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.