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06-09-2018 | Cardiovascular disorders | Review | Article

Molecular Mechanisms Underlying the Cardiovascular Benefits of SGLT2i and GLP-1RA

Journal: Current Diabetes Reports

Authors: Dorrin Zarrin Khat, Mansoor Husain

Publisher: Springer US

Abstract

Purpose of Review

In addition to their effects on glycemic control, two specific classes of relatively new anti-diabetic drugs, namely the sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have demonstrated reduced rates of major adverse cardiovascular events (MACE) in subjects with type 2 diabetes (T2D) at high risk for cardiovascular disease (CVD). This review summarizes recent experimental results that inform putative molecular mechanisms underlying these benefits.

Recent Findings

SGLT2i and GLP-1RA exert cardiovascular effects by targeting in both common and distinctive ways (A) several mediators of macro- and microvascular pathophysiology: namely (A1) inflammation and atherogenesis, (A2) oxidative stress-induced endothelial dysfunction, (A3) vascular smooth muscle cell reactive oxygen species (ROS) production and proliferation, and (A4) thrombosis. These agents also exhibit (B) hemodynamic effects through modulation of (B1) natriuresis/diuresis and (B2) the renin-angiotensin-aldosterone system.

Summary

This review highlights that while GLP-1RA exert direct effects on vascular (endothelial and smooth muscle) cells, the effects of SGLT2i appear to include the activation of signaling pathways that prevent adverse vascular remodeling. Both SGLT2i and GLP-1RA confer hemodynamic effects that counter adverse cardiac remodeling.
Literature
1.
Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, et al. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation. 2017;135:e146–603. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​28122885 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
2.
Heart Disease Facts & Statistics | cdc.gov [Internet]. [cited 2017 Dec 1].
3.
Congestive Heart Failure and Cardiac Transplantation: Clinical, Pathology. Google Books [Internet]. [cited 2017 Dec 1].
4.
Hausenloy DJ, Yellon DM. Myocardial ischemia-reperfusion injury: a neglected therapeutic target. J Clin Invest. 2013;123:92–100.PubMedPubMedCentralCrossRef
5.
Miura T, Miki T. Limitation of myocardial infarct size in the clinical setting: current status and challenges in translating animal experiments into clinical therapy. Basic Res Cardiol. 2008;103:501–13.PubMedCrossRef
6.
Giovanna Colombo M, Meisinger C, Amann U, Heier M, von Scheidt W, Kuch B, et al. Association of obesity and long-term mortality in patients with acute myocardial infarction with and without diabetes mellitus: results from the MONICA/KORA myocardial infarction registry CARDIO VASCULAR DIABETOLOGY. Cardiovasc Diabetol. 2015;14.
7.
Olokoba AB, Obateru OA, Olokoba LB. Type 2 diabetes mellitus: a review of current trends. Oman Med J. 2012;27:269–73. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23071876 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
8.
Deshpande AD, Harris-Hayes M, Schootman M. Epidemiology of diabetes and diabetes-related complications. Phys Ther. 2008;88:1254–64. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​18801858 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
9.
Group TA to CCR in DS. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59. Available: http://​www.​nejm.​org/​doi/​abs/​10.​1056/​NEJMoa0802743 (accessed 2017 Dec 1)CrossRef
10.
Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009;339:b4731. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​19959591 (accessed 2017 Apr 23)PubMedPubMedCentralCrossRef
11.
Loke YK, Kwok CS, Singh S. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ. 2011;342:d1309. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​21415101 (accessed 2017 Apr 23)PubMedPubMedCentralCrossRef
12.
Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits. Diabetes Care. 2010;33:428–33. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​20103558 (accessed 2017 Apr 23)PubMedPubMedCentralCrossRef
13.
• Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22. This study elucidated the cardiovascular effect of the GLP-1RA, liraglutide, when added to standard care in patients with type 2 diabetes, which was otherwise unknown. PubMedPubMedCentralCrossRef
14.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jódar E, Leiter LA, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44. Available: http://​www.​nejm.​org/​doi/​10.​1056/​NEJMoa1607141 (accessed 2017 Apr 23)PubMedCrossRef
15.
Lonborg J, Kelbaek H, Vejlstrup N, Botker HE, Kim WY, Holmvang L, et al. Exenatide reduces final infarct size in patients with ST-segment-elevation myocardial infarction and short-duration of ischemia. Circ Cardiovasc Interv. 2012;5:288–95. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22496084 (accessed 2017 Apr 23)PubMedCrossRef
16.
•• Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. This study was the first to demonstrate SGLT2i (namely empagliflozin) to lower the rates of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with type 2 diabetes at high cardiovascular risk, when added to standard care.
17.
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. Available: http://​www.​nejm.​org/​doi/​10.​1056/​NEJMoa1611925 (accessed 2017 Dec 1)PubMedCrossRef
18.
Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet (London, England). 1998;352:854–65. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​9742977 (accessed 2017 Dec 1).
19.
Dluhy RG, McMahon GT. Intensive glycemic control in the ACCORD and ADVANCE trials. N Engl J Med. 2008;358:2630–3. Available: http://​www.​nejm.​org/​doi/​abs/​10.​1056/​NEJMe0804182 (accessed 2017 Dec 1)PubMedCrossRef
20.
ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, Neal B, Billot L, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–72. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​18539916 (accessed 2017 Dec 1)CrossRef
21.
Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, Goff DC, Bigger JT, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​18539917 (accessed 2017 Apr 23)CrossRef
22.
Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39. Available: http://​www.​nejm.​org/​doi/​abs/​10.​1056/​NEJMoa0808431 (accessed 2017 Dec 1PubMedCrossRef
23.
Rosen CJ. The rosiglitazone story—lessons from an FDA advisory committee meeting. N Engl J Med. 2007;357:844–6. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​17687124 (accessed 2017 Dec 1)PubMedCrossRef
24.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​17517853 (accessed 2017 Dec 1)PubMedCrossRef
25.
Hiatt WR, Kaul S, Smith RJ. The cardiovascular safety of diabetes drugs—insights from the rosiglitazone experience. N Engl J Med. 2013;369:1285–7. Available: http://​www.​nejm.​org/​doi/​10.​1056/​NEJMp1309610 (accessed 2017 Dec 1)PubMedCrossRef
26.
Kimura G. Diuretic action of sodium-glucose cotransporter 2 inhibitors and its importance in the management of heart failure. Circ J. 2016;80:2277–81. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27599528 (accessed 2017 Dec 1)PubMedCrossRef
27.
Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care. 2016;39:717–25. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27208375 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
28.
Drucker DJ. The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 2016;24:15–30. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27345422 (accessed 2017 Dec 1)PubMedCrossRef
29.
DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19:1353–62. Available: http://​doi.​wiley.​com/​10.​1111/​dom.​12982 (accessed 2017 Dec 1)PubMedCrossRefPubMedCentral
30.
Arakawa M, Mita T, Azuma K, Ebato C, Goto H, Nomiyama T, et al. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes. 2010;59:1030–7. Available: http://​diabetes.​diabetesjournals​.​org/​cgi/​doi/​10.​2337/​db09-1694 (accessed 2017 Dec 10)PubMedPubMedCentralCrossRef
31.
Gaspari T, Welungoda I, Widdop RE, Simpson RW, Dear AE. The GLP-1 receptor agonist liraglutide inhibits progression of vascular disease via effects on atherogenesis, plaque stability and endothelial function in an ApoE(−/−) mouse model. Diabetes Vasc Dis Res. 2013;10:353–60. Available: http://​journals.​sagepub.​com/​doi/​10.​1177/​1479164113481817​ (accessed 2017 Dec 10)CrossRef
32.
Krasner NM, Ido Y, Ruderman NB, Cacicedo JM. Glucagon-like Peptide-1 (GLP-1) analog liraglutide inhibits endothelial cell inflammation through a calcium and AMPK dependent mechanism. Bauer PM, editor. PLoS One 2014;9:e97554. Available: http://​dx.​plos.​org/​10.​1371/​journal.​pone.​0097554 (accessed 2017 Dec 10).
33.
Hogan AE, Gaoatswe G, Lynch L, Corrigan MA, Woods C, O’Connell J, et al. Glucagon-like peptide 1 analogue therapy directly modulates innate immune-mediated inflammation in individuals with type 2 diabetes mellitus. Diabetologia. 2014;57:781–4. Available: http://​link.​springer.​com/​10.​1007/​s00125-013-3145-0 (accessed 2017 Dec 10)PubMedCrossRef
34.
Hirano T, Mori Y. Anti-atherogenic and anti-inflammatory properties of glucagon-like peptide-1, glucose-dependent insulinotropic polypepide, and dipeptidyl peptidase-4 inhibitors in experimental animals. J Diabetes Investig. 2016;7:80–6.PubMedPubMedCentralCrossRef
35.
Ceriello A, Novials A, Canivell S, La Sala L, Pujadas G, Esposito K, et al. Simultaneous GLP-1 and insulin administration acutely enhances their vasodilatory, antiinflammatory, and antioxidant action in type 2 diabetes. Diabetes Care. 2014;37:1938–43.PubMedCrossRef
36.
Xu L, Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G, et al. SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine. 2017;20:137–49. https://​doi.​org/​10.​1016/​j.​ebiom.​2017.​05.​028.PubMedPubMedCentralCrossRef
37.
Steven S, Oelze M, Hanf A, Kröller-schön S, Kashani F, Roohani S, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol. 2017;13:370–85.PubMedPubMedCentralCrossRef
38.
Nakatsu Y, Kokubo H, Bumdelger B, Yoshizumi M, Yamamotoya T, Matsunaga Y, et al. The SGLT2 inhibitor luseogliflozin rapidly normalizes aortic mRNA levels of inflammation-related but not lipid-metabolism-related genes and suppresses atherosclerosis in diabetic ApoE KO mice. Int J Mol Sci. 2017;18:1704. Available: http://​www.​mdpi.​com/​1422-0067/​18/​8/​1704 PubMedCentralCrossRef
39.
Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, et al. Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol. 2014;66:975–87. Available: http://​doi.​wiley.​com/​10.​1111/​jphp.​12223 (accessed 2017 Dec 10)PubMedCrossRef
40.
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. 2016;2016.
41.
Kern M, Klöting N, Mark M, Mayoux E, Klein T, Blüher M. The SGLT2 inhibitor empagliflozin improves insulin sensitivity in db/db mice both as monotherapy and in combination with linagliptin. Metabolism. 2016;65:114–23. https://​doi.​org/​10.​1016/​j.​metabol.​2015.​10.​010.PubMedCrossRef
42.
Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ. 2000;321:405–12.PubMedPubMedCentralCrossRef
43.
Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-year follow-up of intensive glucose control in type 2 diabetes. https://​doi.​org/​10.​1056/​NEJMoa0806470 2009.
44.
Oeseburg H, de Boer RA, Buikema H, van der Harst P, van Gilst WH, Sillje HHW. Glucagon-like peptide 1 prevents reactive oxygen species-induced endothelial cell senescence through the activation of protein kinase A. Arterioscler Thromb Vasc Biol. 2010;30:1407–14.PubMedCrossRef
45.
Terasaki M, Hiromura M, Mori Y, Kohashi K, Nagashima M, Kushima H, et al. Amelioration of hyperglycemia with a sodium-glucose cotransporter 2 inhibitor prevents macrophage-driven atherosclerosis through macrophage foam cell formation suppression in type 1 and type 2 diabetic mice. 2015.
46.
Dai Y, Mercanti F, Dai D, Wang X, Ding Z, Pothineni NV, et al. LOX-1, a bridge between GLP-1R and mitochondrial ROS generation in human vascular smooth muscle cells. Biochem Biophys Res Commun. 2013;437:62–6. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23806684 (accessed 2017 Dec 1)PubMedCrossRef
47.
Zhao L, Li AQ, Zhou TF, Zhang MQ, Qin XM. Exendin-4 alleviates angiotensin II-induced senescence in vascular smooth muscle cells by inhibiting Rac1 activation via a cAMP/PKA-dependent pathway. AJP Cell Physiol. 2014;307:C1130–41. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25298426 (accessed 2017 Dec 1)CrossRef
48.
Nagayama K, Kyotani Y, Zhao J, Ito S, Ozawa K, Bolstad FA, et al. Exendin-4 prevents vascular smooth muscle cell proliferation and migration by angiotensin II via the inhibition of ERK1/2 and JNK signaling pathways. PLoS One. 2015;10:e0137960. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26379274 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
49.
Shi L, Ji Y, Jiang X, Zhou L, Xu Y, Li Y, et al. Liraglutide attenuates high glucose-induced abnormal cell migration, proliferation, and apoptosis of vascular smooth muscle cells by activating the GLP-1 receptor, and inhibiting ERK1/2 and PI3K/Akt signaling pathways. Cardiovasc Diabetol. 2015;14:18. Available: http://​www.​cardiab.​com/​content/​14/​1/​18 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
50.
Cameron-Vendrig A, Reheman A, Siraj MA, Xu XR, Wang Y, Lei X, et al. Glucagon-like peptide 1 receptor activation attenuates platelet aggregation and thrombosis. Diabetes. 2016;65:1714–23. Available: http://​diabetes.​diabetesjournals​.​org/​lookup/​doi/​10.​2337/​db15-1141 (accessed 2016 Nov 3)PubMedCrossRef
51.
Takeshige Y, Fujisawa Y, Rahman A, Kittikulsuth W, Nakano D, Mori H, et al. A sodium-glucose co-transporter 2 inhibitor empagliflozin prevents abnormality of circadian rhythm of blood pressure in salt-treated obese rats. Hypertens Res. 2016;39:415–22. Available: http://​www.​nature.​com/​doifinder/​10.​1038/​hr.​2016.​2 (accessed 2017 Dec 5)PubMedCrossRef
52.
Rahman A, Kittikulsuth W, Fujisawa Y, Sufiun A, Rafiq K, Hitomi H, et al. Effects of diuretics on sodium-dependent glucose cotransporter 2 inhibitor-induced changes in blood pressure in obese rats suffering from the metabolic syndrome. J Hypertens. 2016;34:893–906. Available: http://​content.​wkhealth.​com/​linkback/​openurl?​sid=​WKPTLP:​landingpage&​an=​00004872-201605000-00015 (accessed 2017 Dec 1).PubMedCrossRef
53.
Rieg T, Gerasimova M, Murray F, Masuda T, Tang T, Rose M, et al. Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol. 2012;303:F963–71. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22832924 (accessed 2017 Dec 5)PubMedPubMedCentralCrossRef
54.
• Frías J, Guja C, Hardy E, Ahmed A, Dong F, et al. Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised control. Lancet Diabetes Endocrinol. 2016. This study exemplies the notion of combination therapy with GLP-1RA and SGLT2i. The study not only evaluates efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin but also compares it to exenatide or dapagliflozin monotherapy in patients with type 2 diabetes inadequately controlled by metformin.
55.
Romaní-Pérez M, Outeiriño-Iglesias V, Moya CM, Santisteban P, González-Matías LC, Vigo E, et al. Activation of the GLP-1 receptor by liraglutide increases ACE2 expression, reversing right ventricle hypertrophy, and improving the production of SP-A and SP-B in the lungs of type 1 diabetes rats. Endocrinology. 2015;156:3559–69. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26196539 (accessed 2017 Dec 1)PubMedCrossRef
56.
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. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27470878 (accessed 2017 Dec 7)PubMedCrossRef
57.
Cherney DZI, Perkins BA, Soleymanlou N, Xiao F, Zimpelmann J, Woerle H-J, et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int. 2014;86:1057–8. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25360497 (accessed 2017 Dec 7)PubMedCrossRef
58.
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. Available: http://​www.​nature.​com/​doifinder/​10.​1038/​nm.​3828%5Cnhttp://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25894829 PubMedCrossRef
59.
