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      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

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          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 ≥3 months) or 7–10% (previous OAD combination therapy for ≥3 months), and BMI ≤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 (∼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.

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          Most cited references 13

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          Diabetes

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            Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.

             ,  D. Kim,  Michael Baron (2004)
            This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy. At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c)
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              Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.

              This study evaluated the effects of exenatide, a novel incretin mimetic, in hyperglycemic patients with type 2 diabetes unable to achieve glycemic control with metformin-sulfonylurea combination therapy. A 30-week, double-blind, placebo-controlled study was performed in 733 subjects (aged 55 +/- 10 years, BMI 33.6 +/- 5.7 kg/m(2), A1C 8.5 +/- 1.0%; means +/- SD) randomized to 5 microg subcutaneous exenatide b.i.d. (arms A and B) or placebo for 4 weeks. Thereafter, arm A remained at 5 microg b.i.d. and arm B escalated to 10 microg b.i.d. Subjects continued taking their dose of metformin and were randomized to either maximally effective (MAX) or minimum recommended (MIN) doses of sulfonylurea. Week 30 A1C changes from baseline (+/-SE) were -0.8 +/- 0.1% (10 microg), -0.6 +/- 0.1% (5 microg), and +0.2 +/- 0.1% (placebo; adjusted P < 0.0001 vs. placebo), yielding placebo-adjusted reductions of -1.0% (10 microg) and -0.8% (5 microg). In the evaluable population, exenatide-treated subjects were more likely to achieve A1C < or =7% than placebo-treated subjects (34% [10 microg], 27% [5 microg], and 9% [placebo]; P < 0.0001). Both exenatide arms demonstrated significant weight loss (-1.6 +/- 0.2 kg from baseline each exenatide arm, -0.9 +/- 0.2 kg placebo; P < or = 0.01 vs. placebo). Mild or moderate nausea was the most frequent adverse event. The incidence of mild/moderate hypoglycemia was 28% (10 microg), 19% (5 microg), and 13% (placebo) and appeared lower with MIN than with MAX sulfonylurea treatment. Exenatide significantly reduced A1C in patients with type 2 diabetes unable to achieve adequate glycemic control with maximally effective doses of combined metformin-sulfonylurea therapy. This improvement in glycemic control was associated with no weight gain and was generally well tolerated.
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                Author and article information

                Journal
                Diabetes Care
                diacare
                Diabetes Care
                American Diabetes Association
                0149-5992
                1935-5548
                January 2009
                : 32
                : 1
                : 84-90
                Affiliations
                [1 ]Diabeteszentrum Bad Lauterberg, Harz, Germany
                [2 ]Öresund Diabetes Team AB, Lund, Sweden
                [3 ]Aarhus University Hospital, Aarhus, Denmark
                [4 ]Seth G.S. Medical College and KEM Hospital, Mumbai, India
                [5 ]Clinic of Diabetology, Sophia, Bulgaria
                [6 ]Benmed Hospital, Benoni, Republic of South Africa
                [7 ]Novo Nordisk, Bagsvaerd, Denmark
                [8 ]Oxford Centre for Diabetes Endocrinology and Metabolism, Oxford, U.K.
                Author notes
                [*]

                A complete list of the LEAD-2 study investigators can be found in an online appendix available at http://dx.doi.org/10.2337/dc08-1355.

                Corresponding author: Michael A. Nauck, nauck@ 123456diabeteszentrum.de

                Article
                32184
                10.2337/dc08-1355
                2606836
                18931095
                Copyright © 2009, American Diabetes Association

                Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

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                Categories
                Emerging Treatments and Technologies

                Endocrinology & Diabetes

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