Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cardiovascular Diabetology
Published in: Cardiovascular Diabetology 1/2018

Open Access 01-12-2018 | Review

Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors

Authors: Charshawn Lahnwong, Siriporn C. Chattipakorn, Nipon Chattipakorn

Published in: Cardiovascular Diabetology | Issue 1/2018

Login to get access

Abstract

Diabetes mellitus currently affects over 350 million patients worldwide and is associated with many deaths from cardiovascular complications. Sodium–glucose co-transporter 2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs with cardiovascular benefits beyond other antidiabetic drugs. In the EMPA-REG OUTCOME trial, empagliflozin significantly decreases the mortality rate from cardiovascular causes [38% relative risk reduction (RRR)], the mortality rate from all-causes (32% RRR) and the rate of heart failure hospitalization (35% RRR) in diabetic patients with established cardiovascular diseases. The possible mechanisms of SGLT-2 inhibitors are proposed to be systemic effects by hemodynamic and metabolic actions. However, the direct mechanisms are not fully understood. In this review, reports concerning the effects of SGLT-2 inhibitors in models of diabetic cardiomyopathy, heart failure and myocardial ischemia from in vitro, in vivo as well as clinical reports are comprehensively summarized and discussed. By current evidences, it may be concluded that the direct effects of SGLT-2 inhibitors are potentially mediated through their ability to reduce cardiac inflammation, oxidative stress, apoptosis, mitochondrial dysfunction and ionic dyshomeostasis.
Literature
1.
Lotfy M, Adeghate J, Kalasz H, Singh J, Adeghate E. Chronic complications of diabetes mellitus: a mini review. Curr Diab Rev. 2017;13:3–10.CrossRef
2.
Gaede P, Lund-Andersen H, Parving H-H, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580–91.PubMedCrossRef
3.
Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Executive summary: heart disease and stroke statistics—2016 update: a report from the american heart association. Circulation. 2016;133:447–54.PubMedCrossRef
4.
Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic cardiomyopathy: mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacol Ther. 2014;142:375–415.PubMedCrossRef
5.
6.
González-Vílchez F, Ayuela J, Ares M, Pi J, Castillo L, Martín-Durán R. Oxidative stress and fibrosis in incipient myocardial dysfunction in type 2 diabetic patients. Int J Cardiol. 2005;101:53–8.PubMedCrossRef
7.
Tate M, Grieve DJ, Ritchie RH. Are targeted therapies for diabetic cardiomyopathy on the horizon? Clin Sci Lond Engl. 1979;2017(131):897–915.
8.
Ferrannini E. Sodium–glucose co-transporters and their inhibition: clinical physiology. Cell Metab. 2017;26:27–38.PubMedCrossRef
9.
Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, et al. Localizations of Na(+)-d-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch. 2015;467:1881–98.PubMedCrossRef
10.
Verbrugge FH. Role of SGLT2 inhibitors in patients with diabetes mellitus and heart failure. Curr Heart Fail Rep. 2017;14:275–83.PubMedCrossRef
11.
Tomlinson B, Hu M, Zhang Y, Chan P, Liu Z-M. Evaluation of the pharmacokinetics, pharmacodynamics and clinical efficacy of empagliflozin for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol. 2017;13:211–23.PubMedCrossRef
12.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.PubMedCrossRef
13.
Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.PubMedCrossRef
14.
Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, et al. Lower risk of heart failure and death in patients initiated on sodium–glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (comparative effectiveness of cardiovascular outcomes in new users of sodium–glucose cotransporter-2 inhibitors). Circulation. 2017;136:249–59.PubMedPubMedCentralCrossRef
15.
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;16:93.PubMedPubMedCentralCrossRef
16.
von Lewinski D, Kolesnik E, Wallner M, Resl M, Sourij H. New antihyperglycemic drugs and heart failure: synopsis of basic and clinical data. Biomed Res Int. 2017;2017:1253425.
17.
Raz I, Mosenzon O, Bonaca MP, Cahn A, Kato ET, Silverman MG, et al. DECLARE-TIMI 58: participants’ baseline characteristics. Diab Obes Metab. 2018;20:1102–10.CrossRef
18.
Mordi NA, Mordi IR, Singh JS, Baig F, Choy A-M, McCrimmon RJ, et al. Renal and Cardiovascular Effects of Sodium–Glucose cotransporter 2 (SGLT2) inhibition in combination with loop Diuretics in diabetic patients with Chronic Heart Failure (RECEDE-CHF): protocol for a randomised controlled double-blind cross-over trial. BMJ Open. 2017;7:e018097.PubMedPubMedCentralCrossRef
19.
Tanaka A, Node K. Emerging roles of sodium–glucose cotransporter 2 inhibitors in cardiology. J Cardiol. 2017;69:501–7.PubMedCrossRef
20.
Rajasekeran H, Lytvyn Y, Cherney DZI. Sodium–glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89:524–6.PubMedCrossRef
21.
Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diab Care. 2016;39:717–25.CrossRef
22.
Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134:752–72.PubMedCrossRef
23.
Marx N, McGuire DK. Sodium–glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J. 2016;37:3192–200.PubMedCrossRef
24.
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 JASH. 2014;8(262–275):e9.
25.
Mazidi M, Rezaie P, Gao H-K, Kengne AP. 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:e004007.PubMedPubMedCentralCrossRef
26.
Baker WL, Buckley LF, Kelly MS, Bucheit JD, Parod ED, Brown R, et al. Effects of sodium–glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis. J Am Heart Assoc. 2017;6:e005686.PubMedPubMedCentralCrossRef
27.
Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diab Obes Metab. 2013;15:853–62.CrossRef
28.
Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diab Obes Metab. 2015;17:1180–93.CrossRef
29.
Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.PubMedPubMedCentralCrossRef
30.
Vallon V, Gerasimova M, Rose MA, Masuda T, Satriano J, Mayoux E, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306:F194–204.PubMedCrossRef
31.
Cherney D, Lund SS, Perkins BA, Groop P-H, Cooper ME, Kaspers S, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016;59:1860–70.PubMedCrossRef
32.
Cherney DZI, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, et al. Renal hemodynamic effect of sodium–glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.PubMedCrossRef
33.
Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium–glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.PubMedPubMedCentralCrossRef
34.
Merovci A, Solis-Herrera C, Daniele G, Eldor R, Fiorentino TV, Tripathy D, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509–14.PubMedPubMedCentralCrossRef
35.
Bonner C, Kerr-Conte J, Gmyr V, Queniat G, Moerman E, Thévenet J, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512–7.PubMedCrossRef
36.
DeFronzo RA, Ferrannini E. Regulation of hepatic glucose metabolism in humans. Diab Metab Rev. 1987;3:415–59.CrossRef
37.
Matsuda M, Defronzo RA, Glass L, Consoli A, Giordano M, Bressler P, et al. Glucagon dose-response curve for hepatic glucose production and glucose disposal in type 2 diabetic patients and normal individuals. Metabolism. 2002;51:1111–9.PubMedCrossRef
38.
39.
