Clinical Care/Education/Nutrition/Psychosocial Research ORIGINAL ARTICLE The Fate of Taspoglutide, a Weekly GLP-1 Receptor Agonist, Versus Twice-Daily Exenatide for Type 2 Diabetes The T-Emerge 2 Trial 1 5 JULIO ROSENSTOCK, MD MARK BOLDRIN, MS low risk of hypoglycemia (1). The most 2 6 BOGDAN BALAS, MD ROBERT RATNER, MD 3 2 common adverse events with exenatide BERNARD CHARBONNEL, MD RAFFAELLA BALENA, MD 4 and liraglutide are gastrointestinal distur- GEREMIA B. BOLLI, MD FOR THE T-EMERGE 2STUDY GROUP* bances such as nausea (8–44 and 8–35%, respectively) and vomiting (4–13 and 7– 12%, respectively), which have limited OBJECTIVEdTaspoglutide is a long-acting glucagon-like peptide 1 receptor agonist devel- fi their use and adherence in clinical prac- oped for treatment of type 2 diabetes. The ef cacy and safety of once-weekly taspoglutide was – compared with twice-daily exenatide. tice (2 5). The investigational GLP-1 receptor ag- RESEARCH DESIGN AND METHODSdOverweight adults with inadequately con- onist taspoglutide has 93% homology with trolled type 2 diabetes on metformin 6 a thiazolidinedione were randomized to subcutaneous endogenous GLP-1 and was considered to taspoglutide 10 mg weekly (n = 399), taspoglutide 20 mg weekly (n = 398), or exenatide 10 mg have potency equivalent to GLP-1 (6). In twice daily (n = 392) in an open-label, multicenter trial. The primary end point was change in short-term phase 2 clinical studies, once- HbA1c after 24 weeks. weekly taspoglutide demonstrated mean- ingful antihyperglycemic and weight loss RESULTSdMean baseline HbA1c was 8.1%. Both doses of taspoglutide reduced HbA1c sig- nificantly more than exenatide (taspoglutide 10 mg: –1.24% [SE 0.09], difference –0.26, 95% CI effects (7,8). Conceivably, weekly adminis- –0.37 to –0.15, P , 0.0001; taspoglutide 20 mg: –1.31% [0.08], difference –0.33, –0.44 to tration of a GLP-1 receptor agonist, such as –0.22, P , 0.0001; exenatide: –0.98% [0.08]). Both taspoglutide doses reduced fasting plasma taspoglutide, could result in beneficial ef- glucose significantly more than exenatide. Taspoglutide reduced body weight (taspoglutide fects on glycemic control as well as greater 10 mg, –1.6 kg; taspoglutide 20 mg, –2.3 kg) as did exenatide (–2.3 kg), which was greater acceptability by patients, enhancing treat- P , than with taspoglutide 10 mg ( 0.05). HbA1c and weight effects were maintained after 52 weeks. ment compliance. More adverse events with taspoglutide 10 and 20 mg than exenatide developed over time (nausea in 53, The American Diabetes Association/ 59, and 35% and vomiting in 33, 37, and 16%, respectively). Allergic and injection-site reactions were more common with taspoglutide. Discontinuations were greater with taspoglutide. Antitaspoglutide European Association for the Study of antibodies were detected in 49% of patients. Diabetes consensus statement, which in- cludes the use of GLP-1 receptor agonists CONCLUSIONSdOnce-weekly taspoglutide demonstrated greater glycemic control than as a secondary option to add to metfor- twice-daily exenatide with comparable weight loss, but with unacceptable levels of nausea/vom- min, recommends head-to-head compar- iting, injection-site reactions, and systemic allergic reactions. ative studies to assess the value of new agents to achieve the currently recom- mended glycemic goals and their safety profiles (9). Accordingly, we designed a lucagon-like peptide 1 (GLP-1) re- liraglutide, a once-daily GLP-1 analog, long-term study (T-Emerge 2) to com- Gceptor agonists have emerged as are currently licensed for the treatment of pare the efficacy and safety of once- antihyperglycemic medications type 2 diabetes. In randomized clinical weekly taspoglutide with twice-daily with added therapeutic value beyond trials, these subcutaneously administered exenatide in patients with type 2 diabetes glucose-lowering properties. Exenatide, compounds have demonstrated antihy- inadequately controlled with metformin, a twice-daily GLP-1 mimetic, and perglycemic and weight loss effects with a thiazolidinedione, or a combination of metformin and thiazolidinedione. Prior ccccccccccccccccccccccccccccccccccccccccccccccccc to the completion of the long-term exten- 1 2 sion arm of this study, the taspoglutide From the Dallas Diabetes and Endocrine Center at Medical City, Dallas, Texas; F. Hoffmann-La Roche Ltd., Basel, Switzerland; the 3Department of Internal Medicine, Endocrinology, and Diabetes, University of phase 3 clinical trials were terminated Nantes, Nantes, France; the 4Department of Internal Medicine, University of Perugia, Perugia, Italy; because of a significantly increased rate 5Roche, Nutley, New Jersey; and 6MedStar Health Research Institute, Hyattsville, Maryland. of