The effect of AZD9567 vs. prednisolone on glycaemic control in patients with type 2 diabetes mellitus: Results from a phase 2a clinical trial.

AIMS: Corticosteroids are the treatment of choice for many inflammatory diseases but often lead to adverse effects, including hyperglycaemia. This study investigated the mechanisms driving differential effects on glucose control for AZD9567, an oral nonsteroidal selective glucocorticoid receptor modulator vs. prednisolone in 46 patients with type 2 diabetes mellitus. METHODS: In this randomized, double-blind, 2-way cross-over study (NCT04556760), participants received either AZD9567 72 mg and prednisolone 40 mg daily (cohort 1); AZD9567 40 mg and prednisolone 20 mg daily (cohort 2); or placebo and prednisolone 5 mg daily (cohort 3). Treatment duration was 3 days with a 3-week washout between treatment periods. Glycaemic control was assessed after a standardized meal and with continuous glucose monitoring. RESULTS: A significant difference between AZD9567 and prednisolone in favour of AZD9567 was observed for the change from baseline to Day 4 glucose excursions postmeal in cohort 1 (glucose area under the curve from 0 to 4 h -4.54%; 95% confidence interval [CI]: -8.88, -0.01; P = .049), but not in cohort 2 (-5.77%; 95% CI: -20.92, 12.29; P = .435). In cohort 1, significant differences between AZD9567 and prednisolone were also seen for the change from baseline to day 4 in insulin and glucagon secretion postmeal (P < .001 and P = .005, respectively) and change from baseline to Day 4 in GLP-1 response (P = .022). Significant differences between AZD9567 and prednisolone for 24-h glucose control were observed for both cohort 1 (-1.507 mmol/L; 95% CI: -2.0820, -0.9314; P < .001) and cohort 2 (-1.110 mmol/L; 95% CI -1.7257, -0.4941; P < .001). CONCLUSION: AZD9567 significantly reduced treatment-induced hyperglycaemia compared with prednisolone.

The absolute risk of incident type 2 diabetes following exposure to systemic corticosteroids in selected steroid-related and phenotypic groups.

AIMS: Exposure to corticosteroids is known to increase the risk of developing type 2 diabetes. We estimated the risk of incident type 2 diabetes in selected patient groups exposed to systemic corticosteroids. MATERIALS AND METHODS: In a retrospective, observational cohort study, using real-world data from UK primary care, patients were selected who had at least one episode of exposure to oral or intravenous corticosteroids for any indication. Corticosteroid-exposed patients were matched with non-exposed patients. Relative dosage was estimated as a weight-based, prednisolone-equivalent dose. Crude rates of progression to type 2 diabetes were determined for patient groups defined by relevant steroid-related and phenotypic characteristics present at corticosteroid exposure. RESULTS: Overall, rates of incidence of type 2 diabetes were 12.5 and 6.7 events per thousand person-years' (pkpy) exposure, respectively, in those who received at least one dose of corticosteroids versus those never exposed. This represented a rate ratio of 1.85 (95% CI 1.74-1.97). The incidence of type 2 diabetes was found to be associated with several of the selected characteristics, both individually and multi-dimensionally. The highest rate of incident type 2 diabetes was observed in very severely obese men aged 46-55 years having had the longest corticosteroid exposure and highest corticosteroid dose (190 incident events pkpy exposure). CONCLUSIONS: Corticosteroid exposure increased the risk of incident type 2 diabetes, and there was evidence of both a dose-response and a duration response. The impact of corticosteroid exposure upon the rate of incident type 2 diabetes appeared, however, to involve a complex, multi-dimensional interaction between the selected characteristics, some of which might be impacted by reverse causality.

Seven Pillars of Small Airways Disease in Asthma and COPD: Supporting Opportunities for Novel Therapies.

Identification of pathologic changes in early and mild obstructive lung disease has shown the importance of the small airways and their contribution to symptoms. Indeed, significant small airways dysfunction has been found prior to any overt airway obstruction being detectable by conventional spirometry techniques. However, most therapies for the treatment of obstructive lung disease target the physiological changes and associated symptoms that result from chronic lung disease, rather than directly targeting the specific underlying causes of airflow disruption or the drivers of disease progression. In addition, although spirometry is the current standard for diagnosis and monitoring of response to therapy, the most widely used measure, FEV1 , does not align with the pathologic changes in early or mild disease and may not align with symptoms or exacerbation frequency in the individual patient. Newer functional and imaging techniques allow more effective assessment of small airways dysfunction; however, significant gaps in our understanding remain. Improving our knowledge of the role of small airways dysfunction in early disease in the airways, along with the identification of novel end points to measure subclinical changes in this region (ie, those not captured as symptoms or identified through standard FEV1), may lead to the development of novel therapies that directly combat early airways disease processes with a view to slowing disease progression and reversing damage. This expert opinion paper discusses small airways disease in the context of asthma and COPD and highlights gaps in current knowledge that impede earlier identification of obstructive lung disease and the development and standardization of novel small airways-specific end points for use in clinical trials.

