Top

22-05-2018 | Cardiovascular disorders | Article

Effect of canagliflozin on left ventricular diastolic function in patients with type 2 diabetes

Journal: Cardiovascular Diabetology

Authors: Daisuke Matsutani, Masaya Sakamoto, Yosuke Kayama, Norihiko Takeda, Ryuzo Horiuchi, Kazunori Utsunomiya

Publisher: BioMed Central

Abstract

Background

Type 2 diabetes mellitus (T2DM) greatly increases the risks of cardiovascular disease and heart failure. In particular, left ventricular diastolic dysfunction that develops from the early stages of T2DM is an important factor in the onset and exacerbation of heart failure. The effect of sodium-glucose cotransporter 2 inhibitors on left ventricular diastolic function has not been elucidated. We have performed the first prospective study on the effects of canagliflozin on left ventricular diastolic function in T2DM.

Methods

This study was performed to evaluate the effects of additional treatment with canagliflozin for 3 months on left ventricular diastolic function in patients with T2DM. A total of 38 patients with T2DM were consecutively recruited for this study. Left ventricular diastolic function was assessed by echocardiography. The primary study outcome was a change in the septal E/e′ as a parameter of left ventricular diastolic function.

Results

A total of 37 patients (25 males and 12 females) were included in the analysis. Mean age of participants was 64.2 ± 8.1 years (mean ± SD), mean duration of diabetes was 13.5 ± 8.1 years, and mean HbA1c was 7.9 ± 0.7%. Of the participants, 86.5% had hypertension, 100% had dyslipidemia, and 32.4% had cardiovascular disease. Canagliflozin significantly improved left ventricular diastolic function (septal E/e′ ratio 13.7 ± 3.5–12.1 ± 2.8, p = 0.001). Furthermore, among the various parameters that changed through the administration of canagliflozin, only changes in hemoglobin significantly correlated with changes in the septal E/e′ ratio (p = 0.002). In multiple regression analysis, changes in hemoglobin were also revealed to be an independent predictive factor for changes in the septal E/e′ ratio.

Conclusions

This study showed for the first time that canagliflozin could improve left ventricular diastolic function within 3 months in patients with T2DM. The benefit was especially apparent in patients with substantially improved hemoglobin values.

Trial registration UMIN Clinical Trials Registry UMIN000028141

Chen G, McAlister FA, Walker RL, Hemmelgarn BR, Campbell NR. Cardiovascular outcomes in Framingham participants with diabetes: the importance of blood pressure. Hypertension. 2011;57(5):891–7.CrossRefPubMedPubMedCentral

Vazquez-Benitez G, Desai JR, Xu S, Goodrich GK, Schroeder EB, Nichols GA, Segal J, Butler MG, Karter AJ, Steiner JF, et al. Preventable major cardiovascular events associated with uncontrolled glucose, blood pressure, and lipids and active smoking in adults with diabetes with and without cardiovascular disease: a contemporary analysis. Diabetes Care. 2015;38(5):905–12.CrossRefPubMedPubMedCentral

Kannel WB, McGee DL. Diabetes and cardiovascular disease. The Framingham study. Jama. 1979;241(19):2035–8.PubMed

Klapholz M, Maurer M, Lowe AM, Messineo F, Meisner JS, Mitchell J, Kalman J, Phillips RA, Steingart R, Brown EJ Jr, et al. Hospitalization for heart failure in the presence of a normal left ventricular ejection fraction: results of the New York Heart Failure Registry. J Am Coll Cardiol. 2004;43(8):1432–8.CrossRefPubMed

Fischer M, Baessler A, Hense HW, Hengstenberg C, Muscholl M, Holmer S, Doring A, Broeckel U, Riegger G, Schunkert H. Prevalence of left ventricular diastolic dysfunction in the community. Results from a Doppler echocardiographic-based survey of a population sample. Eur Heart J. 2003;24(4):320–8.CrossRefPubMed

Paulus WJ, Tschope C, Sanderson JE, Rusconi C, Flachskampf FA, Rademakers FE, Marino P, Smiseth OA, De Keulenaer G, Leite-Moreira AF, et al. How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J. 2007;28(20):2539–50.CrossRefPubMed

van den Hurk K, Alssema M, Kamp O, Henry RM, Stehouwer CD, Smulders YM, Nijpels G, Paulus WJ, Dekker JM. Independent associations of glucose status and arterial stiffness with left ventricular diastolic dysfunction: an 8-year follow-up of the Hoorn Study. Diabetes Care. 2012;35(6):1258–64.CrossRefPubMedPubMedCentral

