Empagliflozin as a new management strategy on outcomes in patients with type 2 diabetes mellitus
Abstract
Patients with type 2 diabetes mellitus have an increased risk of cardiovascular (CV) complications. Although hyperglycaemia contributes to the pathogenesis of atherosclerosis and heart failure in these patients, glucose-lowering strategies did not have a significant effect on reducing CV risk, particularly in patients with a long duration of type 2 diabetes mellitus and prevalent CV disease (CVD). Sodium-glucose linked transporter-2 (SGLT2) inhibitors are a new class of anti-hyperglycaemic medications that increase glycaemic control via insulin-dependent mechanism of action associated with increased urinary glucose excretion.
In this review, we present an analysis of the Empa-Reg Outcomes investigation, focussed on assessing the CV safety of empagliflozin, an inhibitor of SGLT2. We discuss the impressive results of trials that provide evidence on the cardiac and renal properties of empagliflozin. We present and analyse the current hypothesis on the mechanism of action of glucose-lowering medication, which has such a severe and complex impact on outcomes in patients with type 2 diabetes at high CV risk.
About the Authors
Vladimir V. SalukhovRussian Federation
MD, PhD
Competing Interests: No conflict of interests
Tatiana Y. Demidova
Russian Federation
MD, PhD, Professor
Competing Interests: No conflict of interests
References
1. Tancredi M, Rosengren A, Svensson AM, et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med. 2015;373(18):1720-1732. doi: 10.1056/NEJMoa1504347
2. Gregg EW, Williams DE, Geiss L. Changes in diabetes-related complications in the United States. N Engl J Med. 2014;371(3):286-287. doi: 10.1056/NEJMc1406009
3. Emerging Risk Factors C, Di Angelantonio E, Kaptoge S, et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52-60. doi: 10.1001/jama.2015.7008
4. Халимов Ю.Ш., Салухов В.В., Улупова Е.О. Гипогликемии как основной фактор выбора целей гликемического контроля и тактики лечения больных сахарным диабетом типа 2. // Consilium medicum. – 2012. – Т. 14. – №12 – С.٢٥-٣٠. [Khalimov YuSh, Salukhov VV, Ulupova EO. Gipoglikemii kak osnovnoy faktor vybora tseley glikemicheskogo kontrolya i taktiki lecheniya bol'nykh sakharnym diabetom tipa 2. Consilium medicum. 2012:14(12):25-30 (in Russ)]
5. Defronzo R. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. Neth J Med. 1997;50(5):191-197. doi: 10.1016/s0300-2977(97)00012-0
6. DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287. doi: 10.1007/s00125-010-1684-1
7. Obunai K, Jani S, Dangas GD. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am. 2007;91(6):1169-1184, x. doi: 10.1016/j.mcna.2007.06.003
8. Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56(4):686-695. doi: 10.1007/s00125-012-2817-5
9. ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328. doi: 10.1056/NEJMoa1203858
10. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1998;352(9131):837-853. doi: 10.1016/s0140-6736(98)07019-6
11. Dormandy JA, Charbonnel B, Eckland DJA, 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. The Lancet. 2005;366(9493):1279-1289. doi: 10.1016/s0140-6736(05)67528-9
12. Miyazaki Y, Mahankali A, Matsuda M, et al. Improved Glycemic Control and Enhanced Insulin Sensitivity in Type 2 Diabetic Subjects Treated With Pioglitazone. Diabetes Care. 2001;24(4):710-719. doi: 10.2337/diacare.24.4.710
13. Шамхалова М.Ш., Ярек-Мартынова И.Р., Трубицына Н.П., и др. Особенности сахароснижающей терапии у больных сахарным диабетом и хронической болезнью почек // Сахарный диабет. – 2013. – Т. 16. – №3 – C. 97-102. [Shamkhalova MS, Yarek-Martynova IR, Trubitcyna NP, Shestakova MV. Glucose-lowering therapies in patients with diabetes mellitus and chronic kidney disease. Diabetes mellitus. 2013;16(3):97-102. (in Russ)] doi: 10.14341/2072-0351-823
14. Шестакова М.В., Шамхалова М.Ш., Ярек-Мартынова И.Я., и др. Сахарный диабет и хроническая болезнь почек: достижения, нерешенные проблемы и перспективы лечения // Сахарный диабет. – 2011. – Т. 14. – №1 – C. 81-88. [Shestakova MV, Shamkhalova MS, Yarek-Martynova IY, et al. Diabetes mellitus and chronic kidney disease: achievements, unresolved problems, and prospects for therapy. Diabetes mellitus. 2011;14(1):81-88. (in Russ)] doi: 10.14341/2072-0351-6254
