Efficacy and Safety of Lixisenatide in Japanese Patients with Type 2 Diabetes Insufficiently Controlled with Basal Insulin±Sulfonylurea: A Subanalysis of the GetGoal-L-Asia Study

Abstract

The aim of the study was to evaluate the efficacy and safety of once-daily lixisenatide 20 μg as add-on to basal insulin with or without sulfonylurea in Asian patients with type 2 diabetes mellitus. The study as a subanalysis of the 159 Japanese patients from the 24-week double-blind GetGoal-L-Asia study (NCT00866658) who received once-daily lixisenatide or placebo. The primary endpoint was change from baseline in HbA1c evaluated using analysis of covariance. Once-daily lixisenatide significantly reduced mean HbA1c [least squares mean difference vs. placebo − 1.1% (− 12 mmol/mol); p<0.0001]. Significantly more patients in the lixisenatide group reached HbA1c targets of < 7% (53 mmol/mol; 31.4 vs. 2.3% for placebo; p<0.0001) and ≤ 6.5% (48 mmol/mol; 12.9 vs. 1.2% for placebo; p=0.0028). Lixisenatide significantly reduced 2-h postprandial plasma glucose (least squares mean difference vs. placebo−8.64 mmol/l; p<0.0001), glucose excursion (least squares mean difference vs. placebo − 7.80 mmol/l; p<0.0001) and fasting plasma glucose (least squares mean difference vs. placebo − 0.96 mmol/l; p=0.0126). Body weight was reduced with lixisenatide but with no significant difference vs. placebo. Gastrointestinal adverse events were more frequent with lixisenatide (61.1 vs. 11.5% for placebo) but were generally transient and mild-to-moderate in intensity. The incidence of symptomatic hypoglycemia was 39.0 vs. 13.5% in patients receiving sulfonylureas and 32.3 vs. 22.9% in those not receiving sulfonylureas, for lixisenatide and placebo, respectively. In Japanese patients with type 2 diabetes mellitus, once-daily lixisenatide was well tolerated and led to significant and clinically relevant improvement in glycemic control, with a pronounced effect on postprandial plasma glucose.