Furuhashi M, Matsumoto M, Hiramitsu S, Omori A, Tanaka M, Moniwa N, et al. Possible increase in serum FABP4 level despite adiposity reduction by canagliflozin, an SGLT2 inhibitor. PLoS One. 2016;11:1–13.CrossRef
60.
Sarraju A, Kim SH, Knowles JW. Cardiometabolic effects of glucagon-like peptide-1 agonists. Curr Atheroscler Rep. 2016;18:7. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26782825 (accessed 2018 Jan 15)PubMedCrossRef
61.
Farngren J, Persson M, Ahrén B. Effect of the GLP-1 receptor agonist lixisenatide on counter-regulatory responses to hypoglycemia in subjects with insulin-treated type 2 diabetes. Diabetes Care. 2015;39:dc151274. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26537183 (accessed 2018 Jan 15)CrossRef
62.
Carlessi R, Chen Y, Rowlands J, Cruzat VF, Keane KN, Egan L, et al. GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation. Sci Rep. 2017;7:2661. Available: http://​www.​nature.​com/​articles/​s41598-017-02838-2 (accessed 2018 Jan 15)PubMedPubMedCentralCrossRef
63.
Andreozzi F, Raciti GA, Nigro C, Mannino GC, Procopio T, Davalli AM, et al. The GLP-1 receptor agonists exenatide and liraglutide activate glucose transport by an AMPK-dependent mechanism. J Transl Med. 2016;14:229. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27473212 (accessed 2018 Jan 15)PubMedPubMedCentralCrossRef
64.
DeNicola M, Du J, Wang Z, Yano N, Zhang L, Wang Y, et al. Stimulation of glucagon-like peptide-1 receptor through exendin-4 preserves myocardial performance and prevents cardiac remodeling in infarcted myocardium. Am J Physiol Endocrinol Metab. 2014;307:E630–43.PubMedPubMedCentralCrossRef
65.
Aravindhan K, Bao W, Harpel MR, Willette RN, Lepore JJ, Jucker BM. Cardioprotection resulting from glucagon-like peptide-1 administration involves shifting metabolic substrate utilization to increase energy efficiency in the rat heart. PLoS One. 2015;10:e0130894.PubMedPubMedCentralCrossRef
66.
Cai Q, Li B, Yu F, Lu W, Zhang Z, Yin M, et al. Investigation of the protective effects of phlorizin on diabetic cardiomyopathy in db/db mice by quantitative proteomics. J Diabetes Res. 2013;2013:263845.PubMedPubMedCentralCrossRef
67.
Briand F, Mayoux E, Brousseau E, Burr N, Urbain I, Costard C, et al. Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LDL catabolism. Diabetes. 2016;65:2032–8.PubMedCrossRef
68.
Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ. Glucagon-like peptide-1 receptor signaling modulates. Cell Apoptosis. 2002.
69.
Noyan-Ashraf MH, Abdul Momen M, Ban K, Sadi AM, Zhou YQ, Riazi AM, et al. GLP-1R agonist liraglutide activates cytoprotective pathways and improves outcomes after experimental myocardial infarction in mice. Diabetes. 2009;58:975–83.PubMedPubMedCentralCrossRef
70.
Ishibashi Y, Matsui T, Yamagishi S. Tofogliflozin, a highly selective inhibitor of SGLT2 blocks proinflammatory and proapoptotic effects of glucose overload on proximal tubular cells partly by suppressing oxidative stress generation. Horm Metab Res. 2016;48:191–5.PubMed
71.
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
72.
Hamouda NN, Sydorenko V, Qureshi MA, Alkaabi JM, Oz M, Howarth FC. Dapagliflozin reduces the amplitude of shortening and Ca2+ transient in ventricular myocytes from streptozotocin-induced diabetic rats. Mol Cell Biochem. 2014;400:57–68.PubMedCrossRef
73.
Wakisaka M, Nagao T, Yoshinari M. Sodium glucose cotransporter 2 (SGLT2) plays as a physiological glucose sensor and regulates cellular contractility in rat mesangial cells. PLoS One. 2016;11:1–15.CrossRef
74.
Chen J, Wang D, Wang F, Shi S, Chen Y, Yang B, et al. Exendin-4 inhibits structural remodeling and improves Ca 2+ homeostasis in rats with heart failure via the GLP-1 receptor through the eNOS/cGMP/PKG pathway. Peptides. 2017;90:69–77. Available: http://​linkinghub.​elsevier.​com/​retrieve/​pii/​S019697811730049​9 (accessed 2018 Jan 15)PubMedCrossRef
75.
Younce CW, Burmeister MA, Ayala JE. Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am J Physiol Physiol. 2013;304:C508–18. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23302777 (accessed 2018 Jan 15)CrossRef
76.
Smith RJ, Goldfine AB, Hiatt WR. Evaluating the cardiovascular safety of new medications for type 2 diabetes: time to reassess? Diabetes Care. 2016;39:738–42. Available: http://​care.​diabetesjournals​.​org/​lookup/​doi/​10.​2337/​dc15-2237 (accessed 2017 Dec 1)PubMedCrossRef
77.
Young LH. Insulin resistance and the effects of thiazolidinediones on cardiac metabolism. Am J Med. 2003;75S–80S. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​14678870 (accessed 2017 May 13).
78.
