Characterization of the COPD alveolar niche using single-cell RNA sequencing.

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant cellular metabolism and reduced cellular stress tolerance in COPD. Using transcriptomic network analyses, we predict capillary endothelial cells are inflamed in COPD, particularly through increased CXCL-motif chemokine signaling. Finally, we detect a high-metallothionein expressing macrophage subpopulation enriched in advanced COPD. Collectively, these findings highlight cell-specific mechanisms involved in the pathobiology of advanced COPD.

Ferric carboxymaltose for iron deficiency at discharge after acute heart failure: a multicentre, double-blind, randomised, controlled trial.

BACKGROUND: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure. METHODS: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 µg/L, or 100-299 µg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed. FINDINGS: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group. INTERPRETATION: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death. FUNDING: Vifor Pharma.

iGlarLixi Reduces Glycated Hemoglobin to a Greater Extent Than Basal Insulin Regardless of Levels at Screening: Post Hoc Analysis of LixiLan-L.

INTRODUCTION: The treatment of patients with type 2 diabetes uncontrolled on basal insulin and oral glucose-lowering drugs was investigated previously in the LixiLan-L trial. In the LixiLan-L trial, patients experienced a 6-week run-in with insulin glargine U100 (iGlar) as part of the screening phase, followed by treatment with a fixed-ratio combination of iGlar + lixisenatide (iGlarLixi) or iGlar alone over 30 weeks. In the study reported here, we investigated the achievement of glycemic control in those who completed the 30-week LixiLan-L trial, as assessed by change in glycated hemoglobin (HbA1c) levels from screening, both for the overall category and for screening HbA1c subcategories. METHODS: This post hoc analysis of the LixiLan-L trial included both the screening phase and the treatment period for 30-week completers and evaluated the change in HbA1c from screening to Week 30, patients reaching HbA1c < 7% at Week 30, and iGlar and lixisenatide (Lixi) doses at Week 30 overall and according to HbA1c subcategory at screening (HbA1c ≤ 8%, 8% < HbA1c ≤ 9%, and HbA1c > 9%). Documented symptomatic hypoglycemia during the treatment period was also assessed. RESULTS: HbA1c reductions (least squares mean) from screening to Week 30 were greater for iGlarLixi than iGlar, both overall (- 1.7 vs. - 1.1%) and in all subgroups (HbA1c ≤ 8%, 8% < HbA1c ≤ 9%, and HbA1c > 9%): - 1.1, - 1.4, - 2.4 (iGlarLixi) vs. - 0.5, - 1.0, - 1.8% (iGlar), respectively (all p < 0.0001). The end-of-treatment mean HbA1c level for iGlarLixi across all groups was < 7%. More patients achieved an HbA1c of < 7% with iGlarLixi than with iGlar, both overall (59.9 vs. 31.2%) and within each subgroup [74.2, 54.7, 52.2 (iGlarLixi) vs. 37.2, 31.6, 23.5% (iGlar), respectively]. A higher initial screening HbA1c corresponded with a greater mean reduction in HbA1c for both treatment strategies. In all HbA1c screening categories, the risk of hypoglycemia was not increased with iGlarLixi versus iGlar during the treatment phase. CONCLUSION: iGlarLixi controlled HbA1c levels more effectively than iGlar across all HbA1c screening subgroups and in the overall study population without increasing the risk of hypoglycemia. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT02058160. FUNDING: Sanofi.

Efficacy of antihyperglycemic therapies and the influence of baseline hemoglobin A(1C): a meta-analysis of the liraglutide development program.

OBJECTIVE: To compare liraglutide versus common antihyperglycemic treatments in reducing hemoglobin A1c (A1C) values across multiple levels of baseline glycemic control and in reaching glycemic targets. METHODS: Pooled patient data from 7 phase 3, multinational, randomized controlled trials in patients with type 2 diabetes were stratified by baseline A1C values into 5 categories: ≤7.5%, >7.5% to 8.0%, >8.0% to 8.5%, >8.5% to 9.0%, and y9.0%. The changes in A1C from baseline to week 26 of treatment and patient proportions reaching A1C targets of <7.0% and ≤6.5% were compared between liraglutide (1.8 mg daily) and sitagliptin, glimepiride, rosiglit-azone, exenatide, and insulin glargine across all baseline A1C categories. RESULTS: Irrespective of treatment, reductions in A1C levels were generally greater in groups with higher baseline A1C values. After 26 weeks of treatment, liraglutide produced the greatest reductions in A1C values across all baseline categories, ranging from 0.7% to 1.8% (baseline A1C categories ≤7.5% to >9.0%, respectively), followed by insulin glargine (0.3% to 1.5%) and then by glimepiride (0.4% to 1.3%). Generally, larger percentages of patients achieved the A1C target of ≤6.5% with liraglutide therapy across all baseline categories (from 62% of patients with A1C values ≤7.5% to 10% of patients with A1C values >9.0%) in comparison with other treatments (ranging from 49% to 0% of patients, respectively). Similarly, greater proportions of patients also reached the A1C target of <7.0% with liraglutide therapy across all baseline categories (from 83% of patients with A1C values ≤7.5% to 25% of patients with A1C values >9.0%) versus comparators (from 74% to 5% of patients, respectively). CONCLUSION: Across a wide spectrum of baseline A1C categories, liraglutide is an efficacious treatment option for patients with type 2 diabetes.

