|Inhibition of the Sodium–Proton Antiporter (Exchanger) is a Plausible Mechanism of Potential Benefit and Harm for Drugs Designed to Block Sodium Glucose Co-transporter 2
|Peter A. McCullough1, 2, 3, 4, *(), Aaron Y. Kluger, Kristen M. Tecson3, 4, 5, Clay M. Barbin1, 2, Andy Y. Lee1, 2, Edgar V. Lerma6, Zachary P. Rosol1, 2, Sivan L. Kluger7, 8, Janani Rangaswami7, 8
|1 Baylor University Medical Center, Dallas, TX 75226
2 Baylor Heart and Vascular Hospital, Dallas, TX 75226
3 Baylor Heart and Vascular Institute, Dallas, TX 75226
4 Texas A & M College of Medicine Health Science Center, Dallas, TX 75226
5 Baylor Scott & White Research Institute, Dallas, TX 75226
6 UIC/Advocate Christ Medical Center, Oak Lawn, IL, 60453
7 Einstein Medical Center, Philadelphia, PA, 19141
8 Sidney Kimmel College of Thomas Jefferson University, Philadelphia, PA, 19107
Clinical trials of sodium glucose co-transporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes and comorbid cardiovascular and kidney disease have shown reductions in major adverse cardiovascular events, heart failure hospitalizations, and attenuation of the progression of kidney disease. The magnitude of benefit appears to be greater than expected due to glycemic control, reduced blood pressure, and loss of adiposity. This impact is also independent from reduced renal function and lesser degrees of natriuresis and glycosuria. However, these agents have also been associated with limb amputation, Fournier’s gangrene, diabetic ketoacidosis, metabolic bone disease, and increased hematopoiesis. A strong off-target effect of SGLT2i on the sodium–proton antiporter (exchanger) on the cell surface and intracellular organelles explains the wide-ranging effects of these agents. By slowing the restoration of pH within cells, SGLT2i activate secondary processes that mimic ischemic preconditioning in the heart and kidney and increased hematopoiesis in bone marrow which would explain salutary effects. Conversely, the inability to rapidly recover pH in ischemic peripheral tissues explains the progression of diabetic extremity ulcers, gangrene, propensity for metabolic bone disease, and diabetic ketoacidosis in patients who are predisposed. This paper will review the evidence for the strong off-target effect of SGLT2i on the sodium-proton exchanger and its potential effect on the organ systems and processes in which SGLT2i appear to have activity.
Published: 30 June 2018
Peter A. McCullough, E-mail: firstname.lastname@example.org
Cite this article:
Peter A. McCullough, Aaron Y. Kluger, Kristen M. Tecson, Clay M. Barbin, Andy Y. Lee, Edgar V. Lerma, Zachary P. Rosol, Sivan L. Kluger, Janani Rangaswami. Inhibition of the Sodium–Proton Antiporter (Exchanger) is a Plausible Mechanism of Potential Benefit and Harm for Drugs Designed to Block Sodium Glucose Co-transporter 2. Reviews in Cardiovascular Medicine, 2018, 19(2): 51-63.
https://rcm.imrpress.com/EN/10.31083/j.rcm.2018.02.021 OR https://rcm.imrpress.com/EN/Y2018/V19/I2/51
|  Armstrong DG, Boulton AJM, Bus SA. Diabetic Foot Ulcers and Their Recurrence. The New England Journal of Medicine. 2017;376:2367-2375.
 Avkiran M and Marber MS. Na(+)/H(+) exchange inhibitors for cardioprotective therapy: progress, problems and prospects. Journal of the American College of Cardiology . 2002;39:747-53.
 Ayoub IM, Kolarova J, Gazmuri RJ. Cariporide given during resuscitation promotes return of electrically stable and mechanically competent cardiac activity. Resuscitation. 2010;81:106-10.
 Baartscheer A, Schumacher CA, Wüst RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60:568-573.
 Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose cotransporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262-75.e9.
 Beydoun R, Hamood MA, Gomez Zubieta DM, et al. Na+/H+ Exchanger 9 Regulates Iron Mobilization at the Blood-Brain Barrier in Response to Iron Starvation. J Biol Chem. 2017;292:4293- 4301.
 Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of Bone Mineral Density and Bone Biomarkers in Patients With Type 2 Diabetes Treated With Canagliflozin. J Clin Endocrinol Metab. 2016;101:44-51.
 Blau JE, Bauman V, Conway EM, et al. Canagliflozin triggers the FGF23/1,25-dihydroxyvitamin D/PTH axis in healthy volunteers in a randomized crossover study. JCI Insight. 2018;3. pii: 99123.