Frantz S, Hu K, Widder J, Bayer B, Witzel CC, Schmidt I, et al. Peroxisome proliferator activated-receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction. Br J Pharmacol. 2004;141:9–14. Available: http://​onlinelibrary.​wiley.​com/​store/​10.​1038/​sj.​bjp.​0705585/​asset/​sj.​bjp.​0705585.​pdf;jsessionid=​5A70CB66C4175CC0​884D1F6E08E5C911​.​f01t01?​v=​1&​t=​j2o3a0tk&​s=​26aa795ad4833291​736e0970513e411c​aac037af (accessed 2017 May 13)PubMedCrossRef
79.
Horio T, Suzuki M, Suzuki K, Takamisawa I, Hiuge A, Kamide K, et al. Pioglitazone improves left ventricular diastolic function in patients with essential hypertension. Am J Hypertens. 2005;18:949–57. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​16053992 (accessed 2017 May 13)PubMedCrossRef
80.
Hernandez AV, Usmani A, Rajamanickam A, Moheet A. Thiazolidinediones and risk of heart failure in patients with or at high risk of type 2 diabetes mellitus. Am J Cardiovasc Drugs. 2011;11:115–28. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​21294599 (accessed 2017 May 13)PubMedCrossRef
81.
Horita S, Nakamura M, Satoh N, Suzuki M, Seki G. Thiazolidinediones and edema: recent advances in the pathogenesis of thiazolidinediones-induced renal sodium retention. PPAR Res. 2015;2015:646423. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26074951 (accessed 2017 May 13)PubMedPubMedCentralCrossRef
82.
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet. 2009;373:2125–35. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​19501900 (accessed 2017 May 13)PubMedCrossRef
83.
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, 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;366:1279–89. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​16214598 (accessed 2017 Dec 1)PubMedCrossRef
84.
Liao H-W, Saver JL, Wu Y-L, Chen T-H, Lee M, Ovbiagele B. Pioglitazone and cardiovascular outcomes in patients with insulin resistance, pre-diabetes and type 2 diabetes: a systematic review and meta-analysis. BMJ Open. 2017;7:e013927. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​28057658 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
85.
Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28:1547–54. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​15983299 (accessed 2017 Dec 2)PubMedCrossRef
86.
Sakamoto J, Kimura H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, et al. Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun. 2000;278:704–11. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​11095972 (accessed 2017 Dec 2)PubMedCrossRef
87.
Mortensen K, Christensen LL, Holst JJ, Orskov C. GLP-1 and GIP are colocalized in a subset of endocrine cells in the small intestine. Regul Pept. 2003;114:189–96. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​12832109 (accessed 2017 Dec 1)PubMedCrossRef
88.
BRUBAKER PL. The glucagon-like peptides: pleiotropic regulators of nutrient homeostasis. Ann N Y Acad Sci. 2006;1070:10–26. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​16888147 (accessed 2017 Dec 1)PubMedCrossRef
89.
Lim GE, Brubaker PL. Glucagon-like peptide 1 secretion by the L-cell the view from within. 2006.
90.
Manandhar B, Ahn J-M. Glucagon-like peptide-1 (GLP-1) analogs: recent advances, new possibilities, and therapeutic implications. J Med Chem. 2015;58:1020–37. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25349901 (accessed 2017 Dec 1)PubMedCrossRef
91.
Madsbad S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab. 2016;18:317–32. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26511102 (accessed 2017 Dec 1)PubMedCrossRef
92.
Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26. Available: http://​www.​nejm.​org/​doi/​10.​1056/​NEJMoa1307684 (accessed 2017 May 13)PubMedCrossRef
93.
White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35. Available: http://​www.​nejm.​org/​doi/​10.​1056/​NEJMoa1305889 (accessed 2017 Dec 1)PubMedCrossRef
94.
Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42. Available: http://​www.​nejm.​org/​doi/​10.​1056/​NEJMoa1501352 (accessed 2017 May 13)PubMedCrossRef
95.
Margulies KB, Hernandez AF, Redfield MM, Givertz MM, Oliveira GH, Cole R, et al. Effects of iraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction. JAMA. 2016;316:500. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27483064 (accessed 2017 Dec 1)–8.PubMedPubMedCentralCrossRef
96.
Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32:515–31. Available: https://​academic.​oup.​com/​edrv/​article-lookup/​doi/​10.​1210/​er.​2010-0029 (accessed 2017 Dec 1)PubMedCrossRef
97.
Turko IV, Li L, Aulak KS, Stuehr DJ, Chang J-Y, Murad F. Protein tyrosine nitration in the mitochondria from diabetic mouse heart: implications to dysfunctional mitochondria in diabetes. J Biol Chem. 2003;278:33972–7. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​12821649 (accessed 2017 Apr 22)PubMedCrossRef
98.
Vallon V, Platt KA, Cunard R, Schroth J, Whaley J, Thomson SC, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011;22:104–12. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​20616166 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
99.
Wright EM, Loo DDF, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91:733–94. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​21527736 (accessed 2017 Dec 1)PubMedCrossRef
100.
Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol. 2010;5:133–41. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​19965550 (accessed 2017 Dec 1)PubMedCrossRef
101.
Gorboulev V, Schurmann A, Vallon V, Kipp H, Jaschke A, Klessen D, et al. Na+−D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes. 2012;61:187–96. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22124465 (accessed 2017 Dec 1)PubMedCrossRef
102.
