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.

Asthma impacts on workplace productivity in employed patients who are symptomatic despite background therapy: a multinational survey.

Background: Asthma affects millions of people worldwide, with many patients experiencing symptoms that affect their daily lives despite receiving long-term controller medication. Purpose: Work is a large part of most people's lives, hence this study investigated the impact of uncontrolled asthma on work productivity in adults receiving asthma maintenance therapy. Patients and methods: An online survey was completed by employed adults in Brazil, Canada, Germany, Japan, Spain and the UK. Participants were confirmed as symptomatic using questions from the Royal College of Physicians' 3 Questions for Asthma tool. The survey contained the Work Productivity and Activity Impairment - Specific Health Problem questionnaire and an open-ended question on the effect of asthma at work. Results: Of the 2,055 patients on long-term maintenance therapy screened, 1,598 were symptomatic and completed the survey. The average percentage of work hours missed in a single week due to asthma symptoms was 9.3%, ranging from 3.5% (UK) to 17.4% (Brazil). Nearly three-quarters of patients reported an impact on their productivity at work caused by asthma. Overall work productivity loss (both time off and productivity whilst at work) due to asthma was 36%, ranging from 21% (UK) to 59% (Brazil). When asked how asthma made participants feel at work, many respondents highlighted how their respiratory symptoms affect them. Tiredness, weakness and mental strain were also identified as particular challenges, with respondents describing concerns about the perception of colleagues and feelings of inferiority. Conclusions: This study emphasizes the extent to which work time is adversely affected by asthma in patients despite the use of long-term maintenance medication, and provides unique personal insights. Strategies to improve patients' lives may include asthma education, optimizing asthma management plans and running workplace well-being programs. Clinicians, employers and occupational health teams should be more aware of the impact of asthma symptoms on employees, and work together to help overcome these challenges.

Slope of change in HbA1c from baseline with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes.

AIMS: To analyse the effect of baseline glycated haemoglobin (HbA1c) on the reduction in HbA1c with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes. MATERIALS AND METHODS: Using regression analyses of individual patient data from two Phase III studies, we compared the change in HbA1c according to a unit change in baseline HbA1c (the slope) with empagliflozin 10 mg or 25 mg vs sitagliptin (monotherapy) after 24 weeks, and with empagliflozin 25 mg vs glimepiride (as add-on to metformin) after 52 weeks. RESULTS: Steeper slopes of HbA1c decline were observed with empagliflozin 10 or 25 mg vs sitagliptin monotherapy at week 24. Regression analysis showed slopes of -0.59 (95% CI -0.70, -0.47), -0.49 (95% CI -0.62, -0.37) and -0.29 (95% CI -0.42, -0.15) for empagliflozin 10 mg, empagliflozin 25 mg and sitagliptin, respectively (P < .001 and P < .05 for empagliflozin 10 mg and empagliflozin 25 mg, respectively, vs sitagliptin). Similarly, a steeper slope of HbA1c decline was observed with empagliflozin 25 mg vs glimepiride as add-on to metformin at week 52. Regression analysis showed slopes of - 0.52 (95% CI -0.59, -0.44) and -0.32 (95% CI -0.39, -0.25) for empagliflozin 25 mg and glimepiride, respectively (P < .001 for empagliflozin 25 mg vs glimepiride). CONCLUSIONS: Incremental reductions in HbA1c with increasing baseline HbA1c are greater with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes.

Physicians' perception of guideline-recommended low-density lipoprotein target values: characteristics of misclassified patients.

AIMS: The present study investigated the awareness of primary care physicians for patient characteristics relevant for designation of low-density lipoprotein (LDL) target values. METHODS AND RESULTS: Physicians (n = 907) were asked to estimate guideline-recommended LDL target value for 30 of their patients with hyperlipidaemia. In total, 25 250 patients were allocated on that basis in three different groups (LDL target <100, <130, and <160 mg/dL), in which by guideline criteria 68.0, 21.9, and 10.1% of patients, respectively, were allocated. We analysed (by logistic regression) whether physicians utilized risk factors and co-morbidities appropriately for assignment of correct LDL target values. Overall, physicians estimated recommended LDL target values correctly in 55.1% of male vs. 49.1% of female patients (P < 0.001). In the group with LDL targets of <100 mg/dL, correct assignment was most often given to male patients with a history of myocardial infarction (MI; 77.1%). In comparison with this group, increasing probabilities for incorrect assignment were found in patients with documented coronary artery disease (CAD) without a history of MI [odds ratio (OR): 2.08, 95% confidence intervals (95% CI): 1.87-2.33], CAD-equivalent conditions (OR: 2.30, 95% CI: 2.08-2.55), and a 10-year risk >20% based on calculated risk scores (OR: 2.69, 95% CI: 2.40-3.02). Next, physicians were grouped, based on the number of correct assignments they gave to their patients, in quartiles of guideline knowledge. In patients from physicians of the top performing quartile (>90% of correct assignments), LDL levels were significantly lower than in the second, third, and fourth quartiles (LDL 134.3, 138.8, 145.5, 151.4 mg/dL, P < 0.001 between all groups). CONCLUSION: In primary care, about half of high-risk patients receive correct assignment of guideline-recommended LDL targets by their physicians. Perception of correct LDL target values varied largely depending on patients' gender and co-morbid conditions. Poor perception of risk resulted in lower rates of objective LDL target achievement.