Glycated hemoglobin as a surrogate for evaluating the effectiveness of drugs in diabetes mellitus trials: a systematic review and trial-level meta-analysis

Abstract

Objective The objective of this study was to investigate whether glycated hemoglobin (HbA1c) is a valid surrogate for evaluating the effectiveness of antihyperglycemic drugs in diabetes mellitus (DM) trials. Methods We conducted a systematic review of placebo-controlled randomized clinical trials (RCTs) evaluating the effect of a treatment on HbA1c (mean difference between groups) and clinical outcomes (relative risk of mortality, myocardial infarction, stroke, heart failure, and/or kidney injury) in patients with DM. Then, we investigated the association between treatment effects on HbA1c and clinical outcomes using regression analysis at the trial level. Lastly, we interpreted the correlation coefficients (R) using the cut-off points suggested by the Institute for Quality and Efficiency in Healthcare (IQWiG). HbA1c was considered a valid surrogate if it demonstrated a strong association: lower limit of the 95 percent confidence interval (95 percent CI) of R greater than or equal to .85. Results Nineteen 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 for any clinical outcome: mortality (R = .34; 95 percent CI −.14 to .69), myocardial infarction (R = .20; −.30 to .61), heart failure (R = .08; −.40 to .53), kidney injury (R = −.04; −.52 to .47), and stroke (R = .81; .54 to .93). Conclusions The evidence from multiple placebo-controlled RCTs does not support the use of HbA1c as a surrogate to measure the effectiveness of antihyperglycemic drugs in DM studies.

Is HbA1c a valid surrogate for mortality in type 2 diabetes? Evidence from a meta-analysis of randomized trials

“…In addition, LogRRs are closer to 0 than LogORs enhancing the similarity of both results. Consistent with the recently published meta-analysis by Rivera et al, we found no convincing evidence for surrogacy of HbA1c in terms of mortality [ 12 ]. The differences in LogRRs and correlation coefficients between the study by Rivera et al (LogRR 0.320 [95% CI − 0.151; 0.791]; Pearson's correlation coefficient 0.328 [− 0.148; 0.681]) and our present analysis (LogRR 0.129 [− 0.043; 0.302]; correlation − 0.010 [− 0.145; 0.134]) might be attributable to methodological differences, differences in the inclusion criteria or publication periods of the trials.…”

“…Based on the evidence of numerous randomized trials, we conclude that HbA1c is not a valid surrogate marker for all-cause mortality in people with type 2 diabetes. Our results strengthen the rationale that clinical decisions should not only be guided by glycemic parameters, but should also take into account patient-relevant outcomes [ 12 , 24 ].…”

“…Systematic empirical evidence on the surrogate validity of HbA1c for patient-relevant outcomes is scarce. Indeed, we are only aware of two meta-analyses that assessed the surrogacy for all-cause and cardiovascular mortality or clinical outcomes as primary endpoints [ 11 , 12 ].…”

“…Rivera et al recently reported the results of a systematic review of randomized trials with trial-level meta-analysis. They found no evidence to support the use of HbA1c as a surrogate for all-cause mortality in people with type 2 diabetes [ 12 ]. However, the restrictive, somewhat arbitrary inclusion criteria (at least 1000 participants and 20 events of clinical outcomes per trial, follow-up and/or duration of intervention of at least 52 weeks) in the meta-analysis on all-cause mortality led to the inclusion of only 19 cardiovascular outcome trials (CVOT) compromising the representativeness of the results.…”

The Combination Clinical Value of Plasma Brain Natriuretic Peptide and Serum HbAlc in the Diagnosis of Chronic Pulmonary Heart Disease

“…In recent years, with the change of people's lifestyle and environmental deterioration, the incidence of clinical pulmonary heart disease is increasing year by year [ 20 ]. In a variety of visceral heart disease, about 20%~40% are pulmonary heart disease [ 21 – 24 ]. Pulmonary heart disease is mostly induced by chronic obstructive pulmonary disease, and it is a slow occurrence and development process [ 25 ].…”