Once-weekly insulin efsitora alfa: Design and rationale for the QWINT phase 3 clinical development programme.

AIMS: Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This review describes the study design and rationale of the efsitora phase 3 Once Weekly (QW) Insulin Therapy (QWINT) clinical development programme, including the five trials, QWINT-1 through QWINT-5. MATERIALS AND METHODS: The five trials included insulin-naïve adults (QWINT-1 and -2) with type 2 diabetes (T2D), adults with T2D previously treated with basal insulin (QWINT-3 and -4), and QWINT-5 in adults with type 1 diabetes. All five trials were designed as multicentre, randomized, controlled, open-label, treat-to-target studies to investigate the efficacy and safety of efsitora versus active once-daily basal insulin comparators (insulin glargine U100 or insulin degludec U100). The primary objective of each trial is to compare the change in HbA1c from baseline to week 26 or 52 between efsitora and the active comparator. The key secondary objectives include change in fasting glucose, insulin dose and continuous glucose monitoring variables, and patient-reported outcome questionnaires. CONCLUSIONS: The QWINT development programme includes a racially and geographically diverse population to provide important information regarding the efficacy and safety of efsitora and its clinical management of people with diabetes.

Indicators of Kidney Fibrosis in Patients with Type 2 Diabetes and Chronic Kidney Disease Treated with Dulaglutide.

INTRODUCTION: In the AWARD-7 study in patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide slowed the decline in estimated glomerular filtration rate (eGFR) and decreased the urine albumin/creatinine ratio compared to insulin glargine at the end of 52 weeks of treatment. In this exploratory post hoc analysis, changes in two fibrosis biomarkers, serum PRO-C6 (type VI collagen formation) and urine C3M (type III collagen degradation), were evaluated. METHODS: In the groups treated with dulaglutide 1.5 mg or insulin glargine (N = 330), serum PRO-C6 and urine C3M were measured using competitive enzyme-linked immunosorbent assays. Biomarker changes were assessed by a mixed-effects model for repeated measures. Pearson correlation analyses were conducted to determine associations between changes in kidney fibrosis biomarkers and eGFR measures at 52 weeks. RESULTS: At weeks 26 and 52 of treatment in the overall population, serum PRO-C6 levels were significantly lower in the dulaglutide group versus insulin glargine group with percent change from baseline of (least squares mean ± standard error) -4.6% ± 1.9 and -0.2% ± 2.2 versus 5.7% ± 2.0 and 8.0% ± 2.3 (p < 0.01), respectively, and urine C3M levels were significantly higher in the dulaglutide group versus insulin glargine group with percent change from baseline of 10.9% ± 8.2 and 20.7% ± 8.8 versus -10.0% ± 6.5 and -16.9% ± 6.4 (p < 0.05), respectively. These findings appeared greater in the subgroup with macroalbuminuria. Serum PRO-C6 negatively correlated with eGFR, while urine C3M positively correlated with eGFR. CONCLUSION: Dulaglutide treatment was associated with biomarker changes that indicated lower type VI collagen formation and higher type III collagen degradation compared to treatment with insulin glargine, suggesting a potential drug effect to reduce kidney fibrosis.

Efficacy and safety outcomes of dulaglutide by baseline HbA1c: A post hoc analysis of the REWIND trial.

