Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo

Ambrosi, Pı̈erre; Daumas, Aurélie; Villani, Patrick; Giorgi, Roch

doi:10.1159/000506004

Cited by 11 publications

(14 citation statements)

References 26 publications

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“…According to the suggestion by Shoar et al [1], we tested the robustness of the correlation between HbA1c reduction and MACE decrease, performing sensitivity analyses [2].…”

Section: Dear Editormentioning

confidence: 99%

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Dear Editor,According to the suggestion by Shoar et al[1], we tested the robustness of the correlation between HbA1c reduction and MACE decrease, performing sensitivity analyses [2].The predictive value of HbA1c for coronary events has been consistently shown in the early period following an acute coronary event [3]. There is also some evidence that HbA1c predicts survival in diabetic patients with stable coronary artery disease [4].

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confidence: 99%

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Authors’ Reply to the Letter by Shoar et al. on “Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo”

et al. 2020

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Dear Editor,According to the suggestion by Shoar et al.[1], we tested the robustness of the correlation between HbA1c reduction and MACE decrease, performing sensitivity analyses [2].The predictive value of HbA1c for coronary events has been consistently shown in the early period following an acute coronary event [3]. There is also some evidence that HbA1c predicts survival in diabetic patients with stable coronary artery disease [4]. In our meta-analysis, 2 trials included patients with a recent acute coronary syndrome and 12 trials included patients either at high risk or with definite coronary artery disease (stable or unstable). Excluding the 2 trials performed after an acute coronary syndrome did not modify the correlation (R = 0.88, p = 0.0004).In the 5 trials testing a DPP-4 inhibitor, the relative MACE reduction was at most 3%, despite a significant (modest) reduction in HbA1c. Excluding these 5 trials did not modify the correlation between HbA1c reduction and MACE decrease (R = 0.84, p = 0.004).Lastly, we excluded the SUSTAIN-6 trial showing the higher MACE decrease (26%). The correlation was not significantly modified (R = 0.88, p < 0.001).Thus, we are confident that HbA1c reduction explains, at least in part, the decrease in MACE observed with the new antidiabetic drugs.

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“…According to the suggestion by Shoar et al [1], we tested the robustness of the correlation between HbA1c reduction and MACE decrease, performing sensitivity analyses [2].…”

Section: Dear Editormentioning

confidence: 99%

“…

…”

mentioning

confidence: 99%

Authors’ Reply to the Letter by Shoar et al. on “Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo”

et al. 2020

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“…The timely publication of the paper by Ambrosi et al [7] in a recent issue of Cardiology highlights a valuable standpoint for clinical trials of antidiabetic drugs to consider HbA 1c as a predictive measure for the CV benefits of the new medications being tested. As this meta-analysis concludes, mean decrease in HbA 1c is directly correlated with a reduction in major CV events.…”

Section: Dear Editormentioning

confidence: 99%

“…The meta-analysis by Ambrosi et al [7] truly highlights the easing role of a universally accepted marker as a surrogate for the prediction of CV outcomes in clinical trials of antidiabetic drugs. However, the above-men-tioned points can widen our perspectives from which this clinical surrogate is viewed by investigators of future research studies.…”

Section: Dear Editormentioning

confidence: 99%

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Letter to the Editor Concerning “Glycosylated Hemoglobin as a Surrogate for the Prediction of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo”

