Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes.

BACKGROUND: Semaglutide, a glucagon-like peptide-1 receptor agonist, has been shown to reduce the risk of adverse cardiovascular events in patients with diabetes. Whether semaglutide can reduce cardiovascular risk associated with overweight and obesity in the absence of diabetes is unknown. METHODS: In a multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial, we enrolled patients 45 years of age or older who had preexisting cardiovascular disease and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 27 or greater but no history of diabetes. Patients were randomly assigned in a 1:1 ratio to receive once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. The primary cardiovascular end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in a time-to-first-event analysis. Safety was also assessed. RESULTS: A total of 17,604 patients were enrolled; 8803 were assigned to receive semaglutide and 8801 to receive placebo. The mean (±SD) duration of exposure to semaglutide or placebo was 34.2±13.7 months, and the mean duration of follow-up was 39.8±9.4 months. A primary cardiovascular end-point event occurred in 569 of the 8803 patients (6.5%) in the semaglutide group and in 701 of the 8801 patients (8.0%) in the placebo group (hazard ratio, 0.80; 95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product occurred in 1461 patients (16.6%) in the semaglutide group and 718 patients (8.2%) in the placebo group (P<0.001). CONCLUSIONS: In patients with preexisting cardiovascular disease and overweight or obesity but without diabetes, weekly subcutaneous semaglutide at a dose of 2.4 mg was superior to placebo in reducing the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke at a mean follow-up of 39.8 months. (Funded by Novo Nordisk; SELECT ClinicalTrials.gov number, NCT03574597.).

Semaglutide and cardiovascular outcomes in patients with obesity and prevalent heart failure: a prespecified analysis of the SELECT trial.

BACKGROUND: Semaglutide, a GLP-1 receptor agonist, reduces the risk of major adverse cardiovascular events (MACE) in people with overweight or obesity, but the effects of this drug on outcomes in patients with atherosclerotic cardiovascular disease and heart failure are unknown. We report a prespecified analysis of the effect of once-weekly subcutaneous semaglutide 2·4 mg on ischaemic and heart failure cardiovascular outcomes. We aimed to investigate if semaglutide was beneficial in patients with atherosclerotic cardiovascular disease with a history of heart failure compared with placebo; if there was a difference in outcome in patients designated as having heart failure with preserved ejection fraction compared with heart failure with reduced ejection fraction; and if the efficacy and safety of semaglutide in patients with heart failure was related to baseline characteristics or subtype of heart failure. METHODS: The SELECT trial was a randomised, double-blind, multicentre, placebo-controlled, event-driven phase 3 trial in 41 countries. Adults aged 45 years and older, with a BMI of 27 kg/m2 or greater and established cardiovascular disease were eligible for the study. Patients were randomly assigned (1:1) with a block size of four using an interactive web response system in a double-blind manner to escalating doses of once-weekly subcutaneous semaglutide over 16 weeks to a target dose of 2·4 mg, or placebo. In a prespecified analysis, we examined the effect of semaglutide compared with placebo in patients with and without a history of heart failure at enrolment, subclassified as heart failure with preserved ejection fraction, heart failure with reduced ejection fraction, or unclassified heart failure. Endpoints comprised MACE (a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death); a composite heart failure outcome (cardiovascular death or hospitalisation or urgent hospital visit for heart failure); cardiovascular death; and all-cause death. The study is registered with ClinicalTrials.gov, NCT03574597. FINDINGS: Between Oct 31, 2018, and March 31, 2021, 17 604 patients with a mean age of 61·6 years (SD 8·9) and a mean BMI of 33·4 kg/m2 (5·0) were randomly assigned to receive semaglutide (8803 [50·0%] patients) or placebo (8801 [50·0%] patients). 4286 (24·3%) of 17 604 patients had a history of investigator-defined heart failure at enrolment: 2273 (53·0%) of 4286 patients had heart failure with preserved ejection fraction, 1347 (31·4%) had heart failure with reduced ejection fraction, and 666 (15·5%) had unclassified heart failure. Baseline characteristics were similar between patients with and without heart failure. Patients with heart failure had a higher incidence of clinical events. Semaglutide improved all outcome measures in patients with heart failure at random assignment compared with those without heart failure (hazard ratio [HR] 0·72, 95% CI 0·60-0·87 for MACE; 0·79, 0·64-0·98 for the heart failure composite endpoint; 0·76, 0·59-0·97 for cardiovascular death; and 0·81, 0·66-1·00 for all-cause death; all pinteraction>0·19). Treatment with semaglutide resulted in improved outcomes in both the heart failure with reduced ejection fraction (HR 0·65, 95% CI 0·49-0·87 for MACE; 0·79, 0·58-1·08 for the composite heart failure endpoint) and heart failure with preserved ejection fraction groups (0·69, 0·51-0·91 for MACE; 0·75, 0·52-1·07 for the composite heart failure endpoint), although patients with heart failure with reduced ejection fraction had higher absolute event rates than those with heart failure with preserved ejection fraction. For MACE and the heart failure composite, there were no significant differences in benefits across baseline age, sex, BMI, New York Heart Association status, and diuretic use. Serious adverse events were less frequent with semaglutide versus placebo, regardless of heart failure subtype. INTERPRETATION: In patients with atherosclerotic cardiovascular diease and overweight or obesity, treatment with semaglutide 2·4 mg reduced MACE and composite heart failure endpoints compared with placebo in those with and without clinical heart failure, regardless of heart failure subtype. Our findings could facilitate prescribing and result in improved clinical outcomes for this patient group. FUNDING: Novo Nordisk.

