Advertisement
Mayo Clinic Proceedings Home

Five-Year Efficacy and Safety Data of Exenatide Once Weekly

Long-term Results From the DURATION-1 Randomized Clinical Trial

      Abstract

      Objective

      To evaluate the 5-year efficacy and safety of once weekly exenatide.

      Patients and Methods

      The Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial consisted of a 30-week controlled phase (2 mg of exenatide once weekly vs 10 μg of exenatide twice daily) with an open-ended uncontrolled extension (once weekly exenatide only) in patients with type 2 diabetes mellitus on background glucose-lowering therapies (April 15, 2006, through February 21, 2012). At week 30, patients initially receiving 10 μg of exenatide twice daily switched to 2 mg of exenatide once weekly. Study end points included changes from baseline in hemoglobin A1c, fasting plasma glucose, weight, lipids, and blood pressure. Long-term safety data included adverse events, liver and renal function, and heart rate.

      Results

      Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment. Hemoglobin A1c levels were significantly and durably reduced from baseline (least-squares mean, –1.6%; 95% CI, –1.8% to –1.4%; vs –1.9% for exenatide once weekly at week 30), and 65 (43.9%) of 148 patients achieved hemoglobin A1c levels of less than 7.0%. Significant improvements in fasting plasma glucose level (–28.8 mg/dL; 95% CI, −36.2 to −21.5 mg/dL), weight (–3.0 kg; 95% CI, –4.6 to –1.3 kg), lipids, and diastolic blood pressure were observed, with minimal heart rate increase. Frequencies of nausea and injection-site reactions or nodules were decreased vs the initial 30-week controlled phase. Minor hypoglycemia occurred predominantly with sulfonylurea use, and no major hypoglycemia or new safety signals were observed.

      Conclusion

      Long-term once weekly exenatide treatment was generally well tolerated with sustained glycemic improvement, weight reduction, and improved markers of cardiovascular risk in patients with type 2 diabetes.

      Trial Registration

      Abbreviations and Acronyms:

      BP (blood pressure), FPG (fasting plasma glucose), GLP-1RA (glucagon-like peptide 1 receptor agonist), HbA1c (hemoglobin A1c), HDL-C (high-density lipoprotein cholesterol), ITT (intent to treat), LDL-C (low-density lipoprotein cholesterol), LS (least-squares), T2DM (type 2 diabetes mellitus)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • DeFronzo R.A.
        Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus.
        Diabetes. 2009; 58: 773-795
        • Fonseca V.A.
        Defining and characterizing the progression of type 2 diabetes.
        Diabetes Care. 2009; 32: S151-S156
        • Stratton I.M.
        • Adler A.I.
        • Neil H.A.
        • et al.
        Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study.
        BMJ. 2000; 321: 405-412
        • Kahn S.E.
        • Haffner S.M.
        • Heise M.A.
        • et al.
        Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.
        N Engl J Med. 2006; 355: 2427-2443
        • Matthews D.R.
        • Cull C.A.
        • Stratton I.M.
        • Holman R.R.
        • Turner R.C.
        UK Prospective Diabetes Study (UKPDS) Group. UKPDS 26: sulphonylurea failure in non-insulin-dependent diabetic patients over six years.
        Diabet Med. 1998; 15: 297-303
        • Garber A.J.
        • Abrahamson M.J.
        • Barzilay J.I.
        • et al.
        AACE comprehensive diabetes management algorithm 2013.
        Endocr Pract. 2013; 19: 327-336
        • Inzucchi S.E.
        • Bergenstal R.M.
        • Buse J.B.
        • 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
        • Giugliano D.
        • Maiorino M.I.
        • Bellastella G.
        • Chiodini P.
        • Esposito K.
        Multiple HbA1c targets and insulin analogues in type 2 diabetes: a systematic review.
        J Diabetes Complications. 2011; 25: 275-281
        • Karl D.M.
        • Gill J.
        • Zhou R.
        • Riddle M.C.
        Clinical predictors of risk of hypoglycaemia during addition and titration of insulin glargine for type 2 diabetes mellitus.
        Diabetes Obes Metab. 2013; 15: 622-628
        • Rosenstock J.
        • Ahmann A.J.
        • Colon G.
        • Scism-Bacon J.
        • Jiang H.
        • Martin S.
        Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy.
        Diabetes Care. 2008; 31: 20-25
        • Henderson J.N.
        • Allen K.V.
        • Deary I.J.
        • Frier B.M.
        Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness.
        Diabet Med. 2003; 20: 1016-1021
        • Pontiroli A.E.
        • Miele L.
        • Morabito A.
        Increase of body weight during the first year of intensive insulin treatment in type 2 diabetes: systematic review and meta-analysis.
        Diabetes Obes Metab. 2011; 13: 1008-1019
      1. AstraZeneca. Bydureon Prescribing Information. 2014. http://www.azpicentral.com/bydureon/pi_bydureon.pdf#page=1. Accessed October 10, 2014.