 Blair HC, Larrouture QC, Tourkova IL, et al. Support of bone mineral deposition by regulation of pH. Am J Physiol Cell Physiol. 2018;315:C587-C597.
 Bourgeois S, Meer LV, Wootla B, et al. NHE4 is critical for the renal handling of ammonia in rodents. J Clin Invest. 2010;120:1895- 904.
 Brouwer TF, Vehmeijer JT, Kalkman DN, et al. Intensive Blood Pressure Lowering in Patients With and Patients Without Type 2 Diabetes: A Pooled Analysis From Two Randomized Trials. Diabetes Care. 2018;41:1142-1148.
 Brown DW, Giles WH, Croft JB. Hematocrit and the risk of coronary heart disease mortality. Am Heart J. 2001;142:657-63.
 Carreño JE, Verdugo FJ, Contreras F, et al. Spironolactone inhibits the activity of the Na+/H+ exchanger in the aorta of mineralocorticoid-induced hypertensive rats. J Renin Angiotensin Aldosterone Syst. 2015;16:1225-31.
 Castañeda-Corral G, Rocha-González HI, Araiza-Salda༚ CI, et al. Blockade of peripheral and spinal Na+/H+ exchanger increases formalin-induced long-lasting mechanical allodynia and hyperalgesia in rats. Brain Res. 2012;1475:19-30.
 Chaitman BR. A review of the GUARDIAN trial results: clinical implications and the significance of elevated perioperative CK-MB on 6-month survival. J Card Surg. 2003;18:13-20.
 Chang YK, Choi H, Jeong JY, et al. Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury. PloS one. 2016;11:e0158810.
 Cherney DZ, Perkins BA, Soleymanlou N, 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.
 Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587-97.
 Cherney DZI, Cooper ME, Tikkanen I, et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93:231-244.
 Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes, obesity & metabolism. 2015;17:1180-93.
 Chin KL, Ofori-Asenso R, Hopper I, et al. Potential mechanisms underlying the cardiovascular benefits of sodium glucose cotransporter 2 inhibitors: a systematic review of data from preclinical studies. Cardiovasc Res. 2018.
 Cingolani HE and Ennis IL. Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation. 2007;115:1090-100.
 Clegg LE, Heerspink HJL, Penland RC, et al. Reduction of Cardiovascular Risk and Improved Estimated Glomerular Filtration Rate by SGLT2 Inhibitors, Including Dapagliflozin, Is Consistent Across the Class: An Analysis of the Placebo Arm of EXSCEL. Diabetes Care. 2019;42:318-326.
 Clements-Jewery H, Sutherland FJ, Allen MC, et al. Cardioprotective efficacy of zoniporide, a potent and selective inhibitor of Na+/H+ exchanger isoform 1, in an experimental model of cardiopulmonary bypass. Br J Pharmacol. 2004;142:57-66.
 de Albuquerque Rocha N, Neeland IJ, McCullough PA, et al. Effects of sodium glucose co-transporter 2 inhibitors on the kidney. Diab Vasc Dis Res. 2018;15:375-386.
 Diabetes patients reminded of importance of preventative foot care, SGLT2 inhibitors: information on potential risk of toe amputation to be included in prescribing information. Europen Medicines Agency. 2017;EMA:118223.
 Diering GH and Numata M. Endosomal pH in neuronal signaling and synaptic transmission: role of Na+/H+ exchanger NHE5. Front Physiol. 2014;4:412.
 Douros A, Dell'Aniello S, Yu OHY, et al. Sulfonylureas as second line drugs in type 2 diabetes and the risk of cardiovascular and hypoglycaemic events: population based cohort study. BMJ. 2018;362:k2693.
 Donowitz M, Ming Tse C, Fuster D. SLC9/NHE gene family, a plasma membrane and organellar family of Na+/H+ exchangers. Mol Aspects Med. 2013;34:236-51.
 Fenton RA, Poulsen SB, de la Mora Chavez S, et al. Renal tubular NHE3 is required in the maintenance of water and sodium chloride homeostasis. Kidney Int. 2017;92:397-414.
 Ferrannini E, Baldi S, Frascerra S, 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.
 Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016;39:1108-14.
 FDA Briefing Document: Endocrine and Metabolic Drug Advisory Committee Meeting Empagliflozin. Food and Drug Administration. 2016. https://www.fda.gov/downloads/AdvisoryCommittees/UCM5 08422.pdf
 Fitchett D, Zinman B, Wanner C, et al. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J. 2016;37:1526-34.
