Dapagliflozin: potential beneficial effects in the prevention and treatment of renal and cardiovascular complications in patients with type 2 diabetes

Expert Opinion on Pharmacotherapy

Volumn 18, Issue 5, 2017, Pages 517-527

  Fioretto, Paola ^a   Avogaro, Angelo ^a  

^a UNIVERSITY OF PADOVA   (Italy)

Author keywords

Albuminuria; antidiabetic drugs; cardiovascular risk; dapagliflozin; diabetic kidney disease; GFR; glycemic control; sodium glucose cotransporter 2 inhibitors; type 2 diabetes

Indexed keywords

CYTOKINE; DAPAGLIFLOZIN; GLICLAZIDE; HYDROCHLOROTHIAZIDE; METFORMIN; PLACEBO; SODIUM GLUCOSE COTRANSPORTER 2; TOLL LIKE RECEPTOR 4; TRANSFORMING GROWTH FACTOR BETA; TUMOR NECROSIS FACTOR; URIC ACID; 2-(3-(4-ETHOXYBENZYL)-4-CHLOROPHENYL)-6-HYDROXYMETHYLTETRAHYDRO-2H-PYRAN-3,4,5-TRIOL; ANTIDIABETIC AGENT; BENZHYDRYL DERIVATIVE; GLUCOSIDE; SLC5A2 PROTEIN, HUMAN;

ALBUMINURIA; BLOOD PRESSURE; CARDIOVASCULAR EFFECT; CARDIOVASCULAR RISK; CARDIOVASCULAR SYSTEM; CREATININE CLEARANCE; DIABETIC NEPHROPATHY; DISEASE COURSE; DRUG EFFICACY; DRUG SAFETY; END STAGE RENAL DISEASE; GLOMERULUS FILTRATION RATE; GLYCEMIC CONTROL; HEART FAILURE; HEART FUNCTION; HUMAN; HYPERGLYCEMIA; INSULIN SENSITIVITY; INTRAPERITONEAL FAT; KIDNEY DISEASE; KIDNEY INJURY; LIPOLYSIS; MORBIDITY; MORTALITY; NON INSULIN DEPENDENT DIABETES MELLITUS; QUALITY OF LIFE; REVIEW; ANTAGONISTS AND INHIBITORS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DIABETIC NEPHROPATHIES; KIDNEY FAILURE, CHRONIC;

BENZHYDRYL COMPOUNDS; CARDIOVASCULAR DISEASES; DIABETES MELLITUS, TYPE 2; DIABETIC NEPHROPATHIES; GLUCOSIDES; HUMANS; HYPERGLYCEMIA; HYPOGLYCEMIC AGENTS; KIDNEY FAILURE, CHRONIC; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 85016280881     PISSN: 14656566     EISSN: 17447666     Source Type: Journal    
DOI: 10.1080/14656566.2017.1300253     Document Type: Review

References (133)