Left atrial functional measurements' utility in predicting long-term risk of atrial fibrillation after isolated CABG.

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia following coronary artery bypass grafting (CABG). We hypothesized that measures of left atrial (LA) function would be useful in predicting AF in patients undergoing CABG. METHODS AND RESULTS: In the study, 611 patients were included after CABG. All patients had echocardiograms performed preoperatively and LA functional measurements were assessed. These measurements were LA maximum volume index (LAVmax), LA minimum volume index (LAVmin) and LA emptying fraction (LAEF). The endpoint was AF occurring >14 days after surgery. During the follow-up period of a median of 3.7 years, 52 (9%) developed AF. The mean age was 67 years, 84% were male and the average left ventricle ejection fraction was 50%. Patients who developed AF had a lower CCS class and lower LAEF (40 vs. 45%), otherwise no clinical differences were observed between outcome groups. No functional LA measurements were significant predictors of AF in the whole CABG population. However, in patients with normal-sized LA (n = 532, events: 49), both LAEF and LAVmin were univariable predictors of AF. When the functional measurements were adjusted for the CHADS2 score, both LAVmin (HR = 1.07 [1.01-1.13], p = .014) and LAEF (HR: 1.02 [1.00-1.03], p = .023), remained significant predictors. CONCLUSION: No echocardiographic measurements were significant predictors of AF after CABG. In patients with a normal LA size, LAVmin as well as LAEF were significant predictors of AF.

MR-proANP measured at admission is associated with incident atrial fibrillation in STEMI patients.

Atrial fibrillation (AF) is common following ST-segment elevation myocardial infarction (STEMI). Increased blood levels of mid regional pro atrial natriuretic peptide (MR-proANP) have been associated with a greater risk of incident AF. However, knowledge of the value of MR-proANP in predicting incident AF after STEMI is sparse. To assess whether MR-proANP measured at admission is associated with development of incident AF in patients with STEMI. 673 STEMI patients with no history of AF treated with primary percutaneous coronary intervention (pPCI) were prospectively enrolled from September 2006 to December 2008. Blood samples were drawn before the procedure. MR-proANP was measured by an automated processing assay. End point was incident AF. Median follow-up time was 5.5 years (interquartile-range 4.7-6.0), during which 63 patients developed AF. In a multivariable Cox regression model adjusted for relevant clinical and biochemical variables, MR-proANP was significantly associated with the development of AF (HR 1.18 per 100 pmol, 95% CI 1.11-1.28, p < 0.001). In a subgroup of patients who underwent echocardiography (N = 360), MR-proANP remained significantly associated with the development of AF (HR 1.39 per 100 pmol, 95% CI 1.13-1.71, p = 0.002) after adjusting for clinical and biochemical variables and left ventricular ejection fraction. When stratifying patients according to tertiles of MR-proANP, patients in the upper tertile displayed an 11 times greater risk of developing AF during follow-up as compared to patients in the lower tertile (HR 11.1, 95% CI 4.4-28.2, p < 0.001). Plasma MR-proANP measured at admission is an independent predictor of incident AF after STEMI.

Impact on HbA1c and body weight of switching from other GLP-1 receptor agonists to semaglutide: A model-based approach.

