Top

Published in:

Open Access 01-12-2018 | Original investigation

Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy

Authors: Concetta Irace, Francesco Casciaro, Faustina Barbara Scavelli, Rosa Oliverio, Antonio Cutruzzolà, Claudio Cortese, Agostino Gnasso

Published in: Cardiovascular Diabetology | Issue 1/2018

Abstract

Background

Cardiovascular protection following empagliflozin therapy is not entirely attributable to the glucose lowering effect. Increased hematocrit might influence the shear stress that is the main force acting on the endothelium, regulating its anti-atherogenic function.

Objective

We designed the study with the aim of investigating the effect of empagliflozin on blood viscosity and shear stress in the carotid arteries. A secondary endpoint was the effect of empagliflozin on carotid artery wall thickness.

Methods

The study was a non-randomized, open, prospective cohort study including 35 type 2 diabetic outpatients who were offered empagliflozin or incretin-based therapy (7 liraglutide, 8 sitagliptin) in combination with insulin and metformin. Blood viscosity, shear stress and carotid wall thickness were measured at baseline and at 1 and 3 months of treatment. Blood viscosity was measured with a viscometer, and shear stress was calculated using a validated formula. Intima-media thickness (IMT) of the carotid artery was detected by ultrasound and was measured with dedicated software.

Results

Blood viscosity (4.87 ± 0.57 vs 5.32 ± 0.66 cP, p < 0.02) and shear stress significantly increased in the Empagliflozin group while no change was detected in the Control group (4.66 ± 0.56 vs 4.98 ± 0.73 cP, p = NS). IMT significantly decreased in the Empagliflozin group after 1 and 3 months (baseline: 831 ± 156, 1-month 793 ± 150, 3-month 766 ± 127 μm; p < 0.0001), while in the liraglutide group, IMT significantly decreased only after 3 months (baseline 879 ± 120; 1-month 861 ± 163; 3-month 802 ± 114 μm; p < 0.001). In the sitagliptin group, IMT remained almost unchanged (baseline 901 ± 135; 1-month 902 ± 129; 3-month 880 ± 140 μm; p = NS).

Conclusions

This study is the first to describe a direct effect of empagliflozin on blood viscosity and wall shear stress. Furthermore, IMT was markedly reduced early on in the Empagliflozin group.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Michaela Mattheus M, Devins T, Johansen OE, Woerle HJ, Broed UC, Inzucchi SE, for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMed

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. CANVAS Program Collaborative Group. N Engl J Med. 2017;377:644–57.CrossRefPubMed

Zou H, Zhou B, Xu G. SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease. Cardiovasc Diabetol. 2017. https://doi.org/10.1186/s12933-017-0547-1.PubMedPubMedCentral

Oguma T, Nakayama K, Kuriyama C, Matsushita Y, Yoshida K, Hikida K, Obokata N, Tsuda-Tsukimoto M, Saito A, Arakawa K, Ueta K, Shiotani M. Intestinal sodium glucose cotransporter 1 inhibition enhances glucagon like peptide 1 secretion in normal and diabetic rodents. J Pharmacol Exp Ther. 2015;354:279–89.CrossRefPubMed

Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero RM, Woerle HJ, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diabates Vasc Dis Res. 2015;12:90–100.CrossRef

Lytvyn Y, Biornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation. 2017;136:1643–58.CrossRefPubMed

Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, Barron B, Mayoux E, Rector RS, Whaley A, DeMarco V. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017. https://doi.org/10.1186/s12933-016-0489-z.

Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Johansen OE. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17:1180–93.CrossRefPubMedPubMedCentral

Pfeifer M, Towensend RR, Davies MJ, Vijapurkar U, Ren J. Effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, on blood pressure and markers of arterial stiffness in patients with type 2 diabetes mellitus: a post hoc analysis. Cardiovasc Diabetol. 2017. https://doi.org/10.1186/s12933-017-0511-0.PubMedPubMedCentral

10.

Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium–glucose cotransporter 2 inhibitor therapy indicates recovery of tubule-interstitial function in diabetic kidneys. J Clin Med Res. 2016;8:844–7.CrossRefPubMedPubMedCentral

11.

Gnasso A, Carallo C, Irace C, Spagnuolo V, De Novara G, Mattioli PL, Pujia A. Association between intima-media thickness and wall shear stress in common carotid arteries in healthy male subjects. Circulation. 1996;94:3257–62.CrossRefPubMed

12.

Cooke JP, Rossitch E, Andon NA, LoScalzo J, Dzau VJ. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest. 1999;88:1663–71.CrossRef

13.

Irace C, Cortese C, Fiaschi E, Carallo C, Farinaro E, Gnasso A. Wall shear stress is associated with intima-media thickness and carotid atherosclerosis in subjects at low coronary heart disease. Stroke. 2004;35:464–8.CrossRefPubMed

14.

Standard Italiani per la cura del Diabete Mellito 2016. vol. 5, p. 91–117. http://www.standarditaliani.it. Accessed 20 June 2016.

15.

Irace C, Carallo C, De Franceschi MS, Scicchitano F, Milano M, Tripolino C, Scavelli F, Gnasso A. Human common carotid wall shear stress as a function of age and gender: a 12-year follow-up study. Age. 2012;34:1553–62.CrossRefPubMed

16.

Imprialos KP, Boutari C, Stavropoulos K, Doumas M, Kara Giannis AI. Stroke paradox with SGLT-2 inhibitors: a play of chance or a viscosity-mediated reality? J Neurol Neurosurg Psichiatry. 2017;88:249–53.CrossRef

17.

Kim Y, Babu AR. Clinical potential of sodium–glucose cotransporter 2 inhibitors in the management of type 2 diabetes. Diabetes Metab Syndr Obes. 2012;5:313–27.PubMedPubMedCentral

18.

Shah NK, Deeb WE, Choksi R, Epstein BJ. Dapagliflozin: a novel sodium–glucose cotransporter type 2 inhibitor for the treatment of type 2 diabetes mellitus. Pharmacotherapy. 2012;32:80–94.CrossRefPubMed

19.

Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium–glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;84:262–75.CrossRef

20.

Stavropoulos K, Imprialos KP, Bouloukou S, Boutari C, Doumas M. Hematocrit and Stroke: a forgotten and neglected link? Semin Thromb Hemost. 2017;43:591–8.CrossRefPubMed

21.

Tamariz LJ, Young JH, Pankow JS, Yeh HC, Schmidt MI, Astor B, Brancati FL. Blood viscosity and hematocrit as risk factors for type 2 diabetes mellitus: the atherosclerosis risk in communities (ARIC) study. Am J Epidemiol. 2008;168:1153–60.CrossRefPubMedPubMedCentral

22.

Irace C, Carallo C, Scavelli F, De Franceschi MS, Esposito T, Gnasso A. Blood viscosity in subjects with normoglycemia and prediabetes. Diabetes Care. 2014;37:488–92.CrossRefPubMed

23.

Gnasso A, Cacia M, Cortese C, Succurro E, Andreozzi F, Carallo C, Irace C. No effect on the short-term of a decrease in blood viscosity on insulin resistance. Clin Hemorheol Microcirc. 2017. https://doi.org/10.3233/CH-170288.PubMed

24.

Salazar Vázquez BY, Martini J, Chávez Negrete A, Tsai AG, Forconi S, Cabrales P, Johnson PC, Intaglietta M. Cardiovascular benefits in moderate increases of blood and plasma viscosity surpass those associated with lowering viscosity: experimental and clinical evidence. Clin Hemorheol Microcirc. 2010;44:75–85.PubMed

25.

List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium–glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–7.CrossRefPubMed

26.

Devineni D, Morrow L, Hompesch M, Skee D, Vandebosch A, Murphy J, Ways K, Schwartz S. Canaglifloz in improves glycemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes Metab. 2012;14:539–45.CrossRefPubMed

27.

Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberq K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How does empagliflozin reduce cardiovascular mortality? Insight from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41:356–63.CrossRefPubMed

28.

Schou M, Gullestad L, Fitchett D, Zinman B, Inzucchi SE, Hehnke U, von Eynatten M, George J, Johansen OE, Wanner C. Empagliflozin exerts short- and long-term effects on plasma volume in patients with type 2 diabetes: insight from EMPA-REG OUTCOME. Circulation. 2017;136:A15997.

29.

Carallo C, Tripolino C, De Franceschi MS, Irace C, Xu XY, Gnasso A. Carotid endothelial shear stress reduction with aging is associated with plaque development in 12 years. Atherosclerosis. 2016;251:63–9.CrossRefPubMed

30.

Gnasso A, Irace C, Carallo C, De Franceschi MS, Motti C, Mattioli PL, Pujia A. In vivo association between low wall shear stress and plaque in subjects with asymmetrical carotid atherosclerosis. Stroke. 1997;28:993–8.CrossRefPubMed

31.

Irace C, Gnasso A, Cirillo F, Leonardo G, Ciamei M, Crivaro A, Renzulli A, Cotrufo M. Arterial remodeling of the common carotid artery after aortic valve replacement in patients with aortic stenosis. Stroke. 2002;33:2446–50.CrossRefPubMed

32.

O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med. 1999;340:14–22.CrossRefPubMed

33.

Braamskamp MJAM, Langslet G, McCrindle BW, Cassiman D, Francis GA, Gagne C, Gaudet D, Morrison KM, Wiegman A, Turner T, Miller E, Kusters DM, Raichlen JS, Martin PD, Stein EA, Kastelein JJP, Hutten BA. Effect of rosuvastatin on carotid intima-media thickness in children with heterozygous familial hypercholesterolemia: the CHARON study, hypercholesterolemia in children and adolescents taking rosuvastatin open label. Circulation. 2017;136:359–66.CrossRefPubMed

34.

Sala-Vila A, Romero-Mamani ES, Gilabert R, Núñez I, de la Torre R, Corella D, Ruiz-Gutiérrez V, López-Sabater MC, Pintó X, Rekondo J, Martínez-González MÁ, Estruch R, Ros E. Changes in ultrasound-assessed carotid intima-media thickness and plaque with a Mediterranean diet: a sub-study of the PREDIMED trial. Arterioscler Thromb Vasc Biol. 2014;34:439–45.CrossRefPubMed

35.

Geng DF, Jin DM, Wu W, Fang C, Wang JF. Effect of alpha-glucosidase inhibitors on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis. 2011;218:214–9.CrossRefPubMed

36.

Lorenz MW, Price JF, Robertson C, Bots ML, Polak JF, Poppert H, Kavousi M, Dörr M, Stensland E, Ducimetiere P, Ronkainen K, Kiechl S, Sitzer M, Rundek T, Lind L, Liu J, Bergström G, Grigore L, Bokemark L, Friera A, Yanez D, Bickel H, Ikram MA, Völzke H, Johnsen SH, Empana JP, Tuomainen TP, Willeit P, Steinmetz H, Desvarieux M, Xie W, Schmidt C, Norata GD, Suarez C, Sander D, Hofman A, Schminke U, Mathiesen E, Plichart M, Kauhanen J, Willeit J, Sacco RL, McLachlan S, Zhao D, Fagerberg B, Catapano AL, Gabriel R, Franco OH, Bülbül A, Scheckenbach F, Pflug A, Gao L, Thompson SG. Carotid intima-media thickness progression and risk of vascular events in people with diabetes: results from the PROG-IMT collaboration. Diabetes Care. 2015;38:1921–9.CrossRefPubMedPubMedCentral

37.

Espeland MA, O’leary DH, Terry JG, Morgan T, Evans G, Mudra H. Carotid intima-media thickness as a surrogate for cardiovascular disease events in trials of HMG-CoA reductase inhibitors. Curr Control Trials Cardiovasc Med. 2005;6:3.CrossRefPubMedPubMedCentral

38.