From AM, Scott CG, Chen HH. Changes in diastolic dysfunction in diabetes mellitus over time. Am J Cardiol. 2009;103(10):1463–6.CrossRefPubMedPubMedCentral

Zhang X, Chen C. A new insight of mechanisms, diagnosis and treatment of diabetic cardiomyopathy. Endocrine. 2012;41(3):398–409.CrossRefPubMed

10.

Ernande L, Derumeaux G. Diabetic cardiomyopathy: myth or reality? Arch Cardiovasc Dis. 2012;105(4):218–25.CrossRefPubMed

11.

Inoue T, Maeda Y, Sonoda N, Sasaki S, Kabemura T, Kobayashi K, Inoguchi T. Hyperinsulinemia and sulfonylurea use are independently associated with left ventricular diastolic dysfunction in patients with type 2 diabetes mellitus with suboptimal blood glucose control. BMJ Open Diabetes Res Care. 2016;4(1):e000223.CrossRefPubMedPubMedCentral

12.

Hashikata T, Yamaoka-Tojo M, Kakizaki R, Nemoto T, Fujiyoshi K, Namba S, Kitasato L, Hashimoto T, Kameda R, Maekawa E, et al. Teneligliptin improves left ventricular diastolic function and endothelial function in patients with diabetes. Heart Vessels. 2016;31(8):1303–10.CrossRefPubMed

13.

Horio T, Suzuki M, Suzuki K, Takamisawa I, Hiuge A, Kamide K, Takiuchi S, Iwashima Y, Kihara S, Funahashi T, et al. Pioglitazone improves left ventricular diastolic function in patients with essential hypertension. Am J Hypertens. 2005;18(7):949–57.CrossRefPubMed

14.

Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366(9493):1279–89.CrossRefPubMed

15.

Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman EB, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–26.CrossRefPubMed

16.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.CrossRefPubMed

17.

Gautam S, Agiro A, Barron J, Power T, Weisman H, White J. Heart failure hospitalization risk associated with use of two classes of oral antidiabetic medications: an observational, real-world analysis. Cardiovasc Diabetol. 2017;16(1):93.CrossRefPubMedPubMedCentral

18.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.CrossRefPubMed

19.

Mahaffey KW, Neal B, Perkovic V, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Fabbrini E, Sun T, Li Q, et al. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2017;137:323–34.CrossRefPubMed

20.

Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr. 2005;18(12):1440–63.CrossRefPubMed

21.

Ommen SR, Nishimura RA, Appleton CP, Miller FA, Oh JK, Redfield MM, Tajik AJ. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation. 2000;102(15):1788–94.CrossRefPubMed

22.

La Rovere MT, Pinna GD, Raczak G. Baroreflex sensitivity: measurement and clinical implications. Ann Noninvasive Electrocardiol. 2008;13(2):191–207.CrossRefPubMed

23.

Malliani A, Pagani M, Lombardi F. Physiology and clinical implications of variability of cardiovascular parameters with focus on heart rate and blood pressure. Am J Cardiol. 1994;73(10):3c–9c.CrossRefPubMed

24.

Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Barsotti E, Clerico A, Muscelli E. Renal handling of ketones in response to sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care. 2017;40(6):771–6.CrossRefPubMed

25.

Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res. 2016;8(12):844–7.CrossRefPubMedPubMedCentral

26.

Heerspink HJL, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853–62.CrossRefPubMedCentral

27.

O’Neill J, Fasching A, Pihl L, Patinha D, Franzen S, Palm F. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am J Physiol Renal Physiol. 2015;309(3):F227–34.CrossRefPubMed

28.

Hirata A, Minamino T, Asanuma H, Fujita M, Wakeno M, Myoishi M, Tsukamoto O, Okada K, Koyama H, Komamura K, et al. Erythropoietin enhances neovascularization of ischemic myocardium and improves left ventricular dysfunction after myocardial infarction in dogs. J Am Coll Cardiol. 2006;48(1):176–84.CrossRefPubMed

29.

van der Meer P, Lipsic E. Erythropoietin: repair of the failing heart. J Am Coll Cardiol. 2006;48(1):185–6.CrossRefPubMed

30.

