Liraglutide is effective and well tolerated in combination with an oral antidiabetic drug in Japanese patients with type 2 diabetes: A randomized, 52-week, open-label, parallel-group trial

Kohei Kaku, Arihiro Kiyosue, Yuri Ono, Toshihiko Shiraiwa, Shizuka Kaneko, Keiji Nishijima, Heidrun Bosch-Traberg, Yutaka Seino, Kohei Kaku, Arihiro Kiyosue, Yuri Ono, Toshihiko Shiraiwa, Shizuka Kaneko, Keiji Nishijima, Heidrun Bosch-Traberg, Yutaka Seino

Abstract

Introduction: The safety and efficacy of liraglutide in combination with an oral antidiabetic drug (OAD) compared with combination of two OADs were assessed in Japanese patients with type 2 diabetes.

Materials and methods: This was a 52-week, open-label, parallel-group trial in which patients whose type 2 diabetes was inadequately controlled with a single OAD (glinide, metformin, α-glucosidase inhibitor or thiazolidinedione) were randomized 2:1 to either pretrial OAD in combination with liraglutide 0.9 mg/day (liraglutide group; n = 240) or pretrial OAD in combination with an additional OAD (additional OAD group; n = 120). The primary outcome measure was the incidence of adverse events (AEs).

Results: Overall, 86.3% of patients in the liraglutide group and 85.0% of patients in the additional OAD group experienced AEs; these were similar in nature and severity. Adverse event rates were 361 and 331 per 100 patient-years of exposure, respectively. Confirmed hypoglycemia was rare (seven episodes in two patients on liraglutide, and two in two patients on additional OAD). There were no reported pancreatitis events, and no unexpected safety signals were identified. Mean reductions in glycosylated hemoglobin were significantly greater in the liraglutide group than the additional OAD group [estimated mean treatment difference -0.27% (95% confidence interval (CI) -0.44, -0.09; P = 0.0026)]; reductions in mean fasting plasma glucose levels were also greater with liraglutide [estimated mean difference -5.47 mg/dL (-0.30 mmol/L; 95% CI: -10.83, -0.10; P = 0.0458)].

Conclusions: Liraglutide was well tolerated and effective as combination therapy with an OAD in Japanese patients with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT01512108.

Keywords: Liraglutide; Oral antidiabetic drug; Type 2 diabetes mellitus.

Figures

Figure 1
Figure 1
Participant flow during the trial. †Three patients in the liraglutide group were withdrawn after randomization, but before exposure to the trial product (consent withdrawal n = 1; randomization in error n = 1; non‐compliance n = 1). The remainder were withdrawn after exposure to at least one dose. OAD, oral antidiabetic drug.
Figure 2
Figure 2
Mean glycosylated hemoglobin by treatment week (full analysis set). Last observation carried forward imputed data. HbA1c, glycosylated hemoglobin; OAD, oral antidiabetic drug.

