The Role of the Kidney and SGLT2 Inhibitors in Type 2 Diabetes

Canadian Journal of Diabetes

Volumn 39, Issue 5, 2015, Pages S167-S175

  Katz, Pamela M ^a   Leiter, Lawrence A ^b  

^a UNIVERSITY OF MANITOBA   (Canada)

^b ST MICHAEL'S HOSPITAL   (Canada)

Author keywords

Efficacy; Kidney; Safety; Sodium glucose cotransporter type 2 (SGLT2) inhibitors; Type 2 diabetes

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; EMPAGLIFLOZIN; GLIMEPIRIDE; GLIPIZIDE; GLUCOSE; HEMOGLOBIN; INSULIN; METFORMIN; PHLORIZIN; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; SODIUM GLUCOSE COTRANSPORTER 2; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; AGENTS AFFECTING WATER, MOLECULE OR ION TRANSPORT; ANTIDIABETIC AGENT; SLC5A2 PROTEIN, HUMAN;

ADD ON THERAPY; BALANITIS; BLADDER CANCER; BLOOD PRESSURE; BODY COMPOSITION; BODY WEIGHT; CEREBROVASCULAR ACCIDENT; CHRONIC KIDNEY DISEASE; DRUG COST; DRUG EFFICACY; DRUG MECHANISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG WITHDRAWAL; END STAGE RENAL DISEASE; FRACTURE; FUNGAL GENITAL INFECTION; GLUCOSE BLOOD LEVEL; GLUCOSE URINE LEVEL; GLUCOSURIA; GLYCEMIC CONTROL; HEART INFARCTION; HUMAN; HYPOGLYCEMIA; IC50; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN RESISTANCE; KETOACIDOSIS; KIDNEY DISEASE; KIDNEY FUNCTION; KIDNEY TUBULE ABSORPTION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET BETA CELL; PROTEIN EXPRESSION; REVIEW; URINARY TRACT INFECTION; VULVOVAGINITIS; WEIGHT REDUCTION; ADVERSE EFFECTS; ANTAGONISTS AND INHIBITORS; CHEMICALLY INDUCED; COMBINATION DRUG THERAPY; DIABETES MELLITUS, TYPE 1; DIABETES MELLITUS, TYPE 2; DRUG EFFECTS; HYPERGLYCEMIA; KIDNEY; LIFESTYLE; METABOLISM; MULTIMODALITY CANCER THERAPY; PATHOPHYSIOLOGY; PERSONALIZED MEDICINE; PRACTICE GUIDELINE;

COMBINED MODALITY THERAPY; DIABETES MELLITUS, TYPE 1; DIABETES MELLITUS, TYPE 2; DRUG THERAPY, COMBINATION; HUMANS; HYPERGLYCEMIA; HYPOGLYCEMIA; HYPOGLYCEMIC AGENTS; KIDNEY; LIFE STYLE; MEMBRANE TRANSPORT MODULATORS; PRACTICE GUIDELINES AS TOPIC; PRECISION MEDICINE; RENAL REABSORPTION; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 84955608712     PISSN: 14992671     EISSN: 23523840     Source Type: Journal    
DOI: 10.1016/j.jcjd.2015.09.001     Document Type: Review

References (74)