et al. 2020

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Dear Editor,As an indicator of long-term glycemic control in patients with diabetes mellitus (DM), glycosylated hemoglobin (HbA 1c) has proved to be superior over fasting blood sugar as a reliable and a more accurate measure of diabetes treatment [1]. Although the clinical implications of HbA 1c have been highlighted by widely cited guidelines in relation to the microvascular complications of DM [2], the role of HbA 1c in predicting cardiovascular (CV) outcome is being cumulatively investigated [3].An increasing body of knowledge supports the independent and linear association of HbA 1c level and the severity of atherosclerotic peripheral arterial disease (PAD) [4,5], the literature has taken the prognostic value of HbA 1c to the next level, i.e., predicting the incidence of macrovascular diseases in nondiabetic individuals [3,5,6].The timely publication of the paper by Ambrosi et al. [7] in a recent issue of Cardiology highlights a valuable standpoint for clinical trials of antidiabetic drugs to consider HbA 1c as a predictive measure for the CV benefits of the new medications being tested. As this meta-analysis concludes, mean decrease in HbA 1c is directly correlated with a reduction in major CV events. Furthermore, such a relationship is independent of the weight loss observed during the study period of the included clinical trials. We sought to provide a few perspectives from which this research study could be interpreted more practically.This meta-analysis could have drawn a clearer picture of the history of DM-related CV complications at the baseline for each of the included clinical trials. While there might have been a lack of information at the individual level, the frequency of CV disease of any type at the time of enrollment has been depicted for each trial and it ranged from 41 to 100% of the patients. If provided, the relationship between post-treatment HbA 1c alteration and the de novo incidence of CV complications of DM would be much clearer.Although the change in HbA 1c was correlated with the change in CV events at the end of the follow-up period, the duration of follow-up was not highlighted in the meta-analysis. Previous studies have shown the clinical utility of HbA 1c as a predictor of short-term mortality after acute coronary syndrome, and it also bears prognostic value for long-term CV complications of lesser severity. In either case, more elaboration on the follow-up period

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Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

Wallach,

Yoon,

Doernberg

et al. 2024

JAMA

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ImportanceSurrogate markers are increasingly used as primary end points in clinical trials supporting drug approvals.ObjectiveTo systematically summarize the evidence from meta-analyses, systematic reviews and meta-analyses, and pooled analyses (hereafter, meta-analyses) of clinical trials examining the strength of association between treatment effects measured using surrogate markers and clinical outcomes in nononcologic chronic diseases.Data sourcesThe Food and Drug Administration (FDA) Adult Surrogate Endpoint Table and MEDLINE from inception to March 19, 2023.Study SelectionThree reviewers selected meta-analyses of clinical trials; meta-analyses of observational studies were excluded.Data Extraction and SynthesisTwo reviewers extracted correlation coefficients, coefficients of determination, slopes, effect estimates, or results from meta-regression analyses between surrogate markers and clinical outcomes.Main Outcomes and MeasuresCorrelation coefficient or coefficient of determination, when reported, was classified as high strength (r ≥ 0.85 or R2 ≥ 0.72); primary findings were otherwise summarized.ResultsThirty-seven surrogate markers listed in FDA’s table and used as primary end points in clinical trials across 32 unique nononcologic chronic diseases were included. For 22 (59%) surrogate markers (21 chronic diseases), no eligible meta-analysis was identified. For 15 (41%) surrogate markers (14 chronic diseases), at least 1 meta-analysis was identified, 54 in total (median per surrogate marker, 2.5; IQR, 1.3-6.0); among these, median number of trials and patients meta-analyzed was 18.5 (IQR, 12.0-43.0) and 90 056 (IQR, 20 109-170 014), respectively. The 54 meta-analyses reported 109 unique surrogate marker–clinical outcome pairs: 59 (54%) reported at least 1 r or R2, 10 (17%) of which reported at least 1 classified as high strength, whereas 50 (46%) reported slopes, effect estimates, or results of meta-regression analyses only, 26 (52%) of which reported at least 1 statistically significant result.Conclusions and RelevanceMost surrogate markers used as primary end points in clinical trials to support FDA approval of drugs treating nononcologic chronic diseases lacked high-strength evidence of associations with clinical outcomes from published meta-analyses.

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Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo

Cited by 11 publications

References 26 publications

Authors’ Reply to the Letter by Shoar et al. on “Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo”

Authors’ Reply to the Letter by Shoar et al. on “Glycosylated Hemoglobin as a Surrogate for the Prevention of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo”

Letter to the Editor Concerning “Glycosylated Hemoglobin as a Surrogate for the Prediction of Cardiovascular Events in Cardiovascular Outcome Trials Comparing New Antidiabetic Drugs to Placebo”

Associations Between Surrogate Markers and Clinical Outcomes for Nononcologic Chronic Disease Treatments

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