Relationship of baseline HbA_1c and efficacy of current glucose-lowering therapies: A meta-analysis of randomized clinical trials

Aims: Baseline glycated haemoglobin (HbA_1c) concentrations vary between clinical trials of glucose-lowering agents and this may affect interpretation of clinical efficacy. The objective of this study is to quantify the relationship between baseline HbA_1c and reduction of HbA _1c in clinical trials. Methods: PubMed literature searches from 1991 to 2007. Randomized controlled studies with placebo-controlled or comparator arms [≥ 9 patients in the intent-to-treat (ITT) population] ranging in duration from 23 to 52 weeks, in which baseline and change in glycated haemoglobin (HbA_1c) were reported. The relationship between baseline HbA_1c and change in HbA_1c was analysed by a weighted least-squared regression model accounting for ITT population and variance of HbA_1c change. Fourteen per cent of independently abstracted studies met the selection criteria. Results: Meta-analysis from 59 clinical trials (8479 patients) produced weighted R² of 0.35 (P < 0.0001) for the association of baseline HbA_1c and absolute change in HbA _1c. Subanalysis of eight metformin clinical trials demonstrated a stronger association [weighted R² of 0.67 (P = 0.0130)]. Exclusion of metformin clinical trials from the overall meta-analysis (n = 51) yielded a weighted R² of 0.31 (P < 0.0001). Subanalyses of clinical trials of glucose-lowering therapies predominantly targeting fasting (n = 37) or postprandial (n = 22) blood glucose produced weighted R² values of 0.27 (P < 0.001) and 0.42 (P < 0.005), respectively. Conclusions: These data demonstrate a positive relationship between baseline HbA_1c and the magnitude of HbA_1c change across 10 categories of glucose-lowering therapies, irrespective of class or mode of action. These observations should be considered when assessing clinical efficacy of diabetes therapies derived from clinical trials.