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Exenatide versus glargine - complementary therapies rather than competing
Too many problems to present a seemingly promising new therapeutic tool.
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Laurence Kennedy, MD, FRCP (London), FRCP (Edin) Division of Endocrinology, University of Florida, Gainesville, FL 32610
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kenneal{at}medicine.ufl.edu Laurence Kennedy
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Given that the effectiveness of glargine insulin as additional therapy causing less hypoglycemia than other insulins in patients with uncontrolled diabetes despite treatment with one or two oral agents has been established while the “signature trials” of exenatide have been underway(1), it was inevitable that this study would be done. I wish to raise two questions. First, was the trial a fair comparison? And second, should we really think of these as competing treatments rather than as potentially complementary? Where the study fails, in my opinoin, is in the application of the glargine titration algorithm. From a starting dose of 10 units, glargine was to be increased by 2 units every 3 days to achieve a fasting blood glucose of < 100 mg/dl. By the end of the study, 26 weeks, the average glargine dosage was just 25 units, but the average fasting glucose was, by my calculation, about 135 mg/dl, far above the stated goal; so one has to ask why the achieved insulin dosage was not higher. In the Treat-to- Target trial the average daily dose of glargine insulin required to achieve a mean A1C of 6.96% and a fasting glucose of about 117 mg/dl over a similar period of time, in patients with fairly similar body weight as in this study, was 47 units (1), so it seems likely that glargine was not used optimally in the current study. Heine and colleagues argue that their glargine titration schedule and approach to encouraging patient adherence – actually, no evidence of any such encouragement after the initial visit – may be more reflective of real-world use than earlier trials like Treat- to Target. If so, then real world use has to change, if necessary involving regular contact with patients to ensure adequate titration of basal insulin to achieve appropriate fasting glucose levels (2). Turning to my second question, I don’t think it is necessarily sensible to compare these as alternative treatment options, except insofar as it illustrates the different effects of the two interventions. Figure 3 in the paper shows that glargine insulin is clearly more effective in reducing fasting glucose, exenatide obviously superior in reducing the postprandial glucose excursion. So glargine seems an appropriate treatment choice when fasting glucose levels remain considerably elevated, as is usually the case when A1C is > 8%. "Fix the fasting first" is an appropriate adage here. As Monnier et al have demonstrated, the post- prandial glucose excursion starts playing a dominant role in determining A1C at levels of < 7.5% (3), so exenatide and glargine may be ideal complementary treatments, along with oral agents, to make the final push for a normal A1C. References: 1) Riddle MC, Rosenstock J, Gerich J. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care 26:3080-3086; 2003. 2) Kennedy L, Herman WH, Strange P, et al. Impact of active versus usual algorithmic titration of basal insulin and point-of-care versus laboratory measurement of HbA1c on glycemic control in patients with type 2 diabetes. Diabetes Care 29: January 2006, in press. 3) Monnier L, Lapinski H, Colette C. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26:881-885; 2003. Conflict of Interest:I have been a Consultant for sanofi-aventis and have received honoraria for speaking engagements from sanofi-aventis and from Amylin Pharmaceuticals. |
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Federico Relimpio, M.D. Servicio de Endocrinología, Hospitales Universitarios Virgen del Rocío, Seville, Spain., Fernando Losada
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federico.relimpio.sspa{at}juntadeandalucia.es Federico Relimpio, et al.
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To the editor: In a recent issue of Annals of Internal Medicine, both efficacy and safety of exenatide, a new compound targeting Type 2 diabetes, have been carefully analysed (1). As compared to insulin glargine, twice daily subcutaneous administration of this interesting polypeptide achieved a similar degree of blood sugar control while causing a modest and parallel weight loss (a very valuable issue in obese Type 2 diabetic patients) at the expense of some gastrointestinal side effects. This seemingly encouraging results should not conceal certain issues of concern. First, in spite of the authors attempt to minimize the issue, it is undeniable that exenatide was poorly tolerated: nausea was very frequent in the group assigned to the new drug (57.1%), the absolute number of patients withdrawn from the study in this group doubled the respective number in the glargine group (54 vs. 25), being the main reason the presence of an adverse event (27 vs. 2). Second, the inclusion criteria required the presence of a HbA1c level comprised between 7 and 10%, and baseline mean HbA1c values were 8.2-8.3%. This means that half of the study group had HbA1c values comprised between 7% and 8.2-8.3%, in a range commonly considered by many clinicians as not so poor blood sugar control. Only the other half would actually worry to a greater extent usual clinicians dealing with Type 2 diabetes. Third, a final HbA1c mean value of roughly 7% was reached in both study groups. As a mean, it could be considered a good result and it is in accordance with data proceeding from other published papers dealing with the same clinical issue. But it must be stressed that half of the patients had final HbA1c levels above that figure (that means greater than current ADA HbA1c target of 7%). In this very sense, the comment made by Comi (2) in the same issue of the journal, regarding that patients achieved very good control seems to me clearly inappropriate. Instead, the editorialist should have underscored the compelling need to change therapy in a substantial proportion of patients at the end of the study. Fourth, exenatide use involves twice daily injections. Currently, new alternatives are being developed to deal with the same clinical problem in a less aggressive way (e.g. inhaled insulin or triple therapy with a secretagogue, metformin and a glitazone) with similar clinical efficacy in terms of blood sugar control. Too many problems to present a seemingly promising new therapeutic tool. 1.- Heine et al. Exenatide versus Insulin Glargine in Patients with Suboptimally Controlled Type 2 Diabetes. A Randomized Trial. Ann Intern Med 2005; 143:559-569. 2.. Comi. Treatment of Type 2 Diabetes Mellitus: A Weighty Enigma. Ann Intern Med 2005; 143: 609-610. Conflict of Interest:None declared |
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