Namiuchi S, Kagaya Y, Ohta J, Shiba N, Sugi M, Oikawa M, Kunii H, Yamao H, Komatsu N, Yui M, et al. High serum erythropoietin level is associated with smaller infarct size in patients with acute myocardial infarction who undergo successful primary percutaneous coronary intervention. J Am Coll Cardiol. 2005;45(9):1406–12.CrossRefPubMed

31.

Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton GB, Thompson RB, Petrofski JA, Annex BH, Stamler JS, et al. A novel protective effect of erythropoietin in the infarcted heart. J Clin Investig. 2003;112(7):999–1007.CrossRefPubMedPubMedCentral

32.

Parissis JT, Kourea K, Panou F, Farmakis D, Paraskevaidis I, Ikonomidis I, Filippatos G, Kremastinos DT. Effects of darbepoetin alpha on right and left ventricular systolic and diastolic function in anemic patients with chronic heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am Heart J. 2008;155(4):751-e1.CrossRef

33.

Pappas KD, Gouva CD, Katopodis KP, Nikolopoulos PM, Korantzopoulos PG, Michalis LK, Goudevenos JA, Siamopoulos KC. Correction of anemia with erythropoietin in chronic kidney disease (stage 3 or 4): effects on cardiac performance. Cardiovasc Drugs Ther. 2008;22(1):37–44.CrossRefPubMed

34.

Martini J, Tsai AG, Cabrales P, Johnson PC, Intaglietta M. Increased cardiac output and microvascular blood flow during mild hemoconcentration in hamster window model. Am J Physiol Heart Circ Physiol. 2006;291(1):H310–7.CrossRefPubMed

35.

Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “Thrifty Substrate” hypothesis. Diabetes Care. 2016;39(7):1108–14.CrossRefPubMed

36.

Heise T, Jordan J, Wanner C, Heer M, Macha S, Mattheus M, Lund SS, Woerle HJ, Broedl UC. Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016;38(10):2265–76.CrossRefPubMed

37.

Oh J, Kang SM, Hong N, Youn JC, Han S, Jeon ES, Cho MC, Kim JJ, Yoo BS, Chae SC, et al. Hemoconcentration is a good prognostic predictor for clinical outcomes in acute heart failure: data from the Korean Heart Failure (KorHF) Registry. Int J Cardiol. 2013;168(5):4739–43.CrossRefPubMed

38.

Greene SJ, Gheorghiade M, Vaduganathan M, Ambrosy AP, Mentz RJ, Subacius H, Maggioni AP, Nodari S, Konstam MA, Butler J, et al. Haemoconcentration, renal function, and post-discharge outcomes among patients hospitalized for heart failure with reduced ejection fraction: insights from the EVEREST trial. Eur J Heart Fail. 2013;15(12):1401–11.CrossRefPubMedPubMedCentral

39.

Pham SV, Chilton RJ. EMPA-REG OUTCOME: the cardiologist’s point of view. Am J Cardiol. 2017;120(1s):S53–s58.CrossRefPubMed

40.

Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524–6.CrossRefPubMed

41.

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

42.

Sato T, Aizawa Y, Yuasa S, Kishi S, Fuse K, Fujita S, Ikeda Y, Kitazawa H, Takahashi M, Sato M, et al. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol. 2018;17(1):6.CrossRefPubMedPubMedCentral

43.

Bouchi R, Terashima M, Sasahara Y, Asakawa M, Fukuda T, Takeuchi T, Nakano Y, Murakami M, Minami I, Izumiyama H, et al. Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol. 2017;16(1):32.CrossRefPubMedPubMedCentral

44.

Solini A, Giannini L, Seghieri M, Vitolo E, Taddei S, Ghiadoni L, Bruno RM. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16(1):138.CrossRefPubMedPubMedCentral

45.

Shigiyama F, Kumashiro N, Miyagi M, Ikehara K, Kanda E, Uchino H, Hirose T. Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study. Cardiovasc Diabetol. 2017;16(1):84.CrossRefPubMedPubMedCentral

46.