Byrkjeland R, Stensaeth KH, Anderssen S, Njerve IU, Arnesen H, Seljeflot SS. Effects of exercise training on carotid intima-media thickness in patients with type 2 diabetes and coronary artery disease. Influence of carotid plaques. Cardiovasc Diabetol. 2016. https://doi.org/10.1186/s12933-016-0336-2.PubMedPubMedCentral

39.

Katakami N, Mita T, Yoshii H, Shiraiwa T, Yasuda T, Okada Y, Umayahara Y, Kaneto H, Osonoi T, Yamamoto T, Kuribayashi N, Maeda K, Yokoyama H, Kosugi K, Ohtoshi K, Hayashi I, Sumitani S, Tsugawa M, Ohashi M, Taki H, Nakamura T, Kawashima S, Sato Y, Watada H, Shimomura I, UTOPIA study investigators. Rationale, design, and baseline characteristics of the Utopia Trial for preventing diabetic atherosclerosis using an SGLT2 inhibitor: a prospective, randomized, open-label, parallel-group comparative study. Diabetes Ther. 2017. https://doi.org/10.1007/s13300-017-0292-1.

40.

Tanaka A, Murohara T, Taguchi I, Eguchi K, Suzuki M, Kitakaze M, Sato Y, Ishizu T, Higashi Y, Yamada H, Nanasato M, Shimabukuro M, Teragawa H, Ueda S, Kodera S, Matsuhisa M, Kadokami T, Kario K, Nishio Y, Inoue T, Maemura K, Oyama J, Ohishi M, Sata M, Tomiyama H, Node K. PROTECT Study Investigators Rationale and design of a multicenter randomized controlled study to evaluate the preventive effect of ipragliflozin on carotid atherosclerosis: the PROTECT study. Cardiovasc Diabetol. 2016. https://doi.org/10.1186/s12933-016-0449-7.

41.

Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R, Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E, Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR. TECOS study group. N Engl J Med. 2015;373:232–42.CrossRefPubMed

42.

Mita T, Katakami N, Shiraiwa T, Yoshii H, Onuma T, Kuribayashi N, Osonoi T, Kaneto H, Kosugi K, Umayahara Y, Yamamoto T, Matsumoto K, Yokoyama H, Tsugawa M, Gosho M, Shimomura I, Watada H, on behalf of the Collaborators on the Sitagliptin Preventive Study of Intima-Media Thickness Evaluation (SPIKE) Trial. 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. 2016;39:455–64.CrossRefPubMed

43.

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Bernard Zinman B, Bergenstal RM, Buse JB, for the LEADER Steering Committee on behalf of the LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.CrossRefPubMedPubMedCentral

Title: Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy
Authors: Concetta Irace
Francesco Casciaro
Faustina Barbara Scavelli
Rosa Oliverio
Antonio Cutruzzolà
Claudio Cortese
Agostino Gnasso
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Cardiovascular Diabetology / Issue 1/2018
Electronic ISSN: 1475-2840
DOI: https://doi.org/10.1186/s12933-018-0695-y

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy

Abstract

Background

Objective

Methods

Results

Conclusions

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Objective

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Increased epicardial adipose tissue thickness is a predictor of new-onset diabetes mellitus in patients with coronary artery disease treated with high-intensity statins

Risk of heart failure hospitalization among users of dipeptidyl peptidase-4 inhibitors compared to glucagon-like peptide-1 receptor agonists

Prevalence and incidence of complications at diagnosis of T2DM and during follow-up by BMI and ethnicity: a matched case–control analysis

Effect of statins on fasting glucose in non-diabetic individuals: nationwide population-based health examination in Korea

The high need for trials assessing functional outcome after stroke rather than stroke prevention with GLP-1 agonists and DPP-4 inhibitors

Impact of type 2 diabetes mellitus in the utilization and in-hospital outcomes of surgical aortic valve replacement in Spain (2001–2015)

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page