Mechanisms of Cardiovascular Benefits of Sodium Glucose Co-Transporter 2 (SGLT2) Inhibitors: A State-of-the-Art Review

Gary D Lopaschuk, Subodh Verma, Gary D Lopaschuk, Subodh Verma

Abstract

Recent clinical trials have shown that sodium glucose co-transport 2 (SGLT2) inhibitors have dramatic beneficial cardiovascular outcomes. These include a reduced incidence of cardiovascular death and heart failure hospitalization in people with and without diabetes, and those with and without prevalent heart failure. The actual mechanism(s) responsible for these beneficial effects are not completely clear. Several potential theses have been proposed to explain the cardioprotective effects of SGLT2 inhibition, which include diuresis/natriuresis, blood pressure reduction, erythropoiesis, improved cardiac energy metabolism, inflammation reduction, inhibition of the sympathetic nervous system, prevention of adverse cardiac remodeling, prevention of ischemia/reperfusion injury, inhibition of the Na+/H+-exchanger, inhibition of SGLT1, reduction in hyperuricemia, increasing autophagy and lysosomal degradation, decreasing epicardial fat mass, increasing erythropoietin levels, increasing circulating pro-vascular progenitor cells, decreasing oxidative stress, and improving vascular function. The strengths and weaknesses of these proposed mechanisms are reviewed in an effort to try to synthesize and prioritize the mechanisms as they relate to clinical event reduction.

Keywords: EPO, erythropoietin; LV, left ventricular; NLRP3, nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3; ROS, reactive oxygen species; SGLT, sodium glucose co-transporter; SNS, sympathetic nervous system; T2DM, type 2 diabetes mellitus; erythropoetin; inflammation; ketones; renal function; sympathetic nervous system.

© 2020 The Authors.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Possible Mechanisms by Which SGLT2 Inhibitors Decrease the Severity of Heart Failure Improved cardiac energetics with SGLT2 inhibition. NLRP3 = nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3; SGLT2 = sodium glucose co-transporter 2.
Figure 2
Figure 2
SGLT2 Inhibition Increases Cardiac Energy Production SGLT2 inhibitors can increase cardiac energy metabolism. Reproduced with permission from Verma et al. (41). ATP = adenosine triphosphate; SGLT2 = sodium glucose co-transporter 2.
Figure 3
Figure 3
Multiple Sites for the Beneficial Effects of SGLT2 Inhibition Proposed renal mechanisms for increased erythropoietin (EPO) with sodium glucose co-transporter 2 (SGLT2) inhibitors.
Central Illustration
Central Illustration
Potential Direct Myocardial and Indirect ± Systemic Effects of SGLT2i CAMKII = calmodulin-dependent protein kinase II; EPO = erythropoietin; NHE = sodium/hydrogen exchanger; NLRP3 = nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3; SGLT2i = sodium glucose co-transporter 1(2) inhibitor; SNS = sympathetic nervous system.