AIMS: Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue approved for the treatment of type 2 diabetes. The impact of switching treatment from another GLP-1 receptor agonist (GLP-1RA) to semaglutide was investigated by analyses of exposure-response models. METHODS: HbA1c and body weight time-course models were developed, using up to 30 weeks of observations from four trials in the semaglutide phase 3 programme. Given the recommended dosing for each GLP-1RA, pharmacokinetic profiles were simulated based on published population pharmacokinetic models and exposure was adjusted by the relative potencies to ensure that model predictions matched the effects observed in clinical trials. After 26 weeks of simulated treatment with liraglutide, dulaglutide or exenatide extended-release, simulated semaglutide treatment was initiated 1 day after the last once-daily dose of liraglutide and 1 week after the last once-weekly doses of dulaglutide or exenatide extended-release. RESULTS: The potency-adjusted total effective GLP-1RA concentration increased after switching from another GLP-1RA to semaglutide and was associated with reductions ranging from ~0.3% to ~0.8%-points for HbA1c and from ~2% to ~4% for body weight with semaglutide 1.0 mg. Temporary slight deteriorations in HbA1c were observed after switching to semaglutide 0.25 mg from liraglutide 1.2/1.8 mg or dulaglutide 1.5 mg. CONCLUSIONS: Exposure-response modelling suggests that switching to semaglutide from liraglutide, dulaglutide or exenatide extended-release results in further reductions in HbA1c and body weight. Initial slight deterioration in outcome values when switching to semaglutide 0.25 mg could be avoided by initiating semaglutide treatment at a higher dose.

Plasma neutrophil gelatinase-associated lipocalinin in the general population: association with inflammation and prognosis.

OBJECTIVE: Neutrophil gelatinase-associated lipocalin (NGAL) is a glycoprotein stored in granules of neutrophil leukocytes participating in inflammatory and atherosclerotic processes and possibly plaque rupture. Despite the putative role of NGAL in atherosclerosis and acute myocardial infarction, human studies of plasma NGAL are still limited. APPROACH AND RESULTS: We prospectively followed 5599 randomly selected men and women from the community in the fourth Copenhagen Heart Study. Plasma NGAL was measured at study entry. Participants were followed for 10 years. During follow-up, 20% died (n=1120) and 15% (n=884) developed a major adverse cardiovascular event. Plasma NGAL associated strongly with all inflammatory markers (high-sensitivity C-reactive protein, total leukocyte count, neutrophil count) and inversely with estimated glomerular filtration rate (all, P<0.001). Multivariate analysis identified neutrophil leukocyte count as the main determinant of plasma NGAL. During follow-up, participants with increasing NGAL had increased risk of all-cause mortality and major adverse cardiovascular event (both, P<0.001). Even after adjustment for confounding risk factors by Cox regression analysis, NGAL remained an independent predictor of both all-cause mortality and major adverse cardiovascular event. When added to the Framingham risk score, NGAL improved c-statistics and correctly reclassified ≈15% into more appropriate risk groups. In comparison with high-sensitivity C-reactive protein, when both markers were added to the Framingham risk score, NGAL conferred 3× to 4× the risk. CONCLUSIONS: Plasma NGAL is strongly associated with inflammation in the general population. NGAL independently associated with 10-year outcome, and when added to the Framingham risk score, NGAL both improves c-statistics and correctly reclassifies participants into more accurate risk categories.

Left atrial reservoir strain predicts ischaemic stroke after coronary artery bypass grafting independent of postoperative atrial fibrillation.

Aims: Measures of left atrial (LA) function are known to predict both ischaemic stroke and atrial fibrillation in specific patient groups. The aim of this study was to investigate the value of LA reservoir strain for predicting ischaemic stroke in patients undergoing coronary artery bypass grafting (CABG) and investigate whether the presence of postoperative atrial fibrillation (POAF) modified this relationship. Methods and results: Patients undergoing isolated CABG were included. The primary endpoint was ischaemic stroke. The association between LA reservoir strain and ischaemic stroke was investigated in uni- and multivariable Cox proportional hazards regression models including adjustment for POAF.We included 542 patients (mean age 67.3±8.9 years, 16.4% female). During a median follow-up period of 3.9 years, 21 patients (3.9%) experienced an ischaemic stroke. In total, 96 patients (17.7%) developed POAF during the index hospitalization. In a multivariable-adjusted Cox proportional hazards regression model, LA reservoir strain was significantly associated with the development of ischaemic stroke [HR (hazard ratio) 1.09 (95% CI 1.02-1.17) per 1% decrease, P = 0.011]. The presence of POAF did not modify this association (p for interaction = 0.07). The predictive value of the LA reservoir strain persisted in multiple sensitivity analyses including restricting the analysis to patients with normal left atrial volumes (LAV<34 ml/m2), patients without POAF, patients without prior stroke, and when excluding patients who developed atrial fibrillation at any time during follow-up. Conclusion: LA reservoir strain was independently associated with ischaemic stroke in CABG patients. The predictive value of LA reservoir strain was unaffected by the presence of POAF. Prospective studies are warranted to validate the potential usefulness of LA reservoir strain to predict postoperative ischaemic stroke in the setting of CABG.