1. American Diabetes Association. Standards of medical care in diabetes–2015. Diabetes Care. 2015;38:S3–S93.
2. Afkarian M, Sachs MC, Kestenbaum B, et al. Kidney disease and increased mortality risk in type 2 diabetes. J Am Soc Nephrol. 2013;24:302–308.
3. Shaw JE, Sicree RA, Zimmet PZ., Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87:4–14.
4. Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus–present and future perspectives. Nat Rev Endocrinol. 2011;8:228–236.
5. Guariguata L, Whiting DR, Hambleton I, et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract. 2014;103:137–149.
6. Gregg EW, Li Y, Wang J, et al. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370:1514–1523.•• This paper shows the declining prevalence of diabetic complications in recent decades, with the exception of end-stage renal disease.
7. Reutens AT. Epidemiology of diabetic kidney disease. Med Clin North Am. 2013;97:1–18.
8. Ninomiya T, Perkovic V, De Galan BE, et al. Albuminuria and kidney function independently predict cardiovascular and renal outcomes in diabetes. J Am Soc Nephrol. 2009;20:1813–1821.
9. Fioretto P, Dodson PM, Ziegler D, et al. Residual microvascular risk in diabetes:unmet needs and future directions. Nat Rev Endocrinol. 2010;6:19–25.
10. Chao EC, Henry RR. SGLT2 inhibition–a novel strategy for diabetes treatment. Nat Rev Drug Discov. 2010;9:551–559.
11. Vivian EM. Sodium-glucose co-transporter 2 (SGLT2) inhibitors:a growing class of antidiabetic agents. Drugs Context. 2014;3:1–19.
12. Nauck MA. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther. 2014;8:1335–1380.
13. Washburn WN, Poucher SM. Differentiating sodium-glucose co-transporter-2 inhibitors in development for the treatment of type 2 diabetes mellitus. Expert Opin Investig Drugs. 2013;22:463–486.
14. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33–59.
15. 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;159:262–274.
16. Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure:a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8:262–275 e269.
17. Hinnen D. Glucuretic effects and renal safety of dapagliflozin in patients with type 2 diabetes. Ther Adv Endocrinol Metab. 2015;6:92–102.
18. Lambers HHJ, 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;15:853–862.
19. Berhan A, Barker A. Sodium glucose co-transport 2 inhibitors in the treatment of type 2 diabetes mellitus:a meta-analysis of randomized double-blind controlled trials. BMC Endocr Disord. 2013;13:58.
20. Liakos A, Karagiannis T, Bekiari E, et al. Update on long-term efficacy and safety of dapagliflozin in patients with type 2 diabetes mellitus. Ther Adv Endocrinol Metab. 2015;6:61–67.
21. Bristol Meyers Squibb/AstraZeneca. Forxiga (dapagliflozin) 5mg tablets. Summary of product characteristics. 2014.
22. European Medicines Agency. Forxiga (dapagliflozin) 5 mg film-coated tablets:Summary of product characteristics. 2014 [cited 2015 May02]. Available from:http://www.ema.europa.eu
23. Zhang M, Zhang L, Wu B, et al. Dapagliflozin treatment for type 2 diabetes:a systematic review and meta-analysis of randomized controlled trials. Diabetes Metab Res Rev. 2014;30:204–221.
24. Goring S, Hawkins N, Wygant G, et al. Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy:a systematic review and network meta-analysis. Diabetes Obes Metab. 2014;16:433–442.
25. Sun YN, Zhou Y, Chen X, et al. The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes mellitus:meta-analysis of randomised controlled trials. BMJ Open. 2014;4:e004619.
26. Plosker GL. Dapagliflozin:a review of its use in patients with type 2 diabetes. Drugs. 2014;74:2191–2209.
27. Parikh S, Wilding J, Jabbour S, et al. Dapagliflozin in type 2 diabetes:effectiveness across the spectrum of disease and over time. Int J Clin Pract. 2015;69:186–198.
28. Matthaei S, Bowering K, Rohwedder K, et al. Durability and tolerability of dapagliflozin over 52 weeks as add-on to metformin and sulphonylurea in type 2 diabetes. Diabetes Obes Metab. 2015;17:1075–1084.
29. Rosenstock J, Hansen L, Zee P, et al. Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy:a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015;38:376–383.
30. Grandy S, Sternhufvud C, Ryden A, et al. Patient-reported outcomes among patients with type 2 diabetes mellitus treated with dapagliflozin in a triple-therapy regimen for 52 weeks. Diabetes Obes Metab. 2016;18:306–309.
31. Schwartz SS, Katz A. Sodium-glucose cotransporter-2 inhibitor combination therapy to optimize glycemic control and tolerability in patients with type 2 diabetes:focus on dapagliflozin-metformin. Diabetes Metab Syndr Obes. 2016;9:71–82.
32. Ptaszynska A, Johnsson KM, Parikh SJ, et al. Safety profile of dapagliflozin for type 2 diabetes:pooled analysis of clinical studies for overall safety and rare events. Drug Saf. 2014;37:815–829.
33. Min T, Handley J, Williams D, et al. Renal function and dapagliflozin in routine clinical practice. J Diabetes. 2015;7:591–592.