A review of 25 years' experience with the NovoPen family of insulin pens in the management of diabetes mellitus.

NovoPen, the first insulin pen, was introduced in 1985. This review article is an update of a review paper published in 2006 on 20 years' use of the NovoPen family of insulin pens in the management of diabetes mellitus. The literature searches conducted in the earlier review article were updated with search results for new articles published since April 2005. This was followed by an iterative search of references cited in identified publications and by searches of abstracts from proceedings of major international diabetes conferences since 2005. Most of the original studies identified in the 2006 review showed that insulin regimens using the NovoPen family of insulin pens were at least as effective (and in some cases superior) in maintaining glycaemic control and were as safe (in terms of hypoglycaemia) as conventional insulin regimens employing vials and syringes. Most patients preferred the various NovoPen insulin pens over vials and syringes, with some evidence suggesting that the use of discreet devices, such as those of the NovoPen family, facilitates intensive insulin therapy regimens, thereby helping to improve lifestyle flexibility. The new search results showed that the current generation of the device for the adult population, NovoPen 4, retains these benefits and further meets patients' needs by improving ease of use, convenience and discretion, which may be particularly important for those with manual dexterity, visual or auditory impairments. There was also evidence that healthcare professionals would be more likely to recommend NovoPen 4 to their patients than other devices. The recently introduced NovoPen Echo, designed specifically for the paediatric population, combines half-increment dosing with a memory function that can be used to retrieve information about the time and amount of the last dose, potentially reducing the fear of double dosing or missing a dose. Evidence obtained from the new searches suggested that paediatric patients, their parents and healthcare professionals were highly satisfied with NovoPen Echo overall, with most paediatric patients rating it their favourite pen compared with other insulin pens. In conclusion, new data published over the last 5 years on the use of NovoPen devices add to the large body of published evidence supporting the patient-related benefits of durable insulin injection pens in the treatment of diabetes since the first such pen was introduced in 1985. Together, the benefits of NovoPen are considered likely to improve both patients' quality of life and their compliance with therapy.

Comparison of intuitiveness, ease of use, and preference in two insulin pens.

BACKGROUND: The intuitiveness, instruction time, and handling of the Levemir (insulin detemir) FlexPen and the Lantus OptiClik pen (with insulin glargine) were investigated. METHODS: This randomized open-label crossover study involved two groups of insulin-device-naive Japanese patients with type 2 diabetes [mean (SD) age 61.9 +/- 12.3 years, 57% male]. Patients were evaluated on the ease-of-use of each insulin pen without instruction [intuitiveness group (n = 32)], or with instruction [instruction time group (n = 29)]. Patient preferences for the respective devices were assessed by questionnaire. RESULTS AND DISCUSSION: FlexPen required significantly less instruction time (p < .001) and was objectively more intuitive to use (p < .001) than OptiClik. Nevertheless, few patients in the intuitiveness group felt confident injecting either pen prior to instruction (FlexPen, 31%; OptiClik, 16%). No patients in the instruction time group found FlexPen difficult to learn, whereas 45% of patients found OptiClik difficult or very difficult to learn. FlexPen was rated simpler to use (77% versus 12%; p < .001), easier to inject (67% versus 13%; p < .001), and more convenient (71% versus 12%; p < .001) compared with OptiClik. More patients would trust FlexPen to deliver insulin injections (p < .01) and would prefer to use FlexPen compared with OptiClik (82% versus 13%; p < .001). CONCLUSIONS: FlexPen was faster to teach, simpler to use, and more trusted by patients compared with OptiClik. Mean injection time was significantly shorter for FlexPen than OptiClik, with or without instruction. This study highlights not only how easy it is for patients to learn to use FlexPen, but also how easily health care providers can teach patients to use it.

Patient acceptance and issues of education of two durable insulin pen devices.