Semaglutide for cardiovascular event reduction in people with overweight or obesity: SELECT study baseline characteristics.

OBJECTIVE: This paper describes the baseline characteristics of the Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) study, one of the largest cardiovascular (CV) outcome studies in the field of obesity, which evaluates the effect of semaglutide versus placebo on major CV events. METHODS: SELECT enrolled individuals with overweight or obesity without diabetes, with prior myocardial infarction, stroke, and/or peripheral artery disease. This study reports participants' baseline characteristics in the full study population and subgroups defined by baseline glycated hemoglobin (HbA1c ; <5.7%, ≥5.7 to <6.0%, ≥6.0 to <6.5%), baseline waist to height ratio tertile, and qualifying prior CV event or condition. RESULTS: The study enrolled 17,605 participants (72.5% male) with an average (SD) age of 61.6 (8.9) years and BMI of 33.34 (5.04) kg/m2 . The most common prior CV event was myocardial infarction (76.3% of participants), followed by stroke (23.3%) and peripheral artery disease (8.6%). Furthermore, 24.3% had a heart failure diagnosis. Two-thirds of participants (66%) had HbA1c in the prediabetes range (5.7%-6.4%). Across groups of increasing HbA1c , prevalence of all CV risk factors increased. CONCLUSIONS: The enrolled population in SELECT includes participants across a broad range of relevant risk categories. This will allow the study to garner information about the CV benefits of semaglutide across these relevant clinical subgroups.

Soluble form of membrane attack complex independently predicts mortality and cardiovascular events in patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention.

BACKGROUND: The complement system is an important mediator of inflammation, which plays a pivotal role in atherosclerosis and acute myocardial infarction (AMI). Animal studies suggest that activation of the complement cascade resulting in the formation of soluble membrane attack complex (sMAC), contributes to both atherosclerosis and plaque rupture and may be the direct cause of tissue damage related to ischemia/reperfusion injury. However clinical data of sMAC during an AMI is sparse. Accordingly the aim was to investigate the prognostic role of sMAC in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: We included 725 STEMI-patients admitted to a single, high-volume invasive heart centre, treated with primary percutaneous coronary intervention (PCI), from September 2006 to December 2008. Blood samples were drawn immediately before PCI. Plasma sMAC was measured using an in-house immunoassay. Endpoints were all-cause mortality (n = 62) and the combined endpoint (n = 122) of major cardiovascular events (MACE) defined as cardiovascular mortality and admission due recurrent AMI or heart failure. Follow-up time was 12 months. RESULTS: During 12 months of follow-up 62 patients died from all causes and 122 patients reached the combined end-point of MACE. Patients with high sMAC (>75th percentile) had increased risk of both all-cause mortality and MACE. Even after adjustment for confounding risk factors by Cox-regression analyses, high levels of sMAC remained an independent predictor of all-cause mortality (hazard ratio 1.81 [95% CI 1.06-3.06; P = .029]) and MACE (hazard ratio 1.70 [95% CI 1.16-2.48; P = .006]). CONCLUSIONS: High plasma sMAC independently predicts all-cause mortality and MACE in STEMI-patients treated with PCI.

Right ventricular strain predicts adverse outcomes in patients undergoing coronary artery bypass grafting.

