Dataset Information

Effect of empagliflozin on total myocardial infarction events by type and additional coronary outcomes: insights from the randomized EMPA-REG OUTCOME trial.

ABSTRACT:

Background

The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized.

Methods

This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total (first plus recurrent) events of centrally adjudicated fatal and non-fatal myocardial infarction (MI) using a negative binomial model with robust confidence intervals (CI) that preserves randomization and accounts for the within-patient correlation of multiple events. Post hoc, we analyzed types of MI: type 1 (related to plaque-rupture/thrombus), type 2 (myocardial supply-demand imbalance), type 3 (sudden-death related, i.e. fatal MI), type 4 (percutaneous coronary intervention-related), and type 5 (coronary artery bypass graft-related). MIs could be assigned to > 1 type.

Results

There were 421 total MIs (including recurrent); 299, 86, 26, 19, and 1 were classified as type 1, 2, 3, 4, and 5 events, respectively. Overall, empagliflozin reduced the risk of total MI events by 21% [rate ratio for empagliflozin vs. placebo, 0.79 (95% CI, 0.620-0.998), P = 0.0486], largely driven by its effect on type 1 [rate ratio, 0.79 (95% CI, 0.61-1.04)] and type 2 MIs [rate ratio, 0.67 (95% CI, 0.41-1.10)].

Conclusions

In T2D patients with ASCVD, empagliflozin reduced the risk of MIs, with consistent effects across the two most common etiologies, i.e. type 1 and 2.

Trail registration

URL: https://www.

Clinicaltrials

gov ; Unique identifier: NCT01131676.

SUBMITTER: Fitchett D

PROVIDER: S-EPMC11241944 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature

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Publications

Effect of empagliflozin on total myocardial infarction events by type and additional coronary outcomes: insights from the randomized EMPA-REG OUTCOME trial.

Fitchett David D Zinman Bernard B Inzucchi Silvio E SE Wanner Christoph C Anker Stefan D SD Pocock Stuart S Mattheus Michaela M Vedin Ola O Lund Søren S SS

Cardiovascular diabetology 20240711 1

<h4>Background</h4>The effect of empagliflozin, a sodium-glucose-co-transporter-2 inhibitor, on risk for myocardial infarction has not been fully characterized.<h4>Methods</h4>This study comprised prespecified and post-hoc analyses of the EMPA-REG OUTCOME trial in which 7020 people with type 2 diabetes (T2D) and cardiovascular disease [mostly atherosclerotic (ASCVD)] were randomized to empagliflozin or placebo and followed for a median 3.1 years. We assessed the effect of empagliflozin on total ...[more]

PMID: 38992713

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Project description:AIMS/HYPOTHESIS:After coronary artery bypass graft (CABG) surgery in individuals with type 2 diabetes, there remains a considerable residual cardiovascular risk. In the EMPA-REG OUTCOME® trial in participants with type 2 diabetes and established cardiovascular disease, empagliflozin reduced the risk of cardiovascular death by 38%, all-cause mortality by 32%, hospitalisation for heart failure by 35% and incident or worsening nephropathy by 39% vs placebo when given in addition to standard of care. The aim of this post hoc analysis of the EMPA-REG OUTCOME® trial was to determine the effects of the sodium glucose cotransporter 2 inhibitor empagliflozin on cardiovascular events and mortality in participants with type 2 diabetes and a self-reported history of CABG surgery. METHODS:The EMPA-REG OUTCOME® trial was a randomised, double-blind, placebo-controlled trial. Participants with type 2 diabetes and established cardiovascular disease were randomised 1:1:1 to receive placebo, empagliflozin 10 mg or empagliflozin 25 mg, once daily, in addition to standard of care. In subgroups by self-reported history of CABG (yes/no) at baseline, we assessed: cardiovascular death; all-cause mortality; hospitalisation for heart failure; and incident or worsening nephropathy (progression to macroalbuminuria, doubling of serum creatinine, initiation of renal replacement therapy or death due to renal disease). Differences in risk between empagliflozin and placebo were assessed using a Cox proportional hazards model. RESULTS:At baseline, 25% (1175/4687) of participants who received empagliflozin and 24% (563/2333) of participants who received placebo had a history of CABG surgery. In participants with a history of CABG surgery, HRs (95% CI) with empagliflozin vs placebo were 0.52 (0.32, 0.84) for cardiovascular mortality, 0.57 (0.39, 0.83) for all-cause mortality, 0.50 (0.32, 0.77) for hospitalisation for heart failure and 0.65 (0.50, 0.84) for incident or worsening nephropathy. Results were consistent between participants with and without a history of CABG surgery (p > 0.05 for treatment by subgroup interactions). CONCLUSIONS/INTERPRETATION:In participants with type 2 diabetes and a self-reported history of CABG surgery, treatment with empagliflozin was associated with profound reductions in cardiovascular and all-cause mortality, hospitalisation for heart failure, and incident or worsening nephropathy. These data have important implications for the secondary prevention of cardiovascular events after CABG in individuals with type 2 diabetes. TRIAL REGISTRATION:ClinicalTrials.gov NCT01131676.

Project description:BackgroundGlucose variability has been associated with cardiovascular outcomes in type 2 diabetes, however, the interplay between glucose variability, empagliflozin and cardiovascular death has not been explored. In the EMPA-REG OUTCOME trial, empagliflozin reduced the risk of cardiovascular death by 38%. We explore post-hoc the association between HbA1c variability and cardiovascular death, and the potential mediating effects of HbA1c variability on empagliflozin's cardiovascular death reductions.MethodsIn total, 7,020 patients with type 2 diabetes and established cardiovascular disease received placebo, empagliflozin 10 mg or 25 mg. We defined within-patient HbA1c variability as standard deviation, coefficient of variation and range of HbA1c measurements (%) post-baseline. First, we compared HbA1c variability until week 28 and 52 by Wilcoxon tests. We explored the association between cardiovascular death and HbA1c variability in placebo and pooled empagliflozin arms separately with landmark analyses at week 28 and 52, and additionally with HbA1c variability as a time-dependent co-variate. We used Cox regression models adjusted for baseline risk factors including changes in HbA1c from baseline to week 12, and the interaction term HbA1c variability* treatment.ResultsHbA1c variability was lower with empagliflozin compared to placebo. In all Cox analyses, high HbA1c variability increased the risk for cardiovascular death in both treatment arms with no interaction with treatment: e.g. an increase in HbA1c variability of one unit for the standard deviation at week 28 was associated with a subsequent increased risk of CV death with HRs of 1.97 (95% CI 1.36, 2.84) and 1.53 (1.01, 2.31) in the placebo and empagliflozin groups, separately, interaction p-value 0.3615.ConclusionsHbA1c variability was reduced by empagliflozin and high values of HbA1c variability were associated with an increased risk of cardiovascular death. Empagliflozin's reduction in cardiovascular death did not appear to be mediated by reductions in HbA1c variability. ClinicalTrials.gov number, NCT01131676.

Project description:Evidence concerning the importance of glucose lowering in the prevention of cardiovascular (CV) outcomes remains controversial. Given the multi-faceted pathogenesis of atherosclerosis in diabetes, it is likely that any intervention to mitigate this risk must address CV risk factors beyond glycemia alone. The SGLT-2 inhibitor empagliflozin improves glucose control, body weight and blood pressure when used as monotherapy or add-on to other antihyperglycemic agents in patients with type 2 diabetes. The aim of the ongoing EMPA-REG OUTCOME™ trial is to determine the long-term CV safety of empagliflozin, as well as investigating potential benefits on macro-/microvascular outcomes.Patients who were drug-naïve (HbA1c ?7.0% and ?9.0%), or on background glucose-lowering therapy (HbA1c ?7.0% and ?10.0%), and were at high risk of CV events, were randomized (1:1:1) and treated with empagliflozin 10 mg, empagliflozin 25 mg, or placebo (double blind, double dummy) superimposed upon the standard of care. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. CV events will be prospectively adjudicated by an independent Clinical Events Committee. The trial will continue until ?691 confirmed primary outcome events have occurred, providing a power of 90% to yield an upper limit of the adjusted 95% CI for a hazard ratio of <1.3 with a one-sided ? of 0.025, assuming equal risks between placebo and empagliflozin (both doses pooled). Hierarchical testing for superiority will follow for the primary outcome and key secondary outcomes (time to first occurrence of CV death, non-fatal myocardial infarction, non-fatal stroke or hospitalization for unstable angina pectoris) where non-inferiority is achieved.Between Sept 2010 and April 2013, 592 clinical sites randomized and treated 7034 patients (41% from Europe, 20% from North America, and 19% from Asia). At baseline, the mean age was 63?±?9 years, BMI 30.6?±?5.3 kg/m2, HbA1c 8.1?±?0.8%, and eGFR 74?±?21 ml/min/1.73 m2. The study is expected to report in 2015.EMPA-REG OUTCOME™ will determine the CV safety of empagliflozin in a cohort of patients with type 2 diabetes and high CV risk, with the potential to show cardioprotection.Clinicaltrials.gov NCT01131676.

Dataset Information

Effect of empagliflozin on total myocardial infarction events by type and additional coronary outcomes: insights from the randomized EMPA-REG OUTCOME trial.

Background

Methods

Results

Conclusions

Trail registration

Clinicaltrials

Publications

Effect of empagliflozin on total myocardial infarction events by type and additional coronary outcomes: insights from the randomized EMPA-REG OUTCOME trial.

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