References

    1. Inzucchi SE, Bergenstal RM, Buse JB, et al 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.
    1. Japan Diabetes Society . Treatment Guide for Diabetes: 2012–2013. Available at: . Accessed March 2014.
    1. Holst JJ. The physiology of glucagon‐like peptide 1. Physiol Rev 2007; 87: 1409–1439.
    1. Knudsen LB, Nielsen PF, Huusfeldt PO, et al Potent derivatives of glucagon‐like peptide‐1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 2000; 43: 1664–1669.
    1. Agerso H, Jensen LB, Elbrond B, et al The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long‐acting GLP‐1 derivative, in healthy men. Diabetologia 2002; 45: 195–202.
    1. Marre M, Shaw J, Brändle M, et al Liraglutide, a once‐daily human GLP‐1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD‐1 SU). Diabet Med 2009; 26: 268–278.
    1. Nauck M, Frid A, Hermansen K, et al Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)‐2 study. Diabetes Care 2009; 32: 84–90.
    1. Garber A, Henry R, Ratner R, et al Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD‐3 Mono): a randomised, 52‐week, phase III, double‐blind, parallel‐treatment trial. Lancet 2009; 373: 473–481.
    1. Zinman B, Gerich J, Buse JB, et al Efficacy and safety of the human glucagon‐like peptide‐1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD‐4 Met+TZD). Diabetes Care 2009; 32: 1224–1230.
    1. Russell‐Jones D, Vaag A, Schmitz O, et al Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD‐5 met+SU): a randomised controlled trial. Diabetologia 2009; 52: 2046–2055.
    1. Buse JB, Rosenstock J, Sesti G, et al 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.
    1. Nauck M, Frid A, Hermansen K, et al Long‐term efficacy and safety comparison of liraglutide, glimepiride and placebo, all in combination with metformin in type 2 diabetes: 2‐year results from the LEAD‐2 study. Diabetes Obes Metab 2013; 15: 204–212.
    1. Garber A, Henry RR, Ratner R, et al Liraglutide, a once‐daily human glucagon‐like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab 2011; 13: 348–356.
    1. Buse JB, Sesti G, Schmidt WE, et al Switching to once‐daily liraglutide from twice‐daily exenatide further improves glycemic control in patients with type 2 diabetes using oral agents. Diabetes Care 2010; 33: 1300–1303.
    1. Kaku K, Rasmussen MF, Clauson P, et al 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.
    1. Kaku K, Rasmussen MF, Nishida T, et al Fifty‐two‐week, randomized, multicenter trial to compare the safety and efficacy of the novel glucagon‐like peptide‐1 analog liraglutide vs glibenclamide in patients with type 2 diabetes. J Diabetes Investig 2011; 2: 441–447.
    1. Seino Y, Rasmussen MF, Nishida T, et al Efficacy and safety of the once‐daily human GLP‐1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. Curr Med Res Opin 2010; 26: 1013–1022.
    1. Seino Y, Rasmussen MF, Nishida T, et al 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.
    1. Japanese Ministry of Health, Labor and Welfare . Guideline for Clinical Evaluation of Oral Hypoglycemic Agents, 9 July 2010. Available at: . Accessed May 2014.
    1. 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.
    1. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. Last amended by the 59th WMA General Assembly, Seoul 2008.
    1. ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (R1), Step 4, dated 10 June 1996.
    1. Seaquist ER, Anderson J, Childs B, et al Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Diabetes Care 2013; 36: 1384–1395.
    1. Pratley RE, Nauck M, Bailey T, et al Liraglutide versus sitagliptin in patients with type 2 diabetes inadequately controlled on metformin: a 26‐week, randomised, parallel‐group, open‐label trial. Lancet 2010; 375: 1447–1456.
    1. Davies MJ, Kela R, Khunti K. Liraglutide – overview of the preclinical and clinical data and its role in the treatment of type 2 diabetes. Diabetes Obes Metab 2011; 13: 207–220.
    1. Steinberg W, DeVries JH, Wadden TA, et al Longitudinal monitoring of lipase and amylase in adults with type 2 diabetes and obesity: evidence from two phase 3 randomized clinical trials with the once‐daily GLP‐1 analog liraglutide. Gastroenterology 2012; 142: S850–S851.
    1. Nicolucci A, Rossi MC. Incretin‐based therapies: a new potential treatment approach to overcome clinical inertia in type 2 diabetes. Acta Biomed 2008; 79: 184–191.
    1. Farilla L, Hui H, Bertolotto C, et al Glucagon‐like peptide‐1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology 2002; 143: 4397–4408.
    1. Rolin B, Larsen MO, Gotfredsen CF, et al The long‐acting GLP‐1 derivative NN2211 ameliorates glycemia and increases β‐cell mass in diabetic mice. Am J Physiol Endocrinol Metab 2002; 283: E745–E752.
    1. Hui H, Nourparvar A, Zhao X, et al Glucagon‐like peptide‐1 inhibits apoptosis of insulin‐secreting cells via a cyclic 5′‐adenosine monophosphate‐dependent protein kinase A‐ and a phosphatidylinositol 3‐kinase‐dependent pathway. Endocrinology 2003; 144: 1444–1455.
    1. Li Y, Hansotia T, Yusta B, et al Glucagon‐like peptide‐1 receptor signaling modulates β‐cell apoptosis. J Biol Chem 2003; 278: 471–478.
    1. Bregenholt S, Møldrup A, Blume N, et al The long‐acting glucagon‐like peptide‐1 analogue, liraglutide, inhibits β‐cell apoptosis in vitro. Biochem Biophys Res Commun 2005; 330: 577–584.

Source: PubMed

Sponsors en medewerkers

Medische omstandigheden

Geneesmiddelinterventies

3
Abonneren