltzis D, Dushay JR, Loader J, Wu J, Greenman RL, Roustit M et al (2016) Effect of linagliptin on vascular function: a randomized, placebo-controlled study. J Clin Endocrinol Metab 101:4205–4213CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kitao N, Miyoshi H, Furumoto T, Ono K, Nomoto H, Miya A et al (2017) The effects of vildagliptin compared with metformin on vascular endothelial function and metabolic parameters: a randomized, controlled trial (Sapporo Athero-Incretin Study 3). Cardiovasc Diabetol 16(1):125CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Nohria A, Gerhard-Herman M, Creager MA, Hurley S, Mitra D, Ganz P (2006) Role of nitric oxide in the regulation of digital pulse volume amplitude in humans. J Appl Physiol 101:545–548CrossRefPubMedGoogle Scholar
  33. 33.
    Allan RB, Delaney CL, Miller MD, Spark JI (2013) A comparison of flow-mediated dilatation and PAT for measurement of endothelial function in healthy individuals and patient with peripheral artery disease. Eur J Vasc Endovasc Surg 45:263–269CrossRefPubMedGoogle Scholar
  34. 34.
    Manrique C, Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR et al (2016) Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice. Cardiovasc Diabetol 15:94CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Duvnjak L, Blaslov K (2016) Dipeptidyl peptidase-4 inhibitors improve arterial stiffness, blood pressure, lipid profile and inflammation parameters in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 8:26CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Koren S, Shemesh-Bar L, Tirosh A, Peleg RK, Berman S, Hamad RA et al (2012) The effect of sitagliptin versus glibenclamide on arterial stiffness, blood pressure, lipids, and inflammation in type 2 diabetes mellitus patients. Diabetes Technol Ther 14:561–567CrossRefPubMedGoogle Scholar
  37. 37.
    Zografou I, Sampanis C, Gkaliagkousi E, Iliadis F, Papageorgiou A, Doukelis P et al (2015) Effect of vildagliptin on hsCRP and arterial stiffness in patients with type 2 diabetes mellitus. Hormones (Athens) 14:118–125Google Scholar
  38. 38.
    Gordin D, Saraheimo M, Tuomikangas J, Soro-Paavonen A, Forsblom C, Paavonen K et al (2016) Influence of postprandial hiperglycemic conditions on arterial stiffness in patients with type 2 diabetes. J Clin Endocrinol Metab 101(3):1134–1143CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Upala S, Wirunsawanya K, Jaruvongvanich V, Sanguankeo A (2017) Effects of statin therapy on arterial stiffness: a systematic review and meta-analysis of randomized controlled trial. Int J Cardiol 227:338–341CrossRefPubMedGoogle Scholar
  40. 40.
    Striepe K, Jumar A, Ott C, Karg MV, Scheneider MP, Kannenkeril D et al (2017) Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus. Circulation 16:1167–1169CrossRefGoogle Scholar
  41. 41.
    Mamey A, Kunchakarra S, Byme L, Brown NJ (2010) Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension 56:728–733CrossRefGoogle Scholar
  42. 42.
    Ritchie LD, Campbell NC, Murchie P (2011) New NICE guidelines for hypertension. BMJ 343:d5644CrossRefPubMedGoogle Scholar
  43. 43.
    Kawase H, Bando YK, Nishimura K, Aoyama M, Monji A, Murohara T (2016) A dipeptidyl peptidase-4 inhibitor ameliorates hypertensive cardiac remodeling via angiotensin-II/sodium-proton pump exchanger-1 axis. J Mol Cell Cardiol 98:37–47CrossRefPubMedGoogle Scholar
  44. 44.
    Jackson EK, Mi Z, Tofovic SP, Gilleapie DG (2015) Effect of dipeptidyl peptidase 4 inhibition on arterial blood pressure is context dependent. Hypertension 65:238–249CrossRefPubMedGoogle Scholar
  45. 45.
    Barbieri M, Rizzo MR, Marfella R, Boccardi V, Esposito A, Pansini A et al (2013) Decreased carotid atherosclerotic process by control of daily acute glucose fluctuations in diabetic patients treated by DPP-IV inhibitors. Atherosclerosis 227(2):349–354CrossRefPubMedGoogle Scholar
  46. 46.
    Ishikawa S, Shimano M, Watarai M, Koyasu M, Uchikawa T, Ishii H et al (2014) Impact of sitagliptin on carotid intima-media thickness in patients with coronary artery disease and impaired glucose tolerance or mild diabetes mellitus. Am J Cardiol 114:384–388CrossRefPubMedGoogle Scholar
  47. 47.
    Mita T, Katakami N, Yoshii H, Onuma T, Kaneto H, Osonoi T et al (2016) Alogliptin, a dipeptidyl peptidase 4 inhibitor, prevents the progression of carotid atherosclerosis in patients with type 2 diabetes: the study of preventive effects of alogliptin on diabetic atherosclerosis (SPEAD-A). Diabetes Care 39:139–148CrossRefPubMedGoogle Scholar
  48. 48.
    Mita T, Katakami N, Shiraiwa T, Yoshii H, Onuma T, Kuribayashi N et al (2016) Sitagliptin attenuates the progression of carotid intima-media thickening in insulin treated patients with type 2 diabetes: the sitagliptin preventive study of intima-media thickness evaluation (SPIKE). A randomized controlled trial. Diabetes Care 39:455–464CrossRefPubMedGoogle Scholar
  49. 49.
    Alam MA, Chowdhury MRH, Jain P, Sagor MAT, Reza HM (2015) DPP-4 inhibitor sitagliptin prevents inflammation and oxidative stress of heart and kidney in two kidney and one clip (2K1C) rats. Diabetol Metab Syndr 7:107CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sauder KA, West SG, McCrea CE, Campbell JM, Jenkins AL, Jenkins DJ et al (2014) Test–retest reliability of peripheral artery tonometry in the metabolic syndrome. Diabetes Vasc Dis Res 11:201–207CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia S.r.l., part of Springer Nature 2018

Authors and Affiliations

  • Luciana Neves Cosenso-Martin
    • 1
  • Luiz Tadeu Giollo-Júnior
    • 2
  • Letícia Aparecida Barufi Fernandes
    • 2
  • Cláudia Bernardi Cesarino
    • 3
  • Marcelo Arruda Nakazone
    • 4
  • Maurício de Nassau Machado
    • 4
  • Juan Carlos Yugar-Toledo
    • 2
  • José Fernando Vilela-Martin
    • 5
  1. 1.Internal Medicine Division, Hospital de BaseState Medical School at São José do Rio Preto (FAMERP)São José do Rio PretoBrazil
  2. 2.Hypertension ClinicState Medical School at São José do Rio Preto (FAMERP)São José do Rio PretoBrazil
  3. 3.Hypertension ClinicState Nursing School at São José do Rio Preto (FAMERP)São José do Rio PretoBrazil
  4. 4.Cardiology Department, Hospital de BaseState Medical School at São José do Rio Preto (FAMERP)São José do Rio PretoBrazil
  5. 5.Hypertension Clinic, Internal Medicine Department, Hospital de BaseState Medical School at São José do Rio Preto (FAMERP)São José do Rio PretoBrazil

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