Keller U, Schnell H, Sonnenberg GE, Gerber PP, Stauffacher W. Role of glucagon in enhancing ketone body production in ketotic diabetic man. Diabetes. 1983;32:387–91.PubMedCrossRef
40.
Méry PF, Brechler V, Pavoine C, Pecker F, Fischmeister R. Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature. 1990;345:158–61.PubMedCrossRefADS
41.
Ali S, Ussher JR, Baggio LL, Kabir MG, Charron MJ, Ilkayeva O, et al. Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. Mol Metab. 2015;4:132–43.PubMedCrossRef
42.
Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190–5.PubMedCrossRef
43.
Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obes Silver Spring Md. 2012;20:1645–52.CrossRef
44.
Suzuki M, Takeda M, Kito A, Fukazawa M, Yata T, Yamamoto M, et al. Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models. Nutr Diab. 2014;4:e125.CrossRef
45.
Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids. 2004;70:243–51.PubMedCrossRef
46.
47.
Janardhan A, Chen J, Crawford PA. Altered systemic ketone body metabolism in advanced heart failure. Tex Heart Inst J. 2011;38:533–8.PubMedPubMedCentral
48.
49.
Snorek M, Hodyc D, Sedivý V, Durišová J, Skoumalová A, Wilhelm J, et al. Short-term fasting reduces the extent of myocardial infarction and incidence of reperfusion arrhythmias in rats. Physiol Res. 2012;61:567–74.PubMedCrossRef
50.
Srivastava S, Kashiwaya Y, King MT, Baxa U, Tam J, Niu G, et al. Mitochondrial biogenesis and increased uncoupling protein 1 in brown adipose tissue of mice fed a ketone ester diet. FASEB J Off Publ Fed Am Soc Exp Biol. 2012;26:2351–62.
51.
Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “Thrifty Substrate” hypothesis. Diab Care. 2016;39:1108–14.CrossRef
52.
Neeland IJ, McGuire DK, Chilton R, Crowe S, Lund SS, Woerle HJ, et al. Empagliflozin reduces body weight and indices of adipose distribution in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2016;13:119–26.PubMedCrossRef
53.
Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97:1020–31.PubMedCrossRef
54.
Yokono M, Takasu T, Hayashizaki Y, Mitsuoka K, Kihara R, Muramatsu Y, et al. SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol. 2014;727:66–74.PubMedCrossRef
55.
Zhou L, Cryan EV, D’Andrea MR, Belkowski S, Conway BR, Demarest KT. Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J Cell Biochem. 2003;90:339–46.PubMedCrossRef
56.
Chen J, Williams S, Ho S, Loraine H, Hagan D, Whaley JM, et al. Quantitative PCR tissue expression profiling of the human SGLT2 gene and related family members. Diab Ther. 2010;1:57–92.CrossRef
57.
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;15:157.PubMedPubMedCentralCrossRef
58.
Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148.PubMedPubMedCentralCrossRef
59.
Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16:9.PubMedPubMedCentralCrossRef
60.
Hammoudi N, Jeong D, Singh R, Farhat A, Komajda M, Mayoux E, et al. Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovasc Drugs Ther. 2017;31:233–46.PubMedPubMedCentralCrossRef
61.
Liang L, Jiang J, Frank SJ. Insulin receptor substrate-1-mediated enhancement of growth hormone-induced mitogen-activated protein kinase activation. Endocrinology. 2000;141:3328–36.PubMedCrossRef
62.
Zhou Y, Wu W. The sodium–glucose co-transporter 2 inhibitor, empagliflozin, protects against diabetic cardiomyopathy by inhibition of the endoplasmic reticulum stress pathway. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2017;41:2503–12.CrossRef
63.
Ye Y, Bajaj M, Yang H-C, Perez-Polo JR, Birnbaum Y. SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther. 2017;31:119–32.PubMedCrossRef
64.
