Renal, metabolic and cardiovascular considerations of SGLT2 inhibition

Key Points

  • The kidneys contribute to the maintenance of normal glucose homeostasis by using glucose as a metabolic fuel, by producing glucose via gluconeogenesis, and by reabsorbing all filtered glucose

  • Under physiological conditions SGLT2 reabsorbs the majority (80–90%) of filtered glucose, while SGLT1 reabsorbs the remaining 10–20% of glucose

  • Kidneys contribute to the development of hyperglycaemia in diabetes by producing excess amounts of glucose and by increasing glucose reabsorption in response to an elevated threshold for glucosuria and an increase in the maximum glucose reabsorptive capacity (TmG)

  • SGLT2 inhibitors improve glucose tolerance by reducing both the threshold for glucosuria and the TmG and by ameliorating glucotoxicity leading to enhanced β-cell function and improved insulin sensitivity in muscle

  • The efficacy of SGLT2 inhibitors is partially offset by an increase in endogenous glucose production and enhanced glucose reabsorption by SGLT1

  • Findings from the EMPA-REG OUTCOME study suggest that the SGLT2 inhibitors might be beneficial in reducing cardiovascular events and preventing the progression of renal disease in patients with type 2 diabetes mellitus at high cardiovascular risk

Abstract

The kidney has a pivotal role in maintaining glucose homeostasis by using glucose as a metabolic fuel, by producing glucose through gluconeogenesis, and by reabsorbing all filtered glucose through the sodium–glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In patients with diabetes, the maximum glucose reabsorptive capacity (TmG) of the kidney, as well as the threshold for glucose spillage into the urine, are elevated, contributing to the pathogenesis of hyperglycaemia. By reducing the TmG and, more importantly, the threshold of glucosuria, SGLT2 inhibitors enhance glucose excretion, leading to a reduction in fasting and postprandial plasma glucose levels and improvements in both insulin secretion and insulin sensitivity. The beneficial effects of SGLT2 inhibition extend beyond glycaemic control, however, with new studies demonstrating that inhibition of renal glucose reabsorption reduces blood pressure, ameliorates glucotoxicity and induces haemodynamic effects that lead to improved cardiovascular and renal outcomes in patients with type 2 diabetes mellitus. In this Review we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on renal function, glucose homeostasis, and cardiovascular disease.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Role of the kidney in glucose homeostasis.
Figure 2: Glucose handling by the kidney.
Figure 3: Effect of dapagliflozin on maximum renal glucose reabsorption (TmG) and glucose threshold.
Figure 4: Effect of dapagliflozin on HbA1c and body weight.
Figure 5: Effect of dapagliflozin on tissue sensitivity to insulin and β-cell function.
Figure 6: Effect of diabetes and SGLT2 inhibition on afferent and efferent arteriolar tone, glomerular filtration rate (GFR), and sodium (Na+) excretion.
Figure 7: Effect of empagliflozin on cardiovascular events.
Figure 8: Potential mechanisms for the beneficial effect of empagliflozin on cardiovascular outcomes.
Figure 9: Beneficial effects of SGLT2 inhibition on glucose homeostasis and the cardiovascular and renal systems.

References

  1. 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). First study to demonstrate that improved glycaemic control reduces microvascular complications in T2DM.

  2. 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). First study to demonstrate that improved glycaemic control decreases microvascular complications in T1DM.

  3. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  5. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. 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). Review of the relationship between insulin resistance and the development of atherosclerotic cardiovascular disease.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  9. 9

    Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129–139 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 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. 11

    Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015). First study to demonstrate that an SGLT2 inhibitor, empagliflozin decreases MACE (Major Adverse Cardiovascular Events) and hospitalization for heart failure in patients with T2DM.

    CAS  Article  Google Scholar 

  12. 12

    Marso, S. P. et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375, 311–322 (2016). First study to demonstrate that a glucagon-like peptide-1 (GLP-1) receptor agonist reduces MACE in patients with T2DM.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  13. 13

    Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 374, 323–334 (2016). Kidney disease was a secondary end point in the EMPA-REG OUTCOME study. Empagliflozin significantly decreased the composite renal end point of doubling of serum creatinine; development of eGFR <45 ml/min per 1.73m2; development of macroalbuminuria; initiation of renal replacement therapy; or death from renal disease.

    Article  CAS  Google Scholar 

  14. 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). Classic review of the pathophysiology of T2DM and implications for therapy.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  15. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 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).