 Fitchett DH, Udell JA, Inzucchi SE. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur J Heart Fail. 2017;19:43-53.
 Fliegel L, Dyck JR. Molecular biology of the cardiac sodium/hydrogen exchanger. Cardiovasc Res. 1995;29: 155-159.
 Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a therapeutic target for diabetes: basic physiology and consequences. Diab Vasc Dis Res. 2015;12:78-89.
 Gilbert MP and Pratley RE. The impact of diabetes and diabetes medications on bone health. Endocr Rev. 2015;36:194-213.
 Guidance for Industry Diabetes Mellitus - Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) December 2008.
 Heerspink HJ, Perkins BA, Fitchett DH, et al. 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.
 Heise T, Jordan J, Wanner C, et al. Pharmacodynamic Effects of Single and Multiple Doses of Empagliflozin in Patients With Type 2 Diabetes. Clin Ther. 2016;38:2265-2276.
 Home PD, Pocock SJ, Beck-Nielsen H, 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.
 Rimeporide in Patients With Duchenne Muscular Dystrophy (RIM4DMD). 2016. https://clinicaltrials.gov/ct2/show/NCT02710591
 Inoue BH, dos Santos L, Pessoa TD, et al. Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am J Physiol Regul Integr Comp Physiol. 2012;302:R166- 74.
 Invokana and Invokamet (canagliflozin): Drug Safety Communication - New Information on Bone Fracture Risk and Decreased Bone Mineral Density. Food and Drug Administration. 2018. https://www.fda.gov/Drugs/DrugSafety/ucm461449.htm
 Inzucchi S. SGLT2 inhibition and cardiovascular outcomes. EASD Virtual Meeting. 2016.
 Inzucchi SE, Iliev H, Pfarr E, et al. Empagliflozin and Assessment of Lower-Limb Amputations in the EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41:e4-e5.
 Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90-100.
 Kaneko M, Narukawa M. Assessment of the Risk of Hospitalization for Heart Failure With Dipeptidyl Peptidase-4 Inhibitors, Saxagliptin, Alogliptin, and Sitagliptin in Patients With Type 2 Diabetes, Using an Alternative Measure to the Hazard Ratio. Ann Pharmacother. 2017;51:570-576.
 Karmazyn M, Sostaric JV, Gan XT. The myocardial Na+/H+ exchanger: a potential therapeutic target for the prevention of myocardial ischaemic and reperfusion injury and attenuation of postinfarction heart failure. Drugs. 2001;61:375-89.
 Kaul S, Bolger AF, Herrington D, et al. Thiazolidinedione drugs and cardiovascular risks: a science advisory from the American Heart Association and American College Of Cardiology Foundation. J Am Coll Cardiol. 2010;55:1885-94.
 Kili’c A, Huang CX, Rajapurohitam V, et al. Early and transient sodiumhydrogen exchanger isoform 1 inhibition attenuates subsequent cardiac hypertrophy and heart failure following coronary artery ligation. J Pharmacol Exp Ther. 2014;351:492-9.
 Kosiborod M, Cavender MA, Fu AZ, 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;136:249-259.
 Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular Events Associated With SGLT-2 Inhibitors Versus Other Glucose- Lowering Drugs: The CVD-REAL 2 Study. 2018;71:2628-2639.
 Kumar S, Costello AJ, Colman PG. Fournier's gangrene in a man on empagliflozin for treatment of Type 2 diabetes. Diabet Med. 2017;34:1646-1648.
 Lamoureux L, Radhakrishnan J, Mason TG, et al. Adverse postresuscitation myocardial effects elicited by buffer-induced alkalemia ameliorated by NHE-1 inhibition in a rat model of ventricular fibrillation. J Appl Physiol (1985) . 2016;121:1160-1168.
 Layton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am J Physiol Renal Physiol. 2015;308:F1343-57.
 Lee G, Choi S, Kim K, et al. Association of Hemoglobin Concentration and Its Change With Cardiovascular and All-Cause Mortality. J Am Heart Assoc. 2018;7: e007723.
 Lee SH, Kim T, Park ES, et al. NHE10, an osteoclast-specific member of the Na+/H+ exchanger family, regulates osteoclast differentiation and survival [corrected]. Biochem Biophys Res Commun. 2008;369:320-6.
 Ljunggren Ö, Bolinder J, Johansson L, et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab. 2012;14:990-9.
 Li L, Shen J, Bala MM, Busse JW, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. BMJ. 2014;348:g2366.
 Lin PJ, Williams WP, Luu Y, et al. Secretory carrier membrane proteins exchanger NHE7. J Cell Sci. 2005;118:1885-97.