Efficacy and safety of AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, in patients with asthma: a phase 2a randomized, double blind, placebo-controlled crossover trial.

BACKGROUND: Inhaled corticosteroids reduce inflammation in asthma but chronic use may cause adverse effects. AZD7594, an inhaled non-steroidal selective glucocorticoid receptor modulator, has the potential of an improved risk-benefit profile. We investigated the safety and efficacy of AZD7594 in asthma. METHODS: This phase 2a multi-center, randomized, double-blind, placebo-controlled crossover study enrolled adults with asthma aged 18 to 75 years. Patients were treated with budesonide 200 µg twice daily for 2-3 3 weeks (run in part one). If controlled, as demonstrated by an asthma control questionnaire-5 score of < 1.5, patients entered a three-week run-in (part two) where they received a short acting bronchodilator alone. Thereafter, patients with a fractional exhaled nitric oxide (FENO) ≥25 ppb and pre-dose FEV1 40 to 90% predicted were randomized to one of nine treatment sequences. Each patient received placebo and two of three dose levels of AZD7594 (58, 250, 800 µg) once daily via inhalation, in 14-day treatment periods, separated by three-week washout periods. The primary endpoint was the change from baseline in morning trough FEV1 versus placebo on day 15. Secondary endpoints included measures of airway inflammation and asthma control. RESULTS: Fifty-four patients were randomized and received at least 1 dose of treatment, 48 patients completed the study. Overall 52 patients received placebo, 34 received AZD7594 58 µg, 34 received AZD7594 250 µg, and 34 received AZD7594 800 µg. AZD7594 800 µg demonstrated a significant improvement in Day 15 morning trough FEV1versus placebo (LS means difference 0.148 L 95% CI 0.035-0.261, p = 0.011), with a dose-dependent response seen in the 250 µg (0.076 L -0·036-0·188, p = 0.183) and 58 µg (0·027 L -0·086-0·140, p = 0.683). All secondary endpoints showed statistically significant improvement at the 800 µg dose. All doses demonstrated a significant reduction in FENO at day 15 p < 0.01. No statistically significant difference in plasma cortisol level was observed between AZD7594 and placebo at any dose. AZD7594 was considered safe and well tolerated. CONCLUSIONS: Two-week treatment with AZD7594 demonstrated a favorable risk-benefit profile in patients with mild to moderate asthma. Further clinical studies are needed to fully characterize AZD7594. TRIAL REGISTRATION: ClinicalTrials.gov number NCT02479412 .

The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial.

Background: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations. Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38α would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations. Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations. Results: The p38 isoform most relevant to lung inflammation was p38α, and AZD7624 specifically inhibited p38α and p38ß isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-α by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout. Conclusion: Although p38α is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD.

The management of depression in older nursing home residents.

OBJECTIVES: Depression remains underrecognized and undertreated in older people. We estimated the prevalence of depression in older nursing home (NH) residents and described its pharmacological management. DESIGN: Cross-sectional study. SETTING: Residents in 1,492 NHs in five states (Kansas, Maine, Mississippi, New York, South Dakota). PARTICIPANTS: Forty-two thousand nine hundred one residents aged 65 and older with depression documented as an active clinical condition on the Minimum Data Set (MDS) assessment. MEASUREMENTS: Data were from the Systematic Assessment of Geriatric drug use via Epidemiology database. We grouped antidepressant medications by class: tricyclic antidepressants (TCAs), tetracyclics, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors, and others. Logistic regression models revealed predictors of receipt of any antidepressant and, among those treated, predictors of receipt of an SSRI. RESULTS: Eleven percent of the residents were identified as depressed on the MDS. Of these, 55% received antidepressant therapy. Of depressed residents receiving antidepressant therapy, 32% received doses less than the manufacturers' recommended minimum effective dose for treating depression, with residents on TCAs more likely to receive less than the recommended dose for treating depression. The oldest-old (> or = 85 years) (odds ratio (OR) = 0.93, 95% confidence interval (CI) = 0.88-0.98), black residents (OR = 0.83, 95% CI = 0.75-0.92), and those with severe cognitive impairment (OR = 0.69, 95% CI = 0.64-0.75) were the least likely to receive an antidepressant. In those treated, cardiovascular diseases were associated with an increased likelihood of SSRI use. Despite control for comorbid conditions, women were less likely than men to receive an SSRI (OR = 0.77, 95% CI = 0.72-0.82). CONCLUSIONS: Although depression is a treatable illness, the majority of NH residents may be inadequately treated.