    CAS  Article  Google Scholar 

  19. 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). Overview of SGLT2-induced changes in intermediary metabolism and their implications for the development of ketoacidosis in T2DM patients treated with an SGLT2 inhibitor.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21

    Wright, E. M., Loo, D. D. & Hirayama, B. A. Biology of human sodium glucose transporters. Physiol. Rev. 91, 733–794 (2011). Review of the basic physiology of SGLT transporters.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Kanai, Y., Lee, W. S., You, G., Brown, D. & Hediger, M. A. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Invest. 93, 397–404 (1994).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24

    Merovci, A. et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest. 124, 509–514 (2014). Clinical study in patients with T2DM, demonstrating that treatment with an SGLT2 inhibitor induces glucosuria and reduces the plasma glucose concentration, leading to amelioration of glucotoxicity with improved insulin sensitivity in muscle.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 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). Treatment with the SGLT2 inhibitor dapagliflozin reduced both the maximum tubular reabsorptive capacity for glucose (Tm G ) and the renal threshold for glucosuria. From the clinical standpoint, the reduction in the renal threshold to <2.2 mmol/l (<40 mg/dl) is the primary mechanism responsible for the glucosuria and reduction in HbA 1c with SGLT2 inhibition.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  27. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 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).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 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). The amount of glucosuria induced by SGLT2 inhibitors is always less than expected based on the complete inhibition of SGLT2. This difference is explained by the ability of SGLT1 to markedly increase its reabsorption of glucose following SGLT2 inhibition.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. 31

    Freitas, H. S. et al. Na+–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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  33. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. 34

    Felicetta, J. V. & Sowers, J. R. Systemic hypertension in diabetes mellitus. Am. J. Cardiol. 61, 34H–40H (1988).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. 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). Classic physiologic study demonstrating that inhibition of renal glucose transport with phlorizin can normalize glucose tolerance and insulin sensitivity in a rodent model of diabetes. This study, along with another36, provided proof of concept for the development of SGLT2 inhibitor therapy for T2DM.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  37. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  38. 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).

    CAS  Article  Google Scholar 

  39. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  41. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42

    Komoroski, B. et al. Dapagliflozin, a novel SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Ther. 85, 520–526 (2009).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44

    Gorboulev, V. et al. Na+-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61, 187–196 (2012).

    CAS  Article  Google Scholar 

  45. 45

    Powell, D. R. et al. Improved glycemic control in mice lacking Sglt1 and Sglt2. Am. J. Physiol. Endocrinol. Metab. 304, E117–E130 (2013).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 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). This study demonstrated the important role of SGLT1 in glucose reabsorption following SGLT2 inhibition and explains why SGLT2 inhibitors never produce the expected amount of glucosuria even when with complete transporter inhibition.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 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).

    Google Scholar 

  48. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50

    Cariou, B. & Charbonnel, B. Sotagliflozin as a potential treatment for type 2 diabetes mellitus. Expert Opin. Investig. Drugs 24, 1647–1656 (2015). Discussion of combined SGLT2/SGLT1 therapy as a treatment for T2DM.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 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). Review of the efficacy and safety of the currently approved SGLT2 inhibitors for the treatment of T2DM.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  58. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  61. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  62. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 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). Clinical study demonstrating the efficacy of add-on SGLT2 inhibitor therapy in patients with poorly controlled T2DM treated with insulin.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  64. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  65. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  66. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  70. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  71. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  72. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. 73

    Merovci, A. et al. Dapagliflozin lowers plasma glucose concentration and improves β-cell function. J. Clin. Endocrinol. Metab. 100, 1927–1932 (2015). Clinical study in patients with T2DM demonstrating that treatment with an SGLT2 inhibitor induces glucosuria and reduces the plasma glucose concentration, leading to a marked improvement in β-cell function by ameliorating glucotoxicity.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  74. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  77. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  78. 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).

    CAS  Article  Google Scholar 

  79. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  81. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 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). Comprehensive review of the blood pressure lowering effect of SGLT2 inhibition.

    CAS  Article  Google Scholar 

  83. 83

    Jiang, F. et al. Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets. Nat. Rev. Cardiol. 11, 413–426 (2014).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84

    Feig, D. I., Kang, D. H. & Johnson, R. J. Uric acid and cardiovascular risk. N. Engl. J. Med. 359, 1811–1821 (2008).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  86. 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). Overview of the potential mechanisms by which SGLT2 inhibitors prevented cardiovascular events in the EMPA-REG OUTCOME Study.

    Article  CAS  Google Scholar 

  87. 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). Review of the potential mechanisms by which SGLT2 inhibitors prevent diabetic nephropathy.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  88. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  90. 90

    Ruggenenti, P. et al. Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Diabetes Care 35, 2061–2068 (2012).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  91. 91

    Arakawa, K. et al. Improved diabetic syndrome in C57BL/KsJ-db/db mice by oral administration of the Na+–glucose cotransporter inhibitor T-1095. Br. J. Pharmacol. 132, 578–586 (2001).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  92. 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). First description in man of the ability of SGLT2 inhibitors to reverse hyperfiltration in patients with diabetes.

