Mediation analysis of time‐to‐event endpoints accounting for repeatedly measured mediators subject to time‐varying confounding

Vansteelandt, Stijn; Linder, M.; Vandenberghe, S.; Stéen, Johan; Madsen, Jesper

doi:10.1002/sim.8336

Cited by 58 publications

(72 citation statements)

References 21 publications

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“…The exact nature of the relationship between any baseline characteristic, including BMI, and CV benefit of liraglutide and semaglutide (via glycaemic control and/or weight loss and/or other mechanisms) remains difficult to establish, 3,8 with published meta-analysis results showing that baseline BMI was not associated with achieved glycaemic control across seven different antihyperglycaemic treatments. 9 Thus, the doseresponse curves for any treatment may differ for MACE, glucose levels and weight, and our analyses have shown that there appeared to be generally no effect of baseline BMI on MACE.…”

Section: Discussionmentioning

confidence: 99%

Effects of glucagon‐like peptide‐1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials

Verma

McGuire

Bain

et al. 2020

Diabetes Obesity Metabolism

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Associations between body mass index (BMI) and the cardiovascular (CV) and kidney efficacy of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) are uncertain; therefore, data analysed separately from the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial and the Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN 6) were examined. These international, randomized, placebo-controlled trials investigated liraglutide and semaglutide (both subcutaneous) in patients with T2D and at high risk of CV events. In post hoc analyses, patients were categorized by baseline BMI (<25, ≥25-<30, ≥30-<35 and ≥35 kg/m 2), and CV and kidney outcomes with GLP-1 RA versus placebo were analysed. All baseline BMI data from LEADER (n = 9331) and SUSTAIN 6 (n = 3290) were included (91% and 92% of patients with overweight or obesity, respectively). In SUSTAIN 6, nominally significant heterogeneity of semaglutide efficacy by baseline BMI was observed for CV death/myocardial infarction/stroke (major adverse CV events, primary outcome of both; P interaction = .02); otherwise, there was no statistical heterogeneity for either GLP-1 RA versus placebo across BMI categories for key CV and kidney outcomes. The lack of statistical heterogeneity from these cardiorenal outcomes implies that liraglutide and semaglutide may be beneficial for many patients and is probable not to depend on their baseline BMI, but further study is needed.

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Section: Discussionmentioning

confidence: 99%

Effects of glucagon‐like peptide‐1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials

Verma

McGuire

Bain

et al. 2020

Diabetes Obesity Metabolism

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show abstract

“…In these models, we used the change from baseline as a time-dependent covariate and included the baseline value also as described by Vansteelandt and colleagues. 12 The mediated proportion was calculated as the difference in log hazard ratios (HRs) between the models without and with the mediator, divided by the log HR from the model without the mediator. STATA 14.2 (StataCorp LP, College Station, TX, USA) was used for all analyses.…”

Section: Discussionmentioning

confidence: 99%

Diuretic and renal effects of spironolactone and heart failure hospitalizations: a TOPCAT Americas analysis

Kalogeropoulos

Thankachen

Butler

et al. 2020

European J of Heart Fail

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“…However, the Vansteelandt method may also adjust for postbaseline confounders, such as concomitant medication, by including them as covariates in the models. Further details of this method have been published separately (10).…”

Section: Vansteelandt Methodsmentioning

confidence: 99%

“…In the present exploratory analyses, we sought to identify potential mediators for the CV benefit observed with liraglutide using data from the LEADER trial. We explored these with several mediation methods, including a new statistical methodology designed to integrate sequential confounders (a limitation of existing methods for mediation analysis) (10).…”

mentioning

confidence: 99%

Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial

et al. 2020

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The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA 1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA 1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS These analyses identify HbA 1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation. Liraglutide is a glucagon-like peptide 1 receptor agonist (GLP-1 RA) approved for the management of hyperglycemia in type 2 diabetes and for reduction of cardiovascular (CV) risk in patients with type 2 diabetes and clinical CV disease (CVD) (1,2). It is also approved at a higher dose for the treatment of obesity (3,4). The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial was initiated to assess the CV safety of liraglutide in patients with type 2 diabetes and

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Mediation analysis of time‐to‐event endpoints accounting for repeatedly measured mediators subject to time‐varying confounding

Cited by 58 publications

References 21 publications

Effects of glucagon‐like peptide‐1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials

Effects of glucagon‐like peptide‐1 receptor agonists liraglutide and semaglutide on cardiovascular and renal outcomes across body mass index categories in type 2 diabetes: Results of the LEADER and SUSTAIN 6 trials

Diuretic and renal effects of spironolactone and heart failure hospitalizations: a TOPCAT Americas analysis

Cardiovascular Risk Reduction With Liraglutide: An Exploratory Mediation Analysis of the LEADER Trial

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