15. Kimura G. Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis. J Am Soc Hypertens. 2016;10(3):271-278. doi: 10.1016/j.jash.2016.01.009
16. 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(5):587-597. doi: 10.1161/CIRCULATIONAHA.113.005081
17. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720
18. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508. doi: 10.1172/JCI72227
19. 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(5):717-725. doi: 10.2337/dc16-0041
20. Kalra S, Singh V, Nagrale D. Sodium-Glucose Cotransporter-2 Inhibition and the Glomerulus: A Review. Adv Ther. 2016;33(9):1502-1518. doi: 10.1007/s12325-016-0379-5
21. DeFronzo RA, Cooke CR, Andres R, et al. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975;55(4):845-855. doi: 10.1172/JCI107996
22. Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. The Lancet. 2016;387(10017):435-443. doi: 10.1016/s0140-6736(15)00805-3
23. Briand F, Mayoux E, Brousseau E, et al. Empagliflozin, via Switching Metabolism Toward Lipid Utilization, Moderately Increases LDL Cholesterol Levels Through Reduced LDL Catabolism. Diabetes. 2016;65(7):2032-2038. doi: 10.2337/db16-0049
24. Ferrannini G, Hach T, Crowe S, et al. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1730-1735. doi: 10.2337/dc15-0355
25. Amato MC, Giordano C, Galia M, et al. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010;33(4):920-922. doi: 10.2337/dc09-1825
26. Ridderstråle M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691-700. doi: 10.1016/s2213-8587(14)70120-2
27. Bolinder J, Ljunggren O, Kullberg J, 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(3):1020-1031. doi: 10.1210/jc.2011-2260
28. 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(4):262-274. doi: 10.7326/0003-4819-159-4-201308200-00007
29. 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(5):587-597. doi: 10.1161/CIRCULATIONAHA.113.005081
30. Rajasekeran H, Lytvyn Y, Cherney DZ. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524-526. doi: 10.1016/j.kint.2015.12.038
31. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-428. doi: 10.2337/dc14-1096
32. 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(42):3192-3200. doi: 10.1093/eurheartj/ehw110
33. Odden MC, Amadu AR, Smit E, et al. Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2002. Am J Kidney Dis. 2014;64(4):550-557. doi: 10.1053/j.ajkd.2014.04.024
34. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811-1821. doi: 10.1056/NEJMra0800885
35. Lytvyn Y, Skrtic M, Yang GK, et al. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2015;308(2):F77-83. doi: 10.1152/ajprenal.00555.2014
36. Lin B, Koibuchi N, Hasegawa Y, 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. doi: 10.1186/s12933-014-0148-1
37. Taegtmeyer H. Adaptation and Maladaptation of the Heart in Diabetes: Part I: General Concepts. Circulation. 2002;105(14):1727-1733. doi: 10.1161/01.cir.0000012466.50373.e8
38. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920
39. Vallon V, Gerasimova M, Rose MA, 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(2):F194-204. doi: 10.1152/ajprenal.00520.2013
40. Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014;307(3):F317-325. doi: 10.1152/ajprenal.00145.2014
41. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-142. doi: 10.1111/j.1464-5491.2009.02894.x
42. Malatiali S, Francis I, Barac-Nieto M. Phlorizin prevents glomerular hyperfiltration but not hypertrophy in diabetic rats. Exp Diabetes Res. 2008;2008:305403. doi: 10.1155/2008/305403
43. Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-971. doi: 10.1038/ki.2013.356
44. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-473. doi: 10.1111/dom.12090
45. Климонтов В.В., Мякина Н.Е. Хроническая болезнь почек при сахарном диабете. – Новосибирск: Издательство НГУ; 2014. [Klimontov VV, Myakina NE. Khronicheskaya bolezn' pochek pri sakharnom diabete. Novosibirsk: Izdatel'stvo NGU; 2014. (in Russ)]
46. Cherney D, Lund SS, Perkins BA, 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(9):1860-1870. doi: 10.1007/s00125-016-4008-2
47. Pollock CA, Lawrence JR, Field MJ. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am J Physiol. 1991;260(6):F946-F952.
