1. Journal Club 埼玉医科大学 総合医療センター 内分泌・糖尿病内科 Department of Endocrinology and Diabetes, Saitama Medical Center, Saitama Medical University 松田 昌文 Matsuda, Masafumi 2010 年７月 29 日 8:30-8:55 ８階 医局 Buse JB, Drucker DJ, Taylor KL, Kim T, Walsh B, Hu H, Wilhelm K, Trautmann M, Shen LZ, Porter LE; DURATION-1 Study Group. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010 Jun;33(6):1255-61. Epub 2010 Mar 9. Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, Wilhelm K, Malone J, Porter LE; for the DURATION-2 Study Group. Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomised trial. Lancet. 2010 Jun 25. [Epub ahead of print] Diamant M, Van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, Trautmann M. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010 Jun 26;375(9733):2234-43.

2. GLP-1

5. a nasal spray formulation of recombinant human GLP-1 a stabilized GLP-1 analogue

6. Taspoglutide (R1583/BIM51077) is a human GLP-1 analog with a pharmacokinetic profile suitable for weekly subcutaneous administration, through two amino acid substitutions in positions 8 and 35 with aminoisobutyric acid and a sustained release formulation. The compound has been licensed exclusively to Roche for development and marketing worldwide except Japan, where it will be comarketed with Teijin, and France, where Ipsen retains the right to comarket the product.

7. Figure 2—Effects of taspoglutide and placebo on A1C. All taspoglutide doses were statistically significant (P<0.0001) (A). Black, placebo; magenta, 5 mg once weekly; green, 10 mg once weekly; yellow, 20 mg once weekly; purple, 10 mg once every 2 weeks; orange, 20 mg once every 2 weeks. Diabetes Care 32:1237–1243, 2009

8. Figure 2—Effects of taspoglutide and placebo on body weight (D). Black, placebo; magenta, 5 mg once weekly; green, 10 mg once weekly; yellow, 20 mg once weekly; purple, 10 mg once every 2 weeks; orange, 20 mg once every 2 weeks. Diabetes Care 32:1237–1243, 2009

10. (=4.53kg)

12. In the DURATION-1 study, the safety and efficacy of 30 weeks of treatment with the GLP- 1 receptor agonist exenatide once weekly (exenatide QW; 2mg) was compared to exenatide BID in 295 patients with type 2 diabetes. We now report the safety and efficacy of exenatide QW in a) patients who continued treatment for an additional 22 weeks (52 weeks total), and b) patients who switched from exenatide BID to exenatide QW after 30 weeks. Background

13. In this randomized, multicenter, comparator- controlled, openlabel trial, 258 patients entered the 22-week open-ended assessment phase (n=128 QW-only; n=130 BID→QW). A1C, fasting plasma glucose (FPG), body weight, blood pressure, fasting lipids, safety, and tolerability were assessed. Methods

19. Results Patients continuing exenatide QW maintained A1C improvements through 52 weeks (-2.0% [-2.1 to -1.8%]; LS mean [95% CI]). Patients switching from exenatide BID to exenatide QW achieved further A1C improvements; both groups exhibited the same A1C reduction and mean A1C (6.6%) at week 52. At week 52, 71% and 54% of all patients achieved an A1C 40 mg/dL and body weight was reduced by >4 kg after 52 weeks. Nausea occurred less frequently in this assessment period and was predominantly mild. No major hypoglycemia was observed.

20. Conclusion Exenatide QW elicited sustained improvements in glycemic control and body weight through 52 weeks of treatment; patients switching to exenatide QW experienced further improvements in A1C and FPG, with sustained weight loss.

21. Message １日２回 Byetta® を打たなくても１週間 に一度長期作用性 Exenatide を用いれば OK

23. International Diabetes Center at Park Nicollet, Minneapolis, MN, USA (R M Bergenstal MD); Rockwood Clinic, Spokane WA, USA (C Wysham MD); Amylin Pharmaceuticals, San Diego, CA, USA (L MacConell PhD, J Malloy PhD, B Walsh PhD, P Yan PhD, K Wilhelm MD, L E Porter MD); and Eli Lilly, Indianapolis, IN, USA (J Malone MD) www.thelancet.com Published online June 26, 2010 DOI:10.1016/S0140-6736(10)60590-9

24. Background Most patients with type 2 diabetes begin pharmacotherapy with metformin, but eventually need additional treatment. We assessed the safety and efficacy of once weekly exenatide, a glucagon-like peptide 1 receptor agonist, versus maximum approved doses of the dipeptidyl peptidase- 4 inhibitor, sitagliptin, or the thiazolidinedione, pioglitazone, in patients treated with metformin.

