Search

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., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., Competing Interests: KGJ has spoken on behalf of, and worked as a consultant for, AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi, GlaxoSmithKline, Mundipharma, Napp, Novartis and Pfizer, outside the submitted work. MT has received honoraria from the following companies marketing respiratory and allergy products: Aerocrine, Boehringer Ingelheim International GmbH, GlaxoSmithKline, Merck Sharp & Dohme, Novartis and Pfizer, outside the submitted work; he is also a member of the BTS/SIGN Asthma guideline steering group and the NICE Asthma Diagnosis and Monitoring guideline development group. MRR reports personal fees from AstraZeneca, Boehringer Ingelheim International GmbH, Chiesi, Menarini, Mundipharma, Novartis, Pfizer, Teva and Bial, and grants and personal fees from GlaxoSmithKline, outside the submitted work. JMF reports being a member of advisory boards for AstraZeneca, Boehringer Ingelheim International GmbH, Novartis, Sanofi-Regeneron, Circassia and Teva; has been paid honoraria for lecturing at symposia organized by these companies; and has also undertaken clinical trials through his employer, the University of British Columbia, for these companies and GlaxoSmithKline. Funding was also provided to the University of British Columbia by Boehringer Ingelheim International GmbH during the conduct of this study. In the last 5 years IP has received speaker’s honoraria for speaking at sponsored meetings from AstraZeneca, Boehringer Ingelheim International GmbH, Aerocrine, Almirall, Novartis, Teva, Chiesi and GlaxoSmithKline, and payments for organizing educational events from AstraZeneca and Teva. He has received honoraria for attending advisory panels with Genentech, Regeneron, AstraZeneca, Boehringer Ingelheim International GmbH, GlaxoSmithKline, Novartis, Teva, Merck, Sanofi, Circassia, Chiesi and Knopp. He has received sponsorship to attend international scientific meetings from Boehringer Ingelheim International GmbH, GlaxoSmithKline, AstraZeneca, Teva and Chiesi. He has received a grant from Chiesi to support a phase 2 clinical trial in Oxford. JMH is an employee of Boehringer Ingelheim International GmbH and UE is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. CV has spoken on behalf of, and worked as a consultant for, Boehringer Ingelheim International GmbH and Novartis. The authors report no other conflicts of interest in this work.

Aims: To analyse the effect of baseline glycated haemoglobin (HbA 1c ) on the reduction in HbA 1c 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 HbA 1c according to a unit change in baseline HbA 1c (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 HbA 1c 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 HbA 1c with increasing baseline HbA 1c are greater with empagliflozin compared with sitagliptin or glimepiride in patients with type 2 diabetes.

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.

Background External genital warts (EGWs, condylomata acuminata) are a common, highly contagious disease caused by human papillomavirus (HPV), predominantly HPV 6 and HPV 11. Green tea catechins have been identified for their immunostimulatory, antiproliferative and antitumour properties. Two phase III trials evaluated treatment of EGWs with ointment containing a mixture of green tea catechins (Polyphenon E), U.S. adopted name: sinecatechins). Objectives To obtain additional data on the efficacy and safety of Polyphenon E ointment in the treatment of EGWs from two randomized, double-blind, vehicle-controlled trials. Methods Men and women aged > or = 18 years (n = 1005), with two to 30 EGWs (12-600 mm(2) total area) applied vehicle (G(Veh); n = 207), Polyphenon E ointment 10% (G(10%); n = 401) or Polyphenon E ointment 15% (G(15%); n = 397) three times daily until complete clearance of all EGWs (baseline + new EGWs) or for a maximum of 16 weeks. Results A total of 1004 patients were evaluable for safety and 986 for efficacy; 838 completed treatment after 16 weeks. Complete clearance of all EGWs was obtained in 53.6% (G(10%)) and 54.9% (G(15%)) of patients with Polyphenon E vs. vehicle (35.4%) (P < 0.001). Statistically significant differences in clearance rates appeared after 6 weeks of active treatment. Odds ratios vs. G(Veh) for G(10%) [2.10; 95% confidence interval (CI) 1.49-2.98] and G(15%) (2.22; 95% CI 1.57-3.14) indicated about a twofold higher chance of complete clearance under active treatment. Time to complete clearance was shorter with active treatment (hazard ratios 1.57 and 1.87, respectively, for G(10%) and G(15%) vs. G(Veh) groups; P < 0.001). Recurrence rates during follow-up were low and similar across groups: 5.8%, 6.8% and 6.5% (G(Veh), G(10%) and G(15%) groups, respectively). Adverse events were evenly distributed across groups ( approximately 30% of patients). Severe local signs were more frequent but moderate in the active treatment groups (1.5%, 9.2% and 13.5% for G(Veh), G(10%) and G(15%) groups, respectively). Conclusions Polyphenon E ointment is effective and well tolerated in the treatment of EGWs.