34. Sonesson C, Johansson PA, Johnsson E, et al. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories:a meta-analysis. Cardiovasc Diabetol. 2016;15:37.
35. Cefalu WT, Leiter LA, De Bruin TW, et al. Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes:a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care. 2015;38:1218–1227.
36. Lin HW, Tseng CH. A review on the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol. 2014;2014:1–6.
37. Dziuba J, Alperin P, Racketa J, et al. Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes. Diabetes Obes Metab. 2014;16:628–635.
38. Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus:therapeutic implications. Diabet Med. 2010;27:136–142.
39. Mogensen CE. Maximum tubular reabsorption capacity for glucose and renal hemodynamcis during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest. 1971;28:101–109.
40. Davidson JA, Kuritzky L. Sodium glucose co-transporter 2 inhibitors and their mechanism for improving glycemia in patients with type 2 diabetes. Postgrad Med. 2014;126:33–48.
41. DeFronzo RA, Hompesch M, Kasichayanula S, et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013;36:3169–3176.
42. Thomson SC, Vallon V, Blantz RC. Kidney function in early diabetes:the tubular hypothesis of glomerular filtration. Am J Physiol Renal Physiol. 2004;286:F8–15.
43. Wada J, Makino H. Inflammation and the pathogenesis of diabetic nephropathy. Clin Sci (Lond). 2013;124:139–152.
44. Sasson AN, Cherney DZ. Renal hyperfiltration related to diabetes mellitus and obesity in human disease. World J Diabetes. 2012;3:1–6.
45. Komala MG, Panchapakesan U, Pollock C, et al. Sodium glucose cotransporter 2 and the diabetic kidney. Curr Opin Nephrol Hypertens. 2013;22:113–119.
46. Panchapakesan U, Pegg K, Gross S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy? PLoS One. 2013;8:e54442.
47. 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;32:515–531.
48. Novikov A, Vallon V. Sodium glucose cotransporter 2 inhibition in the diabetic kidney:an update. Curr Opin Nephrol Hypertens. 2016;25:50–58.
49. Skrtic M, Cherney DZ. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr Opin Nephrol Hypertens. 2015;24:96–103.
50. Barnett AH, Mithal A, Manassie J, et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease:a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014;2:369–384.
51. Kohan DE, Fioretto P, Tang W, et al. 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;85:962–971.
52. Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes Metab. 2014;16:1016–1027.
53. Kohan DE, Fioretto P, Johnsson K, et al. The effect of dapagliflozin on renal function in patients with type 2 diabetes. J Nephrol. 2016;29:391–400.
54. Yavin Y, Mansfield TA, Ptaszynska A, et al. Effect of the SGLT2 inhibitor dapagliflozin on potassium levels in patients with type 2 diabetes mellitus:a pooled analysis. Diabetes Ther. 2016;7:125–137.
55. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–334.
56. Thomas MC. Renal effects of dapagliflozin in patients with type 2 diabetes. Ther Adv Endocrinol Metab. 2014;5:53–61.
57. Gilbert RE. Sodium-glucose linked transporter-2 inhibitors:potential for renoprotection beyond blood glucose lowering? Kidney Int. 2014;86:693–700.
58. Lambers Heerspink HJ, Johnsson E, Gause-Nilsson I, et al. Dapagliflozin reduces albuminuria in patients with diabetes and hypertension receiving renin-angiotensin blockers. Diabetes Obes Metab. 2016;18:590–597.
59. Sjostrom CD, Johansson P, Sugg J, et al. Dapagliflozin reduces albuminuria on top of renin-angiotensin system blockade in diabetic patients with moderate renal impairment [Abstract]. Cape Town, South Africa:Publisher; 2015 Mar 13-17.
60. Fioretto P, Stefansson BV, Johnsson E, et al. Dapagliflozin reduces albuminuria over 2 years in patients with type 2 diabetes mellitus and renal impairment. Diabetologia. 2016;59:2036–2039.• This study shows a direct reduction of albuminuria by dapagliflozin.
61. 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;59:1860–1870.
62. Bailey CJ, Iqbal N, T’Joen C, et al. Dapagliflozin monotherapy in drug-naive patients with diabetes:a randomized-controlled trial of low-dose range. Diabetes Obes Metab. 2012;14:951–959.
63. 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;33:2217–2224.
64. Ji L, Ma J, Li H, et al. Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus:a randomized, blinded, prospective phase III study. Clin Ther. 2014;36:84–100 e109.
65. Kaku K, Kiyosue A, Inoue S, et al. Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. Diabetes Obes Metab. 2014;16:1102–1110.
66. List JF, Woo V, Morales E, et al. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009;32:650–657.
67. Kaku K, Inoue S, Matsuoka O, et al. Efficacy and safety of dapagliflozin as a monotherapy for type 2 diabetes mellitus in Japanese patients with inadequate glycaemic control:a phase II multicentre, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2013;15:432–440.
