Renal, metabolic and cardiovascular considerations of SGLT2 inhibition

Nature Reviews Nephrology

Volumn 13, Issue 1, 2017, Pages 11-26

  DeFronzo, Ralph A ^a   Norton, Luke ^a   Abdul Ghani, Muhammad ^a  

^a UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; EMPAGLIFLOZIN; GLIMEPIRIDE; HEMOGLOBIN A1C; METFORMIN; SODIUM GLUCOSE COTRANSPORTER 1; SODIUM GLUCOSE COTRANSPORTER 2; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SOTAGLIFLOZIN; GLUCOSE; GLUCOSE BLOOD LEVEL; SLC5A1 PROTEIN, HUMAN; SLC5A2 PROTEIN, HUMAN;

CARDIOVASCULAR DISEASE; CARDIOVASCULAR MORTALITY; DIABETES MELLITUS; DIABETIC NEPHROPATHY; DRUG BIOAVAILABILITY; DRUG EFFICACY; GLUCONEOGENESIS; GLUCOSE HOMEOSTASIS; GLUCOSE METABOLISM; GLUCOSE TRANSPORT; GLUCOSURIA; GLUCOTOXICITY; GLYCEMIC CONTROL; HEART PROTECTION; HEMOGLOBIN BLOOD LEVEL; HUMAN; IMMUNOLOCALIZATION; INSULIN RELEASE; INSULIN SENSITIVITY; KIDNEY FUNCTION; KIDNEY PROXIMAL TUBULE; KIDNEY TUBULE ABSORPTION; NONHUMAN; PRIORITY JOURNAL; PROTEINURIA; RENAL MEDULLARY CELL; REVIEW; ANIMAL; ANTAGONISTS AND INHIBITORS; CARDIOVASCULAR DISEASES; GLUCOSE BLOOD LEVEL; HOMEOSTASIS; KIDNEY; METABOLISM; PHYSIOLOGY;

ANIMALS; BLOOD GLUCOSE; CARDIOVASCULAR DISEASES; GLUCOSE; HOMEOSTASIS; HUMANS; KIDNEY; RENAL REABSORPTION; SODIUM-GLUCOSE TRANSPORTER 1; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 85003855318     PISSN: 17595061     EISSN: 1759507X     Source Type: Journal    
DOI: 10.1038/nrneph.2016.170     Document Type: Review

References (135)

1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352, 837-853 (1998).
2. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977-986 (1993).
3. Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577-1589 (2008).
4. Hayward, R. A. et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 372, 2197-2206 (2015).
5. Ferrannini, E. & DeFronzo, R. A. Impact of glucose lowering drugs on cardiovascular disease in type 2 diabetes. Eur. Heart J. 36, 2288-2296 (2015).
6. DeFronzo, R. A. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia 53, 1270-1287 (2010).
7. Action to Control Cardiovascular Risk in Diabetes Study Group. et al. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545-2559 (2008).
8. Patel, A. et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560-2572 (2008).
9. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129-139 (2009).
10. Look Ahead Research Group. Eight-year weight losses with an intensive lifestyle intervention: the look AHEAD study. Obesity (Silver Spring) 22, 5-13 (2014).
11. Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117-2128 (2015).
12. Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311-322 (2016).
13. Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 374, 323-334 (2016).
14. DeFronzo, R. A. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58, 773-795 (2009).
15. Stumvoll, M., Meyer, C., Mitrakou, A., Nadkarni, V. & Gerich, J. E. Renal glucose production and utilization: new aspects in humans. Diabetologia 40, 749-757 (1997).
16. Gustavson, S. M. et al. Effects of hyperglycemia, glucagon, and epinephrine on renal glucose release in the conscious dog. Metabolism 53, 933-941 (2004).
17. Stumvoll, M. et al. Uptake and release of glucose by the human kidney. Postabsorptive rates and responses to epinephrine. J. Clin. Invest. 96, 2528-2533 (1995).
18. Vallon, V. 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. 306, F194-F204 (2014).
19. Handelsman, Y. 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. 22, 753-762 (2016).
20. Vrhovac, I. et al. Localizations of Na D glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch. 467, 1881-1898 (2014).
21. Wright, E. M., Loo, D. D. & Hirayama, B. A. Biology of human sodium glucose transporters. Physiol. Rev. 91, 733-794 (2011).
22. Bonner, C. et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat. Med. 21, 512-517 (2015).
23. +/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Invest. 93, 397-404 (1994).
24. Merovci, A. et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest. 124, 509-514 (2014).
25. Farber, S. J., Berger, E. Y. & Earle, D. P. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J. Clin. Invest. 30, 125-129 (1951).
26. DeFronzo, R. A. et al. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care 36, 3169-3176 (2013).
27. Mogensen, C. E. Maximum tubular reabsorption capacity for glucose and renal hemodynamcis during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand. J. Clin. Lab. Invest. 28, 101-109 (1971).
28. Kamran, M., Peterson, R. G. & Dominguez, J. H. Overexpression of GLUT2 gene in renal proximal tubules of diabetic Zucker rats. J. Am. Soc. Nephrol. 8, 943-948 (1997).
29. Abdul-Ghani, M. A., DeFronzo, R. A. & Norton, L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. Diabetes 62, 3324-3328 (2013).
30. Rahmoune, H. et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54, 3427-3434 (2005).
31. +-glucose transporter 2 messenger ribonucleic acid expression in kidney of diabetic rats correlates with glycemic levels: involvement of hepatocyte nuclear factor 1α expression and activity. Endocrinology 149, 717-724 (2008).
32. Abdul-Ghani, M. A., Norton, L. & DeFronzo, R. A. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr. Rev. 32, 515-531 (2011).
33. Vallon, V. et al. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am. J. Physiol. Renal Physiol. 304, F156-F167 (2013).
34. Felicetta, J. V. & Sowers, J. R. Systemic hypertension in diabetes mellitus. Am. J. Cardiol. 61, 34H-40H (1988).
35. Rossetti, L., Shulman, G. I., Zawalich, W. & DeFronzo, R. A. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J. Clin. Invest. 80, 1037-1044 (1987).
36. Rossetti, L., Smith, D., Shulman, G. I., Papachristou, D. & DeFronzo, R. A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest. 79, 1510-1515 (1987).
37. Kahn, B. B., Shulman, G. I., DeFronzo, R. A., Cushman, S. W. & Rossetti, L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression. J. Clin. Invest. 87, 561-570 (1991).
38. Katsuno, K. et al. Sergliflozin, a novel selective inhibitor of low-affinity sodium glucose cotransporter (SGLT2), validates the critical role of SGLT2 in renal glucose reabsorption and modulates plasma glucose level. J. Pharmacol. Exp. Ther. 320, 323-330 (2007).
39. Sha, S. et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects. Diabetes Obes. Metab. 13, 669-672 (2011).
40. Polidori, D. et al. Validation of a novel method for determining the renal threshold for glucose excretion in untreated and canagliflozin-treated subjects with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 98, E867-E871 (2013).
41. Grempler, R. et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT 2 inhibitors. Diabetes Obes. Metab. 14, 83-90 (2012).
42. Komoroski, B. et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Ther. 85, 520-526 (2009).
43. Sarashina, A. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of single doses of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, in healthy Japanese subjects. Drug Metab. Pharmacokinet. 28, 213-219 (2013).
44. +-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61, 187-196 (2012).
45. Powell, D. R. et al. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am. J. Physiol. Endocrinol. Metab. 304, E117-E130 (2013).
46. Rieg, T. et al. Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia. Am. J. Physiol. Renal Physiol. 306, F188-F193 (2014).
47. McKeown, J. W., Brazy, P. C. & Dennis, V. T. Intrarenal heterogeneity for fluid, phosphate, and glucose absorption in the rabbit. Am. J. Physiol. 237, F3112-F3318 (1979).
