Effect of Anti-diabetic Drugs on Glycemic Variability

Summary

Objectives Primary objective: To access the change from baseline to week 12 in MAGE index of glycemic variability measured by CGMS for dapagliflozin versus. gliclazide MR. Secondary objectives: 1. Change from baseline to week 12 in glycated hemoglobin A1c (HbA1c), fasting plasma glucose, postprandial glucose and achievement of HbA1c ≤6.5% and \<7% at the end of the study) for dapagliflozin versus gliclazide MR. 2. Change from baseline to week 12 in glycemic variability defined by the interquartile range (IQR - interval between 25th and 75th percentiles) measured by CGMS for dapagliflozin versus gliclazide MR. 3. Change from baseline to week 12 in glycemic variability measured by the Standard Deviation of the mean glycemia (SD) measured by CGMS for dapagliflozin versus gliclazide MR. 4. Change from baseline to week 12 in glycemic variability measured by the Coefficient of Variation (CV) measured by CGMS for dapagliflozin versus gliclazide MR. 5. Change from baseline to week 12 in the time spent on hypoglycemic range (glycemia \<70mg/dL) measured by CGMS for dapagliflozin versus gliclazide MR. Study design This is a single-center, prospective, randomized, open-label, comparative, phase IV study to compare the effects of gliclazide MR and dapagliflozin on Glycemic Variability in patients with Type 2 Diabetes Mellitus (T2DM). All patients should be treatment naïve or receive standard of care therapy for T2DM as well as for co-morbidities based on accepted guidelines and local best practices. Target patient population Approximately 120 patients with T2DM will be randomized from study site. Patients who were treated with metformin only and had inadequate glycemic control at the time of enrollment as well as treatment naïve or non-medically treated (e.g., diet) patients, will be enrolled and receive either dapagliflozin 10mg qd or comparator gliclazide MR 120mg qd in addition to standard of care treatment for T2DM and co-morbidities. Investigational product, dosage and mode of administration Dapagliflozin 10mg tablets administered orally once daily for 12 weeks. Comparator, dosage and mode of administration Gliclazide MR 60mg tablets administered orally, 2 tablets once daily for 12 weeks. Duration of treatment The treatment with study medication or comparator will have a total duration of 15 weeks.