Patients undergoing coronary artery bypass grafting (CABG) face an elevated risk of heart failure (HF) and cardiovascular (CV) death. Detailed myocardial tissue analyses of the right ventricle are now possible and may hold prognostic value in these patients. Accordingly, we aimed to evaluate the usefulness of right ventricular (RV) layer-specific RV free wall strain (RVFWS) for predicting HF and/or CV death. Patients undergoing CABG at Gentofte Hospital from 2006 to 2011 with a preoperative echocardiogram underwent RVWFS analysis. RVFWS was obtained by speckle tracking. The outcome was defined as a composite of HF and/or CV death. Cox proportional hazards regression, Harrell's C-statistics, and competing risk regression were used to assess the prognostic value of RVFWS. Of 317 patients, 30 (9.5%) reached the endpoint at a median follow-up of 3.5 years. The mean age was 67 years, 83% were men, and the mean LVEF was 50%. In univariable analyses, endo-RVFWS (HR 1.08, P < 0.001), mid-RVFWS (HR 1.07, P = 0.002), and epi-RVFWS (HR 1.07, P = 0.004, per 1% absolute decrease) were associated with a higher risk of HF or/and CV death. Furthermore, all three layers remained independently associated with the outcome after multivariable adjustment for baseline clinical and echocardiographic measurements. Low endo-RVFWS was associated with a more than threefold increased risk of the outcome (HR = 3.04 (1.45-6.38) P = 0.003). The same was observed for mid-RVFWS (HR = 3.16 (1.45-6.91) P = 0.004), and epi-RVFWS (HR = 3.00 (1.46-6.17) P = 0.003). In patients undergoing CABG, RVFWS assessed by speckle-tracking is a predictor of adverse outcomes.

The use of triage in Danish emergency departments.

INTRODUCTION: The emergency departments (EDs) handle approximately 1,000,000 contacts annually. Danish health care is undergoing reorganization that involves the creation of fewer and larger EDs to handle these contacts. There is therefore a need to prioritize the use of resources to optimize treatment. We thus wanted to investigate if Danish EDs are using triage systems and, if so, which systems they are using. MATERIAL AND METHODS: We performed a cross-sectional study on triage at all EDs in the 20 Danish hospitals that have been designated for emergency care. RESULTS: The response rate was 100% (n = 20). We found that triage was used at 75% (n = 15) of the EDs. Adaptive process triage (ADAPT) was the most frequently used validated triage system (25% (n = 5)), while 40% (n = 8) used non-validated systems. Triage was performed by nurses at 73% (n = 11) of the EDs using triage. CONCLUSION: Triage systems were used in 75% of Danish EDs. ADAPT was the primary triage system in 25% of the EDs, while 40% used non-validated triage systems. An improvement in the quality of health care in Danish EDs may possibly be achieved by implementing validated triage, i.e. ADAPT. FUNDING: not relevant. TRIAL REGISTRATION: not relevant.

Early systolic lengthening by speckle tracking echocardiography predicts outcome after coronary artery bypass surgery.

BACKGROUND: Early systolic lengthening (ESL), a paradoxical stretch of myocardial fibers, has been linked to loss of myocardial viability and contractile dysfunction. We assessed the long-term prognostic potential of ESL in coronary artery bypass graft (CABG) patients. METHODS: We retrospectively included patients (n = 709; mean age 68 years; 85% men) who underwent speckle tracking echocardiography (median 15 days) prior to CABG. Endpoints were cardiovascular death (CVD) and all-cause mortality. We assessed amplitude of ESL (%), defined as peak positive strain, and duration of ESL (ms), determined as time from Q-wave on the ECG to peak positive strain. We applied Cox models adjusted for clinical risk assessed as EuroSCORE II. RESULTS: During median follow-up of 3.8 years [IQR 2.7-4.9 years], 45 (6%) experienced CVD and 80 (11%) died. In survival analyses adjusted for EuroSCORE II, each 1% increase in amplitude of ESL was associated with CVD (HR 1.35 [95%CI 1.09-1.68], P = 0.006) and all-cause mortality (HR 1.29 [95%CI 1.08-1.54], P = 0.004). Similar findings applied to duration of ESL (per 10ms increase) and CVD (HR 1.12 [95%CI 1.02-1.23], P = 0.016) and all-cause mortality (HR 1.09 [95%CI 1.01--1.17], P = 0.031). The prognostic value of ESL amplitude was modified by sex (P interaction < 0.05), such that the prognostic value was greater in women for both endpoints. When adding ESL duration to EuroSCORE II, the net reclassification index improved significantly for both CVD and all-cause mortality. CONCLUSIONS: Assessment of ESL provides independent and incremental prognostic information in addition to the EuroSCORE II for CVD and all-cause mortality in CABG patients.

Early diastolic strain rate in relation to long term prognosis following isolated coronary artery bypass grafting.

BACKGROUND: The ratio of early mitral inflow velocity to early diastolic strain rate (E/e'sr) is a novel echocardiographic measure to estimate early left ventricular (LV) filling pressure. We hypothesize that E/e'sr is a predictor of outcome following coronary artery bypass grafting (CABG) and that it is superior to the conventionally used E/e'. METHODS & RESULTS: Consecutive patients undergoing isolated CABG at Gentofte Hospital (n = 652) were included. The mean age of the study population was 67 ± 9 years, 84% were male, mean LVEF was 50 ± 11%. Prior to surgery, all patients underwent an extensive echocardiographic examination. The outcome was all-cause mortality. During follow-up (median 3.8 years [IQR: 2.7; 4.9 years]), a total of 73 (11.2%) died. Both E/e' and E/e'sr were significant predictors in univariable models. In a multivariable model, E/e'sr remained an independent predictor of outcome (HR:1.05 [1.01-1.10], p = 0.049, per 10 cm increase) whereas E/e' did not (HR:1.05 [0.99-1.11], p = 0.053, per 1-unit increase). The relationship between E/e'sr, and the outcome was significantly modified by GLS (p for interaction = 0.043). In the multivariable model, E/e'sr was still significantly associated with the outcome in patients with high GLS (≥13.6%) (HR:1.18 [1.02-1.36], p = 0.029) but not in patients with low GLS (HR 1.04 CI95%: [0.99-1.10], p = 0.14). E/e' was not a significant predictor of all-cause mortality after multivariable adjustment in neither of the groups. E/e'sr improved net reclassification with 33% when added to EuroSCOREII. CONCLUSION: Following CABG, preoperative E/e'sr is an independent predictor of all-cause mortality, especially in patients with preserved systolic function and superior to E/e'.

Global longitudinal strain predicts cardiovascular events after coronary artery bypass grafting.

OBJECTIVE: To determine the prognostic value of global longitudinal strain (GLS) after coronary artery bypass grafting (CABG). METHODS: We performed a retrospective cohort study on patients undergoing CABG between 2006 and 2011 who had an echocardiogram available for strain analysis. The patients were followed up through nationwide registries for development of all-cause mortality, cardiovascular death (CVD) and major adverse cardiovascular events (MACEs) defined as heart failure hospitalisation and/or CVD. Multivariable Cox regression was applied to adjust for the European System for Cardiac Operative Risk Evaluation II (EuroSCORE-II). Additive value was assessed by Net Reclassification Index (NRI) improvement. RESULTS: Of the 709 patients included, 80 died during a median follow-up of 3.8 years. Of these, 45 had CVD, and 72 patients experienced MACE. Mean age was 68 years and 85% were men. Left ventricular ejection fraction (LVEF) was 50% and GLS was -13%.GLS was an independent predictor when adjusted for the EuroSCORE-II (all-cause mortality: HR=1.07 (1.01-1.13), p=0.018; CVD: HR=1.11 (1.03-1.20), p=0.007; MACE: HR=1.12 (1.06-1.19), p<0.001, per 1% absolute decrease). GLS significantly improved the NRI score by 0.30 when added to the EuroSCORE-II for predicting MACE, but not significantly for the other endpoints.LVEF modified the association between GLS and outcomes (p for interaction<0.05 for CVD and MACE). GLS remained an independent predictor of outcomes in patients with preserved LVEF (LVEF≥50%) and improved the NRI score when added to the EuroSCORE-II for predicting CVD and MACE, but not all-cause mortality in these patients. CONCLUSION: GLS is an independent predictor of long-term outcomes after CABG. The predictive value appears strongest among patients with preserved LVEF.

Prognostic Value and Interplay Between Myocardial Tissue Velocities in Patients Undergoing Coronary Artery Bypass Grafting.