AIM: To assess cardiovascular, glycaemic, weight and safety outcomes of long-term treatment with dulaglutide 1.5 mg compared with placebo in patients with a baseline HbA1c of less than 7% versus 7% or higher. MATERIALS AND METHODS: Intention-to-treat analyses were performed on REWIND participants with a baseline HbA1c measurement, using Cox proportional hazards regression and mixed model for repeated measures. Subgroup analyses with factors for baseline HbA1c categories and their interaction with treatment group, as well as analyses within the HbA1c subgroups, were conducted. Additionally, sensitivity analyses were performed for baseline HbA1c subgroups of 6.5% or less and more than 6.5%. RESULTS: Of the 9876 eligible participants, 3921 and 5955 had a baseline HbA1c of less than 7% and 7% or higher, respectively. Mean baseline HbA1c was 6.3% and 8.0% and the mean duration of diabetes was 9.0 and 11.6 years in the respective subgroups. The less than 7% subgroup was slightly older and less frequently insulin-treated. There was no evidence of a differential dulaglutide treatment effect on body mass index (BMI) reduction, cardiovascular or safety outcomes of interest between the baseline HbA1c subgroups. Treatment-by-baseline HbA1c group interaction was significant for HbA1c change from baseline (P < .001), with a greater reduction in the subgroup with higher baseline HbA1c values. Sensitivity analyses by baseline HbA1c subgroups of 6.5% or less and more than 6.5% showed similar results. CONCLUSIONS: The reduced incidence of cardiovascular events, and the reduction in BMI in participants treated with once-weekly dulaglutide, were independent of the baseline HbA1c level. Conversely, participants with a higher baseline HbA1c level had greater reductions in HbA1c. Dulaglutide has a positive benefit-risk profile and can be considered in patients with comparatively well-controlled HbA1c levels seeking optimal metabolic control and cardiovascular benefits.

Follow-up of SARS-CoV-2 positive subgroup from the Asymptomatic novel CORonavirus iNFection study.

A nested longitudinal study within theAsymptomatic novel CORonavirus iNFfection study followed participants with positive nasopharyngeal swab to query for development of symptoms and assess duration of positive reverse transcription-polymerase chain reaction (RT-PCR) test results. Of the 91 participants initially testing positive, 86 participated in follow-up approximately 14 days after study enrollment; of those 86 participants, 19 (22.1%) developed at least one symptom at any time after the initial positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result. The median number of days to symptom development after their initial positive test result was 6 (range 1-29 days). No participants reported a SARS-CoV-2-related hospitalization. The most frequently reported symptoms were fatigue or muscle aches (10.5%), headache (9.3%), fever (5.8%), and shortness of breath (5.8%). Of the 78 participants who submitted a nasopharyngeal swab for repeat RT-PCR testing, 17 (21.8%) remained positive at Day 14, 4 of which continued to test positive at Day 28. These findings reinforce the probable role of silent SARS-CoV-2 infections in community transmission, and that reliance on symptom development will miss a large proportion of infections. Broad testing programs not limited to individuals presenting with symptoms are critical for identifying persons with SARS-CoV-2 infection and ultimately slowing transmission.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

BACKGROUND: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes. Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months. The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere. In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, defined as the first occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7). During a median follow-up of 5·4 years (IQR 5·1-5·9) comprising 51 820 person-years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77-0·93; p=0·0004). The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68-0·87; p<0·0001), with HRs of 0·89 (0·78-1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39-1·44; p=0·39) for chronic renal replacement therapy. INTERPRETATION: Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes. FUNDING: Eli Lilly and Company.

A cross-sectional community-based observational study of asymptomatic SARS-CoV-2 prevalence in the greater Indianapolis area.

The Asymptomatic novel CORonavirus iNfection (ACORN) study was designed to investigate the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the asymptomatic adult population of the Indianapolis metropolitan area, to follow individuals testing positive for the development of symptoms, and to understand duration of positive test results. ACORN is a cross-sectional community-based observational study of adult residents presenting asymptomatic for COVID-like illness, defined as the self-reported absence of the following three symptoms in the last 7 days: fever (≥100°F), new-onset or worsening cough, and new-onset or worsening shortness of breath. SARS-CoV-2 infection was determined by real-time reverse transcription-polymerase chain reaction in nasopharyngeal swab samples. SARS-CoV-2 infection prevalence was expressed as a point estimate with 95% confidence interval (CI). Test results are reported for 2953 participants who enrolled and underwent nasopharyngeal swab testing between 7 April 2020 and 16 May 2020. Among tested participants, 91 (3.1%; 95% CI: 2.5%-3.7%) were positive for SARS-CoV-2. Overall, baseline characteristics, medical history, and infection risk factors were comparable between SARS-CoV-2 positive and negative participants. Within the ongoing 14-day follow-up period for positive participants, 58 (71.6%) of 81 assessed participants remained asymptomatic while others (n = 23, 28.4%) reported one or more symptoms. Indiana had "Stay-at-Home" orders in place during nearly the entire test period reported here, yet 3.1% of asymptomatic participants tested positive for SARS-CoV-2. These results indicate screening questions had limited predictive utility for testing in an asymptomatic population and suggest broader testing strategies are needed. Importantly, these findings underscore that more research is needed to understand the viral transmission and the role asymptomatic and presymptomatic individuals play in this global pandemic.

Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7).

In patients with type 2 dibetes and moderate-to-severe chronic kidney disease, dulaglutide treatment led to body weight (BW) loss and lesser eGFR decline compared to insulin glargine. As BW may affect muscle mass, creatinine-based eGFR can be altered independently of kidney function. Cystatin C-based eGFR is not affected by muscle mass. The objective of this post-hoc analysis was to determine whether the lesser eGFR decline with dulaglutide was related to BW loss. Baseline characteristics were similar between treatments ([mean ± SD] age, 64.6 ± 8.6 years; women, 48%; BW, 89.1 ± 17.7 kg; eGFR [CKD-EPI-cystatin C] 38 ± 14 mL/min/1.73m2 ). BW decreased with dulaglutide 1.5 and 0.75 mg and increased with insulin glargine ([LSM change (SE)], -2.66 [0.47] kg and -1.71 [0.45] vs 1.57 [0.43] kg; P < 0.001). Changes in eGFR were not significant with dulaglutide 1.5 and 0.75 mg, but eGFR significantly decreased with insulin glargine (eGFR-CKD-EPI-cystatin C [LSM change (95%CI)], -0.7 [-2.5, 1.0] and -0.7 [-2.4, 1.1] vs -3.3 [-5.1, -1.6] mL/min/1.73 m2 ; P ≤ 0.037 vs glargine). Changes in BW did not correlate with changes in eGFR-CKD-EPI-cystatin C (r = -0.041; n = 471; P = 0.379) or eGFR-CKD-EPI-creatinine (r = -0.074; n = 473; P = 0.106). In conclusion, the lesser decline in eGFR observed with dulaglutide was not influenced by BW loss.

Effect of once weekly dulaglutide by baseline beta-cell function in people with type 2 diabetes in the AWARD programme.

Glucagon-like peptide-1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose-dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta-cell function (as measured by HOMA2-%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide-treated patients from AWARD-1, AWARD-3 and AWARD-6 clinical studies were categorised based on their homeostatic model assessment of beta-cell function (HOMA2-%B) tertiles. Changes in glycaemic measures in response to treatment with once-weekly dulaglutide were evaluated in each HOMA2-%B tertile. Patients with low HOMA2-%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB-2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; -1.55% vs. -0.98% [-16.94 vs. -10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; -1.00 vs. -1.18% [-10.93 vs. -12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C-peptide were observed in the low tertile. Similar increases in HOMA2-%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta-cell function.

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice.

Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow-derived myeloid cells and in monocytic RAW264.7 cells, the LPS-induced expression of functionally active TF, assembly of the ternary TF-VIIa-Xa initiation complex of blood coagulation, and the EPCR-dependent activation of protease-activated receptor 2 (PAR2) by the ternary TF-VIIa-Xa complex were required for the normal LPS induction of messenger RNAs encoding the TLR3/4 signaling adaptor protein Pellino-1 and the transcription factor interferon regulatory factor 8. In response to in vivo challenge with LPS, mice lacking EPCR or PAR2 failed to fully initiate an interferon-regulated gene expression program that included the Irf8 target genes Lif, Iigp1, Gbp2, Gbp3, and Gbp6. The inflammation-induced expression of TF and crosstalk with EPCR, PAR2, and TLR4 therefore appear necessary for the normal evolution of interferon-regulated host responses.

Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials.

Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin-to-creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean ± standard deviation values: dulaglutide vs placebo: 87.8 ± 17.7 vs 88.2 ± 17.9 mL/min/1.73 m2 , P = .075; dulaglutide vs active comparators: 89.9 ± 16.7 vs 88.8 ± 16.3 mL/min/1.73 m2 , P = .223; and dulaglutide vs insulin glargine: 85.9 ± 18.2 vs 83.9 ± 18.6 mL/min/1.73 m2 , P = .423). Lower UACR values were observed for dulaglutide vs placebo, active comparators and insulin glargine (at 26 weeks, median [Q1-Q3] values were: dulaglutide vs placebo: 8.0 [4.4-20.4] vs 8.0 [4.4-23.9] mg/g, P = .023; dulaglutide vs active comparators: 8.0 [4.4-21.2] vs 8.9 [4.4-27.4] mg/g, P = .013; and dulaglutide vs insulin glargine: 8.9 [4.4-29.2] vs 12.4 [5.3-50.5] mg/g, P = .029). AEs reflecting potential acute renal failure were 3.4, 1.7 and 7.0 events/1000 patient-years for dulaglutide, active comparators and placebo, respectively. In conclusion, dulaglutide treatment of clinical trial participants with T2D did not affect eGFR and slightly decreased albuminuria.

Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events.

BACKGROUND: Patients with type 2 diabetes (T2D) have a substantial increased risk for cardiovascular (CV) disease and associated mortality than those without diabetes. Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist that is approved for treatment of T2D. METHODS: This meta-analysis evaluates the CV risk in patients with T2D treated with dulaglutide in 9 randomized safety and efficacy trials. Mean (median) treatment duration was 333 (358) days. Reported CV events were independently adjudicated by a treatment-blinded clinical endpoint committee. The primary measure was a 4-component major adverse CV event (4-component MACE) composite endpoint of death due to CV causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina. Additional pre-specified endpoints included adjudicated coronary revascularizations, hospitalization for heart failure, and all-cause mortality. A Cox proportional hazards regression model (stratified by study) was used to estimate the hazard ratio (HR) and confidence interval (CI). Tests of treatment effects for the primary endpoint were conducted at a 2-sided alpha level of 0.0198 and a corresponding 98.02 % CI was calculated. Statistical heterogeneity between the strata (studies) was tested by including in the Cox model an interaction term between treatment and strata. RESULTS: The analysis included 6010 randomized patients [dulaglutide: 3885; comparator therapy (active or placebo): 2125]; cumulative exposure to dulaglutide or comparator therapy was 3941 and 2223 patient-years, respectively. The demographic and baseline CV disease characteristics were similar across groups. Twenty-six (0.67 %) patients in the dulaglutide group versus 25 (1.18 %) in the comparator group experienced a primary 4-component MACE (HR 0.57; adjusted 98.02 % CI 0.30, 1.10). Results for the 3-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke), 6-component MACE (composite endpoint of death due to CV causes, nonfatal MI or stroke, hospitalization for unstable angina or heart failure, or coronary revascularizations) and all-cause mortality were consistent with the primary analysis (HR < 1.0 for all). CONCLUSIONS: These results suggest that dulaglutide does not increase the risk of major CV events in T2D patients. The ongoing CV outcomes study, Researching CV Events with a Weekly Incretin in Diabetes (REWIND), will further assess CV safety of dulaglutide.

Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program.

Dulaglutide (DU) is a once weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved for the treatment of type 2 diabetes mellitus (T2DM). Glycaemic efficacy and safety characteristics of dulaglutide have been assessed in six Phase 3 studies in the AWARD program. The objective of this review article is to summarize these results from the six completed AWARD studies. At the primary endpoint, in five of the six studies, once weekly dulaglutide 1.5 mg was superior to the active comparator [exenatide, insulin glargine (two studies), metformin, and sitagliptin], with a greater proportion of patients reaching glycated hemoglobin A1c (HbA1c) targets of <7.0% (53.0 mmol/mol) and ≤6.5% (47.5 mmol/mol). Dulaglutide 1.5 mg was non-inferior to liraglutide in AWARD-6. Once weekly dulaglutide 0.75 mg was evaluated in five of these trials and demonstrated superiority to the active comparator in four of five AWARD studies (exenatide, glargine, metformin, and sitagliptin), and non-inferiority to glargine in the AWARD-2 study. Similar to other GLP-1 receptor agonists, treatment with dulaglutide was associated with weight loss or attenuation of weight gain and low rates of hypoglycaemia when used alone or with non-insulin-secretagogue therapy. The most frequently reported adverse events were gastrointestinal, including nausea, vomiting, and diarrhea. The incidence of dulaglutide antidrug antibody formation was 1-2.8% with rare injection site reactions. In conclusion, dulaglutide is an effective treatment for T2DM and has an acceptable tolerability and safety profile. Copyright © 2016 John Wiley & Sons, Ltd.