Respiratory tract infections (RTIs) are the most frequent infections in humans, particularly in children. In addition to intervention, increasing interest is focusing on immunomodulatory therapy for recurrent RTIs, which indicate a reduced defense capacity of the respiratory mucosa. LW 50020, an oral immunomodulator that contains the antigens of seven bacteria common in RTIs, has reduced the number, duration, and severity of RTIs in children and adults. This 56-week placebo-controlled, double-blind study in 188 children investigated whether the efficacy of the standard schedule (immunization cycle + one booster cycle) would be enhanced by additional booster cycles. Efficacy and safety over the long term were also assessed. The rate of infection was reduced by 50% with the standard schedule and could not be further decreased by two consecutive booster cycles. With both schedules, this reduction was sustained during a 28-week treatment-free observation period that followed the 28-week treatment period. The number of adverse drug reactions was low, and all were transient, expected, and nonserious. These results confirm that LW 50020 is an effective and safe strategy for RTIs.

Objective: A double-blind, placebo-controlled dose-finding study was performed in 237 patients with predominantly unilateral knee osteoarthritis (OA) evaluating efficacy and safety of a new topical NSAID., Design: The patients applied 3 g tid eltenac gel 0.1%, 0.3%, 1% or placebo gel over a period of 4 weeks. The patients were supplied with paracetamol tablets as an escape analgesic. Primary efficacy end-point was mean global pain in the week preceding the examinatio ns, evaluated on a visual analog scale (VAS). Secondary criteria were Lequesne's score ISK, Jezek score, muscle strength and dolorimeter measurements, walking time, clinical examination results of the knee joint and patient's and investigator's overall efficacy estimates., Results: The graphical depiction of VAS and ISK suggested a dose-related efficacy, but the pre-planned statistical analysis did not show significant differences between treatments. In the patient subgroup with a higher degree of baseline severity of knee OA the ISK showed significant and relevant advantages of eltenac gel 1% to placebo at different examination times. Two patients each of the eltenac gel 1% group and the placebo group showed local intolerance reactions which subsided spontaneously., Conclusion: This study did not provide confirmatory proof of an efficacy of topical eltenac in patients with knee OA. Methodological pitfalls and possible responder subgroups are described. Despite the difficulties, dose-finding studies seem to be feasible even with topical NSAIDs.

Respiratory tract infections (RTIs) are the most common infections in humans, and it is difficult to effectively treat patients with increased susceptibility to these ailments. LW 50020 (Luivac; Paspat oral), an oral immunomodulator consisting of the antigens of seven bacteria commonly involved in RTIs, has been developed for the induction of specific and nonspecific immune responses of the mucosa-associated lymphoid tissue. In this placebo-controlled study, the efficacy and safety of the tablet formulation of LW 50020 were evaluated in children and adults with recurrent RTIs. Tablets were taken once daily during two periods of 4 weeks each, interrupted by a treatment-free interval of 4 weeks. The main endpoint of the study, a clinical severity score that evaluated treatment benefits, was significantly lower in the second study period in patients treated with the bacterial lysate compared to patients given placebo. A comparison of the infection rates in the first and second study periods of patients treated with LW 50020 revealed a placebo-corrected reduction of 39% in children and a placebo-corrected reduction of 44% in adolescents and adults. The placebo-corrected duration of infections was shortened by 47% in children and by 55% in older patients. No serious drug-related side effects occurred. This study demonstrated that the oral bacterial immunomodulator LW 50020 is efficacious in treating patients with recurrent RTIs.