Rieg T, Masuda T, Gerasimova M, Mayoux E, Platt K, Powell DR, et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. AJP Ren Physiol. 2014;306:F188–93. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​24226519 (accessed 2017 Dec 1)CrossRef
103.
Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–70. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25341005 (accessed 2017 Dec 1)PubMedCrossRef
104.
Raskin P. Sodium-glucose cotransporter inhibition: therapeutic potential for the treatment of type 2 diabetes mellitus. Diabetes Metab Res Rev. 2013;29:347–56. Available: http://​doi.​wiley.​com/​10.​1002/​dmrr.​2403 (accessed 2017 Dec 1)PubMedCrossRef
105.
Dandona P, Chaudhuri A. Sodium-glucose co-transporter 2 inhibitors for type 2 diabetes mellitus: an overview for the primary care physician. Int J Clin Pract. 2017;71:e12937. Available: http://​doi.​wiley.​com/​10.​1111/​ijcp.​12937 (accessed 2017 Dec 7)PubMedCentralCrossRef
106.
Song P, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets. 2016;20:1109–25. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26998950 (accessed 2017 Dec 7)PubMedPubMedCentralCrossRef
107.
Solini A, Sebastiani G, Nigi L, Santini E, Rossi C, Dotta F. Dapagliflozin modulates glucagon secretion in an SGLT2-independent manner in murine alpha cells. Diabetes Metab. 2017;43:512–20. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​28499695 (accessed 2017 Dec 7)PubMedCrossRef
108.
Abdul-Ghani MA, DeFronzo RA, Norton L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30–50% of filtered glucose load in humans. Diabetes. 2013;62:3324–8. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​24065789 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
109.
Liu JJ, Lee T, DeFronzo RA. Why do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes. 2012;61:2199–204. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22923645 (accessed 2017 Dec 1)PubMedCrossRef
110.
Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8:330–9. Available: http://​linkinghub.​elsevier.​com/​retrieve/​pii/​S193317111400060​6 (accessed 2017 Dec 1)PubMedCrossRef
111.
Monica Reddy RP, Inzucchi SE. SGLT2 inhibitors in the management of type 2 diabetes. Endocrine. 2016;53:364–72. Available: http://​link.​springer.​com/​10.​1007/​s12020-016-0943-4 (accessed 2017 Dec 1)PubMedCrossRef
112.
Holman RR, Bethel MA, Mentz RJ, Thompson VP, Lokhnygina Y, Buse JB, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39. Available: http://​www.​nejm.​org/​doi/​10.​1056/​NEJMoa1612917 (accessed 2018 Jan 15)PubMedCrossRef
113.
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. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​28522450 (accessed 2018 Jan 15)PubMedPubMedCentralCrossRef
114.
Lytvyn Y, Bjornstad 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. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​29061576 (accessed 2018 Jan 15)PubMedCrossRef
115.
Muskiet MHA, van Bommel EJ, van Raalte DH. Antihypertensive effects of SGLT2 inhibitors in type 2 diabetes. Lancet Diabetes Endocrinol. 2016;4:188–9. Available: http://​linkinghub.​elsevier.​com/​retrieve/​pii/​S221385871500457​X (accessed 2017 Dec 7)PubMedCrossRef
116.
Rask-Madsen C, King GL. Vascular complications of diabetes: mechanisms of injury and protective factors. Cell Metab. 2013;17:20–33. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23312281 (accessed 2017 Dec 10)PubMedPubMedCentralCrossRef
117.
Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, et al. 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;715:246–55. Available: http://​linkinghub.​elsevier.​com/​retrieve/​pii/​S001429991300399​3 (accessed 2017 Dec 10)PubMedCrossRef
118.
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. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​24334175 (accessed 2017 Dec 7)PubMedCrossRef
119.
Han JH, Oh TJ, Lee G, Maeng HJ, Lee DH, Kim KM, et al. The beneficial effects of empagliflozin, an SGLT2 inhibitor, on atherosclerosis in ApoE −/− mice fed a western diet. Diabetologia. 2017;60:364–76. Available: http://​link.​springer.​com/​10.​1007/​s00125-016-4158-2 PubMedCrossRef
120.
Verma S, Fedak PWM, Weisel RD, Butany J, Rao V, Maitland A, et al. Fundamentals of reperfusion injury for the clinical cardiologist. Circulation. 2002;105:2332–6.PubMedCrossRef
121.
Tabatabaei-Malazy O, Fakhrzadeh H, Sharifi F, Mirarefin M, Arzaghi SM, Badamchizadeh Z, et al. Effect of metabolic control on oxidative stress, subclinical atherosclerosis and peripheral artery disease in diabetic patients. J Diabetes Metab Disord. 2015;14:84.PubMedPubMedCentralCrossRef
122.
Saraiva FK, Sposito AC. Cardiovascular effects of glucagon-like peptide 1 (GLP-1) receptor agonists. Cardiovasc Diabetol. 2014;13:142. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25338737 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
123.
Yamagishi S, Matsui T. Pleiotropic effects of glucagon-like peptide-1 (GLP-1)-based therapies on vascular complications in diabetes. Curr Pharm Des. 2011;17:4379–85. Available: http://​www.​eurekaselect.​com/​openurl/​content.​php?​genre=​article&​issn=​1381-6128&​volume=​17&​issue=​38&​spage=​4379 (accessed 2017 Dec 1)PubMedCrossRef
124.