1. Gerich J.E., Meyer C., Woerle H.J., Stumvoll M. Renal gluconeogenesis: Its importance in human glucose homeostasis. Diabetes Care 2001, 24:382-391.
2. Schoolwerth A.C., Smith B.C., Culpepper R.M. Renal gluconeogenesis. Miner Electrolyte Metab 1988, 14:347-361.
3. Meyer C. Abnormal renal, hepatic, and muscle glucose metabolism following glucose ingestion in type 2 diabetes. Am J Physiol Endocrinol Metab 2004, 287:E1049-56.
4. Meyer C., Stumvoll M., Nadkarni V., et al. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest 1998, 102:619-624.
5. Gerich J.E. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: Therapeutic implications. Diabet Med 2010, 27:136-142.
6. Bakris G.L., Fonseca V.A., Sharma K., Wright E.M. Renal sodium-glucose transport: Role in diabetes mellitus and potential clinical implications. Kidney Int 2009, 75:1272-1277.
7. Nauck M. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des Devel Ther 2014, 8:1335.
8. Mather A., Pollock C. Glucose handling by the kidney. Kidney Int 2011, 79:S1-6.
9. Rahmoune H., Thompson P.W., Ward J.M., et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 2005, 54:3427-3434.
10. Mogensen C.E. Maximum tubular reabsorption capacity for glucose and renal hemodynamics during rapid hypertonic glucose infusion in normal and diabetic subjects. Scand J Clin Lab Invest 1971, 28:101-109.
11. Farber S.J., Berger E.Y.E.D. Effect of diabetes and insulin on the maximum capacity of the renal tubules to reabsorb glucose. J Clin Invest 1951, 30:125-129.
12. Ehrenkranz J.R.L., Lewis N.G., Ronald Kahn C., Roth J. Phlorizin: A review. Diabetes Metab Res Rev 2005, 21:31-38.
13. Lisato G., Cusin I., Tiengo A., et al. The contribution of hyperglycaemia and hypoinsulinaemia to the insulin resistance of streptozotocin-diabetic rats. Diabetologia 1992, 35:310-315.
14. Santer R., Calado J. Familial renal glucosuria and SGLT2: From a Mendelian trait to a therapeutic target. Clin J Am Soc Nephrol 2010, 5:133-141.
15. 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 2013, 62:3324-3328.
16. Merovci A., Mari A., Solis C., et al. Dapagliflozin lowers plasma glucose concentration and improves β-cell function. J Clin Endocrinol Metab 2015, 100:1927-1932.
17. Del Prato S. Role of glucotoxicity and lipotoxicity in the pathophysiology of type 2 diabetes mellitus and emerging treatment strategies. Diabet Med 2009, 26:1185-1192.
18. 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.
19. Hach T., Gerich J., Salsali A., et al. Empagliflozin improves glycaemic parameters and cardiovascular risk factors in patients with type 2 diabetes mellitus: Pooled data from four pivotal Phase III studies. Poster No. 943, Presented at Eur Assoc Study Diabetes (EASD), Sept. 23-27, 2013, Barcelona, Spain.
20. Monami M., Nardini C.M.E. Efficacy and safety of sodium glucose co-transport-2 inhibitors in type 2 diabetes: A meta-analysis of randomized clinical trials. Diabetes Obes Metab 2014, 16:457-466.
21. Sha S., Polidori D., Farrell K., et al. Pharmacodynamic differences between canagliflozin and dapagliflozin: Results of a randomized, double-blind, crossover study. Diabetes Obes Metab 2015, 17:188-197.
22. Wilding J.P.H., Blonde L., Leiter L.A., et al. Efficacy and safety of canagliflozin by baseline HbA1c and known duration of type 2 diabetes mellitus. J Diabetes Complications 2015, 29:438-444.
23. Ferrannini E., Ramos S.J., 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.
24. Stenlöf K., Cefalu W.T., Kim K.-A., et al. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 2013, 15:372-382.
25. Roden M., Weng J., Eilbracht J., et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol 2013, 1:208-219. 10.1016/S2213-85871370084-6.
26. Lavalle-González F.J., Januszewicz A., Davidson 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 2013, 56:2582-2592.
27. Häring H.-U., Merker L., Seewaldt-Becker E., et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: A 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 2014, 37:1650-1659.
28. 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.
29. Jabbour S.A., Hardy E., Sugg J., Parikh S. 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.
30. Rosenstock J., Vico M., Wei L., et al. Effects of dapagliflozin, an SGLT2 Inhibitor, on HbA1c, body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 2012, 35:1473-1478. 10.2337/dc11-1693.
31. Forst T., Guthrie R., Goldenberg R., et al. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 2014, 16:467-477.
32. Kovacs C.S., Seshiah V., Swallow R., et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: A 24-week, randomized, placebo-controlled trial. Diabetes Obes Metab 2014, 16:147-158.
33. Schernthaner G., Gross J.L., Rosenstock J., 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 2013, 36:2508-2515.
34. Leiter L.A., Yoon K.-H., Arias P., 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 2015, 38:355-364.
35. Del Prato S., Nauck M., Durán-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.
36. Wilding J.P.H., 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.
37. Rosenstock J., Jelaska A., Zeller C., et al. Impact of empagliflozin added-on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: A 78-week randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 2015.
38. Rosenstock J., Jelaska A., Frappin G., 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 2014, 37:1815-1823.
39. 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.
