Dataset Information

Empagliflozin for Patients With Presumed Resistant Hypertension: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.

ABSTRACT:

Background

Type 2 diabetes (T2D) and resistant hypertension often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676).

Methods

Overall, 7,020 patients received empagliflozin 10, 25 mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ?3 classes of antihypertensive drugs including a diuretic and uncontrolled blood pressure (BP; systolic blood pressure (SBP) ?140 and/or diastolic blood pressure ?90 mm Hg) or ?4 classes of antihypertensive, including a diuretic, and controlled BP. We explored the effect of empagliflozin on cardiovascular (CV) death, heart failure (HF) hospitalization, 3-point major adverse cardiac events, all-cause death, and incident/worsening nephropathy by Cox regression and BP over time by a mixed-repeated-measures-model analysis.

Results

1,579 (22.5%) patients had prHT. The mean difference in change in SBP from baseline to week 12 vs. placebo was -4.5 (95% confidence interval, -5.9 to -3.1) mm Hg (P < 0.001) in prHT and -3.7 (-4.5, -2.9) mm Hg (P < 0.001) in patients without prHT. SBP was more frequently controlled (<130/80 mm Hg) with empagliflozin than with placebo. Patients with prHT had 1.5- to 2-fold greater risk of HF hospitalization, incident/worsening nephropathy, and CV death compared with those without prHT. Empagliflozin improved all outcomes in patients with and without prHT (interaction P > 0.1 for all outcomes).

Conclusions

Empagliflozin induced a clinically relevant reduction in SBP and consistently improved all outcomes regardless of prHT status. Due to these dual effects, empagliflozin should be considered for patients with hypertension and T2D.

SUBMITTER: Ferreira JP

PROVIDER: S-EPMC7814223 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

Empagliflozin for Patients With Presumed Resistant Hypertension: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.

Ferreira João Pedro JP Fitchett David D Ofstad Anne Pernille AP Kraus Bettina Johanna BJ Wanner Christoph C Zwiener Isabella I Zinman Bernard B Lauer Sabine S George Jyothis T JT Rossignol Patrick P Zannad Faiez F

American journal of hypertension 20201201 12

<h4>Background</h4>Type 2 diabetes (T2D) and resistant hypertension often coexist, greatly increasing risk of target-organ damage and death. We explored the effects of empagliflozin in patients with and without presumed resistant hypertension (prHT) in a post hoc analysis of EMPA-REG OUTCOME (NCT01131676).<h4>Methods</h4>Overall, 7,020 patients received empagliflozin 10, 25 mg, or placebo with median follow-up of 3.1 years. We defined baseline prHT as ≥3 classes of antihypertensive drugs includi ...[more]

PMID: 32369546

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Project description:Background Cardio/kidney composite end points are clinically relevant but rarely analyzed in cardiovascular trials. This post hoc analysis of the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial evaluated cardio/kidney composite end points by 2 statistical approaches. Methods and Results A total of 7020 patients with type 2 diabetes mellitus and established cardiovascular disease were treated with empagliflozin 10 or 25 mg (n=4687) or placebo (n=2333) on top of standard care. Cardio/kidney composite end points studied were: (1) cardiac or kidney death, kidney failure, hospitalization for heart failure, sustained decline in estimated glomerular filtration rate ≥40% from baseline, or sustained progression to macroalbuminuria; (2) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained estimated glomerular filtration rate decline ≥40% from baseline; and (3) cardiac or kidney death, kidney failure, hospitalization for heart failure, or sustained doubling in serum creatinine from baseline. Cox regression using time-to-first-event analysis and win ratio (WR) using hierarchical order of events were applied. Empagliflozin reduced the risk of all cardio/kidney composites. The results varied only slightly between Cox and WR (eg, composite 1: hazard ratio, 0.56 [95% CI, 0.49-0.64]; WR, 1.76 [95% CI, 1.53-2.02]. WR prioritizes events by clinical importance; in particular, all fatal events are evaluated, whereas Cox regression ignores deaths when preceded by nonfatal events. Of the 285 cardio/kidney deaths in the analysis, 44 to 56 (15%-20%), depending on the composite, occurred after a nonfatal event and were not evaluated in Cox regression but evaluated by the WR. Conclusions By considering the clinical relevance of different event types, the WR represents an appropriate method to complement the traditional time-to-first-event analysis in cardio/kidney outcomes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: 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.

Project description:Rationale & objectiveKidney function progressively declines in most patients with type 2 diabetes (T2DM). Many develop progressive chronic kidney disease (CKD), but some experience a more rapid decline, with a greater risk of kidney failure and cardiovascular disease. In EMPA-REG OUTCOME, empagliflozin was associated with slower kidney disease progression. This post hoc analysis evaluated the effect of empagliflozin (pooled doses) on the prevalence of a "rapid decliner" phenotype, defined by an annual estimated glomerular filtration rate (eGFR) decline of >3 mL/min/1.73 m2.Study designThis was an exploratory analysis of EMPA-REG OUTCOME, a large randomized, double-blind, placebo-controlled trial in adults with T2DM, established cardiovascular disease and an eGFR of ≥30 mL/min/1.73 m2.Setting & participantsAnalysis was undertaken on 6,967 participants (99.2%) in whom serial eGFR data was available.InterventionsPatients were randomized (1:1:1) to empagliflozin 10 mg, 25 mg, or placebo in addition to standard of care.OutcomesAnnual change in eGFR over the maintenance phase of treatment (week 4 to last value on treatment) was calculated using linear regression models. Logistic regression analysis was used to investigate differences in rapid decline between the treatment groups.ResultsOver the study period, a rapid decliner phenotype was observed in 188 (9.5%) participants receiving placebo and 134 (3.4%) receiving empagliflozin. After adjusting for other risk factors, this equated to a two-third reduction in odds (OR, 0.32; 95% CI, 0.25-0.40; P < 0.001) among participants receiving empagliflozin versus placebo. A comparable risk reduction was observed using a threshold of eGFR decline of >5 mL/min/1.73 m2/y (empagliflozin vs placebo, 43 [1.1%] vs 44 [2.2%] participants; OR, 0.47; 95% CI, 0.31-0.72; P < 0.001).LimitationsThis is a post hoc analysis of a trial undertaken in participants with T2DM and CVD. Generalization of findings to other settings remains to be established.ConclusionsPatients receiving empagliflozin were significantly less likely to experience a rapid decline in eGFR over a median of 2.6 years of exposure to the study drug.FundingThe Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance.Trial registrationclinicaltrials.gov ID: NCT01131676.

Dataset Information

Empagliflozin for Patients With Presumed Resistant Hypertension: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.

Background

Methods

Results

Conclusions

Publications

Empagliflozin for Patients With Presumed Resistant Hypertension: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.

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