Baseline factors associated with glycaemic response to treatment with once-weekly dulaglutide in patients with type 2 diabetes.

Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the reduction in glycated haemoglobin (HbA1c) in response to dulaglutide. Baseline covariates from patients receiving dulaglutide in six phase III studies (n = 2806) were analysed using a gradient-boosting method to assess their relative influence on the change in HbA1c after 26 weeks of treatment. Influential variables (relative influence >5%) were further evaluated in univariate and multivariable modelling. The gradient-boosting analysis showed that the top influential baseline factors associated with HbA1c reduction were: HbA1c (48.8%), age (9.1%), fasting serum glucose (FSG; 8.2%), fasting serum insulin (FSI; 6.7%) and estimated glomerular filtration rate (eGFR; 5.4%). Multivariable regression showed that higher baseline HbA1c was the major factor associated with greater HbA1c reduction [coefficient estimates: -0.6% (-6.6 mmol/mol); p < 0.0001]. Age ≤65 years, lower FSG level, FSI level ≤55 pmol/L and eGFR ≤100 mL/min/1.73 m2 were associated with greater decreases in HbA1c, but the effect was very small [coefficient estimates: -0.05% to -0.2% (-0.6 to -2.2 mmol/mol)]. These data indicate that higher baseline HbA1c, reflecting poor glycaemic status, is the major factor associated with greater reduction in HbA1c in response to dulaglutide treatment.

Dulaglutide and Kidney Function-Related Outcomes in Type 2 Diabetes: A REWIND Post Hoc Analysis.

OBJECTIVE: Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function-related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants. RESEARCH DESIGN AND METHODS: Intent-to-treat analyses were performed on REWIND participants (n = 4,949 DU, n = 4,952 placebo). Time to occurrence of a composite kidney function-related outcome (≥40% sustained decline in estimated glomerular filtration rate [eGFR], per the Chronic Kidney Disease Epidemiology Collaboration 2009 equation, end-stage renal disease, or renal-related death), and mean annual eGFR slope were examined. Analyses were conducted overall and within subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR <30 or ≥30 mg/g) and baseline eGFR (<60 or ≥60 mL/min/1.73 m2). RESULTS: The post hoc composite kidney function-related outcome occurred less frequently among participants assigned to DU than placebo (hazard ratio [HR] 0.75, 95% CI 0.62-0.92, P = 0.004), with no evidence of a differential DU treatment effect by UACR or eGFR subgroup. A ≥40% sustained eGFR decline occurred less frequently among participants assigned to DU than placebo (HR 0.72, 95% CI 0.58-0.88, P = 0.002). The mean annual decline in eGFR slope was significantly smaller for participants assigned to DU than placebo (-1.37 vs. -1.56 mL/min/1.73 m2/year, P < 0.001); results were similar for all subgroups. CONCLUSIONS: The estimated 25% reduced hazard of a kidney function-related outcome among participants assigned to DU highlights its potential for delaying or slowing the development of diabetic kidney disease in people with type 2 diabetes.

Reciprocal changes in renal ACE/ANG II and ACE2/ANG 1-7 are associated with enhanced collecting duct renin in Goldblatt hypertensive rats.