References

    1. Braunwald E. The war against heart failure: the Lancet lecture. Lancet. 2015;385:812–824.
    1. Khan S.S., Butler J., Gheorghiade M. Management of comorbid diabetes mellitus and worsening heart failure. JAMA. 2014;311:2379–2380.
    1. Swoboda P.P., McDiarmid A.K., Erhayiem B. Diabetes mellitus, microalbuminuria, and subclinical cardiac disease: identification and monitoring of individuals at risk of heart failure. J Am Heart Assoc. 2017;6
    1. American Diabetes Association Cardiovascular disease and risk management: standards of medical care in diabetes—2019. Diabetes Care. 2019;42:S103–S123.
    1. Gallo L.A., Wright E.M., Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015;12:78–89.
    1. McMurray J.J.V., Solomon S.D., Inzucchi S.E., for the DAPA-HF Trial Committees and Investigators Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381 1995–200.
    1. Bhatt D.L., Verma S., Braunwald E. The DAP-HF trial: a momentous victory in the war against heart failure. Cell Metab. 2019;30:847–849.
    1. Zinman B., Wanner C., Lachin J.M., for the EMPA-REG OUTCOME Investigators Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.
    1. Neal B., Perkovic V., Mahaffey K.W., for the CANVAS Program Collaborative Group Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–657.
    1. Perkovic V., Jardine M.J., Neal B., for CREDENCE Trial Investigators Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–2306.
    1. Wiviott S.D., Raz I., Bonaca M.P., for the DECLARE-TIMI 58 Investigators Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380 380:347–357.
    1. Zelniker T.A., Wiviott S.D., Raz I. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet. 2019;393:31–39.
    1. Verma S., Juni P., Mazer C.D. Pump, pipes, and filter: do SGLT2 inhibitors cover it all? Lancet. 2019;393:3–5.
    1. Verma S., McMurray J.J.V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108–2117.
    1. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Cardiol. 2017;120:S28–S36.
    1. Butler J., Handelsman Y., Bakris G., Verma S. Use of sodium-glucose co-transport inhibitors in patients with and without type 2 diabetes: implication for incident and prevalent heart failure. Eur J Heart Fail. 2020 Jan 11 [E-pub ahead of print]
    1. Filippatos T.D., Liontos A., Papakitsou I., Elisaf M.S. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad Med. 2019;131:82–88.
    1. Lam C.S.P., Chandramouli C., Ahooja V., Verma S. SGLT-2 inhibitors in heart failure: current management, unmet needs, and therapeutic prospects. J Am Heart Assoc. 2019;8
    1. Mazidi M., Rezaie P., Gao H.K., Kengne A.P. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6
    1. Ferrannini E., Baldi S., Frascerra S. Renal handling of ketones in response to sodium-glucose cotransporter 2 inhibition in patients with type 2 diabetes. Diabetes Care. 2017;40:771–776.
    1. Weber M.A., Mansfield T.A., Cain V.A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4:211–220.
    1. Kario K., Bohm M., Mahfoud F. Twenty-four-hour ambulatory blood pressure reduction patterns after renal denervation in the SPYRAL HTN-OFF MED Trial. Circulation. 2018;138:1602–1604.
    1. Lambers Heerspink H.J., 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;15:853–862.
    1. Hallow K.M., Helmlinger G., Greasley P.J., McMurray J.J.V., Boulton D.W. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab. 2018;20:479–487.
    1. Lopaschuk G.D., Ussher J.R., Folmes C.D., Jaswal J.S., Stanley W.C. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90:207–258.
    1. Zhang L., Jaswal J., Ussher J.R. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail. 2013;6:1039–1048.
    1. Wang W., Zhang L., Battiprolu P.K. Malonyl CoA decarboxylase inhibition improves cardiac function post-myocardial infarction. J Am Coll Cardiol Basic Trans Science. 2019;4:385–400.
    1. Mori J., Basu R., McLean B.A. Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction. Circ Heart Fail. 2012;5:493–503.
    1. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. 2007;356:1140.
    1. AbouEzziddine O.F., Kemp B.J., Borlaug B.A. Energetics in heart failure with preserved ejection fraction. Circ Heart Fail. 2019;12
    1. Ferrannini E., Muscelli E., Frascerra S. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.
    1. Al Jobori H., Daniele G., Adams J. Determinants of the increase in ketone concentration during SGLT2 inhibition in NGT, IFG and T2DM patients. Diabetes Obes Metab. 2017;19:809–813.
    1. Ferrannini E., Baldi S., Frascerra S. Shift to fatty substrates utilization in response to sodium-glucose co-transporter-2 inhibition in nondiabetic subjects and type 2 diabetic patients. Diabetes. 2016;65:1190–1195.
    1. Mudaliar S., Alloju S., Henry R.R. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39:1115–1122.
    1. Ferrannini F., Mark M., Mayoux E. CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39:1108–1114.
    1. Lopaschuk G.D., Verma S. Empagliflozin’s fuel hypothesis: not so soon. Cell Metab. 2016;24:200–202.
    1. Ho K.L., Zhang L., Wagg C. Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency. Cardiovas Res. 2019;115:1606–1616.
