scholarly journals 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”

Cardiology ◽  
2020 ◽  
Vol 145 (6) ◽  
pp. 387-387
Author(s):  
Pierre Ambrosi ◽  
Aurélie Daumas ◽  
Patrick Villani ◽  
Roch Giorgi
Keyword(s):  
Cardiovascular Events ◽  
Glycosylated Hemoglobin ◽  
Antidiabetic Drugs ◽  
Cardiovascular Outcome ◽  
Cardiovascular Outcome Trials

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

Cardiology ◽  
2020 ◽  
Vol 145 (6) ◽  
pp. 370-374
Author(s):  
Pierre Ambrosi ◽  
Aurélie Daumas ◽  
Patrick Villani ◽  
Roch Giorgi
Keyword(s):  
Weight Loss ◽  
Cardiovascular Events ◽  
Glycosylated Hemoglobin ◽  
Surrogate Marker ◽  
Cardiovascular Outcomes ◽  
Antidiabetic Drugs ◽  
Cardiovascular Outcome ◽  
Antidiabetic Drug ◽  
Cardiovascular Outcome Trials ◽  
Antidiabetic Treatment

Background and Objectives: The value of glycosylated hemoglobin (HbA1c) as a surrogate marker for the prevention of cardiovascular outcomes on antidiabetic drugs is debated. The 2008 FDA guidance led to multiple large clinical trials to evaluate the effect of new antidiabetic drugs versus placebo on major adverse cardiac events (MACE). The aim of this study was to evaluate the relation between MACE and HbA1c decrease between antidiabetic drug and placebo across the spectrum of cardiovascular outcome trials (CVOT). Methods: In this systematic review, we included randomized controlled trials that compared an antidiabetic drug to placebo in addition to current standard of care with the primary intention of demonstrating cardiovascular safety. We investigated the relationship between MACE decrease on antidiabetic drug and HbA1c reduction on antidiabetic drug using the coefficient correlation. We also studied the effects of potential confounders on MACE decrease. Results: Fourteen eligible trials including 128,149 patients were included, 12,114 of whom experienced MACE. Mean achieved HbA1c absolute reductions on antidiabetic treatment versus placebo varied from 0.29 to 1%. The decrease of MACE on antidiabetic drug was significantly correlated with mean HbA1c reduction (r = 0.88, 95% CI: 0.67–0.96, p < 0.001) and weight loss (r = 0.81, 95% CI: 0.46–0.94, p < 0.001). In a bivariate model including weight loss, only HbA1c reduction remained significantly correlated with the decrease of MACE on antidiabetic drug (p = 0.019). Conclusion: Across CVOT, the decrease in MACE incidence on various antidiabetic drugs is significantly correlated with HbA1c reduction. This meta-analysis supports HbA1c as an appropriate surrogate endpoint for cardiovascular events. Our analysis supports that changes in HbA1c should be taken into account while interpreting effects of new antidiabetic drugs on cardiovascular outcomes.

4113Glucose lowering drugs or strategies, major adverse cardiovascular events and heart failure outcomes, and association with weight loss - meta-analysis of large cardiovascular outcome trials

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
O R Ghosh-Swaby ◽  
S G Goodman ◽  
L A Leiter ◽  
A Cheng ◽  
K Connelly ◽  
...  
Keyword(s):  
Heart Failure ◽  
Weight Loss ◽  
Risk Reduction ◽  
Cardiovascular Events ◽  
Cardiovascular Outcome ◽  
Major Adverse Cardiovascular Events ◽  
Cardiovascular Risk Reduction ◽  
Cardiovascular Outcome Trials ◽  
Lower Weight ◽  
Meta Regression