40. DeFronzo R.A., Lewin A., Patel S., et al. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 2015, 38:384-393.
41. 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.
42. Toubro S., Cefalu W.T., Xie J., et al. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces body weight mainly through loss of fat mass in subjects with type 2 diabetes. Diabetologia 2012, 55:S313-14.
43. Pi-Sunyer X. The look AHEAD trial: A review and discussion of its outcomes. Curr Nutr Rep 2014, 3:387-391.
44. Cefalu W.T., Stenlöf K., Leiter L.A., et al. Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia 2015, 58:1183-1187.
45. Tikkanen I., Narko K., Zeller C., et al. Empagliflozin improves blood pressure in patients with type 2 diabetes and hypertension. Diabetologia 2013, 56:S377.
46. Weir M.R., Januszewicz A., Gilbert R.E., et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich) 2014, 16:875-882.
47. Sjöström C.D., Johansson P., Ptaszynska A., et al. Dapagliflozin lowers blood pressure in hypertensive and non-hypertensive patients with type 2 diabetes. Diabetes Vasc Dis Res 2015, 147. 9164115585298.
48. Coll-de-Tuero G., Mata-Cases M., Rodriguez-Poncelas A., et al. Chronic kidney disease in the type 2 diabetic patients: Prevalence and associated variables in a random sample of 2642 patients of a Mediterranean area. BMC Nephrol 2012, 13:87.
49. 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 1998, 352:837-853.
50. UK Prospective Diabetes Study UKPDS Group Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes UKPDS 34. Lancet 1998, 352:854-865.
51. Kohan D.E., Fioretto P., Tang W., List J.F. 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 J.-F., Bakris G., Cariou B., et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 2013, 15:463-473.
53. Yale J.-F., 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.
54. Barnett A.H., 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. 10.1016/S2213-85871370208-0.
55. ClinicalTrials.gov A study of the effects of canagliflozin JNJ-28431754 on renal endpoints in adult participants with type 2 diabetes mellitus: Full text view Accessed June 27, 2015. https://clinicaltrials.gov/ct2/show/NCT01989754.
56. ClinicalTrials.gov Evaluation of the effects of canagliflozin on renal and cardiovascular outcomes in participants with diabetic nephropathy: Full text view Accessed June 28, 2015. https://clinicaltrials.gov/ct2/show/NCT02065791?term=CREDENCE%26rank=2.
57. Cherney D., Cooper M., Tikkanen I., et al. 4B.01: Contrasting influences of renal function on blood pressure and HbA1c reductions with empagliflozin in patients with type 2 diabetes and hypertension. J Hypertens 2015, 33(Suppl 1):e53.
58. Cherney D.Z.I., Perkins B.A., Soleymanlou N., et al. Sodium glucose cotransport-2 inhibition and intrarenal RAS activity in people with type 1 diabetes. Kidney Int 2014, 86:1057-1058.
59. Perkins B.A., Cherney D.Z.I., Partridge H., et al. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: Results of an 8-week open-label proof-of-concept trial. Diabetes Care 2014, 37:1480-1483.
60. Henry R.R., Rosenstock J., Edelman S., et al. Exploring the potential of the SGLT2 inhibitor dapagliflozin in type 1 diabetes: A randomized, double-blind, placebo-controlled pilot study. Diabetes Care 2015, 38:412-419.
61. Johnsson K.M., Ptaszynska A., Schmitz B., et al. Urinary tract infections in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013, 27:473-478.
62. Johnsson K.M., Ptaszynska A., Schmitz B., et al. Vulvovaginitis and balanitis in patients with diabetes treated with dapagliflozin. J Diabetes Complications 2013, 27:479-484.
63. FDA Warning FDA Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood Available May 15. http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm.
64. Lin H.-W., Tseng C.-H. A review of the relationship between SGLT2 inhibitors and cancer. Int J Endocrinol 2014, 719578.
65. Reilly T.P., Graziano M.J., Janovitz E.B., et al. Carcinogenicity risk assessment supports the chronic safety of dapagliflozin, an inhibitor of sodium-glucose co-transporter 2, in the treatment of type 2 diabetes mellitus. Diabetes Ther 2014, 5:73-96.
66. Ljunggren Ö., Bolinder J., Johansson L., et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes Metab 2012, 14:990-999.
67. Ptaszynska A., Johnsson K.M., Parikh S.J., 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.
68. Endocrinologic and Metabolic Drugs Advisory Committee Canagliflozin, n.d. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM336236.pdf.
69. Langkilde A.M., Sugg J., Johannson P., et al. Abstract 8947: A meta-analysis of cardiovascular outcomes in clinical trials of dapagliflozin. Circulation 2011, 124:A8947.
70. ClinicalTrials.gov CANVAS: CANagliflozin cardiovascular assessment study; full text view Accessed June 27, 2015. https://clinicaltrials.gov/ct2/show/NCT01032629?term=CANVAS%26rank=1.
71. ClinicalTrials.gov Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events: Full text view Accessed June 28, 2015. https://clinicaltrials.gov/ct2/show/NCT01730534?term=Dapagliflozin+DECLARE%26rank=1.
72. Zinman B., Wanner C., Lachin J.M., et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015, Epub ahead of print.
73. Harper W., Clement M., Goldenberg R., et al. Pharmacologic management of type 2 diabetes. Can J Diabetes 2013, 37(Suppl 1):S61-8.
74. Harper W., Clement M., Goldenberg R., et al. Policies, guidelines and consensus statements: Pharmacologic management of type 2 diabetes: 2015 interim update. Can J Diabetes 2015, 39:250-252.