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 2014 年 4 月 24 日 8:30-8:55 ８階 医局 Fouqueray P1, Pirags V, Inzucchi SE, Bailey CJ, Schernthaner G, Diamant M, Lebovitz HE. The efficacy and safety of imeglimin as add-on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Diabetes Care. 2013 Mar;36(3):565-8. doi: 10.2337/dc12- 0453. Epub 2012 Nov 16.

2. Imeglimin ((6R)-(+)-4-dimethylamino- 2-imino-6methyl-1,2,5,6- tetrahydro- 1,3,5, triazine hydrochloride) is the first in a new tetrahydrotriazine-containing class of oral antidiabetic agents, the glimins. It is an oxidative phosphorylation blocker that acts to inhibit hepatic gluconeogenesis, increase muscle glucose uptake, and restore normal insulin secretion.

3. 1 Poxel SA, Lyon, France 2 Paul Stradins Clinical University Hospital, Riga, Latvia 3 VU University Medical Center, Amsterdam, the Netherlands 4 Rudolfstiftung Hospital, Vienna, Austria 5 State University of New York, Health Sciences Center, Brooklyn, NY 6 Yale School of Medicine, New Haven, CT 7 Aston University, Birmingham, U.K.

4. OBJECTIVE This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes that was inadequately controlled with sitagliptin monotherapy.

5. RESEARCH DESIGN AND METHODS In a multicenter, randomized, double-blind, placebo- controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12 weeks in 170 patients with type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m 2 ) that was inadequately controlled with sitagliptin alone (A1C ≧ 7.5%) during a 12-week run-in period. The primary efficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, stratification by baseline A1C, and percentage of A1C responders.

7. Supplementary Figure 1. Summary of subject disposition Abbreviations: ITT = Intention-to-treat; PP = Per-protocol

8. Figure 2—A: Effect of sitagliptin-imeglimin vs. sitagliptin-placebo: A1C reductions over the 12- week double-blind treatment period. B: Effect of sitagliptin-imeglimin vs. sitagliptin-placebo: change in A1C depending on baseline A1C value.

10. TEAEs: treatment-emergent adverse events

11. RESULTS Imeglimin reduced A1C levels (least- squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (betweengroup difference 0.72%, P < 0.001). The corresponding changes in FPG were 20.93 mmol/L with imeglimin vs. 20.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ‡0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8%of subjects receiving imeglimin achieved a decrease in A1C level of £7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well-tolerated, with a safety profile comparable to placebo and no related treatment-emergent adverse events.

12. CONCLUSIONS Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies.

13. Message Imeglimin という物質も糖尿病治療に使えそう という論文。

15. Diabetes Care 36:565–568, 2013 1 Poxel SA, Lyon, France 2 Department of Internal Medicine, Paul Stradins Clinical University Hospital, Riga, Latvia 3 Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut 4 School of Life and Health Sciences, Aston University, Birmingham, United Kingdom 5 Department of Internal Medicine, Rudolfstiftung Hospital, Vienna, Austria 6 Diabetes Center/Department of Internal Medicine, VU University Medical Center, Amsterdam, the Netherlands 7 Department of Medicine, State University of New York, Health Sciences Center, Brooklyn, New York

16. OBJECTIVE A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone.

17. RESEARCH DESIGN AND METHODS A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500–2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio.

19. RESULTS After 12 weeks, the placebo- subtracted decrease in A1C with metformin- imeglimin was −0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (−0.91 mg/dL and −7.5, respectively) compared with metformin- placebo (0.36 mg/dL and 11.81). Metformin- imeglimin therapy was generally well- tolerated with a comparable safety profile to metformin-placebo.

20. CONCLUSIONS Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.

21. テトラヒドロトリアジンを含む全く新しいクラスの経口 糖尿病治療薬（ glimins ） として注目されているものの 1 つに imeglimin がある。同薬に関する 2 件の概念実証 （ proof-of-concept ）試験は終了しており，現在，第Ⅱ 相臨床試験でメトホルミンへの imeglimin の上乗せ効果 が検証されている。同薬を開発している Poxel 社の Pascale Fouqueray 氏は「メトホルミン単剤治療でのコ ントロールが不十分な 2 型糖尿病患者に imeglimin を上 乗せ投与すれば，より良好な血糖管理が見込め，忍容性 にも問題ないことが 12 週間の第Ⅱ相ランダム化比較試験 （ RCT ）により示された」と Diabetes Care 2012 年 11 月 16 日オンライン版で報告した。同薬の作用機序として は， 2 型糖尿病の 3 大病態を改善する可能性が指摘されて いる。