Timeline

Start

2016-10

Primary completion

2018-02

Completion

2019-01

Publications

• Background DeFronzo RA, Hompesch M, Kasichayanula S, Liu X, Hong Y, Pfister M, Morrow LA, Leslie BR, Boulton DW, Ching A, LaCreta FP, Griffen SC. Characterization of renal glucose reabsorption in response to dapagliflozin in healthy subjects and subjects with type 2 diabetes. Diabetes Care. 2013 Oct;36(10):3169-76. doi: 10.2337/dc13-0387. Epub 2013 Jun 4.
• Background Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E, Sarigianni M, Matthews DR, Tsapas A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013 Aug 20;159(4):262-74. doi: 10.7326/0003-4819-159-4-201308200-00007.
• Background Bailey CJ, Gross JL, Hennicken D, Iqbal N, Mansfield TA, List JF. Dapagliflozin add-on to metformin in type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled 102-week trial. BMC Med. 2013 Feb 20;11:43. doi: 10.1186/1741-7015-11-43.
• Background 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 Jul;35(7):1473-8. doi: 10.2337/dc11-1693. Epub 2012 Mar 23.
• Background Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF. Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract. 2012 May;66(5):446-56. doi: 10.1111/j.1742-1241.2012.02911.x. Epub 2012 Mar 13.
• Background ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodgers A, Williams B, Bompoint S, de Galan BE, Joshi R, Travert F. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008 Jun 12;358(24):2560-72. doi: 10.1056/NEJMoa0802987. Epub 2008 Jun 6.
• Background Zhang CL, Katoh M, Shibasaki T, Minami K, Sunaga Y, Takahashi H, Yokoi N, Iwasaki M, Miki T, Seino S. The cAMP sensor Epac2 is a direct target of antidiabetic sulfonylurea drugs. Science. 2009 Jul 31;325(5940):607-10. doi: 10.1126/science.1172256.
• Background Monnier L, Mas E, Ginet C, Michel F, Villon L, Cristol JP, Colette C. Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA. 2006 Apr 12;295(14):1681-7. doi: 10.1001/jama.295.14.1681.
• Background Kuenen JC, Borg R, Kuik DJ, Zheng H, Schoenfeld D, Diamant M, Nathan DM, Heine RJ; ADAG Study Group. Does glucose variability influence the relationship between mean plasma glucose and HbA1c levels in type 1 and type 2 diabetic patients? Diabetes Care. 2011 Aug;34(8):1843-7. doi: 10.2337/dc10-2217. Epub 2011 Jun 23.
• Background Natali A, Ferrannini E. Endothelial dysfunction in type 2 diabetes. Diabetologia. 2012 Jun;55(6):1559-63. doi: 10.1007/s00125-011-2445-5. Epub 2012 Jan 20.
• Background Bloomgarden ZT. Cardiovascular disease in diabetes. Diabetes Care. 2010 Apr;33(4):e49-54. doi: 10.2337/dc10-zb04. No abstract available.
• Background Di Flaviani A, Picconi F, Di Stefano P, Giordani I, Malandrucco I, Maggio P, Palazzo P, Sgreccia F, Peraldo C, Farina F, Frajese G, Frontoni S. Impact of glycemic and blood pressure variability on surrogate measures of cardiovascular outcomes in type 2 diabetic patients. Diabetes Care. 2011 Jul;34(7):1605-9. doi: 10.2337/dc11-0034. Epub 2011 May 24.
• Background Guerci B, Monnier L, Serusclat P, Petit C, Valensi P, Huet D, Raccah D, Colette C, Quere S, Dejager S. Continuous glucose profiles with vildagliptin versus sitagliptin in add-on to metformin: results from the randomized Optima study. Diabetes Metab. 2012 Oct;38(4):359-66. doi: 10.1016/j.diabet.2012.06.001. Epub 2012 Jul 17.
• Background Marfella R, Barbieri M, Grella R, Rizzo MR, Nicoletti GF, Paolisso G. Effects of vildagliptin twice daily vs. sitagliptin once daily on 24-hour acute glucose fluctuations. J Diabetes Complications. 2010 Mar-Apr;24(2):79-83. doi: 10.1016/j.jdiacomp.2009.01.004. Epub 2009 Mar 4.
• Background Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amplitude of glycemic excursions, a measure of diabetic instability. Diabetes. 1970 Sep;19(9):644-55. doi: 10.2337/diab.19.9.644. No abstract available.
• Background Zaccardi F, Stefano PD, Busetto E, Federici MO, Manto A, Infusino F, Lanza GA, Pitocco D, Ghirlanda G. Group of signs: a new method to evaluate glycemic variability. J Diabetes Sci Technol. 2008 Nov;2(6):1061-5. doi: 10.1177/193229680800200614.
• Background Bergenstal RM, Ahmann AJ, Bailey T, Beck RW, Bissen J, Buckingham B, Deeb L, Dolin RH, Garg SK, Goland R, Hirsch IB, Klonoff DC, Kruger DF, Matfin G, Mazze RS, Olson BA, Parkin C, Peters A, Powers MA, Rodriguez H, Southerland P, Strock ES, Tamborlane W, Wesley DM. Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the Ambulatory Glucose Profile (AGP). Diabetes Technol Ther. 2013 Mar;15(3):198-211. doi: 10.1089/dia.2013.0051. Epub 2013 Feb 28.
• Background Inkster B, Zammitt NN, Frier BM. Drug-induced hypoglycaemia in type 2 diabetes. Expert Opin Drug Saf. 2012 Jul;11(4):597-614. doi: 10.1517/14740338.2012.694424. Epub 2012 Jun 13.
• Background Nauck MA, Del Prato S, Meier JJ, Duran-Garcia S, Rohwedder K, Elze M, Parikh SJ. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care. 2011 Sep;34(9):2015-22. doi: 10.2337/dc11-0606. Epub 2011 Aug 4.
• Background 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(3):740-50. doi: 10.2337/dc13-0467. Epub 2013 Oct 21.
• Background Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S; Dapagliflozin 006 Study Group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med. 2012 Mar 20;156(6):405-15. doi: 10.7326/0003-4819-156-6-201203200-00003.
• Background Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S; Dapagliflozin 006 Study Group. Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab. 2014 Feb;16(2):124-36. doi: 10.1111/dom.12187. Epub 2013 Aug 29.
• Background Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012 Dec 3;72(17):2289-312. doi: 10.2165/11209910-000000000-00000.
• Background Drouin P, Standl E; Diamicron MR Study Group. Gliclazide modified release: results of a 2-year study in patients with type 2 diabetes. Diabetes Obes Metab. 2004 Nov;6(6):414-21. doi: 10.1111/j.1462-8902.2004.00404.x.
• Background McGavin JK, Perry CM, Goa KL. Gliclazide modified release. Drugs. 2002;62(9):1357-64; discussion 1365-6. doi: 10.2165/00003495-200262090-00010.
• Background Avogaro A. Treating diabetes today with gliclazide MR: a matter of numbers. Diabetes Obes Metab. 2012 Jan;14 Suppl 1:14-9. doi: 10.1111/j.1463-1326.2011.01508.x.
• Background Lin SD, Wang JS, Hsu SR, Sheu WH, Tu ST, Lee IT, Su SL, Lin SY, Wang SY, Hsieh MC. The beneficial effect of alpha-glucosidase inhibitor on glucose variability compared with sulfonylurea in Taiwanese type 2 diabetic patients inadequately controlled with metformin: preliminary data. J Diabetes Complications. 2011 Sep-Oct;25(5):332-8. doi: 10.1016/j.jdiacomp.2011.06.004. Epub 2011 Aug 2.
• Background Czerwoniuk D, Fendler W, Walenciak L, Mlynarski W. GlyCulator: a glycemic variability calculation tool for continuous glucose monitoring data. J Diabetes Sci Technol. 2011 Mar 1;5(2):447-51. doi: 10.1177/193229681100500236.
• Background Hill NR, Oliver NS, Choudhary P, Levy JC, Hindmarsh P, Matthews DR. Normal reference range for mean tissue glucose and glycemic variability derived from continuous glucose monitoring for subjects without diabetes in different ethnic groups. Diabetes Technol Ther. 2011 Sep;13(9):921-8. doi: 10.1089/dia.2010.0247. Epub 2011 Jun 29.

Drugs

Indications