The purpose of this study was to investigate the therapeutic benefit of local Glycosaminoglycan polysulfate (GAGPS) injections in the treatment of chronic epicondylalgia. The study was conducted as a prospective, placebo-controlled double-blind trial. Sixty patients with a typical history of pain for at least 3 months who attended two private orthopaedic clinics in Stockholm received 50 mg GAGPS or placebo injections, one injection a week, for five weeks. The main outcome measures were the patients' evaluation of pain in connection with daily activities with a visual analogue scale and the number of treatment failures. The follow-up period was six months. The difference in reduction of painscore (VAS) ranging between 11.1 percentage units at the half-year follow-up and 20.9 percentage units 2 weeks after the treatment period is clinically good. The number of treatment failures in the GAGPS treatment groups at the 6 week follow-up was only 4 (13%) compared with 12 (40%) of the placebo treated patients. At the half-year follow-up 5 of those who received GAGPS had experienced a recurrency. The recurrency rate is thus smaller than most of those reported in controlled studies with corticosteroids. In the GAGPS treated group 13 patients reported on local pain after some injections, 2 cases combined with local haematomas, compared with 5 cases of local pain in the placebo group. The results confirm previous good results of GAGPS injection therapy in subchronic and chronic peritendinitis.

In a randomised, placebo-controlled, double-blind study with parallel group comparison, the efficacy and tolerability of topical treatment with a mucopolysaccharide polysulphate/salicylic acid cream was investigated in 156 patients with acute sprains of the knee or ankle joint. There was a more rapid reduction in pain on movement (the main parameter) in the active drug group compared with the placebo group. On day 9 after randomisation the difference was highly significant. There were no adverse events in the active drug group.

During a 15-month period, 47 elderly female patients admitted to hospital with a fractured neck of femur were studied immediately prior to discharge, in comparison with 34 elderly female control patients undergoing elective surgery who had been admitted over the same period to the same orthopaedic wards. The principal differences between the two populations were that the fracture patients had a lower forearm trabecular bone density, with lower bodyweight (both lower muscle mass and lower fat content), increased body sway, worse eyesight and reduced mental acuity. The serum biochemistry of the two groups was almost indistinguishable except that the fracture patients tended to have slightly lower concentrations of proteins. There was no evidence to implicate dietary vitamin D deficiency, osteomalacia, oestrogen deficiency or alcoholism in the aetiology of the fracture, nor was there evidence to suggest alterations in endocrine function with respect to cacitonin or parathyroid hormone.

Gamma-ray computed tomography (gamma-ray CT), using a special purpose scanner, enables in-vivo quantitative analysis of bone mineralization. Trabecular bone density (TBD), the relative amount of compact bone (bone density, BD) and the total absorption (TA) for a cross-section of the radius are determined from measurements of local linear absorption coefficients. A preliminary study of normal children (n = 49) and adults (n = 34) indicated that TBD is independent of age and sex in the age range 4 to 40 years. DB remains constant throughout childhood but increases after puberty in both women and men. TA is higher for adults than for children, and also higher for men than for women. A correlation between TA and parameters relating to body size indicates a relationship between body weight and bone mass.

Computed tomography of the human radius is performed using a special purpose scanning device which incorporates a radionuclide (125I) as radiation source. Parameters decribing the trabecular bone and the compact bone are determined at a distal and a diaphyseal measuring site respectively. Using this measurement technique changes in bone mineralization in the radius were studied in a group of 23 children following immobilization of an upper limb for fracture healing. An immobilization period of between three to six weeks resulted in a reduction of the relevant parameter value of up to 44% (mean 16%) in the distal part of the radius, whereas no significant change could be seen in the diaphyseal part of the same bone. Rapid remineralization of trabecular bone is indicated by the increase of the corresponding parameter value at a rate of up to several percent per week. However, in some of the patients studied complete normalization was not attained during the first six months following cast removal.

In a girl suffering from idiopathic transient osteoporosis the development of vertebral deformation and recovery could be followed from the age of 3.4 to 9.3 years. Computed bone densitometry (CT) revealed values below normal for trabecular bone density (-2.6 SD at 4.3 years and -2.8 SD at 5.3 years) during the clinically symptomatic phase of the disease and normalization after the age of 6 years (-0.2 SD at 6.7 and 9.3 years). Cortical bone mineral parameters measured by CT and metacarpal bone measurements from conventional X-rays showed values at the lower range of normal and only a weak correlation with clinical symptoms, vertebral deformation and recovery, respectively. CT may probably allow to diagnose osteoporosis before the appearance of deformities or fractures; in milder forms of osteoporosis the diagnosis may be possible by CT only.

Computed tomography was used to find a sensitive parameter for bone mineralization. A precision scanning instrument was constructed for determination of the mineral distribution in sections of the forearm. The quality of the reconstructed images allows separate quantification of compact and spongy bone even when gamma rays are used. Computer simulation and measured of models and macerated human bones showed that under clinical conditions it is possible to quantify spongy bone density within an accuracy of +/-2%.