    1. Bedi K.C., Snyder N.W., Brandimarto J. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706–716.
    1. Aubert G., Martin O.J., Horton J.L. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698–705.
    1. Horton J.L., Davidson M.T., Kurishima C. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight. 2019;4
    1. Verma S., Rawat S., Ho K.L. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. J Am Coll Cardiol Basic Trans Science. 2018;3:575–587.
    1. Santos-Gallego C.G., Requena-Ibanez J.A., San Antonio R. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73:1931–1944.
    1. Shao Q., Meng L., Lee S. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2019;18:165.
    1. Nielsen R., Moller N., Gormsen L.C. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129–2141.
    1. Dick S.A., Epelman S. Chronic heart failure and inflammation: what do we really know? Circ Res. 2016;119:159–176.
    1. Mehta J.L., Pothineni N.V. Inflammation in heart failure: the holy grail? Hypertension. 2016;68:27–29.
    1. Briasoulis A., Androulakis E., Christophides T., Tousoulis D. The role of inflammation and cell death in the pathogenesis, progression and treatment of heart failure. Heart Fail Rev. 2016;21:169–176.
    1. Iannantuoni F., de Marañon A.M., Diaz-Morales N. The SGLT2 inhibitor empagliflozin ameliorates the inflammatory profile in type 2 diabetic patients and promotes an antioxidant response in leukocytes. J Clin Med. 2019;8:1814.
    1. Heerspink H.J.L., Perco P., Mulder S. Canagliflozin reduces inflammation and fibrosis biomarkers: a potential mechanism of action for beneficial effects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019;62:1154–1166.
    1. Leng W., Wu M., Pan H. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Ann Transl Med. 2019;7:429.
    1. Lee T.-M., Chang N.-C., Lion S.-Z. Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017;104:298–310.
    1. Kang S., Verma S., Hassanabad A.F. Direct effects of empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: novel translational clues to explain EMPA-REG OUTCOME results. Can J Cardiol. 2019 Aug 29 [E-pub ahead of print]
    1. Rotkvić P.G., Berković M.C., Bulj N., Rotkvić L. Minireview: are SGLT2 inhibitors heart savers in diabetes? Heart Fail Rev. 2019 Aug 13 [E-pub ahead of print]
    1. Butts B., Gary R.A., Dunbar S.B., Butler J. The importance of NLRP3 inflammasome in heart failure. J Card Fail. 2015;21:586–593.
    1. Benetti E., Mastrocola R., Vitarelli G. Empagliflozin protects against diet-induced NLRP-3 inflammasome activation and lipid accumulation. J Pharmacol Exp Ther. 2016;359:45–53.
    1. Tahara A., Kurosaki E., Yokono M. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharmacol. 2013;715:246–255.
    1. Lee Y.-H., Kim S.R., Han D.H. Senescent T cells predict the development of hyperglycemia in humans. Diabetes. 2019;68:156–162.
    1. Leng W., Ouyang X., Lei X. The SGLT-2 inhibitor dapagliflozin has a therapeutic effect on atherosclerosis in diabetic ApoE−/− mice. Mediators Inflamm. 2016;2016:6305735.
    1. Ye Y., Jia X., Bajaj M., Birnbaum Y. Dapagliflozin attenuates Na+/H+exchanger-1 in cardiofibroblasts via AMPK activation. Cardiovasc Drugs Therap. 2018;32:553–558.
    1. Byrne N.J., Matsumura N., Maayah Z.H. Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ Heart Fail. 2020;13
    1. Youm Y.H., Nguyen K.Y., Trant R.W. The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–269.
    1. Cai X., Yang W., Gao X. The association between the dosage of SGLT2 inhibitor and weight reduction in type 2 diabetes patients: a meta-analysis. Obesity (Silver Spring) 2018;26:70–80.
    1. Pereira M.J., Eriksson J.W. Emerging role of SGLT-2 inhibitors for the treatment of obesity. Drugs. 2019;79:219–230.
    1. Lee P.C., Ganguly S., Goh S.Y. Weight loss associated with sodium-glucose cotransporter-2 inhibition: a review of evidence and underlying mechanisms. Obes Rev. 2018;19:1630–1641.
    1. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56:686–695.
    1. Cannon C.P., Perkovic V., Agarwal R. Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes and chronic kidney disease according to baseline HbA1c, including those with HbA1c <7%: results from the CREDENCE trial. Circulation. 2019;141:407–410.
    1. Connelly K.A., Zhang Y., Vistram A. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. J Am Coll Cardiol Basic Trans Science. 2019;4:27–37.
    1. Chiba Y., Yamada T., Tsukita S. Dapagliflozin, a sodium-glucose co-transporter 2 inhibitor, acutely reduces energy expenditure in BAT via neural signals in mice. PLoS ONE. 2016;11
    1. Yoshikawa T., Kishi T., Shinohara K. Arterial pressure lability is improved by sodium-glucose cotransporter 2 inhibitor in streptozotocin-induced diabetic rats. Hypertens Res. 2017;40:646–651.
    1. Matthews V.B., Elliot R.H., Rudnicka C., Hricova J., Herat L., Schlaich M.P. Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens. 2017;35:2059–2068.
    1. Kimmerly D.S., Shoemaker J.K. Hypovolemia and neurovascular control during orthostatic stress. Am J Physiol. 2002;282:H645–H655.
    1. Jordan J., Tank J., Heusser K. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus. J Am Soc Hypertens. 2017;11:604–612.