Kusaka H, Koibuchi N, Hasegawa Y, Ogawa H, Kim-Mitsuyama S. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol. 2016;15(1):157.CrossRefPubMedPubMedCentral

47.

Wenzel RR, Bruck H, Noll G, Schafers RF, Daul AE, Philipp T. Antihypertensive drugs and the sympathetic nervous system. J Cardiovasc Pharmacol. 2000;35(7 Suppl 4):S43–52.CrossRefPubMed

48.

Yoshikawa T, Kishi T, Shinohara K, Takesue K, Shibata R, Sonoda N, Inoguchi T, Sunagawa K, Tsutsui H, Hirooka Y. Arterial pressure lability is improved by sodium-glucose cotransporter 2 inhibitor in streptozotocin-induced diabetic rats. Hypertens Res. 2017;40:646.CrossRefPubMed

49.

Tomai F, Crea F, Gaspardone A, Versaci F, De Paulis R, de Penta Peppo A, Chiariello L, Gioffre PA. Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation. 1994;90(2):700–5.CrossRefPubMed

50.

Mita T, Katakami N, Shiraiwa T, Yoshii H, Onuma T, Kuribayashi N, Osonoi T, Kaneto H, Kosugi K, Umayahara Y, et al. 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(3):455–64.CrossRefPubMed

51.

Ida S, Murata K, Betou K, Kobayashi C, Ishihara Y, Imataka K, Uchida A, Monguchi K, Kaneko R, Fujiwara R, et al. Effect of trelagliptin on vascular endothelial functions and serum adiponectin level in patients with type 2 diabetes: a preliminary single-arm prospective pilot study. Cardiovasc Diabetol. 2016;15:153.CrossRefPubMedPubMedCentral

52.

Verma S, Garg A, Yan AT, Gupta AK, Al-Omran M, Sabongui A, Teoh H, Mazer CD, Connelly KA. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME trial? Diabetes Care. 2016;39(12):e212–3.CrossRefPubMed

53.

Patorno E, Goldfine AB, Schneeweiss S, Everett BM, Glynn RJ, Liu J, Kim SC. Cardiovascular outcomes associated with canagliflozin versus other non-gliflozin antidiabetic drugs: population based cohort study. BMJ. 2018;360:k119.CrossRefPubMedPubMedCentral

54.

Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes care. 2017;41:356–63.CrossRefPubMed

55.

Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation. 2017;135(e10):e146–603.CrossRefPubMedPubMedCentral

56.

Kane GC, Karon BL, Mahoney DW, Redfield MM, Roger VL, Burnett JC Jr, Jacobsen SJ, Rodeheffer RJ. Progression of left ventricular diastolic dysfunction and risk of heart failure. JAMA. 2011;306(8):856–63.CrossRefPubMedPubMedCentral

57.

Lund LH, Benson L, Dahlstrom U, Edner M, Friberg L. Association between use of beta-blockers and outcomes in patients with heart failure and preserved ejection fraction. JAMA. 2014;312(19):2008–18.CrossRefPubMed

58.

Massie BM, Carson PE, McMurray JJ, Komajda M, McKelvie R, Zile MR, Anderson S, Donovan M, Iverson E, Staiger C, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359(23):2456–67.CrossRefPubMed

59.

Solomon SD, Claggett B, Lewis EF, Desai A, Anand I, Sweitzer NK, O’Meara E, Shah SJ, McKinlay S, Fleg JL, et al. Influence of ejection fraction on outcomes and efficacy of spironolactone in patients with heart failure with preserved ejection fraction. Eur Heart J. 2016;37(5):455–62.CrossRefPubMed

60.

Holland DJ, Kumbhani DJ, Ahmed SH, Marwick TH. Effects of treatment on exercise tolerance, cardiac function, and mortality in heart failure with preserved ejection fraction. A meta-analysis. J Am Coll Cardiol. 2011;57(16):1676–86.CrossRefPubMed

61.

CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med. 1987;316(23):1429–35.CrossRef

Be confident that your patient care is up to date

Medicine Matters is being incorporated into Springer Medicine, our new medical education platform.

Alongside the news coverage and expert commentary you have come to expect from Medicine Matters diabetes, Springer Medicine's complimentary membership also provides access to articles from renowned journals and a broad range of Continuing Medical Education programs. Create your free account »