Li N, Li B, Brun T, Deffert-Delbouille C, Mahiout Z, Daali Y, et al. NADPH oxidase NOX2 defines a new antagonistic role for reactive oxygen species and cAMP/PKA in the regulation of insulin secretion. Diabetes. 2012;61:2842–50. Available: http://​diabetes.​diabetesjournals​.​org/​cgi/​doi/​10.​2337/​db12-0009 (accessed 2017 Dec 1)PubMedPubMedCentralCrossRef
125.
Kappe C, Holst JJ, Zhang Q, Sjöholm Å. Molecular mechanisms of lipoapoptosis and metformin protection in GLP-1 secreting cells. Biochem Biophys Res Commun. 2012;427:91–5. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22982676 (accessed 2017 Dec 1)PubMedCrossRef
126.
Mukai E, Fujimoto S, Sato H, Oneyama C, Kominato R, Sato Y, et al. Exendin-4 suppresses SRC activation and reactive oxygen species production in diabetic Goto-Kakizaki rat islets in an Epac-dependent manner. Diabetes. 2011;60:218–26. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​20978090 (accessed 2017 Dec 1)PubMedCrossRef
127.
Erdogdu O, Eriksson L, Xu H, Sjöholm A, Zhang Q, Nyström T. Exendin-4 protects endothelial cells from lipoapoptosis by PKA, PI3K, eNOS, p38 MAPK, and JNK pathways. J Mol Endocrinol. 2013;50:229–41. Available: http://​jme.​endocrinology-journals.​org/​cgi/​doi/​10.​1530/​JME-12-0166 (accessed 2017 Dec 1)PubMedCrossRef
128.
Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises: part I: aging arteries: a “set up” for vascular disease. Circulation. 2003;107:139–46. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​12515756 (accessed 2017 Dec 2)PubMedCrossRef
129.
Minamino T, Komuro I. Vascular cell senescence: contribution to atherosclerosis. Circ Res. 2007;100:15–26. Available: http://​circres.​ahajournals.​org/​cgi/​doi/​10.​1161/​01.​RES.​0000256837.​40544.​4a (accessed 2017 Dec 2)PubMedCrossRef
130.
Berk BC, Haendeler J, Sottile J. Angiotensin II, atherosclerosis, and aortic aneurysms. J Clin Invest. 2000;105:1525–6. Available: http://​www.​jci.​org/​articles/​view/​9820 (accessed 2017 Dec 2)PubMedPubMedCentralCrossRef
131.
Tanaka A, Murohara T, Taguchi I, Eguchi K, Suzuki M, Kitakaze M, et al. 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;15:133. Available: http://​cardiab.​biomedcentral.​com/​articles/​10.​1186/​s12933-016-0449-7 (accessed 2018 Jan 15)PubMedPubMedCentralCrossRef
132.
Kakouros N, Rade JJ, Kourliouros A, Resar JR. Platelet function in patients with diabetes mellitus: from a theoretical to a practical perspective. Int J Endocrinol. 2011;2011:742719. Available: http://​www.​hindawi.​com/​journals/​ije/​2011/​742719/​ (accessed 2017 Dec 2)PubMedPubMedCentralCrossRef
133.
Shang J, Chen Z, Wang M, Li Q, Feng W, Wu Y, et al. Zucker diabetic fatty rats exhibit hypercoagulability and accelerated thrombus formation in the Arterio-Venous shunt model of thrombosis. Thromb Res. 2014;134:433–9.PubMedCrossRef
134.
Mayer P. Chances and risks of SGLT2 inhibitors. Naunyn Schmiedeberg's Arch Pharmacol. 2012;385:551–4.CrossRef
135.
Cameron-Vendrig A, Reheman A, Siraj MA, Xu XR, Wang Y, Lei X, et al. Glucagon-like peptide 1 receptor activation attenuates platelet aggregation and thrombosis. Diabetes. 2016;65:1714–23.PubMedCrossRef
136.
Oliva RV, Bakris GL. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J Am Soc Hypertens. 2014;8:330–9. https://​doi.​org/​10.​1016/​j.​jash.​2014.​02.​003.PubMedCrossRef
137.
Ohkubo T, Imai Y, Tsuji I, Nagai K, Watanabe N, Minami N, et al. Relation between nocturnal decline in blood pressure and mortality: the Ohasama study. Am J Hypertens. 1997;10:1201–7. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​9397237 (accessed 2017 Dec 5)PubMedCrossRef
138.
MORI H, OKADA Y, KAWAGUCHI M, TANAKA Y. A case of type 2 diabetes with a change from a non-dipper to a dipper blood pressure pattern by dapagliflozin. J UOEH. 2016;38:149–53. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​27302728 (accessed 2017 Dec 5)PubMedCrossRef
139.
Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38:420–8. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​25271206 (accessed 2017 Dec 5)PubMedCrossRef
140.
Sano M. Hemodynamic effects of sodium-glucose cotransporter 2 inhibitors. J Clin Med Res. 2017;9:457–60.PubMedPubMedCentralCrossRef
141.
Subramanya AR, Ellison DH. Distal convoluted tubule. Clin J Am Soc Nephrol. 2014;9:2147–63. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​24855283 (accessed 2017 Dec 5)PubMedPubMedCentralCrossRef
142.
Cuspidi C, Meani S, Salerno M, Valerio C, Fusi V, Severgnini B, et al. Cardiovascular target organ damage in essential hypertensives with or without reproducible nocturnal fall in blood pressure. J Hypertens. 2004;22:273–80. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​15076184 (accessed 2017 Dec 5)PubMedCrossRef
143.
