This systematic review and meta-analysis of double-blind, randomized controlled trials that met predefined methodological criteria summarized treatment effects on A1C levels across OAD drug class, dose, and duration of therapy (). The greatest pooled treatment effect noted was with maximum doses of sulfonylureas after 12 weeks of therapy, followed by TZDs after 13–18 weeks of therapy. Across all OAD classes, an increase in dose yielded a further decrease in A1C initially with a maximum effect achieved by 3–6 months.
The meta-regression analysis also provided a numerical estimate of an effect that has been commented on by previous authors: higher baseline A1C levels are associated with greater declines in A1C with therapy (9
). However, this effect was modest in most studies that were reviewed, such that after controlling for OAD drug class and dose, every 1% higher pretreatment A1C levels predicted a 0.5% greater fall of A1C levels after 6 months of therapy.
This review has several strengths. First, it was restricted to randomized controlled trials that met predetermined methodological criteria to minimize the potential for bias. Of note, the application of these criteria led to the exclusion of 150 out of 211 (71%) manuscripts that may otherwise have been included. Second, it entailed a comprehensive search for all currently used OAD classes for type 2 diabetes treatment. Third, the effect of OADs on A1C level was assessed at different time intervals, ranging from 12 weeks to 2 years. Finally, it focused on the effect of OAD class versus individual drugs and therefore may be relevant to new drugs from the same class.
This review has several limitations. First, most of the studies included participants with relatively newly diagnosed diabetes (median duration of diabetes of 5.2 years). As such, the review's findings may not be relevant to patients with a longer duration of diabetes or with diabetes-related complications. Second, relatively few studies were available for sulfonylureas (n = 6), meglitinides (n = 10), and biguanides (n = 12) thereby affecting the reliability of their respective quantitative estimates. Third, less than 30% of the reviewed papers reported the effect of therapy for periods greater than 24 weeks. Fourth, there is some statistical heterogeneity (ranging up to 90%) in the meta-analyzed results of the included studies, regardless of OAD class, drug, or dose. This heterogeneity may have been due to study differences in design, patient demographics and characteristics, duration of diabetes, and background drug therapy or confounding. Regardless of the cause, heterogeneity was managed by using a random-effects model for meta-analyses. Fifth, some of the summarized trials added oral agents to background therapy that included insulin. If investigators adjusted the dose of insulin during the trial, this may have affected the estimate of the effect of the OAD on the change in A1C. This could not be taken into consideration as insulin doses were not provided in the reports. Finally, it is possible that this review was influenced by publication bias given that studies with positive results are generally more likely to get published, resulting in an overestimate of the benefit of an OAD on A1C reduction.
In summary, the results of this systematic review and meta-analysis suggest that the initiation of an OAD in addition to current therapy yields an additional decrease in A1C level of ~1–1.25% with most of the treatment effect evident by 3–6 months of initiating OAD therapy. This effect was fairly consistent between OAD classes with sulfonylureas and TZDs having the greatest reduction in AIC. The meta-regression analysis numerically demonstrated a small effect of baseline A1C on the fall of A1C with OAD treatment. Further carefully conducted OAD trials are needed to account for 1) combinations of OAD drug use and its impact on A1C levels; 2) the effectiveness of long-term OAD use on A1C levels; and 3) adverse and hypoglycemic events.