68. Bailey CJ, Morales Villegas EC, Woo V, et al. Efficacy and safety of dapagliflozin monotherapy in people with type 2 diabetes:a randomized double-blind placebo-controlled 102-week trial. Diabet Med. 2015;32:531–541.
69. Bailey CJ, Gross JL, Hennicken D, et al. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin:a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013;11:43.
70. Bailey CJ, Gross JL, Pieters A, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin:a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375:2223–2233.
71. Bolinder J, Ljunggren Ö, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16:159–169.
72. Bolinder J, Ljunggren Ö, 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;97:1020–1031.•• Study showing that dapagliflozin can decrease both subcutaneous and visceral fat tissue.
73. Matthaei S, Bowering K, Rohwedder K, et al. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea:a 24-week randomized, double-blind clinical trial. Diabetes Care. 2015;38:365–372.
74. Nauck MA, Del Prato S, Meier JJ, et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin:a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011;34:2015–2022.
75. Schumm-Draeger PM, Burgess L, Koranyi L, et al. Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes:a 16-week randomized, placebo-controlled clinical trial. Diabetes Obes Metab. 2015;17:42–51.
76. Wilding JP, Woo V, Soler NG, et al. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin:a randomized trial. Ann Intern Med. 2012;156:405–415.
77. Del Prato S, Nauck M, Duran-Garcia S, et al. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes:4-year data. Diabetes Obes Metab. 2015;17:581–590.
78. Wilding JP, Woo V, Rohwedder K, et al. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin:efficacy and safety over 2 years. Diabetes Obes Metab. 2014;16:124–136.
79. Zhang L, Feng Y, List J, et al. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus:effects on glycaemic control and body weight. Diabetes Obes Metab. 2010;12:510–516.
80. Henry RR, Murray AV, Marmolejo MH, et al. Dapagliflozin, metformin XR, or both:initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012;66:446–456.
81. Mathieu C, Ranetti AE, Li D, et al. Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38:2009–2017.
82. Sjostrom CD, Hashemi M, Sugg J, et al. Dapagliflozin-induced weight loss affects 24-week glycated haemoglobin and blood pressure levels. Diabetes Obes Metab. 2015;17:809–812.
83. Jabbour SA, Hardy E, Sugg J, et al. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin:a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care. 2014;37:740–750.
84. Rosenstock J, Vico M, Wei L, et al. Effects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care. 2012;35:1473–1478.
85. Strojek K, Yoon KH, Hruba V, et al. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride:a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2011;13:928–938.
86. Strojek K, Yoon KH, Hruba V, et al. Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks:a randomized, double-blind, parallel-group, placebo-controlled trial. Diabetes Ther. 2014;5:267–283.
87. Leiter LA, Cefalu WT, De Bruin TW, et al. Long-term maintenance of efficacy of dapagliflozin in patients with type 2 diabetes mellitus and cardiovascular disease. Diabetes Obes Metab. 2016;18:766–774.
88. Leiter LA, Cefalu WT, De Bruin TW, et al. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease:a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2014;62:1252–1262.
89. Skolnik N, Bonnes H, Yeh H, et al. Dapagliflozin in the treatment of patients with type 2 diabetes presenting with high baseline A1C. Postgrad Med. 2016;128:356–363.
90. Wilding JP, Norwood P, T’Joen C, et al. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers:applicability of a novel insulin-independent treatment. Diabetes Care. 2009;32:1656–1662.
91. Nauck MA, Del Prato S, Duran-Garcia S, et al. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes Metab. 2014;16:1111–1120.
92. Johnsson K, Johnsson E, Mansfield TA, et al. Osmotic diuresis with SGLT2 inhibition:analysis of events related to volume reduction in dapagliflozin clinical trials. Postgrad Med. 2016;128:346–355.
93. 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.
94. Sjostrom CD, Johansson P, Ptaszynska A, et al. Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diab Vasc Dis Res. 2015;12:352–358.
95. Weber MA, Mansfield TA, Alessi F, et al. Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Press. 2016;25:93–103.
96. Weber MA, Mansfield TA, Cain VA, et al. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy:a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4:211–220.
97. Grundy SM, Brewer HB, Jr., Cleeman JI, et al. Definition of metabolic syndrome:report of the national heart, lung, and blood institute/American Heart Association conference on scientific issues related to definition. Circulation. 2004;109:433–438.
98. Peene B, Benhalima K. Sodium glucose transporter protein 2 inhibitors:focusing on the kidney to treat type 2 diabetes. Ther Adv Endocrinol Metab. 2014;5:124–136.
