Insulin versus an oral antidiabetic agent as add-on therapy in type 2 diabetes after failure of an oral antidiabetic regimen: a meta-analysis

BACKGROUND: Although evidence-based guidelines for the treatment of type 2 diabetes mellitus provide clear recommendations for initial therapy, evidence on an optimal treatment strategy after secondary failure is unclear. PURPOSE: To compare the efficacy of add-on therapy using basal insulin versus an additional oral antidiabetic agent in patients with type 2 diabetes and secondary failure. DATA SOURCES: We searched the following electronic databases from inception until June 2007: MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials; Web of Science; Scopus; CINAHL; International Pharmaceutical Abstracts; Academic OneFile; PASCAL; Global Health Database; LILACS; HealthSTAR; PubMed. Reference lists of potentially relevant articles and clinical trial databases were searched, pharmaceutical manufacturers were contacted, and grey literature sources were sought. STUDY SELECTION: Randomized controlled trials (RCTs) involving subjects with type 2 diabetes with secondary failure who were randomly assigned to receive additional basal insulin therapy (insulin glargine, detemir, or NPH [neutral protamine Hagedorn]) versus another oral antidiabetic agent from any class. DATA EXTRACTION: Two reviewers independently screened articles, extracted data and assessed methodological quality. Our primary outcome was glycemic control measured by change in glycosylated hemoglobin (Hb(A1C)) and the proportion of subjects achieving a Hb(A1C) value of ≤ 7%. DATA SYNTHESIS: To compare overall efficacy between the 2 treatment strategies, change in Hb(A1C) was pooled across studies using a random-effects model and weighted mean difference (WMD). Eleven RCTs, involving 757 participants with a median age of 56 and a median known duration of diabetes of 11 years, were included in our analysis. Insulin treatment demonstrated a small but statistically significant improvement in Hb(A1C) compared with the use of an additional oral agent as add-on therapy (WMD -0.17; 95% CI [confidence interval] -0.33 to -0.02). LIMITATIONS: The use of surrogate outcomes and the short duration of the trials makes it impossible to gain information on long-term patient-oriented outcomes. The overall quality of the studies was low, primarily in view of inadequate blinding. CONCLUSIONS: Although add-on therapy using injected insulin shows a slight benefit over an additional oral antidiabetic agent, our results indicate that basal insulin therapy and the use of an oral agent as add-on therapy produce comparable results. Non-therapeutic differences must be considered in the choice of treatment strategies. More high-quality studies with adequate safety data using more aggressive insulin titrations are needed.