    CAS  Article  Google Scholar 

  93. 93

    Hostetter, T. H., Troy, J. L. & Brenner, B. M. Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int. 19, 410–415 (1981).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  95. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02065791 (2016). Well-designed, large, prospective, placebo-controlled study to examine whether SGLT2 inhibitors can prevent or slow the progression of diabetic renal disease.

  99. 99

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01989754 (2016).

  100. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. 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).

    Article  CAS  Google Scholar 

  102. 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).

    CAS  Article  Google Scholar 

  103. 103

    Ferrannini, G. et al. Energy balance after sodium–glucose cotransporter 2 inhibition. Diabetes Care 38, 1730–1735 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  104. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  105. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. 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). This study provides a potential explanation as to why SGLT2 inhibitors cause a small rise in LDL cholesterol.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  107. 107

    Di Angelantonio, E. et al. Association of cardiometabolic multimorbidity with mortality. JAMA 314, 52–60 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  108. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  110. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  111. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  112. 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). Novel hypothesis suggesting that a switch in myocardial metabolism from glucose to ketones may reduce myocardial oxygen consumption and enhance myocardial contractility.

    Article  PubMed  PubMed Central  Google Scholar 

  113. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  114. 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).

    CAS  Article  Google Scholar 

  115. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  116. 116

    Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373, 232–242 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  117. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  118. 118

    Ferrannini, E. The theoretical bases of indirect calorimetry: a review. Metabolism 37, 287–301 (1988).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  119. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  120. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  121. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  122. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  123. 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). This review argues against an important role for the diuretic effect of SGLT2 inhibitors in the prevention of cardiovascular events in the EMPA-REG OUTCOME study.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  124. 124

    McMurray, J. EMPA-REG — the “diuretic hypothesis”. J. Diabetes Complications 30, 3–4 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  125. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  126. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  127. 127

    Ali, S. et al. Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction. Mol. Metab. 4, 132–143 (2015).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  128. 128

    Levelt, E. et al. Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes. Diabetes 65, 44–52 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  130. 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). First report describing the development of diabetic ketoacidosis in diabetic patients treated with a SGLT2 inhibitor.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  131. 131

    Farxiga highlights of prescribing information. azpicentral http://www1.astrazeneca-us.com/pi/pi_farxiga.pdf (accessed 9 March 2016).

  132. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  133. 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. 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).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  135. 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).

Download references

Acknowledgements

R.A.D. is supported by NIH grants RO1DK24093-33 and R01DK103841-01A1. M.A.-G. is supported by NIH grant RO1-DK-097554-3. We are thankful to Ernest Wright and Chiara Ghezzi, University of California Los Angeles, who were helpful in reviewing and commenting on the manuscript before submission.

Author information

Affiliations

Authors

Contributions

All authors contributed equally to researching data for the article, discussion of the content, and revising or editing the manuscript before submission.

Corresponding author

Correspondence to Ralph A. DeFronzo.

Ethics declarations

Competing interests

R.A.D. has consulted for AstraZeneca, Janssen, and Boehringer Ingelheim, is a member of the Speaker's Bureau for AstraZeneca and Novo Nordisk, and has received grant support from AstraZeneca, Janssen, and Boehringer Ingelheim. His salary is supported in part by the South Texas Veterans Health Care System. The other authors declare no competing interests.

PowerPoint slides

Glossary

Maximum renal glucose reabsorptive capacity

(TmG). The TmG represents the maximum capacity of the renal tubule to reabsorb glucose that is filtered by the glomerulus, and is expressed in mg per minute.

Threshold for glucosuria

Represents the plasma glucose concentration at which glucose spillage into the urine is first observed.

Stepped hyperglycaemic clamp

A technique in which the plasma glucose concentration is raised by a fixed amount (for example, 2.2 mmol/l) over a fixed time (for example, 30 minutes) to sequentially raise the plasma glucose concentration to 28–33 mmol/l (500–600 mg/dl). This technique enables the TmG and threshold for glucosuria to be calculated.

First phase insulin secretion

The early response of insulin (within 0–10 minutes) to an acute intravenous injection of glucose.

Second phase insulin secretion

The late response of insulin (within 10–120 minutes) to a sustained rise in plasma glucose concentration brought about by a continuous intravenous infusion of glucose.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

DeFronzo, R., Norton, L. & Abdul-Ghani, M. Renal, metabolic and cardiovascular considerations of SGLT2 inhibition. Nat Rev Nephrol 13, 11–26 (2017). https://doi.org/10.1038/nrneph.2016.170

Download citation

Further reading