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

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


■ 　 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


□ 　 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


□ 　 incretin:・　 GIP (glucose-dependent insulinotropic polypeptide) GLP-1 (glucagonlike peptide 1)

・　 inactivated by DPP4 (dipeptidyl peptidase 4)


□ 　 exenatide (Byetta):・　 GLP-1 receptor analogue・　 injection

□ 　 sitagliptin・　 selective DPP4 inhibitor・　 oral・　 for monotherapy or with metformin or thiazolidinedione


■ 　 Objective:To assess the efficacy and safety of incretin-based therapy (GLP-1 analogues and DPP4 inhibitors) in type2 DM


■ 　 Methods:□ 　 Data source:・　 MEDLINE and Cochrane for English RCT involving incretin therapy・　 search prescribing information, relevant Web, reference and citation, abstracts at recent conferences


□ 　 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


□ 　 Data extraction:・　 two independent reviewers・　 resolved by consensus・　 meta-analyses for efficacy and safety

baseline characteristics (Table1)

Table1. Characteristics of Randomized Controlled Trials of Glucagonlike Peptide 1 Analogues and Dipeptidyl Peptidase 4 Inhibitors Included in the Systematic Review





・　 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　


□ 　 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


□ 　 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


■ 　 Results:□ 　 Search results (Figure1)


　 Figure1. 　 Study Design


■ 　 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


□ 　 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


□ 　 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


Figure2. Weighted Mean Difference in Change in Hemoglobin A1c Percentage Value for GLP-1 Analogues vs Control in Adults With Type 2 Diabetes


□ 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


Table2. Summary of Meta-analyses of Outcomes in Patients With Type 2 Diabetes Treated With Incretin-Based Therapy vs Non-Incretin-Based Therapy (Controls)


□ 　 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


□ 　 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%


Table3. Summary of Adverse Events in Patients With Type 2 Diabetes Treated With Incretin-Based vs Non-Incretin-Based Therapy


□ incretin enhancers (DPP4 inhibitor1)・　 glycemic: HbA1c decline: placebo: significant (Figure 3) other hypoglycemic agents: slightly less effective

% of HbA1c<7%: placebo: significant (Table2)


Weighted Mean Difference in Change in Hemoglobin A1c Percentage Value for DPP4 Inhibitors vs Control in Adults With Type 2 Diabetes


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)


□ incretin enhancers (DPP4 inhibitor1)fasting and postprandial PG placebo: significant (Table 2) sitagliptin > vildagliptin

mixed-meal testing: dose-dependent postprandial PG decrease


□ 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


□ 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


Table3 (cont.) Summary of Adverse Events in Patients With Type 2 Diabetes Treated With Incretin-Based vs Non-Incretin-Based Therapy


Summary of Adverse Events in Patients With Type 2 Diabetes Treated With Incretin-Based vs Non-Incretin-Based Therapy


■ 　 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


□　　 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


□　　 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


□　　 adverse effects:・　 low hypoglycemia: glucose dependent, may occur with insulin secretagogues

・　 GI adverse effects: develop tolerance, withdrawal 4% dose escalation protocol to minimize effects


□　　 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


□　　 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


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Documents

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