In the field of drug development and effectiveness evaluation, the use of surrogate endpoints is acceptable if they reliably predict a positive effect on clinical outcomes such as mortality or morbidity. Hemoglobin A1c (HbA1c) is a widely used surrogate endpoint in phase 3 and 4 clinical trials evaluating drugs in patients with diabetes mellitus (DM). The objective of this study was to investigate whether HbA1c is a valid surrogate endpoint for evaluating the effectiveness of antihyperglycemic drugs in DM trials.

We conducted a systematic review of randomized placebo-controlled trials evaluating the effect of a treatment on levels of HbA1c and clinical outcomes in patients with DM. The association between the effects of treatment on HbA1c levels and clinical outcomes was then investigated using regression analysis at the trial level. The correlation coefficients (R) were interpreted using the cut-off points suggested by the German Institute for Quality and Efficiency in Health Care (IQWiG). HbA1c was considered a valid surrogate endpoint if it demonstrated a strong association with clinical outcomes (i.e., the lower limit of the 95% confidence interval [CI] of R≥ 0.85).

Nineteen phase 3 or 4 randomized controlled trials (RCTs) were identified. All studies included adults with type 2 DM. None of the associations evaluated was strong enough to validate HbA1c as a surrogate endpoint for any clinical outcome: mortality (R 0.34, 95% CI: -0.14, 0.69); myocardial infarction (R 0.20, 95% CI: -0.30, 0.61); heart failure (R 0.08, 95% CI: -0.40, 0.53); kidney injury (R -0.04, 95% CI: -0.52, 0.47); and stroke (R 0.81, 95% CI: 0.54, 0.93).

The evidence from multiple placebo-controlled RCTs of antihyperglycemic drugs in patients with type 2 DM suggests that a reduction in levels of HbA1c does not meet the IQWiG criteria for a valid surrogate endpoint. Consequently, the risk-benefit ratio of antihyperglycemic drugs in terms of patient relevant clinical outcomes, regardless of their hypoglycemic effect, should be the focus of therapeutic, regulatory, and reimbursement decisions.