unwanted adverse events. Neverthe- Corresponding author: Julio Rosenstock, [email protected]. less, we believe that transparent reporting Received 13 April 2012 and accepted 12 August 2012. DOI: 10.2337/dc12-0709. Clinical trial reg. no. NCT00717457, clinicaltrials.gov. of the T-Emerge 2 Study results will pro- This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10 vide important information to help put in .2337/dc12-0709/-/DC1. perspective important safety issues R.B. is currently affiliated with Eli Lilly, Erl Wood Manor, Windlesham Surry, U.K. related to current and future trials with *A complete list of the T-Emerge 2 Study investigators can be found in the Supplementary Data online. © 2012 by the American Diabetes Association. Readers may use this article as long as the work is properly GLP-1 receptor agonists. We report the cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/ key efficacy results from the 24-week, licenses/by-nc-nd/3.0/ for details. open-label, active-controlled core phase care.diabetesjournals.org DIABETES CARE 1 Diabetes Care Publish Ahead of Print, published online November 8, 2012 Taspoglutide compared with exenatide and the 28-week, open-label extension [.240 mg/dL] between weeks 4 and 8, point was determined using ANOVA, phase. We are also presenting the cumu- .12.2 mmol/L [.220 mg/dL] between with treatment, region, and background lative safety data for the entire study up to weeks 8 and 12, and .11.1 mmol/L antihyperglycemic treatment as variables the last dose administered (week 104). [.200 mg/dL] between weeks 12 and and baseline value of the end point as co- 24), additional antihyperglycemic rescue variate. Missing values were imputed as the RESEARCH DESIGN AND medication was prescribed (first choice last observation carried forward. HbA1c METHODSdEligible participants were was a sulfonylurea), and patients contin- was tested in each of the two active arms 18–75 years of age with type 2 diabetes, uedinthestudy. versus exenatide for noninferiority first (if HbA1c between 7 and 10%, and BMI $25 the upper limit of the two-sided 95% CI for kg/m2 (.23 kg/m2 for Asians) and #45 End points and assessments the treatment difference was ,0.4%, a pre- kg/m2 (with stable body weight [65%] for The primary efficacy end point was the specified noninferiority margin). The 3 months), and were receiving a stable dose absolute change from baseline in HbA1c Hochberg procedure was used to control of antihyperglycemic medication (metfor- (%) after 24 weeks of treatment. Second- for the two comparisons. Superiority (if min $1,500 mg/day, a thiazolidinedione ary efficacy end points included changes the upper limit of the two-sided CI limit , [either rosiglitazone $4mg/dayorpioglita- in HbA1c (%), fasting plasma glucose, and was 0) was tested under a gatekeeping zone $30 mg/day], or both) for $3months body weight during 52 weeks of treat- test procedure only if noninferiority was prior to screening. Key exclusion criteria were ment and changes in fasting proinsulin, metinbotharms.Changesinfastingplasma advanced diabetes complications, gastroin- fasting proinsulin-to-insulin ratio, and glucose and body weight were analyzed testinal disease, previous bariatric surgery, homeostasis model assessment of b-cell similarly with the testing sequence. The pancreatitis, cardiovascular disease, or previ- function after 52 weeks of treatment. Ex- other continuous secondary and explor- ous exposure to GLP-1 receptor agonists. ploratory end points included changes in atory end points were assessed using The trial was conducted in accordance lipid profile, high-sensitivity C-reactive ANCOVA but were not part of the testing with the Declaration of Helsinki and national protein, and blood pressure after 52 sequence. HbA1c response rates and related regulations, and the protocol was approved weeks of treatment and the proportion 95% CIs were calculated according to by local independent ethics committees or of patients who received rescue medica- Pearson–Clopper. Patients were included institutional review boards. All participants tion. Samples were assayed by a central in the safety analysis if they received at least provided written consent prior to any pro- laboratory (Covance Central Laboratory, one dose of the study drug and had at least cedure. Geneva, Switzerland). one safety follow-up (or reported an adverse Safety assessments included adverse event). Study design and interventions events, vital signs, physical examinations, T-Emerge 2 was a randomized, open- clinical laboratory tests, electrocardio- RESULTSdThe first participant was label, active-comparator, parallel-group, grams, and testing for antitaspoglutide enrolled on 25 July 2008, and the