Early diastolic tissue velocity (e') by tissue Doppler imaging represents an early marker of left ventricular (LV) dysfunction in ischemic heart disease. We assessed the value of e' for predicting mortality in patients undergoing coronary artery bypass grafting (CABG). We retrospectively investigated patients treated with CABG between 2006-2011. Before surgery, all patients underwent an echocardiogram with tissue Doppler imaging to measure tissue velocities: systolic (s'), e', and late diastolic (a'). The primary outcome was all-cause mortality. Survival analysis was applied. Improvement of EuroSCORE-II was assessed by net reclassification index. Of 660 patients, 72 (11%) died during a median follow-up time of 3.8 years. Mean age was 68 years, LVEF 50%, and 84% were men. All tissue velocities showed a significant negative association with outcome and e' provided highest Harrell's C-statistics (c-stat=0.68). After multivariable adjustment for EuroSCORE-II, LV hypertrophy, LV internal diameter, and global longitudinal strain, declining e' was associated with a higher risk of mortality (HR=1.35 (1.12 to 1.61), p = 0.001, per 1cm/s absolute decrease). LVEF≤40% modified the relationship between both s' and e' and outcome (p for interaction=0.021 and 0.024, respectively), such that neither predicted mortality when LVEF was ≤40%. In patients with LVEF>40%, only e' remained a predictor after multivariable adjustments (HR=1.36 (1.10 to 1.69), p = 0.005, per 1cm/s absolute decrease). A net reclassification index improvement of 0.14 was observed when adding global e' to the EuroSCORE-II. In conclusion, e' is an independent predictor of all-cause mortality in patients undergoing CABG, especially in patients with LVEF>40%, and improves the predictive value of EuroSCORE-II.

Oral Semaglutide Versus Empagliflozin in Patients With Type 2 Diabetes Uncontrolled on Metformin: The PIONEER 2 Trial.

OBJECTIVE: Efficacy and safety of the glucagon-like peptide 1 (GLP-1) analog oral semaglutide and the sodium-glucose cotransporter 2 inhibitor empagliflozin were compared in patients with type 2 diabetes uncontrolled on metformin. RESEARCH DESIGN AND METHODS: Patients were randomized to once-daily open-label treatment with oral semaglutide 14 mg (n = 412) or empagliflozin 25 mg (n = 410) in a 52-week trial. Key end points were change from baseline to week 26 in HbA1c (primary) and body weight (confirmatory secondary). Two estimands addressed efficacy-related questions: treatment policy (regardless of trial product discontinuation or rescue medication) and trial product (on trial product without rescue medication) in all randomized patients. RESULTS: Four hundred (97.1%) patients in the oral semaglutide group and 387 (94.4%) in the empagliflozin group completed the trial. Oral semaglutide provided superior reductions in HbA1c versus empagliflozin at week 26 (treatment policy -1.3% vs. -0.9% [-14 vs. -9 mmol/mol], estimated treatment difference [ETD] -0.4% [95% CI -0.6, -0.3] [-5 mmol/mol (-6, -3)]; P < 0.0001). The treatment difference in HbA1c significantly favored oral semaglutide at week 26 for the trial product estimand (-1.4% vs. -0.9% [-15 vs. -9 mmol/mol], ETD -0.5% [95% CI -0.7, -0.4] [-6 mmol/mol (-7, -5)]; P < 0.0001) and at week 52 for both estimands (P < 0.0001). Superior weight loss was not confirmed at week 26 (treatment policy), but oral semaglutide was significantly better than empagliflozin at week 52 (trial product -4.7 vs. -3.8 kg; P = 0.0114). Gastrointestinal adverse events were more common with oral semaglutide. CONCLUSIONS: Oral semaglutide was superior to empagliflozin in reducing HbA1c but not body weight at 26 weeks in patients with type 2 diabetes uncontrolled on metformin. At week 52, HbA1c and body weight (trial product estimand) were significantly reduced versus empagliflozin. Oral semaglutide was well tolerated within the established safety profile of GLP-1 receptor agonists.

Insulin-Like Growth Factor Binding Protein 4 Fragments Provide Incremental Prognostic Information on Cardiovascular Events in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Fragments of insulin-like growth factor binding protein 4 (IGFBP-4) are potential new biomarkers for cardiac risk assessment. The fragments are generated on specific cleavage by pregnancy-associated plasma protein-A, which exerts proatherogenic activity. This study investigated the prognostic value of IGFBP-4 fragments in patients with ST-segment elevation myocardial infarction. METHODS AND RESULTS: We prospectively included 656 patients with ST-segment elevation myocardial infarction treated with percutaneous coronary intervention from September 2006 to December 2008. Blood samples were drawn before percutaneous coronary intervention, and levels of intact IGFBP-4 and N-terminal and C-terminal IGFBP-4 fragments were measured by specific assays. End points were 5-year all-cause and cardiovascular mortality and the combined end point of major adverse cardiac events. Prognostic potential was evaluated on top of a clinical model in terms of discrimination, calibration, and reclassification analysis. During follow-up, 166 patients experienced a major adverse cardiac event and 136 patients died, of whom 69 died from cardiovascular causes. Both IGFBP-4 fragments were associated with all end points (P<0.001). After multivariable adjustments, both N-terminal and C-terminal IGFBP-4 fragment levels remained associated with all end points, including cardiovascular mortality with hazard ratios per doubling in protein concentration of 2.54 (95% CI 1.59-4.07; P<0.001) and 2.07 (95% CI 1.41-3.04; P<0.001), respectively. Incorporation of IGFBP-4 fragments into a clinical model with 15 risk factors improved C-statistics and model calibration and provided incremental prognostic contribution, as assessed by net reclassification improvement and integrated discrimination improvement. CONCLUSIONS: IGFBP-4 fragments are associated with increased risk of all-cause mortality, cardiovascular mortality, and major adverse cardiac events in patients with ST-segment elevation myocardial infarction.