Tanajak P, Sa-Nguanmoo P, Sivasinprasasn S, Thummasorn S, Siri-Angkul N, Chattipakorn SC, et al. Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. J Endocrinol. 2018;236:69–84.PubMedCrossRef
65.
Lee T-M, Chang N-C, Lin 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.PubMedCrossRef
66.
Shi X, Verma S, Yun J, Brand-Arzamendi K, Singh KK, Liu X, et al. Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: clues to the EMPA-REG OUTCOME trial? Mol Cell Biochem. 2017;433:97–102.PubMedCrossRef
67.
Huang C-C, Monte A, Cook JM, Kabir MS, Peterson KP. Zebrafish heart failure models for the evaluation of chemical probes and drugs. Assay Drug Dev Technol. 2013;11:561–72.PubMedPubMedCentralCrossRef
68.
Januzzi JL, Butler J, Jarolim P, Sattar N, Vijapurkar U, Desai M, et al. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J Am Coll Cardiol. 2017;70:704–12.PubMedCrossRef
69.
Joubert M, Jagu B, Montaigne D, Marechal X, Tesse A, Ayer A, et al. The sodium–glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes. 2017;66:1030–40.PubMedCrossRef
70.
Sato T, Miki T, Ohnishi H, Yamashita T, Takada A, Yano T, et al. Effect of sodium–glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes. Diab Med J Br Diab Assoc. 2017;34:1367–71.CrossRef
71.
Nilsson J, Bengtsson E, Fredrikson GN, Björkbacka H. Inflammation and immunity in diabetic vascular complications. Curr Opin Lipidol. 2008;19:519–24.PubMedCrossRef
72.
73.
Dixit VD. Nlrp3 inflammasome activation in type 2 diabetes: is it clinically relevant? Diabetes. 2013;62:22–4.PubMedCrossRef
74.
75.
Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, et al. Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol. 2010;11:897–904.PubMedPubMedCentralCrossRef
76.
Lee H-M, Kim J-J, Kim HJ, Shong M, Ku BJ, Jo E-K. Upregulated NLRP3 inflammasome activation in patients with type 2 diabetes. Diabetes. 2013;62:194–204.PubMedCrossRef
77.
Fuentes-Antrás J, Ioan AM, Tuñón J, Egido J, Lorenzo O. Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol. 2014;2014:847827.PubMedPubMedCentralCrossRef
78.
Luo B, Li B, Wang W, Liu X, Xia Y, Zhang C, et al. NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS ONE. 2014;9:e104771.PubMedPubMedCentralCrossRefADS
79.
Singh LP. The NLRP3 inflammasome and diabetic cardiomyopathy: editorial to: “Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model” by Beibei Luo et al. Cardiovasc Drugs Ther. 2014;28:5–6.PubMedCrossRef
80.
Griendling KK, Sorescu D, Ushio-Fukai M. NAD(P)H oxidase: role in cardiovascular biology and disease. Circ Res. 2000;86:494–501.PubMedCrossRef
81.
Takimoto E, Kass DA. Role of oxidative stress in cardiac hypertrophy and remodeling. Hypertens Dallas Tex. 1979;2007(49):241–8.
82.
Yamamoto E, Lai Z-F, Yamashita T, Tanaka T, Kataoka K, Tokutomi Y, et al. Enhancement of cardiac oxidative stress by tachycardia and its critical role in cardiac hypertrophy and fibrosis. J Hypertens. 2006;24:2057–69.PubMedCrossRef
83.
Oelze M, Kröller-Schön S, Welschof P, Jansen T, Hausding M, Mikhed Y, et al. The sodium–glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS ONE. 2014;9:e112394.PubMedPubMedCentralCrossRefADS
84.
Wang T, Mao X, Li H, Qiao S, Xu A, Wang J, et al. N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes. Free Radic Biol Med. 2013;63:291–303.PubMedCrossRef
85.
Jadhav A, Tiwari S, Lee P, Ndisang JF. The heme oxygenase system selectively enhances the anti-inflammatory macrophage-M2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in Zucker diabetic fatty rats. J Pharmacol Exp Ther. 2013;345:239–49.PubMedCrossRef
86.
87.
Takemura G, Kanoh M, Minatoguchi S, Fujiwara H. Cardiomyocyte apoptosis in the failing heart—a critical review from definition and classification of cell death. Int J Cardiol. 2013;167:2373–86.PubMedCrossRef
