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

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.

Effect of Qualifying Atherosclerotic Cardiovascular Disease Diagnosis Proximity on Cardiovascular Risk and Benefit of Empagliflozin in the EMPA-REG OUTCOME Trial.

Background: In patients with type 2 diabetes mellitus (T2DM), a history of an ischemic event is associated with increased risk for cardiovascular (CV) disease. Whether patients with T2DM and a recent atherothrombotic diagnosis benefit from early intervention with a sodium-glucose co-transporter 2 inhibitor is unknown. Methods: This study is a secondary analysis of the Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients-Removing Excess Glucose (EMPA-REG OUTCOME), which compared empagliflozin to placebo in adults with T2DM and atherosclerotic CV disease (ASCVD). Participants were categorized based on the time since their last qualifying ASCVD diagnosis (≤ 1 year vs > 1 year). Qualifying ASCVD diagnoses included ischemic or hemorrhagic stroke, myocardial infarction, coronary artery disease, and peripheral artery disease. The primary outcome was a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Results: A total of 6796 participants (n = 4547 empagliflozin, n = 2249 placebo) were included. Median time since the last qualifying ASCVD diagnosis was 3.8 years (quartile 1-quartile 3: 1.5-7.6), and most qualifying diagnoses occurred > 1 year before randomization (≤ 1 year, n = 1214; > 1 year, n = 5582). Empagliflozin reduced the incidence of the primary outcome irrespective of the time since the last qualifying ASCVD diagnosis (≤ 1 year: hazard ratio 0.82, 95% confidence interval: 0.57-1.16; vs > 1 year: hazard ratio 0.85, 95% confidence interval: 0.72-1.00; P for interaction = 0.84). Results were similar for the composite of CV death or hospitalization for heart failure. Conclusions: Empagliflozin improved CV outcomes in participants with T2DM, irrespective of the time since the last qualifying ASCVD diagnosis at randomization. Prospective trials are necessary to investigate the use of sodium-glucose co-transporter 2 inhibitors at the time of an acute ASCVD event. Trial Registration: EMPA-REG OUTCOME (Clinicaltrials.gov identifier: NCT01131676).

Contexte: Chez les patients atteints de diabète de type 2 (DT2), des antécédents d'accidents ischémiques sont associés à un risque accru de maladie cardiovasculaire (CV). On ignore si une intervention précoce par un inhibiteur du cotransporteur sodium-glucose de type 2 pourrait être bénéfique pour les patients atteints de DT2 ayant récemment reçu un diagnostic d'athérothrombose. Méthodologie: Cette étude est une analyse secondaire de l'essai EMPA-REG OUTCOME ( Empa gliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients­ R emoving E xcess G lucose), qui visait à comparer l'empagliflozine à un placebo chez des adultes atteints de DT2 et d'une maladie CV athéroscléreuse. Les participants ont été répartis selon le temps écoulé depuis leur plus récent diagnostic de maladie CV athéroscléreuse admissible (≤ 1 an vs > 1 an). Les diagnostics de maladies CV athéroscléreuses admissibles comprenaient un accident vasculaire cérébral ischémique ou hémorragique, un infarctus du myocarde, une coronaropathie et une artériopathie périphérique. Le critère d'évaluation principal était composé des décès d'origine CV, des infarctus du myocarde non mortels et des accident vasculaire cérébral non mortels. Résultats: Au total, 6796 participants (n = 4547 pour l'empagliflozine, n = 2249 pour le placebo) ont été inclus. Le temps écoulé médian depuis le diagnostic le plus récent de maladie CV athéroscléreuse admissible était de 3,8 ans (quartile 1-quartile 3 : 1,5-7,6). La plupart des diagnostics admissibles avaient été posés plus de 1 an avant la répartition aléatoire (≤ 1 an, n = 1214; > 1 an, n = 5582). L'empagliflozine a réduit la fréquence des événements constituant le critère d'évaluation principal, sans égard au temps écoulé depuis le plus récent diagnostic de maladie CV athéroscléreuse admissible (≤ 1 an : rapport des risques instantanés 0,82, intervalle de confiance à 95 % : 0,57-1,16; vs > 1 an : rapport des risques instantanés 0,85, intervalle de confiance à 95 % : 0,72-1,00; p pour l'interaction = 0,84). Les résultats étaient comparables à ceux observés pour le critère composé des décès d'origine CV et des hospitalisations pour insuffisance cardiaque. Conclusions: L'empagliflozine a amélioré les issues CV chez les patients atteints de DT2 sans égard au temps écoulé depuis le plus récent diagnostic de maladie CV admissible au moment de la répartition aléatoire. Des essais prospectifs sont nécessaires pour étudier l'utilisation des inhibiteurs du cotransporteur sodium-glucose de type 2 lorsqu'une manifestation de maladie CV athéroscléreuse aiguë survient. Inscription de l'essai: EMPA-REG OUTCOME (numéro d'identification dans clinicaltrials.gov : NCT01131676).

Impact of empagliflozin on first and recurrent events leading to or prolonging hospitalisation in the EMPA-REG OUTCOME trial.

In EMPA-REG OUTCOME, empagliflozin reduced the composite of total events leading to/prolonging hospitalisation for any cause and all-cause mortality by 24 % versus placebo in patients with T2DM and ASCVD, with 67.7 events prevented/1000 patient-years and a low NNT. Effects were sustained and were consistent regardless of the reason for hospitalisation.

Kidney and heart failure events are bidirectionally associated in patients with type 2 diabetes and cardiovascular disease.

AIMS: This study aimed to evaluate the bidirectional relationship between kidney and cardiovascular (CV) events in trial participants with type 2 diabetes and CV disease. METHODS AND RESULTS: Post hoc analyses of EMPA-REG OUTCOME using Cox regression models were performed to assess the association of baseline factors with risk of a kidney event and bidirectional associations of incident kidney events and CV events. Among placebo-treated participants, baseline factors significantly associated with greater kidney event risk included lower baseline estimated glomerular filtration rate, albuminuria, higher uric acid, low-density lipoprotein cholesterol levels, and prior heart failure (HF). Coronary artery disease was not associated with increased risk. In placebo-treated participants, occurrence of an incident non-fatal kidney event increased the subsequent risk of hospitalization for HF (HHF) but not 3-point major adverse CV events (non-fatal stroke, non-fatal myocardial infarction, and CV death). Vice versa, HHF (but not myocardial infarction/stroke) increased the risk of subsequent kidney events. These associations were generally also seen in empagliflozin-treated participants and in the overall population. Interestingly, the risk of kidney events following HHF was not significantly increased in the relatively small number of placebo-treated participants already diagnosed with HF at baseline. CONCLUSIONS: These findings demonstrate a bidirectional inter-relationship between HHF and kidney events. Further exploration of this relationship and strategies to optimize the use of therapies to reduce both kidney and HF outcomes is warranted.

Changes in cardiac and vascular haemodynamics as potential mediators of improvements in cardiovascular and kidney outcomes with empagliflozin in type 2 diabetes.

AIMS: Evaluate changes in haemodynamic markers as mediators of cardiovascular (CV) and kidney benefits with empagliflozin. METHODS: Post-hoc analysis of EMPA-REG OUTCOME in patients with type 2 diabetes (T2D) and established CV disease receiving empagliflozin (10 and 25 mg) or placebo. Outcomes were CV death, hospitalisation for heart failure [HF], HF death, incident/worsening nephropathy, new onset macroalbuminuria, and the composite of sustained estimated glomerular filtration rate decline ≥40 % from baseline, renal replacement therapy or renal death. To be considered a mediator, changes in variable (pulse pressure, mean arterial pressure and cardiac workload) over time had to be (1) affected by active treatment, (2) associated with the outcome, and (3) adjustment for changes over time must reduce treatment effect versus an unadjusted analysis. Variables were evaluated in Cox regression analyses. RESULTS: Pulse pressure, mean arterial pressure and cardiac workload were significantly reduced by empagliflozin vs placebo. Using change from baseline to Week 12 or sensitivity analyses (time-dependent updated mean and current change from baseline) of these CV parameters, only small impacts on empagliflozin effect on CV and kidney outcomes were shown. CONCLUSIONS: Improvements in haemodynamic parameters did not substantially mediate empagliflozin benefits on CV and kidney outcomes in patients with T2DM and established CV disease.

Generalizability of REDUCE-IT eligibility criteria in a large diabetes cardiovascular outcomes trial: A post hoc subgroup analysis of EMPA-REG outcome: Analysis of EMPA-REG OUTCOME using REDUCE-IT criteria.

Objectives: REDUCE-IT showed that icosapent ethyl (IPE) improved cardiovascular (CV) outcomes in participants with established CV disease (CVD) or type 2 diabetes (T2D) and at least one additional risk factor plus mild-moderate hypertriglyceridemia and reasonably controlled low-density lipoprotein cholesterol (LDL-C). As the generalizability of REDUCE-IT has not been investigated in a T2D population with established CVD, this post hoc analysis investigated how many participants from EMPA-REG OUTCOME, which tested the effects of empagliflozin versus placebo on CV outcomes in participants with T2D and CVD, would have been eligible for IPE treatment, and whether CV outcomes differed based on eligibility for IPE treatment. Methods: Participants from EMPA-REG OUTCOME were screened for inclusion using both REDUCE-IT-like criteria (baseline statin therapy, triglycerides 135-499 mg/dL and LDL-C 41-100 mg/dL) and slightly amended FDA indication criteria (triglycerides ≥150 mg/dL). Analyses were conducted to characterize the study population and CV outcomes in participants eligible for IPE versus those not eligible for IPE. Results: Of the 7020 participants from EMPA-REG OUTCOME, 1810 (25.8%) fulfilled REDUCE-IT criteria and 3182 (45.3%) fulfilled FDA criteria for IPE treatment. Treatment effects of empagliflozin versus placebo on CV and kidney outcomes and mortality were consistent in participants meeting REDUCE-IT and FDA criteria and those who did not. Conclusions: These results indicate that a sizable proportion of patients with diabetes and established CVD, such as those in EMPA-REG OUTCOME, may be eligible for IPE treatment to lower residual CV risk. Treatment benefit with empagliflozin was consistent, regardless of REDUCE-IT or FDA eligibility criteria.

Empagliflozin in patients with type 2 diabetes mellitus and chronic obstructive pulmonary disease.

AIMS: Type 2 diabetes mellitus (T2DM) and chronic obstructive pulmonary disease (COPD) often co-exist, yielding increased risk of cardiovascular (CV) complications including heart failure (HF). We assessed risk of cardiorenal outcomes, mortality and safety in patients with versus without COPD in the EMPA-REG OUTCOME trial. METHODS: Patients (n = 7,020) with T2DM and CV disease (CVD) were treated with empagliflozin (10 mg or 25 mg) or placebo. Cox regression was used to assess COPD subgroup (placebo only) associations with, and treatment effects of empagliflozin versus placebo on first hospitalization for HF (HHF), CV death, all-cause mortality, incident/worsening nephropathy, and all-cause hospitalization. RESULTS: At baseline, patients with COPD (n = 707) had more HF and used insulin more frequently than those without COPD. During follow-up in the placebo group, those with baseline COPD had increased risk of HHF (HR 2.15 [95% CI 1.32, 3.49]), HHF/CV death (1.60 [1.10, 2.33]), incident/worsening nephropathy (1.68 [1.26, 2.24]), all-cause hospitalization (1.44 [1.19, 1.74]) and all-cause death (1.60 [1.09, 2.35]) compared to those without COPD. Empagliflozin consistently reduced all clinical outcomes, irrespective of COPD status (interaction p-values 0.14 to 0.96), with a confirmed safety profile. CONCLUSIONS: In patients with T2DM and CVD, COPD increased the risk of mortality and cardiorenal outcomes, including HF. Empagliflozin consistently reduced these outcomes versus placebo regardless of COPD, suggesting that empagliflozin's benefits in patients with T2DM and CVD are not mitigated by the presence of COPD.

Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA-REG OUTCOME trial.

AIMS: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of death from heart failure (HF) or hospitalization for heart failure (HHF) versus placebo in patients with type 2 diabetes mellitus (T2DM) and established cardiovascular (CV) disease. We evaluated post hoc the degree to which covariates mediated the effects of empagliflozin on HHF or HF death. METHODS AND RESULTS: A mediator had to fulfil the following criteria: (i) affected by active treatment, (ii) associated with the outcome, and finally (iii) adjustment for it results in a reduced treatment effect compared with unadjusted analysis. Potential mediators were calculated as change from baseline or updated mean and evaluated in univariable analyses as time-dependent covariates in Cox regression of time to HHF or HF death; those with the largest mediating effects were then included in a multivariable analysis. Increases in heart rate, log urine albumin-to-creatinine ratio (UACR), waist circumference, and uric acid were associated with increased risk of HHF or HF death; increases in high-density lipoprotein cholesterol, estimated glomerular filtration rate, haematocrit, haemoglobin, and albumin were associated with reduced risk of HHF or HF death. In univariable analyses, change from baseline in haematocrit, haemoglobin, albumin, uric acid, and logUACR mediated 51%, 54%, 23%, 24%, and 27% of the risk reduction with empagliflozin versus placebo, respectively. Multivariable analysis including haemoglobin, logUACR, and uric acid mediated 85% of risk reduction with similar results when updated means were evaluated. CONCLUSIONS: Changes in haematocrit and haemoglobin were the most important mediators of the reduction in HHF and death from HF in patients with T2DM and established CV disease treated with empagliflozin. Albumin, uric acid, and logUACR had smaller mediating effects in this population.

Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial.

BACKGROUND: In the EMPA-REG OUTCOME trial, ejection fraction (EF) data were not collected. In the subpopulation with heart failure (HF), we applied a new predictive model for EF to determine the effects of empagliflozin in HF with predicted reduced (HFrEF) vs preserved (HFpEF) EF vs no HF. METHODS AND RESULTS: We applied a validated EF predictive model based on patient baseline characteristics and treatments to categorize patients with HF as being likely to have HF with mid-range EF (HFmrEF)/HFrEF (EF <50%) or HFpEF (EF ≥50%). Cox regression was used to assess the effect of empagliflozin vs placebo on cardiovascular death/HF hospitalization (HHF), cardiovascular and all-cause mortality, and HHF in patients with predicted HFpEF, HFmrEF/HFrEF and no HF. Of 7001 EMPA-REG OUTCOME patients with data available for this analysis, 6314 (90%) had no history of HF. Of the 687 with history of HF, 479 (69.7%) were predicted to have HFmrEF/HFrEF and 208 (30.3%) to have HFpEF. Empagliflozin's treatment effect was consistent in predicted HFpEF, HFmrEF/HFrEF and no-HF for each outcome (HR [95% CI] for the primary outcome 0.60 [0.31-1.17], 0.79 [0.51-1.23], and 0.63 [0.50-0.78], respectively; P interaction = 0.62). CONCLUSIONS: In EMPA-REG OUTCOME, one-third of the patients with HF had predicted HFpEF. The benefits of empagliflozin on HF and mortality outcomes were consistent in nonHF, predicted HFpEF and HFmrEF/HFrEF.

Effects of empagliflozin on insulin initiation or intensification in patients with type 2 diabetes and cardiovascular disease: Findings from the EMPA-REG OUTCOME trial.

AIM: To evaluate the effects of empagliflozin versus placebo on subsequent insulin initiation or dosing changes in a large cardiovascular outcomes trial. MATERIALS AND METHODS: In EMPA-REG OUTCOME, 7020 patients with type 2 diabetes and cardiovascular disease received empagliflozin 10 mg, 25 mg, or placebo. Median follow-up was 3.1 years. After 12 weeks of treatment, changes in background antihyperglycaemic therapy were permitted. Among insulin-naïve patients, we assessed the effects of pooled empagliflozin arms versus placebo on time to initiation of insulin. Among insulin-treated patients, we assessed effects on time to an increase or decrease in insulin dose of more than 20%. RESULTS: In 3633 (52%) participants not treated with insulin at baseline, empagliflozin reduced new use of insulin versus placebo by 60% (7.1% vs. 16.4%; adjusted HR 0.40 [95% CI 0.32-0.49]; P < .0001). In 3387 (48%) patients using insulin at baseline, empagliflozin reduced the need for a greater than 20% insulin dose increase by 58% (14.4% vs. 29.3%; adjusted HR 0.42 [95% CI 0.36-0.49]; P < .0001) and increased the proportion achieving sustained greater than 20% insulin dose reductions without subsequent increases in HbA1c compared with placebo (9.2% vs. 4.9%; adjusted HR 1.87 [95% CI: 1.39-2.51]; P < .0001). Sensitivity analyses confirmed consistent findings when insulin dose changes of more than 10% or more than 30% were considered. CONCLUSIONS: In patients with type 2 diabetes and cardiovascular disease, empagliflozin markedly and durably delays insulin initiation and substantial increases in insulin dose, while facilitating sustained reductions in insulin requirements over time.

Patient Phenotypes and SGLT-2 Inhibition in Type 2 Diabetes: Insights From the EMPA-REG OUTCOME Trial.

OBJECTIVES: Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes. BACKGROUND: In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes. METHODS: Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets). RESULTS: In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p > 0.30). CONCLUSIONS: Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676).

Time to cardiovascular benefits of empagliflozin: a post hoc observation from the EMPA-REG OUTCOME trial.

AIMS: In the EMPA-REG OUTCOME trial, in patients with type 2 diabetes and established atherosclerotic cardiovascular (CV) disease, empagliflozin vs. placebo reduced the risk of hospitalization for heart failure (HHF) by 35%, CV death/HHF by 34%, and CV death by 38%, with an early separation of the cumulative incidence curves. We explored at what time point after randomization these benefits became apparent. METHODS AND RESULTS: We expressed time trajectories for the effect of pooled empagliflozin doses vs. placebo on HHF, CV death/HHF, and CV death based on hazard ratios (95% confidence interval) and calculated the hazard ratio on the day the effect reached significance using Cox proportional hazards models. Overall, 7020 patients aged ≥18 years were treated with empagliflozin 10 mg (N = 2345), empagliflozin 25 mg (N = 2342), or placebo (N = 2333) once daily in addition to standard of care. Mean age (years ± SD) was 63.1 ± 8.6, and 72% were male. The benefit of empagliflozin on CV death first reached statistical significance on Day 59 (HR [95% confidence interval]) (0.28 [0.08, 0.96], P = 0.0424) and was generally sustained throughout the trial (overall 0.62 [0.49, 0.77], P < 0.0001). Risk reduction with empagliflozin on HHF reached statistical significance on Day 17 (0.10 [0.01, 0.87], P = 0.0372) and was sustained throughout the study (overall 0.65 [0.50, 0.85], P = 0.0017). For the composite outcome of CV death or HHF, risk reduction with empagliflozin reached statistical significance on Day 27 (0.28 [0.08, 0.97], P = 0.0445) and was sustained throughout follow-up (overall 0.66 [0.55, 0.79], P < 0.0001). CONCLUSIONS: In EMPA-REG OUTCOME, the benefit of empagliflozin in reducing the risk of HHF, CV death/HHF, and CV death emerged within weeks after treatment initiation. The earliest benefit appears to be on HHF.

Use of diuretics and outcomes in patients with type 2 diabetes: findings from the EMPA-REG OUTCOME trial.

AIMS: Loop diuretics (LD) relieve symptoms and signs of congestion due to heart failure (HF), but many patients prescribed LD do not have such a diagnosis. We studied the relationship between HF diagnosis, use of LD, and outcomes in patients with type 2 diabetes mellitus (T2DM) enrolled in the EMPA-REG OUTCOME trial. METHODS AND RESULTS: The relationship between HF diagnosis, use of LD, and outcomes was evaluated in four patient subgroups with T2DM: (i) investigator-reported HF on LD, (ii) investigator-reported HF not on LD, (iii) no HF on LD, and (iv) no HF and not on LD, and we assessed their risk of cardiovascular events. Of 7020 participants, 706 (10%) had a diagnosis of HF at baseline, of whom 334 were prescribed LD. However, 755 (11%) patients who did not have a diagnosis of HF were prescribed LD. Compared to those with neither HF nor prescribed LD (reference group; placebo), those with both HF and receiving LD had the highest rates for all-cause [hazard ratio (HR) (95% confidence interval) 3.19 (2.03-5.01)] and cardiovascular mortality [3.83 [(2.28-6.44)], and HF hospitalizations [9.51 (5.61-16.14)]. Patients without HF but prescribed LD had higher rates for all three outcomes [1.62 (1.10-2.39); 1.97 (1.26-3.08); 3.20 (1.90-5.39)], which were similar to patients with HF who were not receiving LD [1.42 (0.78-2.57); 1.56 (0.78-3.11); 3.00 (1.40-6.40)]. Empagliflozin had similar benefits regardless of subgroup (P for interaction >0.1 for all outcomes). CONCLUSION: Patients with T2DM prescribed LD are at greater risk of cardiovascular events even if they are not reported to have HF; this might reflect under-diagnosis. Empagliflozin was similarly effective in all subgroups investigated.

Cardio/Kidney Composite End Points: A Post Hoc Analysis of the EMPA-REG OUTCOME Trial.

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.

Cardiovascular outcomes and LDL-cholesterol levels in EMPA-REG OUTCOME®.

OBJECTIVE: It is well established that higher low-density lipoprotein (LDL)-cholesterol levels are associated with increased cardiovascular risk. We analyzed whether effects of empagliflozin on cardiovascular outcomes varied by different LDL-cholesterol levels at baseline in EMPA-REG OUTCOME. METHODS: Participants with type 2 diabetes and high cardiovascular risk received empagliflozin (10/25 mg) or placebo in addition to standard of care. We investigated the time to first 3P-MACE, cardiovascular death, hospitalization for heart failure (HHF) and all-cause mortality for empagliflozin versus placebo between baseline LDL-cholesterol categories <1.8, 1.8-<2.2, 2.2- <2.6, 2.6-3.0, and > 3.0 mmol/L, by a Cox regression including the interaction of baseline LDL-cholesterol category and treatment. RESULTS: Of the 7020 participants randomized and treated, 81.0% received lipid lowering therapy (77.0% statins). Mean ± SD LDL-cholesterol was 2.2 ± 0.9 mmol/L, and 38%/18%, had LDL-cholesterol <1.8/>3.0 mmol/L. Age, BMI, and HbA1c levels were balanced between the LDL-cholesterol subgroups, but those in the lowest versus highest group, had more coronary artery disease (83.0% vs 59.9%) and statin treatment (88.2% vs 50.9%). Empagliflozin consistently reduced all outcomes across LDL-cholesterol categories (all interaction p-values > 0.05). CONCLUSION: The beneficial cardiovascular effects of empagliflozin was consistent across higher and lower LDL-cholesterol levels at baseline.

Effects of empagliflozin on first and recurrent clinical events in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a secondary analysis of the EMPA-REG OUTCOME trial.

BACKGROUND: Patients with type 2 diabetes and atherosclerotic cardiovascular disease are at high clinical risk. We assessed the effect of the sodium-glucose co-transporter-2 inhibitor, empagliflozin, on total cardiovascular events and admissions to hospital in the EMPA-REG OUTCOME trial. METHODS: The EMPA-REG OUTCOME trial was a randomised, double-blind, non-inferiority trial of patients (aged ≥18 years) with type 2 diabetes and atherosclerotic cardiovascular disease done between August, 2010, and April, 2015. Participants were randomly assigned (1:1:1) to empagliflozin 10 mg or 25 mg, or placebo. The primary outcome was major adverse cardiovascular events: a composite of cardiovascular death, non-fatal stroke, or non-fatal myocardial infarction. As prespecified, the effects of pooled empagliflozin versus placebo were assessed on total (first plus recurrent) events of major adverse cardiovascular events, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, and admission to hospital for heart failure. We also did post-hoc analyses on additional cardiovascular and admission to hospital outcomes. We used statistical models that preserve randomisation and account for correlation of recurrent events, including negative binomial regression, as prespecified for the primary analyses. The EMPA-REG OUTCOME trial is registered with ClinicalTrials.gov, NCT01131676, and is closed to accrual. FINDINGS: In the EMPA-REG OUTCOME trial, 7020 patients were randomly assigned and treated with empagliflozin 10 mg (n=2345), empagliflozin 25 mg (n=2342), or placebo (n=2333) and followed up for a median of 3·2 years (IQR 2·2 to 3·6) in the pooled empagliflozin group and 3·1 years (2·2 to 3·5) in the placebo group. Analysing total (first plus recurrent) events, empagliflozin versus placebo reduced the risk of major adverse cardiovascular events (rate ratio [RR] 0·78 [95% CI 0·67 to 0·91]; p=0·0020; 12·88 [95% CI 3·74 to 22·02] events prevented per 1000 patient-years); fatal or non-fatal myocardial infarction (0·79 [0·62 to 0·998]; p=0·049; 4·97 [-0·68 to 10·61] events prevented per 1000 patient-years); the composite of fatal or non-fatal myocardial infarction, or coronary revascularisation (0·80 [0·67 to 0·95]; p=0·012; 11·65 [1·25 to 22·05] events prevented per 1000 patient-years); admission to hospital for heart failure (0·58 [0·42 to 0·81]; p=0·0012; 9·67 [3·07 to 16·28] events prevented per 1000 patient-years); and all-cause admission to hospital (0·83 [0·76 to 0·91]; p<0·0001; 50·41 [26·20 to 74·63] events prevented per 1000 patient-years). For outcomes significantly reduced with empagliflozin, risk reductions were numerically larger for total events than for first events. Total fatal or non-fatal stroke was not significantly different between treatment groups (RR 1·10 [95% CI 0·82 to 1·49]; p=0·52). INTERPRETATION: Empagliflozin reduced the total burden of cardiovascular complications and all-cause admission to hospital in patients with type 2 diabetes and atherosclerotic cardiovascular disease. FUNDING: The Boehringer Ingelheim and Lilly Alliance.

Metabolic syndrome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a post hoc analyses of the EMPA-REG OUTCOME trial.

BACKGROUND: Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial. METHODS: A total of 7020 patients with T2D and atherosclerotic cardiovascular disease were treated with empagliflozin (10 mg or 25 mg) or placebo for a median of 3.1 years. The World Health Organization MetS criteria could be determined for 6985 (99.5%) patients. We assessed the association between baseline MetS and multiple cardio-renal endpoints using Cox regression models, and we studied the change in the individual component over time of the MetS using mixed effect models. RESULTS: MetS at baseline was present in 5740 (82%) patients; these were more often white and had more often albuminuria and heart failure, had lower eGFR and HDL-cholesterol, and higher blood pressure, body mass index, waist circumference, and triglycerides. In the placebo group, patients with MetS had a higher risk of all outcomes including cardiovascular death: HR = 1.73 (95% CI 1.01-2.98), heart failure hospitalization: HR = 2.64 (95% CI 1.22, 5.72), and new or worsening nephropathy: HR = 3.11 (95% CI 2.17-4.46). The beneficial effect of empagliflozin was consistent on all cardio-renal outcomes regardless of presence of MetS. CONCLUSIONS: A large proportion of the EMPA-REG OUTCOME population fulfills the criteria for MetS. Those with MetS had increased risk of adverse cardio-renal outcomes. Compared with placebo, empagliflozin improved cardio-renal outcomes in patients with and without MetS. Trial registration Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.

Update to Evidence-Based Secondary Prevention Strategies After Acute Coronary Syndrome.

A recent acute coronary syndrome provides an opportunity to optimise secondary prevention strategies to reduce the risk of future cardiovascular events. This review provides an updated synopsis of current evidence-based approaches. New clinical trial data on the use of antiplatelet and anticoagulants allow choices of the selection and duration of treatment. Lipid lowering after an acute coronary syndrome is now enhanced, with proprotein convertase subtilisin-kexin type 9 inhibitors providing added benefit on top of statin and ezetimibe treatment in high-risk patients. In addition, a recent trial of icosapent ethyl, a highly purified ethyl ester of eicosapentaenoic acid, addresses residual risk in patients with elevated triglycerides already treated with statins. The use of both sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes reduces cardiovascular events independently of glucose lowering.

La survenue récente d'un syndrome coronarien aigu offre l'occasion d'optimiser les stratégies de prévention secondaire en vue de réduire le risque d'événements cardiovasculaires futurs. Le présent article de synthèse offre une vue d'ensemble actualisée des approches contemporaines fondées sur des données probantes. Les nouvelles données d'essais cliniques sur l'utilisation d'antiplaquettaires et d'anticoagulants permettent de choisir un traitement et sa durée. La réduction des lipides après la survenue d'un syndrome coronarien aigu se trouve maintenant améliorée, les bienfaits des inhibiteurs de la proprotéine convertase subtilisine/kexine de type 9 s'ajoutant à ceux du traitement par des statines et l'ézétimibe chez les patients à haut risque. En outre, un essai récent portant sur l'icosapent éthyl, un ester éthylique hautement purifié de l'acide eicosapentaénoïque, aborde le risque résiduel chez les patients présentant une hypertriglycéridémie déjà traités par des statines. L'utilisation d'inhibiteurs du cotransporteur sodium-glucose de type 2 et d'agonistes des récepteurs du peptide-1 apparenté au glucagon chez les patients atteints de diabète de type 2 limite les événements cardiovasculaires indépendamment de la diminution de la glycémie.

Early benefits of empagliflozin in patients with or without heart failure: findings from EMPA-REG OUTCOME.

AIMS: The EMPA-REG OUTCOME trial demonstrated reductions in cardiovascular (CV) death and heart failure (HF) outcomes with empagliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes and established CV disease over a study period of 3 years. We aimed to investigate the early benefit-risk profile of empagliflozin in patients enrolled in the EMPA-REG OUTCOME trial according to HF status at baseline. METHODS AND RESULTS: The effects of treatments on glycated haemoglobin, systolic blood pressure and body weight, and on the HF endpoints of hospitalization for HF (HHF), HHF or CV death, and HHF or all-cause mortality were evaluated at 12 weeks, 6 months, and 1 year after randomization. Occurrence of adverse events (AEs) during these time points was also evaluated. Compared with placebo, empagliflozin lowered glycated haemoglobin, systolic blood pressure, and body weight and rates of all the HF endpoints, as early as at 12 weeks, regardless of HF status at baseline. Favourable clinical and metabolic effects were maintained over time. AEs were generally higher in those with HF than without HF; however, compared with placebo, empagliflozin did not increase risk of developing AEs over the first year of treatment. CONCLUSIONS: In the EMPA-REG OUTCOME trial, the use of empagliflozin led to early and beneficial effects on clinical, metabolic, and HF outcomes in patients with type 2 diabetes with or without HF at baseline, which were already apparent within 12 weeks from initiation of treatment. Over the first year of treatment, no safety concern was detected with the use of empagliflozin.

Heart failure and renal outcomes according to baseline and achieved blood pressure in patients with type 2 diabetes: results from EMPA-REG OUTCOME.

BACKGROUND: The sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin reduced cardiovascular death or heart failure hospitalizations in type 2 diabetes (T2D) in addition to a reduction of SBP. As heart failure patients often present with low SBP, which can challenge treatment initiation, we explored if empagliflozin's effect on SBP was independent of baseline SBP and heart failure status, and if the effect on cardiovascular and heart failure outcomes was influenced by updated mean SBP or by an early change in SBP after drug initiation. METHODS AND RESULTS: A total of 7020 patients were treated with empagliflozin 10 mg, 25 mg or placebo and followed for a median of 3.1 years. All of them had BP measurement at baseline. We evaluated changes in SBP in the context of heart failure status at baseline and according to baseline SBP categories (<120, 120--<130, 130--<140, 140--<160, ≥160 mmHg). The updated mean SBP during the trial was calculated as a time-dependent variable. We then assessed the association of baseline and updated mean SBP with three-point major adverse cardiovascular events (3P-MACE), hospitalization for heart failure, cardiovascular death, hospitalization for heart failure or cardiovascular death, all-cause death, and incident/worsening nephropathy, and whether treatment effect of empagliflozin vs. placebo on these outcomes differed if adjusted for updated mean SBP. Finally, we evaluated the impact of early decline in SBP (≥5 mmHg at week 4) on the treatment effect of empagliflozin vs. placebo on these outcomes. Analyses were performed via Cox regression adjusting for baseline risk factors including a term for treatment subgroup interaction, and by landmark analyses starting at week 4. The difference in SBP reduction at week 12 between empagliflozin and placebo was 3--5 mmHg and similar regardless of baseline SBP category or HF status at baseline. Baseline SBP and updated mean SBP categories showed no association with cardiovascular outcomes, but was associated with new/worsening nephropathy. The treatment effects of empagliflozin on all explored outcomes were independent of updated mean SBP as well of the early drop in SBP on treatment. CONCLUSION: In addition to decreasing SBP, empagliflozin reduced cardiovascular, heart failure and renal outcomes independently of updated mean SBP during the trial, and of the early SBP drop. These results suggest a BP-independent effect of empagliflozin on cardiovascular and heart failure outcomes. CLINICALTRIALS. GOV IDENTIFIER: NCT01131676.