BACKGROUND: Insulin pen devices offer patients a more convenient, accurate, and discreet mode of insulin delivery than traditional syringes and vials. This open-label, randomized, comparative crossover study assessed patient preference for two reusable pens: NovoPen 4 (Novo Nordisk A/S, Copenhagen, Denmark) and OptiClik (Sanofi-Aventis, Bridgewater NJ). METHODS: Thirty-five diabetes patients with no previous experience of pen devices (mean age 56.7 years; range 17-80 years; 57% male) used both pens to deliver a 10 unit saline dose into an injection cushion. Half received guidance according to official instruction manuals, and half were given no instructions. Learning times were also measured. Participants completed a detailed questionnaire to determine their preferences. RESULTS: Overall, 32 of 35 participants preferred NovoPen 4 compared with two of 35 for OptiClik (91.4% vs. 5.7% respectively, P<0.001), and one had no preference. NovoPen 4 was significantly favored over OptiClik in almost all questionnaire criteria, including safety (P<0.001), size of pen (P<0.001), appearance (P<0.001), and ease of use (P<0.001). The majority of patients were able to use NovoPen 4 without guidance (94.4%) compared with just over half for for OptiClik (55.6%, P<0.01). Learning time was also significantly faster for NovoPen 4 (62.6 s) than for OptiClik (95.8 s) (P<0.05). CONCLUSIONS: Patients learned how to use both pens quickly (under 2 min), but NovoPen 4 was preferred by participants over OptiClik. Patient acceptance of a pen device may support insulin initiation, particularly in type 2 diabetes.

Intuitiveness, instruction time, and patient acceptance of a prefilled insulin delivery device and a reusable insulin delivery device in a randomized, open-label, crossover handling study in patients with type 2 diabetes.

BACKGROUND: Because the use of insulin therapy can place a substantial burden on patients with diabetes, insulin administration should be as simple as possible. OBJECTIVES: The primary aim of this trial was to compare the use of 2 insulin delivery devices-one prefilled (NovoMix 30 FlexPen [FP]; Novo Nordisk, Copenhagen, Denmark) and the other reusable (HumaPen Luxura [HL]; Eli Lilly and Company, Indianapolis, Indiana)-in patients with type 2 diabetes in terms of intuitiveness and training time. A secondary aim was to evaluate the ease of use and overall acceptance of the 2 devices. METHODS: This was a randomized, open-label, comparative, crossover handling study in adult patients with type 2 diabetes who had been treated with oral antidiabetic drugs for >or=2 years and had no previous experience with insulin injection devices. Patients were randomly allocated to the intuitiveness group (no instruction in the use of the devices provided) or the instruction group (instruction provided). The time taken to deliver an injection into a cushion was measured for each device in both groups. Patients answered questionnaires concerning the intuitiveness and ease of use of the 2 devices, their trust and confidence in the devices to deliver the insulin dose, and their overall pen preference. RESULTS: Sixty-one patients were enrolled in the study (70.5% male; mean [SD] age, 61.80 [7.60] years), 30 in the intuitiveness group and 31 in the instruction group. When all handling steps for the HL device were included, the mean (SD) injection time was significantly shorter for the FP device compared with the HL device in the intuitiveness group (1.21 [1.04] vs 1.74 [0.79] minutes, respectively; P = 0.035). The outcome was similar in the instruction group (0.71 [0.29] vs 1.09 [0.49] minutes; P < 0.001). When the time for cartridge insertion in the HL device was excluded, there was no significant difference in injection time for the respective devices in either group (intuitiveness group: 1.21 [1.04] and 1.07 [0.91] minutes; instruction group: 0.63 [0.35] and 0.71 [0.29] minutes). Twenty-two patients preferred the FP device in terms of ease of learning, compared with 8 patients preferring the HL device (P = 0.007). CONCLUSIONS: In this study, when all handling steps were included, the FP device was associated with significantly greater intuitiveness and a shorter injection time compared with the HL device. Further research is needed to determine whether these differences between devices are clinically meaningful.

A review of 20 years' experience with the NovoPen family of insulin injection devices.

NovoPen, the first insulin pen injector, was introduced in 1985. This article reviews the published evidence over two decades of use of the NovoPen family of injection devices in diabetes management. A search for NovoPen publications from 1985 onwards was conducted in the following databases: MEDLINE/PubMed, Cochrane Database of Systematic Reviews, American College of Physicians Journal Club, Database of Abstract Reviews and Effects, and Cochrane Controlled Trials Register. Publications were examined and underwent a selection process to identify studies of NovoPen devices (NovoPen [1], NovoPen 2, NovoPen 1.5 and NovoPen 3) in the diabetes/insulin therapy area that contained evidence of the effects of NovoPen in a variety of categories. Of the studies identified, most showed that insulin regimens using the NovoPen family of devices are at least as effective (and in some cases superior) in maintaining glycaemic control and are as safe (in terms of hypoglycaemia) as conventional insulin regimens employing syringes. The published evidence identified also showed that insulin administration via NovoPen devices was for most patients easier, more convenient and quicker than with conventional syringes and that most patients preferred the various NovoPen devices over syringes. There was also some evidence that the use of discreet devices, like those of the NovoPen family, facilitates adherence to intensive insulin therapy regimens, helps to improve lifestyle flexibility and reduces injection pain compared with conventional syringe-based regimens. Together these benefits of NovoPen devices are considered likely to improve both patients' quality of life and compliance with therapy. In conclusion, a large body of published evidence accumulated over the past two decades testifies to the patient-related benefits of the NovoPen family of insulin injection devices in the treatment of diabetes.