48. Powell, D. R. et al. LX4211 increases serum glucagon like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J. Pharmacol. Exp. Ther. 345, 250-259 (2013).
49. Zambrowicz, B. et al. Effects of LX4211, a dual SGLT1/SGLT2 inhibitor, plus sitagliptin on postprandial active GLP 1 and glycemic control in type 2 diabetes. Clin. Ther. 35, 273-285.e7 (2013).
50. Cariou, B. & Charbonnel, B. Sotagliflozin as a potential treatment for type 2 diabetes mellitus. Expert Opin. Investig. Drugs 24, 1647-1656 (2015).
51. Song, P., Onishi, A., Koepsell, H. & Vallon, V. Sodium glucose contransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin. Ther. Targets 20, 1109-1125 (2016).
52. Komoroski, B. et al. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin. Pharmacol. Ther. 85, 513-519 (2009).
53. Vasilakou, D. et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med. 159, 262-274 (2013).
54. Scheen, A. J. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75, 33-59 (2015).
55. Abdul-Ghani, M. A., Norton, L. & DeFronzo, R. A. Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Curr. Diab. Rep. 12, 230-238 (2012).
56. Nauck, M. A. 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 34, 2015-2022 (2011).
57. Nauck, M. A. 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. 16, 1111-1120 (2014).
58. Lavalle-Gonzalez, F. J. et al. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia 56, 2582-2592 (2013).
59. Schernthaner, G. et al. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care 36, 2508-2515 (2013).
60. Del Prato, 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. 17, 581-590 (2015).
61. Leiter, L. A. et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 38, 355-364 (2015).
62. Zhang, L., Feng, Y., List, J., Kasichayanula, S. & Pfister, M. Dapagliflozin treatment in patients with different stages of type 2 diabetes mellitus: effects on glycaemic control and body weight. Diabetes Obes. Metab. 12, 510-516 (2010).
63. Wilding, J. P. 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 32, 1656-1662 (2009).
64. Neal, B. et al. Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS) - a randomized placebo-controlled trial. Am. Heart J. 166, 217-223.e11 (2013).
65. Rosenstock, J. et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care 37, 1815-1823 (2014).
66. Henry, R. R., Thakkar, P., Tong, C., Polidori, D. & Alba, M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add on to insulin in patients with type 1 diabetes. Diabetes Care 38, 2258-2265 (2015).
67. Lamos, E. M., Younk, L. M. & Davis, S. N. Empagliflozin, a sodium glucose co-transporter 2 inhibitor, in the treatment of type 1 diabetes. Expert Opin. Investig. Drugs 23, 875-882 (2014).
68. DeFronzo, R. A., Stonehouse, A. H., Han, J. & Wintle, M. E. Relationship of baseline HbA1c and efficacy of current glucose-loweing therapies: a meta-analysis of randomized clinical trials. Diabet. Med. 27, 309-317 (2010).
69. DeFronzo, R. A. et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 38, 384-393 (2015).
70. Rosenstock, J. 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 38, 376-383 (2015).
71. Ferrannini, E., Ramos, S. J., Salsali, A., Tang, W. & List, J. F. 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 33, 2217-2224 (2010).
72. Ferrannini, E. et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J. Clin. Invest. 124, 499-508 (2014).
73. Merovci, A. et al. Dapagliflozin lowers plasma glucose concentration and improves β-cell function. J. Clin. Endocrinol. Metab. 100, 1927-1932 (2015).
74. Eldor, R. et al. Discordance between central (brain) and pancreatic action of exenatide in lean and obese subjects. Diabetes Care 39, 1804-1810 (2016).
75. Merovci, A. et al. Effect of dapagliflozin with and without acipimox on insulin sensitivity and insulin secretion in T2DM males. J. Clin. Endocrinol. Metab. 101, 1249-1256 (2016).