88.
Takemura G, Fujiwara H. Morphological aspects of apoptosis in heart diseases. J Cell Mol Med. 2006;10:56–75.PubMedCrossRef
89.
Liu Z-W, Zhu H-T, Chen K-L, Dong X, Wei J, Qiu C, et al. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy. Cardiovasc Diabetol. 2013;12:158.PubMedPubMedCentralCrossRef
90.
91.
Ji Y, Zhao Z, Cai T, Yang P, Cheng M. Liraglutide alleviates diabetic cardiomyopathy by blocking CHOP-triggered apoptosis via the inhibition of the IRE-α pathway. Mol Med Rep. 2014;9:1254–8.PubMedCrossRef
92.
Wu T, Dong Z, Geng J, Sun Y, Liu G, Kang W, et al. Valsartan protects against ER stress-induced myocardial apoptosis via CHOP/Puma signaling pathway in streptozotocin-induced diabetic rats. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2011;42:496–502.
93.
Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107:881–91.PubMedCrossRef
94.
Zhao L, Ackerman SL. Endoplasmic reticulum stress in health and disease. Curr Opin Cell Biol. 2006;18:444–52.PubMedCrossRef
95.
Tong Q, Wu L, Jiang T, Ou Z, Zhang Y, Zhu D. Inhibition of endoplasmic reticulum stress-activated IRE1α-TRAF2-caspase-12 apoptotic pathway is involved in the neuroprotective effects of telmisartan in the rotenone rat model of Parkinson’s disease. Eur J Pharmacol. 2016;776:106–15.PubMedCrossRef
96.
Liu H, Baliga R. Endoplasmic reticulum stress-associated caspase 12 mediates cisplatin-induced LLC-PK1 cell apoptosis. J Am Soc Nephrol JASN. 2005;16:1985–92.PubMedCrossRef
97.
Sari FR, Widyantoro B, Thandavarayan RA, Harima M, Lakshmanan AP, Zhang S, et al. Attenuation of CHOP-mediated myocardial apoptosis in pressure-overloaded dominant negative p38α mitogen-activated protein kinase mice. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol. 2011;27:487–96.CrossRef
98.
Cong X-Q, Piao M-H, Li Y, Xie L, Liu Y. Bis(maltolato)oxovanadium(IV) (BMOV) attenuates apoptosis in high glucose-treated cardiac cells and diabetic rat hearts by regulating the unfolded protein responses (UPRs). Biol Trace Elem Res. 2016;173:390–8.PubMedCrossRef
99.
Hernández-Reséndiz S, Buelna-Chontal M, Correa F, Zazueta C. Targeting mitochondria for cardiac protection. Curr Drug Targets. 2013;14:586–600.PubMedCrossRef
100.
101.
Montaigne D, Marechal X, Coisne A, Debry N, Modine T, Fayad G, et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation. 2014;130:554–64.PubMedCrossRef
102.
Lucas E, Vila-Bedmar R, Arcones AC, Cruces-Sande M, Cachofeiro V, Mayor F, et al. Obesity-induced cardiac lipid accumulation in adult mice is modulated by G protein-coupled receptor kinase 2 levels. Cardiovasc Diabetol. 2016;15:155.PubMedPubMedCentralCrossRef
103.
Duncan JG. Peroxisome proliferator activated receptor-alpha (PPARα) and PPAR gamma coactivator-1alpha (PGC-1α) regulation of cardiac metabolism in diabetes. Pediatr Cardiol. 2011;32:323–8.PubMedPubMedCentralCrossRef
104.
Westermann B. Mitochondrial fusion and fission in cell life and death. Nat Rev Mol Cell Biol. 2010;11:872–84.PubMedCrossRef
105.
106.
Ong S-B, Subrayan S, Lim SY, Yellon DM, Davidson SM, Hausenloy DJ. Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury. Circulation. 2010;121:2012–22.PubMedCrossRef
107.
Sharp WW, Beiser DG, Fang YH, Han M, Piao L, Varughese J, et al. Inhibition of the mitochondrial fission protein dynamin-related protein 1 improves survival in a murine cardiac arrest model. Crit Care Med. 2015;43:e38–47.PubMedPubMedCentralCrossRef
108.
109.
110.
Baartscheer A, Schumacher CA, van Borren MMGJ, Belterman CNW, Coronel R, Fiolet JWT. Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res. 2003;57:1015–24.PubMedCrossRef
111.