    1. Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018;71:471–476.
    1. Byrne N.J., Parajuli N., Levasseur J.L. Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. J Am Coll Cardiol Basic Trans Science. 2017;2:347–354.
    1. Shi L., Zhu D., Wang S. Dapagliflozin attenuates cardiac remodeling in mice model of cardiac pressure overload. Am J Hypertens. 2019;32:452–459.
    1. Verma S., Garg A., Yan A.T. 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:e212–e213.
    1. Esterline R.L., Vaag A., Oscarsson J., Vora J. SGLT2 inhibitors: clinical benefits by restoration of normal diurnal metabolism? Eur J Endocrinol. 2018;178:R113–R125.
    1. Lee H.C., Shiou Y.L., Jhuo S.J. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18:45.
    1. Lim V.G., Bell R.M., Arjun S., Kolatsi-Joannou M., Long D.A., Yellon D.M. SGLT2 inhibitor, canagliflozin, attenuates myocardial infarction in the diabetic and nondiabetic heart. J Am Coll Cardiol Basic Trans Science. 2019;4:15–26.
    1. Wakabayashi S., Hisamitsu T., Nakamura T.Y. Regulation of the cardiac Na⁺/H⁺ exchanger in health and disease. J Mol Cell Cardiol. 2013;61:68–76.
    1. Baartscheer A., Schumacher C.A., Wust C.A. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60:568–573.
    1. Uthman L., Baartscheer A., Schumacher C.A. Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients. Front Physiol. 2018;9:1575.
    1. Packer M. Do sodium-glucose co-transporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis. Diabetes Obes Metab. 2018;20:1361–1366.
    1. Iborra-Egea O., Santiago-Vacas E., Yurista S.R. Unraveling the molecular mechanism of action of empagliflozin in heart failure with reduced ejection fraction with or without diabetes. J Am Coll Cardiol Basic Trans Science. 2019;4:831–840.
    1. Mentzer R.M., Bartels C., Bolli R., for the EXPEDITION Study Investigators Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: results of the EXPEDITION study. Ann Thorac Surg. 2008;85:1261–1270.
    1. Bell R.M., Yellon D.M. SGLT2 inhibitors: hypotheses on the mechanism of cardiovascular protection. Lancet Diabetes Endocrinol. 2017;6:435–437.
    1. Connelly K.A., Zhang Y., Desjardins J.F., Thai K., Gilbert R.E. Dual inhibition of sodium-glucose linked cotransporters 1 and 2 exacerbates cardiac dysfunction following experimental myocardial infarction. Cardiovasc Diabetol. 2018;17:99.
    1. Hare J.M., Johnson R.J. Uric acid predicts clinical outcomes in heart failure: insights regarding the role of xanthine oxidase and uric acid in disease pathophysiology. Circulation. 2003;107:1951–1953.
    1. Schernthaner G., Gross J.L., Rosenstock J. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care. 2013;36:2508–2515.
    1. Chino Y., Samukawa Y., Sakai S. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014;35:391–404.
    1. Nussenzweig S.C., Verma S., Finkel T. The role of autophagy in vascular biology. Circ Res. 2015;116:480–488.
    1. Raggi P., Gadiyaram V., Zhang C., Chen Z., Lopaschuk G., Stillman A.E. Statins reduce epicardial adipose tissue attenuation independent of lipid lowering: a potential pleiotropic effect. J Am Heart Assoc. 2019;8
    1. Sato T., Aizawa Y., Yuasa S. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc Diabetol. 2018;17:6.
    1. 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;8:844–847.
    1. Mazer C.D., Connelly P.W., Gilbert R.E. Effect of empagliflozin on erythropoietin levels, iron stores and red blood cell morphology in patients with type 2 diabetes and coronary artery disease. Circulation. 2019 Nov 11 [E-pub ahead of print]
    1. Hess D.A., Terenzi D.C., Trac J.Z. SGLT2 Inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus. Cell Metab. 2019;30:609–613.
    1. Zhou B., Tian R. Mitochondrial dysfunction in pathophysiology of heart failure. J Clin Invest. 2018;128:3716–3726.
    1. Li C., Zhang J., Xue M. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18:15.
    1. Uthman L., Homayr A., Juni R.P. Empagliflozin and dapagliflozin reduce ROS generation and restore NO bioavailability in tumor necrosis factor α-stimulated human coronary arterial endothelial cells. Cell Physiol Biochem. 2019;53:865–886.
    1. Endemann D.H., Schiffrin E.L. Endothelial dysfunction. J Am Soc Nephrol. 2004;15:1983–1992.
    1. Patel A.R., Kuvin J.T., Pandian N.G. Heart failure etiology affects peripheral vascular endothelial function after cardiac transplantation. J Am Coll Cardiol. 2001;37:195–200.
    1. Gaspari T., Spizzo I., Liu H. Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: a potential mechanism for inhibition of atherogenesis. Diabetes Vasc Dis Res. 2017;15:64–73.
    1. Mancini S.J., Boyd D., Katwan O.J. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci Rep. 2018;8:5276.
    1. Juni R.P., Kuster D.W.D., Goebel M. Cardiac microvascular endothelial enhancement of cardiomyocyte function is impaired by inflammation and restored by empagliflozin. J Am Coll Cardiol Basic Trans Science. 2019;4:575–591.
    1. Li H., Shin S.E., Seo M.S. The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. Life Sci. 2018;197:46–55.

Source: PubMed

Sponsorzy i współpracownicy

Warunki medyczne

Interwencje lekowe

3
Subskrybuj