76. Ferrannini, E. et al. Shift to fatty substrates utilization in response to sodium-glucose co-transporter-2 inhibition in nondiabetic subjects and type 2 diabetic patients. Diabetes 65, 1190-1195 (2016).
77. Bonadonna, R. C. et al. Transmembrane glucose transport in skeletal muscle of patients with non insulin-dependent diabetes. J. Clin. Invest. 92, 486-494 (1993).
78. Groop, L. C., Bonadonna, R. C., Shank, M., Petrides, A. S. & DeFronzo, R. A. Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man. Clin. Invest. 87, 83-89 (1991).
79. Bays, H., Mandarino, L. & DeFronzo, R. A. Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J. Clin. Endocrinol. Metab. 89, 463-478 (2004).
80. Hansen, L., Iqbal, N., Ekholm, E., Cook, W. & Hirshberg, B. Postprandial dynamics of plasma glucose, insulin, and glucagon in patients with type 2 diabetes treated with saxagliptin plus dapagliflozin add on to metformin therapy. Endocr. Pract. 20, 1187-1197 (2014).
81. Lambers Heerspink, H. J., 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. 15, 853-862 (2013).
82. Oliva, R. V. & Bakris, G. L. Blood pressure effects of sodium-glucose co-transport 2 (SGLT2) inhibitors. J. Am. Soc. Hypertens. 8, 330-339 (2014).
83. Jiang, F. et al. Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. Nat. Rev. Cardiol. 11, 413-426 (2014).
84. Feig, D. I., Kang, D. H. & Johnson, R. J. Uric acid and cardiovascular risk. N. Engl. J. Med. 359, 1811-1821 (2008).
85. Yamout, H. et al. Efficacy and safety of canagliflozin in patients with type 2 diabetes and stage 3 nephropathy. Am. J. Nephrol. 40, 64-74 (2014).
86. Abdul-Ghani, M., Del Prato, S. & DeFronzo, R. A. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME Study. Diabetes Care 39, 1-9 (2016).
87. Skrtic, M. & Cherney, D. Z. Sodium-glucose cotransporter-2 inhibition and the potential for renal protection in diabetic nephropathy. Curr. Opin. Nephrol. Hypertens. 24, 96-103 (2015).
88. Hostetter, T. H., Rennke, H. G. & Brenner, B. M. The case for intrarenal hypertension in the initiation and progression of diabetic and other glomerulopathies. Am. J. Med. 72, 375-380 (1982).
89. Nelson, R. G. et al. Development and progression of renal disease in Pima Indians with non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 335, 1636-1642 (1996).
90. Ruggenenti, P. et al. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 35, 2061-2068 (2012).
91. +-glucose cotransporter inhibitor T-1095. Br. J. Pharmacol. 132, 578-586 (2001).
92. Cherney, D. Z. et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129, 587-597 (2014).
93. Hostetter, T. H., Troy, J. L. & Brenner, B. M. Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int. 19, 410-415 (1981).
94. Tuttle, K. R. et al. Effect of strict glycemic control on renal hemodynamic response to amino acids and renal enlargement in insulin-dependent diabetes mellitus. N. Engl. J. Med. 324, 1626-1632 (1991).
95. Cherney, D. Z. et al. Empagliflozin reduces microalbuminura and macroalbuminuria in patients with type 2 diabetes. Poster SA-PO-1109 presented at American Society of Nephrology Kidney Week. November 7, 2015: San Diego, CA.
96. Yale, J. F. et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes. Metab. 15, 463-473 (2013).
97. Barnett, A. H. 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. 2, 369-384 (2014).
98. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02065791 (2016).
99. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01989754 (2016).
100. Bolinder, 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. 97, 1020-1031 (2012).
101. Cefalu, W. T. et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 382, 942-950 (2013).
102. Devenny, J. J. et al. Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring) 20, 1645-1652 (2012).
103. Ferrannini, G. et al. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care 38, 1730-1735 (2015).
104. Bode, B. et al. Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes. Diabetes Obes. Metab. 17, 294-303 (2015).
105. Stenlof, K. et al. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr. Med. Res. Opin. 30, 163-175 (2014).
106. Briand, F. et al. Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LLD catabolism. Diabetes 65, 2032-2038 (2016).