48. Bank N, Aynedjian HS. Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats. J Clin Invest. 1990;86(1):309-316. doi: 10.1172/jci114700
49. Vallon V, RICHTER K, BLANTZ RC, et al. Glomerular hyperfiltration in experimental diabetes mellitus potential role of tubular reabsorption. J Am SocNephrol. 1999;10(12):2569-2576.
50. Scheen AJ. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease. Clin Pharmacokinet. 2015;54(7):691-708. doi: 10.1007/s40262-015-0264-4
51. 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. doi: 10.1186/1475-2840-13-28
52. 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(5):587-597. doi: 10.1161/CIRCULATIONAHA.113.005081
53. Shimizu M, Furuichi K, Toyama T, et al. Long-term outcomes of Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy. Diabetes Care. 2013;36(11):3655-3662. doi: 10.2337/dc13-0298
54. Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217-2224. doi: 10.2337/dc10-0612
55. Rahmoune H, Thompson PW, Ward JM, et al. Glucose Transporters in Human Renal Proximal Tubular Cells Isolated From the Urine of Patients With Non-Insulin-Dependent Diabetes. Diabetes. 2005;54(12):3427-3434. doi: 10.2337/diabetes.54.12.3427
56. Ortola FV, Ballermann BJ, Anderson S, et al. Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration. J Clin Invest. 1987;80(3):670-674. doi: 10.1172/JCI113120
57. 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(10):752-772. doi: 10.1161/CIRCULATIONAHA.116.021887
58. Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-862. doi: 10.1111/dom.12127
59. Liu T, Takimoto E, Dimaano VL, et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res. 2014;115(1):44-54. doi: 10.1161/CIRCRESAHA.115.303062
60. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: Comparison with classic diuretics. Diabetes Metab. 2016;42(4):224-233. doi: 10.1016/j.diabet.2016.05.006
61. Franse LV, Pahor M, Di Bari M, et al. Hypokalemia Associated With Diuretic Use and Cardiovascular Events in the Systolic Hypertension in the Elderly Program. Hypertension. 2000;35(5):1025-1030. doi: 10.1161/01.hyp.35.5.1025
62. Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213-1225. doi: 10.1161/CIRCULATIONAHA.105.595496
63. Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab. 2016;18(1):72-81. doi: 10.1111/dom.12585
64. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016;39(7):1108-1114. doi: 10.2337/dc16-0330
65. Neel JV. Diabetes Mellitus: A “Thrifty” Genotype Rendered Detrimental by “Progress”? Am Journal HumGenet. 1962;14(4):353-362.
66. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016;37(27):2129-2200. doi: 10.1093/eurheartj/ehw128
Supplementary files
![]() |
1. Picture 1245 | |
Subject | ||
Type | Other | |
Download
(614KB)
|
Indexing metadata ▾ |
|
2. Picture 3 | |
Subject | ||
Type | Other | |
View
(90KB)
|
Indexing metadata ▾ |
Review
For citations:
Salukhov V.V., Demidova T.Y. Empagliflozin as a new management strategy on outcomes in patients with type 2 diabetes mellitus. Diabetes mellitus. 2016;19(6):494-510.