Key words

sulfonylureas - diabetes mellitus type 2 - GLP-1 analogues

• References

• 1 Morimoto A, Nishimura R, Tajima N. Trends in the epidemiology of patients with diabetes in Japan. Japan Med Assoc J 2010; 53: 36-40
• 2 International Diabetes Federation. IDF Diabetes Atlas 6^th ed. Brussels, Belgium: International Diabetes Federation; 2013. http://www.idf.org/diabetesatlas Accessed May 2014
• 3 Guariguata L, Whiting DR, Hambleton I, Beagley J, Linnenkamp U, Shaw JE. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 2014; 103: 137-149
• 4 Neville SE, Boye KS, Montgomery WS, Iwamoto K, Okamura M, Hayes RP. Diabetes in Japan: a review of disease burden and approaches to treatment. Diabetes Metab Res Rev 2009; 25: 705-716
• 5 Zhang P, Zhang X, Brown J, Vistisen D, Sicree R, Shaw J, Nichols G. Global healthcare expenditure on diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87: 293-301
• 6 Fukushima M, Suzuki H, Seino Y. Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes. Diabetes Res Clin Pract 2004; 66 (Suppl. 01) S37-S43
• 7 Japan Diabetes Society . Treatment guide for diabetes, 2012–2013. Tokyo: Bunkodo Inc.; 2012: 1-50
• 8 Garber AJ. Novel GLP-1 receptor agonists for diabetes. Expert Opin Investig Drugs 2012; 21: 45-57
• 9 Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 2012; 8: 728-742
• 10 Shin SJ. Glucagon-like peptide-1 receptor agonists and their effects on weight reduction. J Diabetes Investig 2012; 3: 490-491
• 11 Seino Y, Rasmussen M, Clauson P, Kaku K. The once-daily human glucagon-like peptide-1 analog, liraglutide, improves β-cell function in Japanese patients with type 2 diabetes. J Diabetes Investig 2012; 3: 388-395
• 12 Seino Y, Fukushima M, Yabe D. GIP and GLP-1, the two incretin hormones: Similarities and differences. J Diabetes Investig 2010; 1: 8-23
• 13 Yabe D, Seino Y. Dipeptidyl peptidase-4 inhibitors and prevention of bone fractures: Effects beyond glyemic control. J Diabetes Investig 2012; 3: 347-348
• 14 Lorenz M, Pfeiffer C, Steinsträsser A, Becker RH, Rütten H, Ruus P, Horowitz M. Effects of lixisenatide once daily on gastric emptying in type 2 diabetes – Relationship to postprandial glycemia. Regul Pept 2013; 185C: 1-8
• 15 Edwards CM, Stanley SA, Davis R, Brynes AE, Frost GS, Seal LJ, Ghatei MA, Bloom SR. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 2001; 281: E155-E161
• 16 Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, Zychma M, Blonde L. LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374: 39-47
• 17 Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V, Rungby J, Landau BR, Schmitz O. One week’s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 2004; 53: 1187-1194
• 18 Seino Y, Min KW, Niemoeller E, Takami A. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab 2012; 14: 910-917
• 19 Yabe D, Kuroe A, Lee S, Watanabe K, Hyo T, Hishizawa M, Kurose T, Deacon CF, Holst JJ, Hirano T, Inagaki N, Seino Y. Little enhancement of meal-induced glucagon-like peptide 1 secretion in Japanese: Comparison of type 2 diabetes patients and healthy controls. J Diabetes Investig 2010; 1: 56-59
• 20 Barnett AH. Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes. Core Evidence 2011; 6: 67-79
• 21 Ahrén B, Dimas L, Miossec P, Saubadu S, Aronson R. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care 2013; 36: 2543-2550
• 22 Bolli GB, Munteanu M, Dotsenko S, Niemoeller E, Boka G, Wu Y, Hanefeld M. Efficacy and safety of lixisenatide once-daily versus placebo in patients with T2DM insufficiently controlled on metformin (GetGoal-F1). Diabet Med 2014; 31: 176-184
• 23 Fonseca VA, Alvarado-Ruiz R, Raccah D, Boka G, Miossec P, Gerich JE. EFC6018 GetGoal-Mono Study Investigators . Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care 2012; 35: 1225-1231
• 24 Pinget M, Goldenberg R, Niemoeller E, Muehlen-Bartmer I, Guo H, Aronson R. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab 2013; 15: 1000-1007
• 25 Rosenstock J, Hanefeld M, Shamanna P, Min KW, Boka G, Miossec P, Zhou T, Muehlen-Bartmer I, Ratner RE. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in Type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J Diabetes Complicat 2014; 28: 386-392
• 26 Riddle M, Aronson R, Home P, Marre M, Niemoeller E, Miossec P. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: a 24-week, randomized, placebo-controlled comparison (GetGoal-L). Diabetes Care 2013; 36: 2489-2496
• 27 Riddle M, Forst T, Aronson R, Sauque-Reyna L, Souhami E, Silvestre L, Ping L, Rosenstock J. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled comparison (GetGoal-Duo-1). Diabetes Care 2013; 36: 2497-2503
• 28 Rosenstock J, Raccah D, Korányi L, Maffei L, Boka G, Miossec P, Gerich JE. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in patients with type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 2013; 36: 2945-2951
• 29 Kashiwagi A, Kasuga M, Araki E. International clinical harmonization of glycated hemoglobin in Japan: From Japan Diabetes Society to National Glycohemoglobin Standardization Program values. J Diabetes Investig 2012; 3: 39-40
• 30 Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35: 1364-1379
• 31 Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Metformin, sulfonylureas, or other antidiabetes drugs and the risk of lactic acidosis or hypoglycemia: a nested case-control analysis. Diabetes Care 2008; 31: 2086-2091
• 32 Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628-2635
• 33 Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083-1091
• 34 Kaku K, Rasmussen MF, Clauson P, Seino Y. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes Obes Metab 2010; 12: 341-347
• 35 Kadowaki T, Namba M, Yamamura A, Sowa H, Wolka AM, Brodows RG. Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes. Endocr J 2009; 56: 415-424
• 36 Seino Y, Rasmussen M, Nishida T, Kaku K. Glucagon-like peptide-1 analog liraglutide in combination with sulfonylurea safely improves blood glucose measures vs sulfonylurea monotherapy in Japanese patients with type 2 diabetes: Results of a 52-week, randomized, multicenter trial. J Diabetes Investig 2011; 2: 280-286
• 37 Inagaki N, Ueki K, Yamamura Y, Saito H, Imaoka T. Long-term safety and efficacy of exenatide twice daily in Japanese patients with suboptimally controlled type 2 diabetes. J Diabetes Investig 2011; 2: 448-456
• 38 Usui R, Yabe D, Kuwata H, Fujiwara S, Watanabe K, Hyo T, Yasuhara A, Iwasaki M, Kitatani N, Kuwabara K, Yokota K, Kurose T, Seino Y. Retrospective analysis of safety and efficacy of insulin-to-liraglutide switch in Japanese type 2 diabetes: A caution against inappropriate use in patients with reduced β-cell function. J Diabetes Investig 2013; 4: 585-594
• 39 Kozawa J, Inoue K, Iwamoto Y, Kurashiki Y, Okauchi Y, Kashine S, Kitamura T, Maeda N, Okita K, Iwahashi H, Funahashi T, Imagawa A, Shimomura I. Liraglutide is effective in type 2 diabetic patients with sustained endogenous insulin-secreting capacity. J Diabetes Investig 2012; 3: 294-297
• 40 Kondo Y, Satoh S, Nagakura J, Kimura M, Nezu U, Terauchi Y. Defining criteria for the introduction of liraglutide using the glucagon stimulation test in patients with type 2 diabetes. J Diabetes Investig 2013; 4: 571-575