Pogwizd SM, Sipido KR, Verdonck F, Bers DM. Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res. 2003;57:887–96.PubMedCrossRef
112.
Lambert R, Srodulski S, Peng X, Margulies KB, Despa F, Despa S. Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport. J Am Heart Assoc. 2015;4:e002183.PubMedPubMedCentralCrossRef
113.
Liu T, Takimoto E, Dimaano VL, DeMazumder D, Kettlewell S, Smith G, et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res. 2014;115:44–54.PubMedPubMedCentralCrossRef
114.
Baartscheer A, Hardziyenka M, Schumacher CA, Belterman CNW, van Borren MMGJ, Verkerk AO, et al. Chronic inhibition of the Na+/H+—exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. Br J Pharmacol. 2008;154:1266–75.PubMedPubMedCentralCrossRef
115.
Baartscheer A, Schumacher CA, van Borren MMGJ, Belterman CNW, Coronel R, Opthof T, et al. Chronic inhibition of Na+/H+—exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure. Cardiovasc Res. 2005;65:83–92.PubMedCrossRef
116.
Baartscheer A, Schumacher CA, Wüst RCI, Fiolet JWT, Stienen GJM, Coronel R, et al. Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia. 2017;60:568–73.PubMedCrossRef
117.
Liu T, O’Rourke B. Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circ Res. 2008;103:279–88.PubMedPubMedCentralCrossRef
118.
119.
Kawase Y, Hajjar RJ. The cardiac sarcoplasmic/endoplasmic reticulum calcium ATPase: a potent target for cardiovascular diseases. Nat Clin Pract Cardiovasc Med. 2008;5:554–65.PubMedCrossRef
120.
Park SH, Khemais-Benkhiat S, Idris-Khodja N, Amoura L, Abbas M, Auger C, et al. Upregulation of sodium–glucose cotransporter 2 (SGLT2) expression in cultured senescent endothelial cells and in arterial sites at risk in vivo in rats. Arch Cardiovasc Dis Suppl. 2018;10:224.
121.
Han Y, Cho Y-E, Ayon R, Guo R, Youssef KD, Pan M, et al. SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery. Am J Physiol Lung Cell Mol Physiol. 2015;309:L1027–36.PubMedPubMedCentralCrossRef
122.
Leng W, Ouyang X, Lei X, Wu M, Chen L, Wu Q, et al. The SGLT-2 inhibitor dapagliflozin has a therapeutic effect on atherosclerosis in diabetic ApoE−/− mice. Mediators Inflamm. 2016;2016:6305735.PubMedPubMedCentralCrossRef
Metadata
Title
Potential mechanisms responsible for cardioprotective effects of sodium–glucose co-transporter 2 inhibitors
Authors
Charshawn Lahnwong
Siriporn C. Chattipakorn
Nipon Chattipakorn
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/s12933-018-0745-5

Other articles of this Issue 1/2018

Cardiovascular Diabetology 1/2018 Go to the issue

Original investigation

Glycemic variability determined with a continuous glucose monitoring system can predict prognosis after acute coronary syndrome

Original investigation

Increased myocardial extracellular volume assessed by cardiovascular magnetic resonance T1 mapping and its determinants in type 2 diabetes mellitus patients with normal myocardial systolic strain

Original investigation

Non-culprit plaque characteristics in acute coronary syndrome patients with raised hemoglobinA1c: an intravascular optical coherence tomography study

Review

Prevalence of cardiovascular disease in type 2 diabetes: a systematic literature review of scientific evidence from across the world in 2007–2017

Commentary

Cardiovascular benefit in the limelight: shifting type 2 diabetes treatment paradigm towards early combination therapy in patients with overt cardiovascular disease

Original investigation

Prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in ST-segment elevation myocardial infarction
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

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

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits