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Abstract Context Control of multiple cardiovascular (CV) risk factors reduces CV events in individuals with type 2 diabetes. Objective To investigate this association in a contemporary clinical trial population, including how CV risk factor control affects the CV benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor. Design Post hoc analysis. Setting Randomized CV outcome trial (EMPA-REG OUTCOME). Participants Type 2 diabetes patients with established CV disease. Intervention Empagliflozin or placebo. Main Outcome Measures Risk of CV outcomes—including the treatment effect of empagliflozin—by achieving 7 goals for CV risk factor control at baseline: (1) glycated hemoglobin <7.5%, (2) low-density lipoprotein cholesterol <100 mg/dL or statin use, (3) systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg, (4) pharmacological renin-angiotensin-aldosterone system blockade, (5) normoalbuminuria, (6) aspirin use, (7) nonsmoking. Results In the placebo group, the hazard ratio (HR) for CV death was 4.00 (95% CI, 2.26–7.11) and 2.48 (95% CI, 1.52–4.06) for patients achieving only 0–3 or 4–5 risk factor goals at baseline, respectively, compared with those achieving 6–7 goals. Participants achieving 0–3 or 4–5 goals also had increased risk for the composite outcome of hospitalization for heart failure or CV death (excluding fatal stroke) (HR 2.89 [1.82–4.57] and 1.90 [1.31–2.78], respectively) and 3-point major adverse CV events (HR 2.21 [1.53–3.19] and 1.42 [1.06–1.89]). Empagliflozin significantly reduced these outcomes across all risk factor control categories (P > 0.05 for treatment-by-subgroup interactions). Conclusions Cardiovascular risk in EMPA-REG OUTCOME was inversely associated with baseline CV risk factor control. Empagliflozin’s cardioprotective effect was consistent regardless of multiple baseline risk factor control.

Phosphate binders (calcium-based and calcium-free) are recommended to lower serum phosphate and prevent hyperphosphataemia in patients with chronic kidney disease, but their effects on mortality and cardiovascular outcomes are unknown. We aimed to update our meta-analysis on the effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease. We did a systematic review of articles published in any language after Aug 1, 2008, up until Oct 22, 2012, by searching Medline, Embase, International Pharmaceutical Abstracts, Cochrane Central Register of Controlled Trials, and Cumulative Index to Nursing and Allied Health Literature. We included all randomised and non-randomised trials that compared outcomes between patients with chronic kidney disease taking calcium-based phosphate binders with those taking non-calcium-based binders. Eligible studies, determined by consensus with predefined criteria, were reviewed, and data were extracted onto a standard form. We combined data from randomised trials to assess the primary outcome of all-cause mortality using the DerSimonian and Laird random effects model. Our search identified 847 reports, of which eight new studies (five randomised trials) met our inclusion criteria and were added to the ten (nine randomised trials) included in our previous meta-analysis. Analysis of the 11 randomised trials (4622 patients) that reported an outcome of mortality showed that patients assigned to non-calcium-based binders had a 22% reduction in all-cause mortality compared with those assigned to calcium-based phosphate binders (risk ratio 0·78, 95% CI 0·61–0·98). Non-calcium-based phosphate binders are associated with a decreased risk of all-cause mortality compared with calcium-based phosphate binders in patients with chronic kidney disease. Further studies are needed to identify causes of mortality and to assess whether mortality differs by type of non-calcium-based phosphate binder. None.

In a randomized trial, 1059 patients with an acute myocardial infarction with ST-segment elevation presented to hospitals that did not have the capability of performing percutaneous coronary intervention (PCI) and received fibrinolysis. They were then assigned to either immediate transfer to a PCI center for catheterization or transfer only if fibrinolysis failed. The immediate-transfer strategy was associated with significantly fewer ischemic complications at 30 days. In patients with an acute myocardial infarction with ST-segment elevation, routine early angioplasty after fibrinolysis was associated with significantly fewer ischemic complications at 30 days. Primary percutaneous coronary intervention (PCI) is an effective treatment for myocardial infarction with ST-segment elevation when it can be performed rapidly. 1 However, primary PCI is performed at less than 25% of acute care hospitals in the United States. 2 , 3 Many patients with myocardial infarction with ST-segment elevation present to hospitals that do not have the capability of performing PCI and therefore cannot undergo PCI within the timelines recommended in the guidelines 4 ; instead, they receive fibrinolysis as the initial reperfusion therapy. Although the proportion of such patients has decreased in recent years, 27.6% of the patients in the National Registry . . .

