1. Amori, R. E. et al. JAMA 2007;298:194-206. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis 亀田総合病院 1 年目初期研修医 大野 真紀

2. Amori, R. E. et al. JAMA 2007;298:194-206. ■ Background: <50% of Type2DM reach HbA1c<7.0% ・ ineffective implementation of therapy ・ efficacy of therapy diminishes as disease progresses and beta cell function declines ・ therapy limited by adverse effect target the decline in beta cell function without weight gain with minimal adverse effects

3. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin: ・ augment glucose-stimulated insulin secretion by intestinally derived peptides → released with glucose in the gut ・ action depends on glucose concentration → cease glucose < 55mg/dL

4. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin: ・ GIP (glucose-dependent insulinotropic polypeptide) GLP-1 (glucagonlike peptide 1) ・ inactivated by DPP4 (dipeptidyl peptidase 4)

5. Amori, R. E. et al. JAMA 2007;298:194-206. □ exenatide (Byetta): ・ GLP-1 receptor analogue ・ injection □ sitagliptin ・ selective DPP4 inhibitor ・ oral ・ for monotherapy or with metformin or thiazolidinedione

6. Amori, R. E. et al. JAMA 2007;298:194-206. ■ Objective: To assess the efficacy and safety of incretin-based therapy (GLP-1 analogues and DPP4 inhibitors) in type2 DM

7. Amori, R. E. et al. JAMA 2007;298:194-206. ■ Methods: □ Data source: ・ MEDLINE and Cochrane for English RCT involving incretin therapy ・ search prescribing information, relevant Web, reference and citation, abstracts at recent conferences

8. Amori, R. E. et al. JAMA 2007;298:194-206. □ Study selection: inclusion: ・ RCT ・ compare incretin therapy with placebo or other medication ・ report HbA1c in nonpregnant adults with type 2 DM exclusion: ・ < 12 weeks in duration

9. Amori, R. E. et al. JAMA 2007;298:194-206. □ Data extraction: ・ two independent reviewers ・ resolved by consensus ・ meta-analyses for efficacy and safety baseline characteristics (Table1)

10. Table1. Characteristics of Randomized Controlled Trials of Glucagonlike Peptide 1 Analogues and Dipeptidyl Peptidase 4 Inhibitors Included in the Systematic Review Amori, R. E. et al. JAMA 2007;298:194-206.

13. ・ efficacy: primary: baseline HbA1c secondary: fasting PG, postprandial PG, proportion of patients achieving HbA1c<7% (body weight and lipid profile if available) ・ safety: hypoglycemia, all adverse events, antibodies to incretin analogue ・ quality: baseline characteristic, allocation concealment, ITT analysis, dropout rate

14. Amori, R. E. et al. JAMA 2007;298:194-206. □ Data synthesis and analysis ・ continuous variable (HbA1c, fasting PG, weight): weighted mean difference, 95% CIs ・ dichotomous variable (HbA1c < 7%, hypoglycemia, adverse events): risk ration, 95% CIs ・ subgroup analyses

15. Amori, R. E. et al. JAMA 2007;298:194-206. □ Data synthesis and analysis: ・ dose-dependent outcomes: data from approved maximum dose only ・ adverse event outcomes: data from all available doses ・ postprandial PG, lipid, antibody: no meta-analyses ・ meta-analyses: random-effects model ・ I-2 statistic for heterogeneity

16. Amori, R. E. et al. JAMA 2007;298:194-206. ■ Results: □ Search results (Figure1)

17. Amori, R. E. et al. JAMA 2007;298:194-206. Figure1. Study Design

18. Amori, R. E. et al. JAMA 2007;298:194-206. ■ Results: □ Study characteristics (Table1):29 articles >30weeks: 3 articles GLP-1 analogue: 8 trials long-acting GLP-1 analogue: 1 trial DPP4 inhibitor vs placebo: 13 trials DPP4 inhibitor vs medication: 4 trials DPP4 inhibitor only for certain meta-analyses: 3 abstracts

19. Amori, R. E. et al. JAMA 2007;298:194-206. □ Methodological quality: ・ double blind: all but for involving insulin ・ eligibility: clearly reported ・ concealment allocation: only 3 trials ・ balanced baseline characteristic: few ・ withdrawal %: 19% in GLP-1 analogue, 18% in DPP4 inhibitor ・ withdrawal reason: loss of efficacy in placebo GI adverse effects in exenatide ・ all funded by pharmaceutical companies

20. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin mimetics (GLP-1 analogue): ・ glycemic: exenatide HbA1c decline: placebo: significant (Figure 2) insuline: no difference % of HbA1c<7%: placebo: significant (Table 2) insuline: no difference

21. Amori, R. E. et al. JAMA 2007;298:194-206. Figure2. Weighted Mean Difference in Change in Hemoglobin A1c Percentage Value for GLP-1 Analogues vs Control in Adults With Type 2 Diabetes

22. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin mimetics (GLP-1 analogue): fasting and postprandial PG placebo: significant (Table 2) insuline: postprandial PG reduced more in exenatide no difference in fasting PG mixed-meal testing: dose-dependent postprandial PG decrease

23. Amori, R. E. et al. JAMA 2007;298:194-206. Table2. Summary of Meta-analyses of Outcomes in Patients With Type 2 Diabetes Treated With Incretin-Based Therapy vs Non-Incretin-Based Therapy (Controls)

24. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin mimetics (GLP-1 analogue): ・ nonglycemic: Weight : significant loss, more pronounced loss when compared with insulin progressive, dose-dependednt, without plateau trend– greater reduction with nausea Lipids: no significant change HDL better than insulin LDL better than placebo

25. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin mimetics (GLP-1 analogue): ・ Adverse events: hypoglycemia: mild to moderate, with SU during initiation of therapy similar with insulin Others: nausea and vomit: dose-dependent, mild to moderate, initial 8 weeks diarrhea antibodies: high, up to 67%

26. Amori, R. E. et al. JAMA 2007;298:194-206. Table3. Summary of Adverse Events in Patients With Type 2 Diabetes Treated With Incretin- Based vs Non-Incretin-Based Therapy

27. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin enhancers (DPP4 inhibitor1) ・ glycemic: HbA1c decline: placebo: significant (Figure 3) other hypoglycemic agents: slightly less effective % of HbA1c<7%: placebo: significant (Table2)

28. Amori, R. E. et al. JAMA 2007;298:194-206. Weighted Mean Difference in Change in Hemoglobin A1c Percentage Value for DPP4 Inhibitors vs Control in Adults With Type 2 Diabetes

29. Amori, R. E. et al. JAMA 2007;298:194-206. Table2 (cont.)Summary of Meta-analyses of Outcomes in Patients With Type 2 Diabetes Treated With Incretin-Based Therapy vs Non-Incretin-Based Therapy (Controls)

30. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin enhancers (DPP4 inhibitor1) fasting and postprandial PG placebo: significant (Table 2) sitagliptin > vildagliptin mixed-meal testing: dose-dependent postprandial PG decrease

31. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin enhancers (DPP4 inhibitor1) ・ nonglycemic: Weight : small increase sitagliptin: better than glipizide vildagliptin: better than thiazolidinediones Lipids: no consistent change some improvements in TG, LDL, HDL

32. Amori, R. E. et al. JAMA 2007;298:194-206. □ incretin enhancers (DPP4 inhibitor1) ・ Adverse events: hypoglycemia: severe in 2 patients mild to moderate, no difference Others: no GI effects, very well tolerated nasopharyngitis, UTI, headache

33. Amori, R. E. et al. JAMA 2007;298:194-206. Table3 (cont.) Summary of Adverse Events in Patients With Type 2 Diabetes Treated With Incretin-Based vs Non-Incretin-Based Therapy

34. Amori, R. E. et al. JAMA 2007;298:194-206. Summary of Adverse Events in Patients With Type 2 Diabetes Treated With Incretin-Based vs Non-Incretin-Based Therapy

35. Amori, R. E. et al. JAMA 2007;298:194-206. ■ Conclusion: incretin-based therapy: ・ moderate effectiveness in glycemia ・ greater reductions in postprandial PG ・ favorable (GLP-1) or neutral (DPP4) effects on weight ・ adverse effects GLP-1: GI adverse effects DPP4 inhibitor: infection and headache

36. Amori, R. E. et al. JAMA 2007;298:194-206. □ moderate effectiveness in glycemia ： ・ relatively low baseline HbA1c (~8%) ・ greater reduction in higher HbA1c □ greater reductions in postprandial PG: ・ postprandial reduction > fasting reduction ・ alternative for targeting postprandial glycemia ・ noninferior to others, except for metformin superior to vildagliptin

37. Amori, R. E. et al. JAMA 2007;298:194-206. □ favorable (GLP-1) or neutral (DPP4) effects on weight: ・ continuous loss without plateau ・ may or may not due to nausea ・ weight loss medication ?: exenatide ・ DPP4 better than SU, thiazolidinediones

38. Amori, R. E. et al. JAMA 2007;298:194-206. □ adverse effects: ・ low hypoglycemia: glucose dependent, may occur with insulin secretagogues ・ GI adverse effects: develop tolerance, withdrawal 4% dose escalation protocol to minimize effects

39. Amori, R. E. et al. JAMA 2007;298:194-206. □ adverse effects: ・ infection and headache: ubiquitous cell-membrane protein, concerns about long-term immune function, relative risk 1.5 → significant burden ・ headache: not related to hypoglycemia

40. Amori, R. E. et al. JAMA 2007;298:194-206. □ Limitation: < less than 30 weeks: long-term data needed race or ethnicity: white dominant children not included not used intention-to-treat analyses: may overestimate glycemic efficacy

41. Amori, R. E. et al. JAMA 2007;298:194-206. □

42. □