        • DeFronzo R.A.
        • Ratner R.E.
        • Han J.
        • Kim D.D.
        • Fineman M.S.
        • Baron A.D.
        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
        • Diamant M.
        • Van Gaal L.
        • Stranks S.
        • et al.
        Safety and efficacy of once-weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes over 84 weeks.
        Diabetes Care. 2012; 35: 683-689
        • Goke R.
        • Fehmann H.C.
        • Linn T.
        • et al.
        Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)-amide receptor of insulin-secreting beta-cells.
        J Biol Chem. 1993; 268: 19650-19655
        • Gentilella R.
        • Bianchi C.
        • Rossi A.
        • Rotella C.M.
        Exenatide: a review from pharmacology to clinical practice.
        Diabetes Obes Metab. 2009; 11: 544-556
        • Madsbad S.
        • Kielgast U.
        • Asmar M.
        • Deacon C.F.
        • Torekov S.S.
        • Holst J.J.
        An overview of once-weekly glucagon-like peptide-1 receptor agonists–available efficacy and safety data and perspectives for the future.
        Diabetes Obes Metab. 2011; 13: 394-407
      2. AstraZeneca. Byetta Prescribing Information. 2014. http://www.azpicentral.com/byetta/pi_byetta.pdf#page=1. Accessed October 10, 2014.

        • Buse J.B.
        • Drucker D.J.
        • Taylor K.L.
        • et al.
        DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks.
        Diabetes Care. 2010; 33: 1255-1261
        • Drucker D.J.
        • Buse J.B.
        • Taylor K.
        • et al.
        Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study.
        Lancet. 2008; 372: 1240-1250
        • Taylor K.
        • Gurney K.
        • Han J.
        • Pencek R.
        • Walsh B.
        • Trautmann M.
        Exenatide once weekly treatment maintained improvements in glycemic control and weight loss over 2 years.
        BMC Endocr Disord. 2011; 11: 9
        • Macconell L.
        • Pencek R.
        • Li Y.
        • Maggs D.
        • Porter L.
        Exenatide once weekly: sustained improvement in glycemic control and cardiometabolic measures through 3 years.
        Diabetes Metab Syndr Obes. 2013; 6: 31-41
        • 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
      3. Home P, Stewart M, Mallory J, et al, eds. Harmony 5 year 3 results: albiglutide vs. placebo and vs. pioglitazone in triple therapy (background metformin and glimepiride) in people with type 2 diabetes. Poster presented at: American Diabetes Association 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA. Poster 963-P.

      4. Weissman P, Stewart M, Cirkel D, Ye J, Ambery P, eds. Harmony 4: 3-year efficacy of albiglutide (albi) vs. insulin glargine (glar) in patients with T2DM. Poster presented at: American Diabetes Association 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA. Poster 961-P.

      5. Bode BW, Stewart M, Cirkel D, et al, eds. Harmony 1 year 3 results: albiglutide vs. placebo in patients with type 2 diabetes mellitus not controlled on pioglitazone (pio) ± metformin (met). Poster presented at: American Diabetes Association 74th Scientific Sessions; June 13-17, 2014; San Francisco, CA. Poster 960-P.

        • Hemming K.
        • Hutton J.L.
        • Maguire M.J.
        • Marson A.G.
        Open label extension studies and patient selection biases.
        J Eval Clin Pract. 2008; 14: 141-144
        • Taylor G.J.
        • Wainwright P.
        Open label extension studies: research or marketing?.
        BMJ. 2005; 331: 572-574
        • Ajala O.
        • English P.
        • Pinkney J.
        Systematic review and meta-analysis of different dietary approaches to the management of type 2 diabetes.
        Am J Clin Nutr. 2013; 97: 505-516
        • Orchard T.J.
        • Temprosa M.
        • Barrett-Connor E.
        • et al.
        • Diabetes Prevention Program Outcomes Study Research Group
        Long-term effects of the Diabetes Prevention Program interventions on cardiovascular risk factors: a report from the DPP Outcomes Study.
        Diabet Med. 2013; 30: 46-55
        • Hanefeld M.
        • Bramlage P.
        Insulin use early in the course of type 2 diabetes mellitus: the ORIGIN trial.
        Curr Diab Rep. 2013; 13: 342-349
        • Reaney M.
        • Mathieu C.
        • Ostenson C.G.
        • et al.
        Patient-reported outcomes among patients using exenatide twice daily or insulin in clinical practice in six European countries: the CHOICE prospective observational study.
        Health Qual Life Outcomes. 2013; 11: 217
        • Wadden T.A.
        • Webb V.L.
        • Moran C.H.
        • Bailer B.A.
        Lifestyle modification for obesity: new developments in diet, physical activity, and behavior therapy.
        Circulation. 2012; 125: 1157-1170
        • UK Hypoglycaemia Study Group
        Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration.
        Diabetologia. 2007; 50: 1140-1147
        • Zammitt N.N.
        • Frier B.M.
        Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities.
        Diabetes Care. 2005; 28: 2948-2961
        • Viana L.V.
        • Leitao C.B.
        • Grillo M.F.
        • et al.
        Hypertension management algorithm for type 2 diabetic patients applied in primary care.
        Diabetol Metab Syndr. 2013; 5: 52
        • Diamant M.
        • Van Gaal L.
        • Guerci B.
        • et al.
        Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial.
        Lancet Diabetes Endocrinol. 2014; 2: 464-473

      Linked Article

      • Long-term Efficacy and Safety of Exenatide Treatment
        Mayo Clinic ProceedingsVol. 90Issue 9
        • Preview
          We read with interest the article by Wysham et al1 describing the 5-year efficacy and safety of once-weekly exenatide. Of 258 extension-phase patients, 153 (59.3%) completed 5 years of treatment in the Diabetes Therapy Utilization: Research Changes in A1C, Weight and Other Factors Through Intervention with Exenatide Once Weekly (DURATION-1) randomized clinical trial. The research determined that 2 mg of exenatide injected subcutaneously once weekly could significantly reduce hemoglobin A1c levels from baseline, and 43.9% of patients achieved hemoglobin A1c levels of less than 7.0%.
        • Full-Text
        • PDF