Plasma Neutrophil Gelatinase-Associated Lipocalin Reflects Both Inflammation and Kidney Function in Patients with Myocardial Infarction.

BACKGROUND/AIMS: Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a marker for acute kidney injury and cardiovascular outcome. However, the relative importance of inflammation versus kidney function on plasma NGAL levels is uncertain, making the interpretation of plasma NGAL unclear. Accordingly, we investigated the relationship between plasma NGAL, inflammation and kidney function in patients with myocardial infarction (MI). METHODS: We prospectively included 584 patients with acute ST-segment elevation MI (STEMI) treated with primary percutaneous coronary intervention (PCI) from 2006 to 2008. Blood samples were drawn immediately before PCI. Additionally, we included 42 patients who had 4 blood samples drawn before and after PCI. Plasma NGAL was measured using a time-resolved immunofluorometric assay. Cross-sectional analyses were performed in these two single-center, prospective study cohorts. RESULTS: Estimated glomerular filtration rate (eGFR) was associated significantly more strongly with plasma NGAL when eGFR was abnormal compared to normal eGFR: a decrease in eGFR of 10 ml/min was associated with an increase in NGAL of 27% (18-36%) versus 4% (1-7%), respectively (p < 0.001). Leukocyte count and C-reactive protein were the main determinants of plasma NGAL in patients with normal eGFR, whereas eGFR was the main determinant at reduced kidney function. CONCLUSIONS: eGFR determines the association of NGAL with either inflammation or kidney function; in patients with normal eGFR, plasma NGAL reflects inflammation but when eGFR is reduced, plasma NGAL reflects kidney function, highlighting the dual perception of plasma NGAL. From a clinical perspective, eGFR may be used to guide the interpretation of elevated NGAL levels in patients with STEMI.

MR-proANP improves prediction of mortality and cardiovascular events in patients with STEMI.

BACKGROUND: Atrial natriuretic peptide (ANP) is released from the atria (on cleavage of proANP) in response to elevated intra-atrial pressure and wall stretch. Clinical data on proANP are still limited, mainly due to limitations in assaying the protein, which recently have been solved. ProANP is elevated in cardiovascular disease and predicts outcome in heart failure. However, knowledge of the prognostic value in acute myocardial infarction remains limited. METHODS: We prospectively included 680 patients with STEMI treated with primary-PCI, from September 2006 to December 2008. Blood samples were drawn immediately before PCI. Plasma MR-proANP was measured using an automated processing assay. Endpoints were all-cause mortality (n = 137) and the combined endpoint (n = 170) of major adverse cardiovascular events (MACE) defined as cardiovascular mortality and admission due to recurrent MI, ischaemic stroke or heart failure. RESULTS: During 5-year follow-up, MR-proANP was associated with increased risk of all-cause mortality and MACE (both p < 0.001). After adjustment for confounding risk factors (age, gender, hypertension, diabetes, hypercholesterolaemia, smoking, previous MI, BMI, eGFR, CRP, peak-TnI, symptom-to-balloon time, multivessel disease, complex lesion, LAD-lesion and use of glycoprotein inhibitor), MR-proANP remained an independent predictor of all-cause mortality and MACE - hazard ratio: 1.68 (95% CI 1.35-2.10; p < 0.001) and 1.68 (95% CI 1.39-2.03; p < 0.001) per standard deviation increase in MR-proANP. MR-proANP significantly increased C-statistics and reclassified 26% of the patients for all-cause mortality and 34% for MACE into higher or lower risk categories, matching actual event rates more accurately. CONCLUSIONS: Plasma MR-proANP independently predicts all-cause mortality and MACE in patients with STEMI.