99. Hayashi T, Yamamoto S, Tomoyasu M, et al. Dapagliflozin increases large, buoyant LDL but reduces small, dense LDL in patients with type 2 diabetes:comparison with sitagliptin [Poster]. New Orleans, LA, USA:Publisher; 2016 Mar 13-17.
100. Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care. 2004;27:1496–1504.
101. Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus:systematic review and network meta-analysis. Diabetes Obes Metab. 2016;18:783–794.
102. 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;65:2032–2038.
103. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis:a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–1693.
104. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100:2849–2852.
105. Handelsman Y, Henry RR, Bloomgarden ZT, et al. American Association of Clinical Endocrinologists and American College of Endocrinology position statement on the association of SGLT-2 inhibitors and diabetic ketoacidosis. Endocr Pract. 2016;22:753–762.
106. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial:a “Thrifty Substrate” hypothesis. Diabetes Care. 2016;39:1108–1114.
107. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? A unifying hypothesis. Diabetes Care. 2016;39:1115–1122.
108. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–2128.•• Study showing significantly decrease in 3-point major adverse cardiac events (MACE) with empagliflozin.
109. Franco OH, Massaro JM, Civil J, et al. Trajectories of entering the metabolic syndrome:the framingham heart study. Circulation. 2009;120:1943–1950.
110. Ptaszynska A, Hardy E, Johnsson E, et al. Effects of dapagliflozin on cardiovascular risk factors. Postgrad Med. 2013;125:181–189.
111. 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.
112. Hamouda NN, Sydorenko V, Qureshi MA, et al. Dapagliflozin reduces the amplitude of shortening and Ca(2+) transient in ventricular myocytes from streptozotocin-induced diabetic rats. Mol Cell Biochem. 2015;400:57–68.
113. Carlson GF, Tou CK, Parikh S, et al. Evaluation of the effect of dapagliflozin on cardiac repolarization:a thorough QT/QTc study. Diabetes Ther. 2011;2:123–132.
114. Efstathiou S, Skeva I, Mountokalakis T. Dapagliflozin may attenuate adipose tissue inflammation and arterial stiffness in type 2 diabetes [poster 1243-P]. Diabetes. 2015;64:A322.
115. Buse JB, Ginsberg HN, Bakris GL, et al. Primary prevention of cardiovascular diseases in people with diabetes mellitus:a scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007;115:114–126.
116. Gross JL, De Azevedo MJ, Silveiro SP, et al. Diabetic nephropathy:diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164–176.
117. 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;37:1526–1534.
118. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes:a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012;55:1577–1596.
119. Rydén L, Grant PJ, Anker SD, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD:the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34:3035–3087.
120. Dutton GR, Lewis CE. The Look AHEAD Trial:implications for lifestyle intervention in type 2 diabetes mellitus. Prog Cardiovasc Dis. 2015;58:69–75.
121. Hudson SR, Chan D, Ng LL. Change in plasma volume and prognosis in acute decompensated heart failure:an observational cohort study. J R Soc Med. 2016;109:337–346.
122. Baartscheer A, Schumacher CA, Wust 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.
123. Lopaschuk GD, Verma S. Empagliflozin’s fuel hypothesis:not so soon. Cell Metab. 2016;24:200–202.
124. Xu Y, Zhu J, Gao L, et al. Hyperuricemia as an independent predictor of vascular complications and mortality in type 2 diabetes patients:a meta-analysis. PLoS One. 2013;8:e78206.
125. Krishnan E, Pandya BJ, Chung L, et al. Hyperuricemia in young adults and risk of insulin resistance, prediabetes, and diabetes:a 15-year follow-up study. Am J Epidemiol. 2012;176:108–116.
126. Ito H, Abe M, Mifune M, et al. Hyperuricemia is independently associated with coronary heart disease and renal dysfunction in patients with type 2 diabetes mellitus. PLoS One. 2011;6:e27817.
127. Cain L, Shankar A, Ducatman AM, et al. The relationship between serum uric acid and chronic kidney disease among Appalachian adults. Nephrol Dial Transplant. 2010;25:3593–3599.
128. Doria A, Krolewski AS. Diabetes:lowering serum uric acid levels to prevent kidney failure. Nat Rev Nephrol. 2011;7:495–496.
129. Fang J, Alderman MH. Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971-1992. National Health and Nutrition Examination Survey. JAMA. 2000;283:2404–2410.
130. Feig DI. Hyperuricemia and hypertension. Adv Chronic Kidney Dis. 2012;19:377–385.
131. Borghi C, Verardi FM, Pareo I, et al. Hyperuricemia and cardiovascular disease risk. Expert Rev Cardiovasc Ther. 2014;12:1219–1225.
132. 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;37:3192–3200.
133. Newman JC, Verdin E. β-hydroxybutyrate:much more than a metabolite. Diabetes Res Clin Pract. 2014;106:173–181.