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

Michael Nauck, Anders Frid, Kjeld Hermansen, Nalini S Shah, Tsvetalina Tankova, Ismail H Mitha, Milan Zdravkovic, Maria Düring, David R Matthews, LEAD-2 Study Group, Michael Nauck, Anders Frid, Kjeld Hermansen, Nalini S Shah, Tsvetalina Tankova, Ismail H Mitha, Milan Zdravkovic, Maria Düring, David R Matthews, LEAD-2 Study Group

Abstract

Objective: The efficacy and safety of adding liraglutide (a glucagon-like peptide-1 receptor agonist) to metformin were compared with addition of placebo or glimepiride to metformin in subjects previously treated with oral antidiabetes (OAD) therapy.

Research design and methods: In this 26-week, double-blind, double-dummy, placebo- and active-controlled, parallel-group trial, 1,091 subjects were randomly assigned (2:2:2:1:2) to once-daily liraglutide (either 0.6, 1.2, or 1.8 mg/day injected subcutaneously), to placebo, or to glimepiride (4 mg once daily). All treatments were in combination therapy with metformin (1g twice daily). Enrolled subjects (aged 25-79 years) had type 2 diabetes, A1C of 7-11% (previous OAD monotherapy for > or =3 months) or 7-10% (previous OAD combination therapy for > or =3 months), and BMI < or =40 kg/m(2).

Results: A1C values were significantly reduced in all liraglutide groups versus the placebo group (P < 0.0001) with mean decreases of 1.0% for 1.8 mg liraglutide, 1.2 mg liraglutide, and glimepiride and 0.7% for 0.6 mg liraglutide and an increase of 0.1% for placebo. Body weight decreased in all liraglutide groups (1.8-2.8 kg) compared with an increase in the glimepiride group (1.0 kg; P < 0.0001). The incidence of minor hypoglycemia with liraglutide ( approximately 3%) was comparable to that with placebo but less than that with glimepiride (17%; P < 0.001). Nausea was reported by 11-19% of the liraglutide-treated subjects versus 3-4% in the placebo and glimepiride groups. The incidence of nausea declined over time.

Conclusions: In subjects with type 2 diabetes, once-daily liraglutide induced similar glycemic control, reduced body weight, and lowered the occurrence of hypoglycemia compared with glimepiride, when both had background therapy of metformin.

Trial registration: ClinicalTrials.gov NCT00318461.

Figures

Figure 1
Figure 1
A1C profiles for the overall study population (A), for subjects with prestudy oral monotherapy (B), and for subjects with prestudy oral combination therapy (C). D: Change in A1C for the overall study population and for subjects treated by prestudy monotherapy or combination therapy. Error bars in A, B, C, and D represent 2 × SEM. Percentages of subjects achieving ADA (E) and AACE (F) A1C goals at the end of the study were determined using a logistic regression analysis. Symbols for A–C: pink boxes, 0.6 mg/day liraglutide; circles, 1.2 mg/day liraglutide; diamonds, 1.8 mg/day liraglutide; triangles, 4 mg/day glimepiride; gray boxes, placebo. QD, every day.

References

    1. UK Prospective Diabetes Study 16: overview of 6 years’ therapy of type II diabetes: a progressive disease. Diabetes 44:1249–1258, 1995
    1. Drucker DJ, Nauck MA: The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl petidase-4 inhibitors in type 2 diabetes. Lancet 368:1696–1705, 2006
    1. Holst JJ: The physiology of glucagon-like peptide 1. Physiol Rev 87:1409–1439, 2007
    1. Meier JJ, Nauck MA, Kranz D, Holst JJ, Deacon CF, Gaeckle D, Schmidt WE, Gallwitz B: Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 53:654–662, 2004
    1. Knudsen LB, Nielsen PF, Huusfeldt PO, Johansen NL, Madsen K, Pedersen FZ, Thogersen H, Wilken M, Agerso H: Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem 43:1664–1669, 2000
    1. Deacon CF, Knudsen LB, Madsen K, Wiberg FC, Jacobsen O, Holst JJ: Dipeptidyl peptidase IV resistant analogues of GLP-1 which have extended metabolic stability and improved biological activity. Diabetologia 41:271–278, 1998
    1. Agersø H, Jensen LB, Elbrønd B, Rolan P, Zdravkovic M: The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 45:195–202, 2002
    1. Elbrønd B, Jakobsen G, Larsen S, Agersø H, Jensen LB, Rolan P, Sturis J, Hatorp V, Zdravkovic M: Pharmacokinetics, pharmacodynamics, safety and tolerability of a single dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male patients. Diabetes Care 25:1398–1404, 2002
    1. 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 α- and β-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 53:1187–1194, 2004
    1. Vilsbøll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courreges J-P, Verhoeven R, Buganova I, Madsbad S: Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care 30:1608–1610, 2007
    1. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR: Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care 27:1335–1342, 2004
    1. Nauck MA, Hompesch M, Filipczak R, Le TD, Zdravkovic M, Gumprecht J: Five weeks of treatment with the GLP-1 analogue liraglutide improves glycemic control and lowers body weight in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 114:417–423, 2006
    1. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, Hale PM, Zdravkovic M, Bode B: Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2008. [Epub ahead of print]. DOI: 10.1015/S0140-6736(08)61246-5
    1. World Medical Association: Declaration of Helsinki: recommendations guiding physicians in biomedical research involving human subjects. JAMA 277:925–926, 1997
    1. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC: Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419, 1985
    1. DeFronzo RA, Ratner RE, Han J, Kim DD, Baron AD: Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28:1092–1100, 2007
    1. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, Sitagliptin Study 020 Group: 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 monotherapy. Diabetes Care 29:2638–2643, 2006
    1. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD: Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27:2628–2635, 2004
    1. 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 28:1083–1091, 2005
    1. Mari A, Degn K, Brock B, Rungby J, Ferrannini E, Schmitz O: Effects of the long-acting human glucagon-like peptide-1 analog liraglutide on β-cell function in normal living conditions. Diabetes Care 30:2032–2033, 2007
    1. Vilsbøll T, Brock B, Perrild H, Levin K, Lervang H-H, Kølendorf K, Krarup T, Schmitz O, Zdravkovic M, Le-Thi T, Madsbad S: Liraglutide, a once-daily human GLP-1 analogue, improves pancreatic B-cell function and arginine-stimulated insulin secretion during hyperglycaemia in patients with type 2 diabetes mellitus. Diabet Med 25:152–156, 2008
    1. Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M, Knudsen LB: The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases β-cell mass in diabetic mice. Am J Physiol Endocrinol Metab 283:E745–E752, 2002
    1. Bregenholt S, Moldrup A, Blume N, Karlsen AE, Friedrichsen BN, Tornhave D, Knudsen LB, Petersen JS: The long-acting glucagon-like peptide-1 analogue, liraglutide, inhibits β-cell apoptosis in vitro. Biochem Biophys Res Commun 330:577–584, 2005

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться