Pharmacotherapy Original research| Volume 34, ISSUE 6, P1301-1313, June 2012

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Long-Term Effects of Adding Exenatide to a Regimen of Metformin and/or Sulfonylurea in Type 2 Diabetes: An Uncontrolled, Open-Label Trial in Hungary



      Studies of the glucagon-like peptide-1 receptor agonists (GLP-1RAs) are needed to determine the durability of metabolic response and tolerability associated with long-term treatment.


      The present study was conducted to provide long-term data on glycemic control, weight changes, and tolerability of exenatide 10 μg BID treatment in patients with type 2 diabetes mellitus who have failed to achieve glycemic targets with oral antihyperglycemic medication.


      In this uncontrolled, open-label trial with treatment up to 156 weeks, patients received exenatide 10 μg BID while continuing treatment with metformin and/or a sulfonylurea (SFU). Intent-to-treat (ITT), 52-, 100-, and 132-week completer populations were defined. Metabolic changes were analyzed in the completer and ITT populations; adverse events (AEs) were summarized in the ITT population. Descriptive statistics were used for absolute and change-from-baseline data. Within-treatment comparisons were conducted using the paired t test.


      Of 155 patients in the ITT population (mean [SD]: age, 59 [9] years; 56% female; duration of diabetes, 9.1 [5.9] years; weight, 88.8 [16.5] kg; body mass index, 31.9 [4.7] kg/m2; hemoglobin [Hb] A1c, 8.7% [1.2%]), 133, 111, and 103 patients completed 52, 100, and 132 weeks of treatment, respectively. In the ITT population, the mean (SE) change in HbA1c from baseline to week 132 was −1.0% (0.10%) (P < 0.0001). In patients completing 52, 100, and 132 weeks, HbA1c changes from baseline to end point were −1.3% (0.10%), −1.0% (0.12%), and −1.0 (0.13%) (P < 0.0001), with 40% of patients achieving HbA1c <7% at 132 weeks. Patients in the ITT and completer populations experienced mean (SE) weight changes of −3.7 (0.39) kg and −3.9 (0.51) kg (P < 0.0001) at week 132. Improved glycemic control and weight loss occurred in 63% of patients in the completer population at week 132. In addition, 38% of completers at week 132 achieved HbA1c <7% without weight gain. No relationship was found between the development of antiexenatide antibodies and change in HbA1c. The most common AEs were gastrointestinal in nature, reported in 46% of patients and leading to discontinuation in 7 cases. Serious AEs were reported in 26% of patients, and 18% withdrew due to a treatment-emergent AE. Of 24% of patients in whom hypoglycemia was reported, 22% were on SFU or metformin + SFU combination, and 2% were on metformin.


      The findings from this open-label, single-arm study characterized the response to exenatide 10 μg BID for up to 132 weeks. Significant, persistent improvements in HbA1c and weight were observed in patients receiving exenatide BID, with reported AEs consistent with those from studies of shorter duration. identifier: NCT00044668.

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        • Gentilella R.
        • Bianchi C.
        • Rossi A.
        • Rotella C.M.
        Exenatide: a review from pharmacology to clinical practice.
        Diabetes Obes Metab. 2009; 11: 544-556
        • Buse J.B.
        • Henry R.R.
        • Han J.
        • Kim D.D.
        • Fineman M.S.
        • Baron A.D.
        • 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
        • Kendall D.M.
        • Riddle M.C.
        • Rosenstock J.
        • et al.
        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
        • DeFronzo R.A.
        • Ratner R.E.
        • Han J.
        • et al.
        Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.
        Diabetes Care. 2005; 28: 1092-1100
        • Zinman B.
        • Hoogwerf B.J.
        • Durán García S.
        • et al.
        The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial [published correction appears in Ann Intern Med. 2007;146:896].
        Ann Intern Med. 2007; 146: 477-485
        • Heine R.J.
        • Van Gaal L.F.
        • Johns D.
        • et al.
        • GWAA Study Group
        Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial.
        Ann Intern Med. 2005; 143: 559-569
        • Nauck M.A.
        • Duran S.
        • Kim D.
        • et al.
        A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study.
        Diabetologia. 2007; 50: 259-267
        • Barnett A.H.
        • Burger J.
        • Johns D.
        • et al.
        Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial.
        Clin Ther. 2007; 29: 2333-2348
        • Davies M.J.
        • Donnelly R.
        • Barnett A.H.
        • et al.
        Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study.
        Diabetes Obes Metab. 2009; 11: 1153-1162
        • Bunck M.C.
        • Diamant M.
        • Eliasson B.
        • et al.
        Exenatide affects circulating cardiovascular risk biomarkers independently of changes in body composition.
        Diabetes Care. 2010; 33: 1734-1737
        • Blevins T.
        • Han J.
        • Nicewarner D.
        • et al.
        Exenatide is non-inferior to insulin in reducing HbA1c: an integrated analysis of 1423 patients with type 2 diabetes.
        Postgrad Med. 2010; 122: 118-128
        • Drucker D.J.
        • Sherman S.I.
        • Gorelick F.S.
        • et al.
        Incretin-based therapies for the treatment of type 2 diabetes: evaluation of the risks and benefits.
        Diabetes Care. 2010; 33: 428-433
        • Klonoff D.C.
        • Buse J.B.
        • Nielsen L.L.
        • et al.
        Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.
        Curr Med Res Opin. 2008; 24: 275-286
        • Bunck M.C.
        • Cornér A.
        • Eliasson B.
        • et al.
        Effects of exenatide on measures of β-cell function after 3 years in metformin-treated patients with type 2 diabetes.
        Diabetes Care. 2011; 34: 2041-2047
      1. World Medical Association Declaration of Helsinki: ethical principles for medical research involving human patients.
        JAMA. 2000; 284: 3043-3045
        • Fineman M.S.
        • Bicsak T.A.
        • Shen L.Z.
        • et al.
        Effect on glycemic control of exenatide (synthetic exendin-4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes.
        Diabetes Care. 2003; 26: 2370-2377
        • Bunck M.C.
        • Diamant M.
        • Cornér A.
        • et al.
        One-year treatment with exenatide improves β-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial.
        Diabetes Care. 2009; 32: 762-768
        • Garber A.
        • Henry R.R.
        • Ratner R.
        • et al.
        • LEAD-3 (Mono) Study Group
        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
        • Schernthaner G.
        • Barnett A.H.
        • Betteridge D.J.
        • et al.
        Is the ADA/EASD algorithm for the management of type 2 diabetes (January 2009) based on evidence or opinion?.
        Diabetologia. 2010; 53: 1258-1269
        • Williamson D.F.
        • Thompson T.J.
        • Thun M.
        • et al.
        Intentional weight loss and mortality among overweight individuals with diabetes.
        Diabetes Care. 2000; 23: 1499-1504
        • Pi-Sunyer X.
        • Blackburn G.
        • Brancati F.L.
        • et al.
        Reduction in weight and cardiovascular disease risk factors in individuals with type 2 diabetes: one-year results of the look AHEAD trial.
        Diabetes Care. 2007; 30: 1374-1383
        • Okerson T.
        • Yan P.
        • Stonehouse A.
        • Brodows R.
        Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes.
        Am J Hypertens. 2010; 23: 334-339
        • Faludi P.
        • Brodows R.
        • Burger J.
        • et al.
        The effect of exenatide re-exposure on safety and efficacy.
        Peptides. 2009; 30: 1771-1774
        • Fineman M.S.
        • Mace K.F.
        • Diamant M.
        • et al.
        Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment.
        Diabetes Obes and Metab. 2012; 14: 546-554
        • Skyler J.S.
        • Bergenstal R.
        • Bonow R.O.
        • et al.
        Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association.
        Diabetes Care. 2009; 32: 187-192
        • Currie C.J.
        • Peters J.R.
        • Tynan A.
        • et al.
        Survival as a function of HbA1c in people with type 2 diabetes: a retrospective cohort study.
        Lancet. 2010; 375: 481-489
        • Zinman B.
        • Schmidt W.E.
        • Moses A.
        • et al.
        Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes: a meta-analysis of the liraglutide clinical trial programme.
        Diabetes Obes Metab. 2012; 14: 77-82
        • Nathan D.M.
        • Buse J.B.
        • Davidson M.B.
        • et al.
        Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes.
        Diabetes Care. 2009; 32: 193-203
        • Rodbard H.W.
        • Jellinger P.S.
        • Davidson J.A.
        • et al.
        Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control.
        Endocr Pract. 2009; 15: 540-559
        • Taylor K.
        • Gurney K.
        • Han J.
        • et al.
        Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years.
        BMC Endocr Disord. 2011; 11: 9