Alterations in the balance between ANG II/ACE and ANG 1-7/ACE2 in ANG II-dependent hypertension could reduce the generation of ANG 1-7 and contribute further to increased intrarenal ANG II. Upregulation of collecting duct (CD) renin may lead to increased ANG II formation during ANG II-dependent hypertension, thus contributing to this imbalance. We measured ANG I, ANG II, and ANG 1-7 contents, angiotensin-converting enzyme (ACE) and ACE2 gene expression, and renin activity in the renal cortex and medulla in the clipped kidneys (CK) and nonclipped kidneys (NCK) of 2K1C rats. After 3 wk of unilateral renal clipping, systolic blood pressure and plasma renin activity increased in 2K1C rats (n = 11) compared with sham rats (n = 9). Renal medullary angiotensin peptide levels were increased in 2K1C rats [ANG I: (CK = 171 ± 4; NCK = 251 ± 8 vs. sham = 55 ± 3 pg/g protein; P < 0.05); ANG II: (CK = 558 ± 79; NCK = 328 ± 18 vs. sham = 94 ± 7 pg/g protein; P < 0.001)]; and ANG 1-7 levels decreased (CK = 18 ± 2; NCK = 19 ± 2 pg/g vs. sham = 63 ± 10 pg/g; P < 0.001). In renal medullas of both kidneys of 2K1C rats, ACE mRNA levels and activity increased but ACE2 decreased. In further studies, we compared renal ACE and ACE2 mRNA levels and their activities from chronic ANG II-infused (n = 6) and sham-operated rats (n = 5). Although the ACE mRNA levels did not differ between ANG II rats and sham rats, the ANG II rats exhibited greater ACE activity and reduced ACE2 mRNA levels and activity. Renal medullary renin activity was similar in the CK and NCK of 2K1C rats but higher compared with sham. Thus, the differential regulation of ACE and ACE2 along with the upregulation of CD renin in both the CK and NCK in 2K1C hypertensive rats indicates that they are independent of perfusion pressure and contribute to the altered content of intrarenal ANG II and ANG 1-7.

Clinical Outcomes by Albuminuria Status with Dulaglutide versus Insulin Glargine in Participants with Diabetes and CKD: AWARD-7 Exploratory Analysis.

Background: In the AWARD-7 trial of participants with type 2 diabetes (T2DM) and moderate-to-severe CKD, dulaglutide (DU) treatment slowed decline in eGFR compared with insulin glargine (IG). Treatment with doses of either DU or IG resulted in similar levels of glycemic control and BP. The aim of this analysis was to determine the risk of clinical event outcomes between treatment groups. Methods: Participants with T2DM and CKD categories 3-4 were randomized (1:1:1) to 0.75 or 1.5 mg DU weekly or IG daily as basal therapy, with titrated insulin lispro, for 1 year. The time to occurrence of the composite outcome of ≥40% eGFR decline, ESKD, or death due to kidney disease was compared using a Cox proportional-hazards model. Results: Patients treated with 1.5 mg DU weekly versus IG daily for 1 year had a lower risk of ≥40% eGFR decline or ESKD events in the overall study population (5% versus 11%; hazard ratio, 0.45; 95% CI, 0.20 to 0.97; P=0.04). Most events occurred in the subset of patients with macroalbuminuria, where risk of the composite outcome was substantially lower for 1.5 mg DU versus IG (7% versus 22%; hazard ratio, 0.25; 95% CI, 0.10 to 0.68; P=0.006). No deaths due to kidney disease occurred. Conclusions: Treatment with 1.5 mg DU weekly was associated with a clinically relevant risk reduction of ≥40% eGFR decline or ESKD compared with IG daily, particularly in the macroalbuminuria subgroup of participants with T2DM and moderate-to-severe CKD.

A thrombin-PAR1/2 feedback loop amplifies thromboinflammatory endothelial responses to the viral RNA analogue poly(I:C).

Activation of blood coagulation and endothelial inflammation are hallmarks of respiratory infections with RNA viruses that contribute significantly to the morbidity and mortality of patients with severe disease. We investigated how signaling by coagulation proteases affects the quality and extent of the response to the TLR3-ligand poly(I:C) in human endothelial cells. Genome-wide RNA profiling documented additive and synergistic effects of thrombin and poly(I:C) on the expression level of many genes. The most significantly active genes exhibiting synergistic induction by costimulation with thrombin and poly(I:C) included the key mediators of 2 critical biological mechanisms known to promote endothelial thromboinflammatory functions: the initiation of blood coagulation by tissue factor and the control of leukocyte trafficking by the endothelial-leukocyte adhesion receptors E-selectin (gene symbol, SELE) and VCAM1, and the cytokines and chemokines CXCL8, IL-6, CXCL2, and CCL20. Mechanistic studies have indicated that synergistic costimulation with thrombin and poly(I:C) requires proteolytic activation of protease-activated receptor 1 (PAR1) by thrombin and transactivation of PAR2 by the PAR1-tethered ligand. Accordingly, a small-molecule PAR2 inhibitor suppressed poly(I:C)/thrombin-induced leukocyte-endothelial adhesion, cytokine production, and endothelial tissue factor expression. In summary, this study describes a positive feedback mechanism by which thrombin sustains and amplifies the prothrombotic and proinflammatory function of endothelial cells exposed to the viral RNA analogue, poly(I:C) via activation of PAR1/2.