 Lincoff AM, Wolski K, Nicholls SJ, et al. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Jama. 2007;298:1180-8.
 Liu J, Guo X, Mohandas N, et al. Membrane remodeling during reticulocyte maturation. Blood. 2010;115:2021-7.
 Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation. 2002;106:3068-72.
 Look AHEAD Research Group, Gregg EW, Jakicic JM, Blackburn G, et al. Association of the magnitude of weight loss and changes in physical fitness with long-term cardiovascular disease outcomes in overweight or obese people with type 2 diabetes: a post-hoc analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes Endocrinol. 2016;4:913-921.
 Lopaschuk GD and Verma S. Empagliflozin's Fuel Hypothesis: Not so Soon. Cell Metab. 2016;24:200-2.
 Madonna R and De Caterina R. Sodium-hydrogen exchangers (NHE) in human cardiovascular diseases: interfering strategies and their therapeutic applications. Vascul Pharmacol. 2013;59:127-30.
 McCullough PA, Barnard D, Clare R, et al. Anemia and associated clinical outcomes in patients with heart failure due to reduced left ventricular systolic function. Clin Cardiol. 2013;36:611-20.
 McMurray JJ, Gerstein HC, Holman RR, et al. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014;2:843-51.
 Mozaffarian D, Benjamin EJ, Go AS, et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation. 2016;133:e38-360.
 Mudaliar S, Polidori D, Zambrowicz B, et al. Sodium-Glucose Cotransporter Inhibitors: Effects on Renal and Intestinal Glucose Transport: From Bench to Bedside. Diabetes Care. 2015;38:2344-53.
 Mudaliar S, Alloju S, Henry RR. Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPAREG OUTCOME Study? A Unifying Hypothesis. Diabetes Care. 2016;39:1115-22.
 Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335-80.
 Neal B, Perkovic V, Zeeuw D, et al. Rationale, design, and baseline characteristics of the Canagliflozin cardiovascular assessment study (CANVAS)–a randomized placebo-controlled trial. Am Heart J. 2013;166:217-223.
 Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377:644-657.
 Ohgaki R, van I, Jzendoorn SC, et al. Organellar Na+/H+ exchangers: novel players in organelle pH regulation and their emerging functions. Biochemistry. 2011;50:443-50.
 Ohgaki R, Wei L, Yamada K, et al. Interaction of the Sodium/Glucose Cotransporter (SGLT) 2 inhibitor Canagliflozin with SGLT1 and SGLT2. J Pharmacol Exp Ther. 2016;358:94-102.
 Owan TE, Hodge DO, Herges RM, et al. Trends in prevalence and outcome of heart failure with preserved ejection fraction. The New England journal of medicine. 2006;355:251-9.
 Packer M. Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure. Circulation. 2017;136:1548-1559.
 Packer M, Anker SD, Butler J, et al. Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients With Heart Failure: Proposal of a Novel Mechanism of Action. JAMA Cardiol. 2017;2:1025-1029.
 Pessoa TD, Campos LC, Carraro-Lacroix L, et al. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol. 2014;25:2028-39.
 Pogwizd SM, Sipido KR, Verdonck F, et al. Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc Res. 2003;57:887-96.
 Powell WR, Christiansen CL, Miller DR. Meta-Analysis of Sulfonylurea Therapy on Long-Term Risk of Mortality and Cardiovascular Events Compared to Other Oral Glucose-Lowering Treatments. Diabetes Ther. 2018;9:1431-1440.
 Rådholm K, Figtree G, Perkovic V, et al. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018;CIRCULATIONAHA.118.034222.
 Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89:524-6.
 Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373:1765-72.
 Rivarola V, Di Giusto G, Christensen MJ, Ford P, Capurro C. AQP2- Induced Acceleration of Renal Cell Proliferation Involves the Activation of a Regulatory Volume Increase Mechanism Dependent on NHE2. J Cell Biochem. 2017;118:967-978.
 Rose KL, Watson AJ, Drysdale TA, et al. Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport. Am J Physiol Endocrinol Metab. 2015;309:E370-9.
 Sano M, Takei M, Shiraishi Y et al. 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.
 Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: Comparison with classic diuretics. Diabetes & metabolism. 2016;42:224-33.
 Scheen AJ. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol. 2014;10:647-663.
 Schmieder R, Ott C, Linz P, Jumar A, et al. OS 12-03 SGLT-2-inhibition with dapagliflozin reduces tissue sodium content. J Hypertens. 2016;34(suppl 1):e76.
 Schneider MP, Raff U, Kopp C, et al. Skin sodium concentration correlates with left ventricular hypertrophy in CKD. J Am Soc Nephrol. 2017;28:1867-1876.