Abstract Background Glucose lowering drugs or strategies (GLDS) have varied effects on major adverse cardiovascular events (MACE) and heart failure (HF) in cardiovascular outcomes trials. Mechanisms driving cardiovascular risk reduction remain elusive. Methods We searched MEDLINE, PubMed, and meeting abstracts up to 11/21/2018 for large GLDS cardiovascular outcome trials (CVOTs) in patients with or at risk for type 2 diabetes. Primary endpoints of MACE and HF were evaluated with random effects risk ratios (RR) and explored by baseline CVD subgroups and meta-regression by weight change across treatment arms. Results In 27 GLDS CVOTs, a total 207,820 patients, median age 63 years, 64% male, 64% CVD and 11% with prior HF were studied over a mean 3.8 years with 20,118 (10%) patients having MACE and 7,212 (4%) a HF event. Compared with standard care, GLDS overall lowered MACE (RR 0.92, P<0.ehz745.01171) but not HF (RR 1.01, P=0.91). Across GLDS, the magnitude and directionality varied modestly for MACE RR (P-int=0.07) but markedly for HF (P-int<0.ehz745.01171). Meta-regression showed a change in HF RR by 6% (95% CI 3%-9%) per 1 kg weight gain/loss between treatment arms (P=0.0006; Figure). In 9 trials of GLDS that achieved marked weight loss (lifestyle, GLP1 agonists, SGLT2 inhibitors), MACE benefit was confined to patients with baseline CVD (RR 0.89 [0.84–0.95] versus without (RR 1.02 [0.91–1.15]; P-int=0.01) with consistent HF effect (RR 0.80 [0.72–0.88] vs RR 0.76 [0.56–1.03]; P-int=0.74). Heart Failure Risk and Changes in Weight Conclusion HF outcomes were improved with GLDS that lower weight. Among diabetes GLDS that lower weight, there was a robust risk reduction in atherothrombotic and heart failure events, with the MACE benefit confined to patients with established CVD. Acknowledgement/Funding Heart and Stroke Foundation

Network meta-analysis of nine large cardiovascular outcome trials of new antidiabetic drugs

2019 ◽  
Vol 13 (3) ◽  
pp. 204-211 ◽  
Author(s):  
Osamah M. Alfayez ◽  
Majed S. Al Yami ◽  
Mohannad Alshibani ◽  
Saad B. Fallatah ◽  
Nasser M. Al Khushaym ◽  
...  
Keyword(s):  
Meta Analysis ◽  
Antidiabetic Drugs ◽  
Cardiovascular Outcome ◽  
Cardiovascular Outcome Trials

Analysis of robustness of the landmark Cardiovascular outcome trials of antidiabetic drugs – A systematic review

2021 ◽  
Vol 17 ◽  
Author(s):  
Debdipta Bose ◽  
Mahanjit Konwar
Keyword(s):  
Statistical Significance ◽  
Rank Correlation ◽  
Primary Objective ◽  
Antidiabetic Drugs ◽  
Cardiovascular Outcome ◽  
P Value ◽  
Fragility Index ◽  
Cardiovascular Outcome Trials ◽  
Lost To Follow Up

Background: It is essential for Randomized controlled trials [RCTs] to report its results in a comprehensive manner. Hence, it is necessary to assess the robustness of the trials with statistically significant and as well as non-significant results. Robustness can be evaluated using fragility index (FI) and reverse fragility index [RFI] is for trials with statistically significant and as well as non-significant results. The primary aim of this study was to calculate FI and RFI for cardiovascular outcome trials [CVOT]. Materials & Methods: PubMed/MEDLINE was searched to identify all RCTs of antidiabetic drugs where the primary objective was to evaluate the cardiovascular outcomes. We recorded the trial characteristics of each CVOT trial. The FI, RFI, Fragility quotient [FQ] and reverse fragility quotient [FQ] was calculated to evaluate the robustness of the trials. Spearman rank correlation test was used for correlation. Findings: A total of 889 studies were identified and 24 RCTs was included. Among the 24 trials, 12 [50%] trials achieved statistical significance. The median FI and RFI were 29 [4-12] and 22.5 [1-37] for trials with statistically significant and non-significant results. The median FQ and RFQ were 0.0075 [0.002-0.013] and 0.0003 [0.0001-0.004] for trials with statistically significant and non-significant results. The hazard ratio, p value and NNT-B had strong negative relation with FI. Interpretation: Our study showed that half of the trials showing superiority of cardioprotective benefits have favourable FI. The trials failed to show superiority also have a reasonable RFI indicating the robustness of these trials. But the results pf the trials where patients lost to follow-up exceed the FI of that trial demands caution during interpretation.

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