Sturrock ND, George E, Pound N, Stevenson J, Peck GM, Sowter H. Non-dipping circadian blood pressure and renal impairment are associated with increased mortality in diabetes mellitus. Diabet Med. 2000;17:360–4. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​10872534 (accessed 2017 Dec 5)PubMedCrossRef
144.
Fogari R, Zoppi A, Malamani GD, Lazzari P, Destro M, Corradi L. Ambulatory blood pressure monitoring in normotensive and hypertensive type 2 diabetes. Prevalence of impaired diurnal blood pressure patterns. Am J Hypertens. 1993;6:1–7. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​8427656 (accessed 2017 Dec 5)PubMedCrossRef
145.
Ayala DE, Moyá A, Crespo JJ, Castiñeira C, Domínguez-Sardiña M, Gomara S, et al. Circadian pattern of ambulatory blood pressure in hypertensive patients with and without type 2 diabetes. Chronobiol Int. 2013;30:99–115. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23098178 (accessed 2017 Dec 5)PubMedCrossRef
146.
Kotsis V, Stabouli S, Papakatsika S, Rizos Z, Parati G. Mechanisms of obesity-induced hypertension. Hypertens Res. 2010;33:386–93. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​20442753 (accessed 2017 Dec 5)PubMedCrossRef
147.
Shimizu I, Yoshida Y, Minamino T. A role for circadian clock in metabolic disease. Hypertens Res. 2016;39:483–91. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26888117 (accessed 2017 Dec 5)PubMedCrossRef
148.
Rieg T, Gerasimova M, Murray F, Masuda T, Tang T, Rose M, et al. Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. AJP Ren Physiol. 2012;303:F963–71. Available: http://​ajprenal.​physiology.​org/​cgi/​doi/​10.​1152/​ajprenal.​00259.​2012 (accessed 2017 Dec 1)CrossRef
149.
Schlatter P, Beglinger C, Drewe J, Gutmann H. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul Pept. 2007;141:120–8. Available: http://​linkinghub.​elsevier.​com/​retrieve/​pii/​S016701150600273​4 (accessed 2017 Dec 5)PubMedCrossRef
150.
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. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​29042392 (accessed 2017 Dec 7)PubMedPubMedCentralCrossRef
151.
Gutzwiller J-P, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89:3055–61. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​15181098 (accessed 2017 Dec 7)PubMedCrossRef
152.
Kim M, Platt MJ, Shibasaki T, Quaggin SE, Backx PH, Seino S, et al. GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat Med. 2013;19:567–75. Available: http://​www.​nature.​com/​doifinder/​10.​1038/​nm.​3128 (accessed 2017 Dec 7)PubMedCrossRef
153.
Ban K, Noyan-Ashraf MH, Hoefer J, Bolz S-S, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and independent pathways. Circulation. 2008;117:2340–50. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​18427132 (accessed 2017 Dec 7)PubMedCrossRef
154.
Movahed M-R, Hashemzadeh M, Jamal MM. Type II diabetes mellitus is independently associated with non-rheumatic aortic valve stenosis or regurgitation. CHEST J. 2005;128:3568–71. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​16304314 (accessed 2017 Dec 7)CrossRef
155.
Chan SY, Loscalzo J. Pathogenic mechanisms of pulmonary arterial hypertension. J Mol Cell Cardiol. 2008;44:14–30. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​17950310 (accessed 2017 Dec 7)PubMedCrossRef
156.
Fiordaliso F, Li B, Latini R, Sonnenblick EH, Anversa P, Leri A, et al. Myocyte death in streptozotocin-induced diabetes in rats in angiotensin II- dependent. Lab Investig. 2000;80:513–27. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​10780668 (accessed 2017 Dec 7)PubMedCrossRef
157.
Patel VB, Bodiga S, Basu R, Das SK, Wang W, Wang Z, et al. Loss of angiotensin-converting enzyme-2 exacerbates diabetic cardiovascular complications and leads to systolic and vascular dysfunction: a critical role of the angiotensin II/AT1 receptor Axis. Circ Res. 2012;110:1322–35. Available: http://​circres.​ahajournals.​org/​cgi/​doi/​10.​1161/​CIRCRESAHA.​112.​268029 (accessed 2017 Dec 7)PubMedPubMedCentralCrossRef
158.
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. Diabetes Obes Metab. 2013;15:853–62. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23668478 (accessed 2017 Dec 7)PubMedCrossRef
159.
Tatarkiewicz K, Polizzi C, Villescaz C, D’Souza LJ, Wang Y, Janssen S, et al. Combined antidiabetic benefits of exenatide and dapagliflozin in diabetic mice. Diabetes Obes Metab. 2014;16:376–80.PubMedCrossRef
160.
Fulcher G, Matthews DR, Perkovic V, de Zeeuw D, Mahaffey KW, Mathieu C, et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18:82–91. Available: http://​doi.​wiley.​com/​10.​1111/​dom.​12589 (accessed 2017 Dec 1)PubMedCrossRef
161.
de Mattos Matheus AS, Tannus LRM, Cobas RA, Palma CCS, Negrato CA, de Brito Gomes M. Impact of diabetes on cardiovascular disease: an update. Int J Hypertens. 2013;2013:1–15. Available: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​23533715 (accessed 2017 Apr 21)CrossRef

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