Background 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. Methods Patients who were drug-naïve (HbA 1c ≥7.0% and ≤9.0%), or on background glucose-lowering therapy (HbA 1c ≥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 α 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. Results 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/m 2 , HbA1c 8.1 ± 0.8%, and eGFR 74 ± 21 ml/min/1.73 m 2 . The study is expected to report in 2015. Discussion 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. Trial registration Clinicaltrials.gov NCT01131676

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.

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.

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: NCT 01131676

There are limited data on the recent trend in the use of optimal evidence-based medical therapies after acute coronary syndromes (ACSs). We sought to evaluate (1) the temporal changes in medical management of patients discharged after an ACS; (2) patient and practice characteristics associated with optimal medical therapy at discharge; and (3) the association between discharge medication use and 1-year outcome. The Canadian ACS I (September 1999-June 2001) and ACS II (October 2002-December 2003) Registries were prospective, multicenter, observational studies of 6853 patients admitted for ACS. We examined the discharge use of medications among 5833 hospital survivors who did not have any contraindications to antiplatelet/anticoagulant, β-blocker, angiotensin-converting enzyme inhibitor, or lipid-modifying therapies. Optimal medical therapy was defined as the use of all indicated medications. Follow-up data at 1 year were collected by telephone interview. We performed hierarchical logistic regression to identify patient characteristics and care patterns associated with optimal medical treatment and to examine its relationship with 1-year mortality. There were significant increases in the discharge use of all 4 classes of medications over time; 28.9% and 51.8% of patients in ACS I and ACS II Registries, respectively, were prescribed optimal medical therapy (P < .001). Advanced age, female sex, prior heart failure, renal dysfunction, and coronary bypass surgery during hospitalization were negative independent predictors of optimal medical therapy. Conversely, enrollment in ACS II Registry, history of dyslipidemia, presence of ST elevation and abnormal cardiac biomarker, previous myocardial infarction, and previous coronary revascularization were independently associated with the use of combination therapy. After adjusting for other validated prognosticators, patients receiving optimal medical therapy had significantly lower 1-year mortality (adjusted odds ratio 0.54, 95% confidence interval 0.36-0.81, P = .003) compared with those given 0 or 1 drug at discharge. Over the 1-year follow-up period, substantial numbers of patients discontinued therapies, whereas others were initiated on treatment. Despite the temporal increases in the combined use of evidence-based pharmacologic therapies, which is associated with improved outcome, medical management of ACS remains suboptimal. Quality improvement strategies are needed to enhance the appropriate use of effective therapies, targeting specifically the high-risk but undertreated patients who may derive the greatest therapeutic benefit.

The renin angiotensin aldosterone system (RAAS) plays an important role in the pathophysiology of cardiovascular disease. Angiotensin converting enzyme inhibitors (ACEi) have proven benefit in reducing cardiovascular events in patients at high risk. Angiotensin receptor blockers (ARB) have been demonstrated to have benefit in the management of heart failure and to be non-inferior to ACEi in patients with left ventricular dysfunction after a myocardial infarction (MI). Yet until now, there has been no trial to support the use of the ARB for vascular protection. The ONTARGET study showed that the ARB telmisartan conserved 95% of the vascular protective properties of the ACEi ramipril, given at similar doses to a similar patient group as had been previously shownin the HOPE study to benefit from ACE inhibition with ramipril. The TRANSCEND study in a similar population of patients who were intolerant of ACEi despite the primary endpoint being neutral, showed a trend to a benefit for the combined secondary endpoint of cardiovascular death, MI and stroke, with excellent tolerance of the ARB. The reasons for neutral result of the TRANSCEND study result include an underpowered study, and pre-treatment with a RAAS inhibitor in a high proportion of patients. These studies indicate that an ARB can be used for vascular protection in high risk individuals in the place of an ACEi. However ACEi will probably remain the first choice due to the greater body of supportive evidence.

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.