Combined treatment with saxagliptin plus dapagliflozin reduces insulin levels by increased insulin clearance and improves β-cell function

Endocrine Practice

Volumn 23, Issue 3, 2017, Pages 258-265

  Ekholm, Ella ^a   Hansen, Lars ^b   Johnsson, Eva ^a   Iqbal, Nayyar ^c   Carlsson, Björn ^a   Chen, Hungta ^c   Hirshberg, Boaz ^d  

^a ASTRAZENECA R AND D   (Sweden)

^b BRISTOL MYERS SQUIBB   (United States)

^c ASTRAZENECA   (United Kingdom)

^d MEDIMMUNE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

2-(3-(4-ETHOXYBENZYL)-4-CHLOROPHENYL)-6-HYDROXYMETHYLTETRAHYDRO-2H-PYRAN-3,4,5-TRIOL; ADAMANTANE; ANTIDIABETIC AGENT; BENZHYDRYL DERIVATIVE; C PEPTIDE; DIPEPTIDE; GLUCOSE BLOOD LEVEL; GLUCOSIDE; INSULIN; METFORMIN; SAXAGLIPTIN; SLC5A2 PROTEIN, HUMAN; SODIUM GLUCOSE COTRANSPORTER 2;

AGED; ANALOGS AND DERIVATIVES; ANALYSIS; ANTAGONISTS AND INHIBITORS; AREA UNDER THE CURVE; BLOOD; CLINICAL TRIAL; COMBINATION DRUG THERAPY; CONTROLLED STUDY; DIABETES MELLITUS, TYPE 2; DOUBLE BLIND PROCEDURE; DRUG EFFECTS; FEMALE; GLUCOSE BLOOD LEVEL; GLUCOSE TOLERANCE TEST; HUMAN; MALE; METABOLISM; MIDDLE AGED; PANCREAS ISLET BETA CELL; PHASE 3 CLINICAL TRIAL; RANDOMIZED CONTROLLED TRIAL;

ADAMANTANE; AGED; AREA UNDER CURVE; BENZHYDRYL COMPOUNDS; BLOOD GLUCOSE; C-PEPTIDE; DIABETES MELLITUS, TYPE 2; DIPEPTIDES; DOUBLE-BLIND METHOD; DRUG THERAPY, COMBINATION; FEMALE; GLUCOSE TOLERANCE TEST; GLUCOSIDES; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; INSULIN-SECRETING CELLS; MALE; METFORMIN; MIDDLE AGED; SODIUM-GLUCOSE TRANSPORTER 2;

EID: 85017901597     PISSN: 1530891X     EISSN: 19342403     Source Type: Journal    
DOI: 10.4158/EP161323.OR     Document Type: Article

References (40)

1. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future. Lancet. 2014;383:1068-1083.
2. DeFronzo RA, Eldor R, Abdul-Ghani M. Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes. Diabetes Care. 2013;36(suppl 2):S127-S138.
3. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-1705.
4. 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.
5. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. 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.
6. Frederich R, McNeill R, Berglind N, Fleming D, Chen R. The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetol Metab Syndr. 2012;4:36.
7. Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-2411.
8. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. 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.
9. Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012;28:513-523.
10. Chacra AR, Tan GH, Apanovitch A, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract. 2009;63:1395-1406.
11. DeFronzo RA, Hissa MN, Garber AJ, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32:1649-1655.
12. Hollander P, Li J, Allen E, Chen R, CV181-013 Investigators. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab. 2009;94:4810-4819.
13. Jabbour SA, Hardy E, Sugg J, Parikh S, Study 10 Group. 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.
14. Rosenstock J, Vico M, Wei L, Salsali A, List JF. 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.
15. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S. 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.
16. 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.
17. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632-2637.
18. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care. 2006;29:2638-2643.
19. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499-508.
20. Leibowitz G, Cahn A, Bhatt DL, et al. Impact of treatment with saxagliptin on glycaemic stability and β-cell function in the SAVOR-TIMI 53 study. Diabetes Obes Metab. 2015;17:487-494.
21. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest. 2014;124:509-514.
22. 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.
23. 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. 2014;20:1187-1197.
24. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, improves model-based indices of beta cell function in patients with type 2 diabetes. Diabetologia. 2014;57:891-901.
25. Velasquez-Mieyer PA, Cowan PA, Umpierrez GE, Lustig RH, Cashion AK, Burghen GA. Racial differences in glucagon-like peptide-1 (GLP-1) concentrations and insulin dynamics during oral glucose tolerance test in obese subjects. Int J Obes Relat Metab Disord. 2003;27:1359-1364.
26. Rudovich N, Pivovarova O, Fisher E, et al. Polymorphisms within insulin-degrading enzyme (IDE) gene determine insulin metabolism and risk of type 2 diabetes. J Mol Med (Berl). 2009;87:1145-1151.
27. Pivovarova O, Bernigau W, Bobbert T, et al. Hepatic insulin clearance is closely related to metabolic syndrome components. Diabetes Care. 2013;36:3779-3785.
28. Jones AG, Hattersley AT. The clinical utility of C-peptide measurement in the care of patients with diabetes. Diabet Med. 2013;30:803-817.
29. Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: progress and potential. Endocr Rev. 1998;19:608-624.
30. Palmer JP, Fleming GA, Greenbaum CJ, et al. C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21-22 October 2001. Diabetes. 2004;53:250-264.
31. Wallace TM, Levy JC, Matthews DR. Use and abuse of HOMA modeling. Diabetes Care. 2004;27:1487-1495.
32. Ferrannini E, Camastra S, Gastaldelli A, et al. Beta-cell function in obesity: effects of weight loss. Diabetes. 2004;53(suppl 3):S26-S33.
33. Viljanen AP, Iozzo P, Borra R, et al. Effect of weight loss on liver free fatty acid uptake and hepatic insulin resistance. J Clin Endocrinol Metab. 2009;94:50-55.
34. Basu R, Dalla Man C, Campioni M, et al. Effects of age and sex on postprandial glucose metabolism: differences in glucose turnover, insulin secretion, insulin action, and hepatic insulin extraction. Diabetes. 2006;55:2001-2014.
35. Jensen MD, Nielsen S, Gupta N, Basu R, Rizza RA. Insulin clearance is different in men and women. Metabolism. 2012;61:525-530.
36. Kotronen A, Vehkavaara S, Seppälä-Lindroos A, Bergholm R, Yki-Järvinen H. Effect of liver fat on insulin clearance. Am J Physiol Endocrinol Metab. 2007;293:E1709-E1715.
37. Osei K, Gaillard T, Schuster D. Thiazolidinediones increase hepatic insulin extraction in African Americans with impaired glucose tolerance and type 2 diabetes mellitus. A pilot study of rosiglitazone. Metabolism. 2007;56:24-29.
38. Tiikkainen M, Häkkinen AM, Korsheninnikova E, Nyman T, Mäkimattila S, Yki-Järvinen H. Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes. 2004;53:2169-2176.
39. Polonsky K, Frank B, Pugh W, et al. The limitations to and valid use of C-peptide as a marker of the secretion of insulin. Diabetes. 1986;35:379-386.
40. Hill NR, Levy JC, Matthews DR. Expansion of the homeostasis model assessment of beta-cell function and insulin resistance to enable clinical trial outcome modeling through the interactive adjustment of physiology and treatment effects: iHOMA2. Diabetes Care. 2013;36:2324-2330.