107. Di Angelantonio, E. et al. Association of cardiometabolic multimorbidity with mortality. JAMA 314, 52-60 (2015).
108. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med. 339, 1349-1357 (1998).
109. Patel, A. et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370, 829-840 (2007).
110. Sattar, N., McLaren, J., Kristensen, S. L., Preiss, D. & McMurray, J. J. SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia 59, 1333-1339 (2016).
111. Scheen, A. J. Reduction in cardiovascular and all cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 42, 71-76 (2016).
112. Ferrannini, E., Mark, M. & Mayoux, E. CV protection in the EMPA-REG OUTCOME trial: a "thrifty substrate" hypothesis. Diabetes Care 39, 1108-1114 (2016).
113. Mudaliar, S., Alloju, S. & Henry, R. R. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? A unifying hypothesis. Diabetes Care 39, 1115-1122 (2016).
114. Scirica, B. M. et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369, 1317-1326 (2013).
115. White, W. B. et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369, 1327-1335 (2013).
116. Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373, 232-242 (2015).
117. Daniele, G. et al. Dapagliflozin enhances fat oxidation but decreases mitochondrial ATP synthesis rate in type 2 diabetes patients. Diabetes Care 39, 2036-2041 (2016).
118. Ferrannini, E. The theoretical bases of indirect calorimetry: a review. Metabolism 37, 287-301 (1988).
119. Cotter, D. G., Schugar, R. C. & Crawford, P. A. Ketone body metabolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, H1060-H1076 (2013).
120. Xie, X. et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. Lancet 387, 435-443 (2016).
121. Cruickshank, K. et al. Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function? Circulation 106, 2085-2090 (2002).
122. Roman, M. J. et al. Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study. Hypertension 50, 197-203 (2007).
123. Scheen, A. J. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: comparison with classic diuretics. Diabetes Metab. 42, 224-233 (2016).
124. McMurray, J. EMPA-REG - the "diuretic hypothesis". J. Diabetes Complications 30, 3-4 (2016).
125. Kimura, G. Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis. J. Am. Soc. Hypertens. 10, 271-278 (2016).
126. Thuesen, L., Christiansen, J. S., Sorensen, K. E., Orskov, H. & Henningsen, P. Low-dose intravenous glucagon has no effect on myocardial contractility in normal man. An echocardiographic study. Scand. J. Clin. Lab. Invest. 48, 71-75 (1988).
127. Ali, S. et al. Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. Mol. Metab. 4, 132-143 (2015).
128. Levelt, E. et al. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes. Diabetes 65, 44-52 (2016).
129. Dziuba, J. et al. Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes. Diabetes Obes. Metab. 16, 628-635 (2014).
130. Peters, A. L. et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 38, 1687-1693 (2015).
131. Farxiga highlights of prescribing information. azpicentral http://www1.astrazeneca-us.com/pi/pi-farxiga.pdf (accessed 9 March 2016).
132. Ptaszynska, A. et al. Assessing bladder cancer risk in type 2 diabetes clinical trials: the dapagliflozin drug development program as a 'case study'. Diabetes Ther. 6, 357-375 (2015).
133. US Food and Drug Administration. FDA Drug Safety Communication: FDA revises label of diabetes drug canagliflozin (Invokana, Invokamet) to include updates on bone fracture risk and new information on decreased bone mineral density. FDA http://www.fda.gov/Drugs/DrugSafety/ucm461449.htm (2016).
134. Ljunggren, O. 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. 14, 990-999 (2012).
135. US Food and Drug Administration. FDA Drug Safety Communication: interim clinical trial results find increased risk of leg and foot amputations, mostly affecting the toes, with the diabetes medicine canagliflozin (Invokana, Invokamet); FDA to investigate. FDA http://www.fda.gov/Drugs/DrugSafety/ucm500965.htm (2016).