 Soler C, Cragoe EJJ, Soley M. Effects of epidermal growth factor on gluconeogenesis and cellular redox state do not require Na+/H+ exchange or Na+/K+-ATPase activities. Regul Pept. 1994;52:1- 6.
 Thomas MC, Tsalamandris C, MacIsaac RJ, et al. The epidemiology of hemoglobin levels in patients with type 2 diabetes. Am J Kidney Dis. 2006;48:537-45.
 Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ. 2018;363:k4365.
 Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia. 2018;61:722-726.
 Uthman L, Baartscheer A, Schumacher CA, et al. Direct Cardiac Actions of Sodium Glucose Cotransporter 2 Inhibitors Target Pathogenic Mechanisms Underlying Heart Failure in Diabetic Patients. Front Physiol. 2018;9:1575.
 Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159:262-74.
 Verma S and McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108-2117.
 Verma S, Rawat S, Ho KL, et al. Empagliflozin Increases Cardiac Energy Production in Diabetes: Novel Translational Insights Into the Heart Failure Benefits of SGLT2 Inhibitors. JACC Basic Transl Sci. 2018;3:575-587.
 Wang A, Li J, Zhao Y, et al. Loss of NHE8 expression impairs intestinal mucosal integrity. Am J Physiol Gastrointest Liver Physiol. 2015;309:G855-64.
 Wakabayashi S, Hisamitsu T, Nakamura TY. Regulation of the cardiac Na+/H+ exchanger in health and disease. J Mol Cell Cardiol. 2013;61:68-76.
 Watts NB, Bilezikian JP, Usiskin K, et al. Effects of Canagliflozin on Fracture Risk in Patients With Type 2 Diabetes Mellitus. J Clin Endocrinol Metab. 2016;101:157-66.
 WHO. Global Report on Diabetes. 2016; http://apps.who.int/iris/bitstream/10665/204871/1/97892 41565257_eng.pdf?ua=1, Accessed December 20, 2016.
 Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2018;308:347- 357.
 Writing Committee, Das SR, Everett BM, et al. ACC Expert Consensus Decision Pathway on Novel Therapies for Cardiovascular Risk Reduction in Patients With Type 2 Diabetes and Atherosclerotic Cardiovascular Disease: A Report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018; S0735-1097:38498-5.
 Xu M, Ouyang Q, Gong J, et al. Mixed Neurodevelopmental and Neurodegenerative Pathology in Nhe6-Null Mouse Model of Christianson Syndrome. eNeuro. 2018;4: ENEURO.0388-17.
 Ye Y, Jia X, Bajaj M, Birnbaum Y. Dapagliflozin Attenuates Na+/H+ Exchanger-1 in Cardiofibroblasts via AMPK Activation. Cardiovasc Drugs Ther. 2018.
 Yuan FL, Wu QY, Miao ZN, et al. Osteoclast-Derived Extracellular Vesicles: Novel Regulators of Osteoclastogenesis and Osteoclast- Osteoblasts Communication in Bone Remodeling. Front Physiol. 2018;9:628.
 Zannad F, Stough WG, Lipicky RJ, et al. Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion. Eur Heart J Cardiovasc Pharmacother. 2016;2:200-5.
 Zelniker TA, Braunwald E. Cardiac and Renal Effects of Sodium- Glucose Co-Transporter 2 Inhibitors in Diabetes: JACC State-ofthe- Art Review. J Am Coll Cardiol. 2018;72:1845-1855.
 Zelniker TA, Wiviott SD, Raz I, et al. 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. 2018; pii: S0140- 6736(18)32590-X.
 Zerbini G, Maestroni A, Mangili R, et al. Amiloride-insensitive Na+-H+ exchange: a candidate mediator of erythrocyte Na+-Li+ countertransport. J Am Soc Nephrol. 1998;9:2203-11.
 Zeymer U, Suryapranata H, Monassier JP, et al. The Na+/H+ exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction: results of the Evaluation of the Safety and Cardioprotective Effects of Eniporide in Acute Myocardial Infarction (ESCAMI) trial. J Am Coll Cardiol. 2001;38:1644-1650.
 Zinman B, Inzucchi SE, Lachin JM, et al. EMPA-REG OUTCOME Investigators (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Empagliflozin and Cerebrovascular Events in Patients With Type 2 Diabetes Mellitus at High Cardiovascular Risk. Stroke. 2017;48:1218-1225.
 Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. The New England journal of medicine. 2016;374:1094.
 Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. The New England journal of medicine. 2015;373:2117-28.
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