25. In this 26-week randomised, double-blind, double-dummy, superiority trial, patients with type 2 diabetes who had been treated with metformin, and at baseline had mean glycosylated haemoglobin (HbA1c) of 8 ・ 5% (SD 1 ・ 1), fasting plasma glucose of 9 ・ 1 mmol/L (164mg/dl) (2 ・ 6), and weight of 88 ・ 0 kg (20 ・ 1), were enrolled and treated at 72 sites in the USA, India, and Mexico. Patients were randomly assigned to receive: 2 mg injected exenatide once weekly plus oral placebo once daily; 100 mg oral sitagliptin once daily plus injected placebo once weekly; or 45 mg oral pioglitazone once daily plus injected placebo once weekly. Primary endpoint was change in HbA1c between baseline and week 26. Analysis was by intention to treat, for all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT00637273 Methods

27. Figure 1: Trial profi le *All protocol violations after randomisation were due to non-compliance with study visits or treatment, or both. †One adverse event was not treatmentemergent. ‡Patients completed study procedures through week 22 in compliance with the protocol and received adequate exposure to the study drug during the treatment period.

28. Figure 2: Change in glycaemic control and bodyweight between baseline and week 26 (A) Change in glycosylated haemoglobin (HbA1c) over 26 weeks. (B) Proportion of patients achieving HbA1c target values at week 26. (C) Change in fasting plasma glucose over 26 weeks. (D) Change in bodyweight over 26 weeks. In A, C, and D data are least squares mean, and error bars are SEs. All p values are adjusted according to the Hochberg method.15 *p<0 ・ 05 for exenatide versus pioglitazone. †p<0 ・ 0001 for exenatide versus pioglitazone. ‡p<0 ・ 05 for exenatide versus sitagliptin. §p<0 ・ 0001 for exenatide versus sitagliptin. ¶p<0 ・ 001 for exenatide versus pioglitazone. ||p<0 ・ 001 for exenatide versus sitagliptin.

29. Figure 2: Change in glycaemic control and bodyweight between baseline and week 26 (E) Scatterplot of change in HbA1c versus change in bodyweight at week 26

35. Results 170 patients were assigned to receive once weekly exenatide, 172 to receive sitagliptin, and 172 to receive pioglitazone. 491 patients received at least one dose of study drug and were included in the intention-to-treat analysis (160 on exenatide, 166 on sitagliptin, and 165 on pioglitazone). Treatment with exenatide reduced HbA1c (least square mean –1 ・ 5%, 95% CI –1 ・ 7 to –1 ・ 4) signifi cantly more than did sitagliptin (–0 ・ 9%, –1 ・ 1 to –0 ・ 7) or pioglitazone (–1 ・ 2%, –1 ・ 4 to –1 ・ 0). Treatment diff erences were –0 ・ 6% (95% CI –0 ・ 9 to –0 ・ 4, p<0 ・ 0001) for exenatide versus sitagliptin, and –0 ・ 3% (–0 ・ 6 to –0 ・ 1, p=0 ・ 0165) for exenatide versus pioglitazone. Weight loss with exenatide (–2 ・ 3 kg, 95% CI–2 ・ 9 to –1 ・ 7) was significantly greater than with sitagliptin (diff erence –1 ・ 5 kg, 95% CI –2 ・ 4 to –0 ・ 7, p=0 ・ 0002) or pioglitazone (diff erence –5 ・ 1 kg, –5 ・ 9 to –4 ・ 3, p<0 ・ 0001). No episodes of major hypoglycaemia occurred. The most frequent adverse events with exenatide and sitagliptin were nausea (n=38, 24%, and n=16, 10%, respectively) and diarrhoea (n=29, 18%, and n=16, 10%, respectively); upper-respiratory-tract infection (n=17, 10%) and peripheral oedema (n=13, 8%) were the most frequent events with pioglitazone.

36. Conclusion The goal of many clinicians who manage diabetes is to achieve optimum glucose control alongside weight loss and a minimum number of hypoglycaemic episodes. Addition of exenatide once weekly to metformin achieved this goal more often than did addition of maximum daily doses of either sitagliptin or pioglitazone. Funding Amylin Pharmaceuticals and Eli Lilly.

37. Editorial Comments Notably, the induction of nausea typically occurs at doses that are not sufficient to reduce fasting glucose concentrations to within the normal range in most patients. By contrast, proof-of- principle studies with intravenous infusion of the natural parent compound of these drugs—the incretin hormone GLP-1— show that normal fasting glucose concentrations,10,11 and near normal postprandial control,12 can be reached with doses that do not produce nausea, vomiting, and other so-called gastrointestinal side-effects simultaneously. Individualised incretin-based treatment for type 2 diabetes Michael A Nauck, Juris J Meier In the future, the choice of incretin-based antidiabetic treatment will be determined by individual characteristics of patients and personal preferences, perhaps with the assistance of pharmacogenomic profiles.

38. Message 週に一度の Exenatide は sitagliptin や pioglitazone に比較しても有用と 考えられる。 用量やコストの問題は今後の課題だが。

40. Diabetes Centre, VU University Medical Centre, Amsterdam, Netherlands (Prof M Diamant MD); Department of Diabetology, Metabolism and Clinical Nutrition, Antwerp University Hospital, Antwerp, Belgium (Prof L Van Gaal MD); Southern Adelaide Diabetes and Endocrine Services, Adelaide, SA, Australia (S Stranks MD); Eli Lilly and Company, Indianapolis, IN, USA (J Northrup MPT, D Cao PhD, M Trautmann MD); and Amylin Pharmaceuticals Inc, San Diego, CA, USA (K Taylor PhD) www.thelancet.com Vol 375 June 26, 2010

41. Background Diabetes treatments are needed that are convenient, provide effective glycaemic control, and do not cause weight gain. We aimed to test the hypothesis that improvement in haemoglobin A1c (HbA1c) achieved with once weekly exenatide was superior to that achieved with insulin glargine titrated to glucose targets.

42. In this 26-week, open-label, randomised, parallel study, we compared exenatide with insulin glargine in adults with type 2 diabetes who had suboptimum glycaemic control despite use of maximum tolerated doses of blood-glucoselowering drugs for 3 months or longer. Patients were randomly assigned to add exenatide (2 mg, once-a-week injection) or insulin glargine (once- daily injection, starting dose 10 IU, target glucose range 4 ・ 0–5 ・ 5 mmol/L) to their blood glucose-lowering regimens. Randomisation was with a one-to-one allocation and block size four, stratified according to country and concomitant treatment (70% metformin only; 30% metformin plus sulphonylurea). Participants and clinical investigators were not masked to assignment, but investigators analysing data were. The primary endpoint was change in HbA1c from baseline, and analysis of this outcome was by modifi ed intention to treat for all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT00641056. Methods

44. Mean doses of insulin glargine increased from a baseline 10 IU per day to 31 IU per day at endpoint (last measurement brought forward). Mean doses of metformin were roughly 2000 mg throughout the study; nearly one in four patients had a reduction in sulphonylurea dose.

45. Figure 2: Mean changes in HbA1c concentration from baseline in patients receiving exenatide once weekly or insulin glargine titrated to target (A) Haemoglobin A1c (HbA1c) changes with time. Baseline values were 8 ・ 3% (SE 0 ・ 07) for both treatment groups. Curves diverge slightly between weeks 14 and 26; these diff erences were not significant. (B) HbA1c changes in patients with baseline HbA1c <8% and ≥8%. Sample sizes were: exenatide, n=102 for baseline <8%, and n=126 for ≥8%; insulin glargine, n=97 for <8%, n=123 for ≥8%. Error bars show standard error. *Between-group diff erence was signifi cant (p<0 ・ 05).

46. Figure 3: Mean changes in bodyweight in patients receiving exenatide once weekly or insulin glargine titrated to target (A)Mean changes in bodyweight with time. Baseline bodyweights were 91 ・ 2 kg (SE 1 ・ 2) for patients taking exenatide and 90 ・ 6 kg (1 ・ 2) for those taking insulin glargine. (B)Mean changes in bodyweight for all patients versus patients receiving study drug plus metformin only. Error bars show standard error. *Between-group difference was significant (p<0 ・ 05).

52. Results 456 patients were randomly allocated to treatment and were included in the modified intention-to-treat analysis (233 exenatide, 223 insulin glargine). Participants who received at least one dose of study drug and for whom baseline and at least one postbaseline measurement of HbA1c were available were included in the primary efficacy analysis. Change in HbA1c at 26 weeks was greater in patients taking exenatide (n=228; –1 ・ 5%, SE 0 ・ 05) than in those taking insulin glargine (n=220; –1 ・ 3%, 0 ・ 06; treatment difference –0 ・ 16%, 0 ・ 07, 95% CI –0 ・ 29 to –0 ・ 03). 12 (5%) of 233 patients allocated to exenatide and two (1%) of 223 taking insulin glargine discontinued participation because of adverse events (p=0 ・ 012). A planned extension period (up to 2 ・ 5 years’ duration) is in progress.

53. Conclusion Once weekly exenatide is an important therapeutic option for patients for whom risk of hypoglycaemia, weight loss, and convenience are particular concerns. Funding Amylin Pharmaceuticals; Eli Lilly and Company.

54. Message 1 日一度のグラルギンよりも１ 週間に一度の Exenatide の方が 血糖管理もよく体重も増加せず、 何と言っても低血糖が少ない！