The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial.

BACKGROUND: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial. METHODS: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries. Men and women (aged ≥50 years) with established or newly detected type 2 diabetes whose HbA1c was 9·5% or less (with no lower limit) on stable doses of up to two oral glucose-lowering drugs with or without basal insulin therapy were eligible if their body-mass index was at least 23 kg/m2. Participants were randomly assigned (1:1) to weekly subcutaneous injections of either masked dulaglutide 1·5 mg or the same volume of masked placebo (containing the same excipients but without dulaglutide). Randomisation was done by a computer-generated random code with an interactive web response system with stratification by site. Participants, investigators, the trial leadership, and all other personnel were masked to treatment allocation until the trial was completed and the database was locked. During the treatment period, participants in both groups were instructed to inject study drug on the same day at around the same time, each week. Strokes were categorised as fatal or non-fatal, and as either ischaemic, haemorrhagic, or undetermined. Stroke severity was assessed using the modified Rankin scale. Participants were seen at 2 weeks, 3 months, 6 months, and then every 3 months for drug dispensing and every 6 months for detailed assessments, until 1200 confirmed primary outcomes accrued. The primary endpoint was the first occurrence of any component of the composite outcome, which comprised non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular or unknown causes. All analyses were done according to an intention-to-treat strategy that included all randomly assigned participants, irrespective of adherence. The trial is registered with ClinicalTrials.gov, number NCT01394952. FINDINGS: Between Aug 18, 2011, and Aug 14, 2013, we screened 12 133 patients, of whom 9901 with type 2 diabetes and additional cardiovascular risk factors were randomly assigned to either dulaglutide (n=4949) or an equal volume of placebo (n=4952). During a median follow-up of 5·4 years, cerebrovascular and other cardiovascular outcomes were ascertained and adjudicated. 158 (3·2%) of 4949 participants assigned to dulaglutide and 205 (4·1%) of 4952 participants assigned to placebo had a stroke during follow-up (hazard ratio [HR] 0·76, 95% CI 0·62-0·94; p=0·010). Dulaglutide reduced ischaemic stroke (0·75, 0·59-0·94, p=0·012) but had no effect on haemorrhagic stroke (1·05, 0·55-1·99; p=0·89). Dulaglutide also reduced the composite of non-fatal stroke or all-cause death (0·88, 0·79-0·98; p=0·017) and disabling stroke (0·74, 0·56-0·99; p=0·042). The degree of disability after stroke did not differ by treatment group. INTERPRETATION: Long-term dulaglutide use might reduce clinically relevant ischaemic stroke in people with type 2 diabetes but does not affect stroke severity. FUNDING: Eli Lilly and Company.

The association between the severity of chronic kidney disease and medical costs among patients with type 2 diabetes.

AIMS: Examine healthcare costs across chronic kidney disease (CKD) stages for US patients with type 2 diabetes (T2D). MATERIALS AND METHODS: IQVIA Real World Data Adjudicated Claims linked electronic medical records and insurance claims from January 1, 2012 through March 31, 2017 were used for this retrospective study. Adults diagnosed with T2D and comorbid CKD were included. General linear models incorporating splines were constructed, and information from these regressions were used to inform the relationship between medical costs and CKD. Multivariable analyses controlled for patient characteristics, vital signs, general health, prior medication use, prior visit to specialists, index A1c, and year of index date. RESULTS: There were 6,645 individuals who met the study criteria. Results generally indicate sharp increases in annual total medical costs and non-drug medical costs in the 1 year post-period for patients with Stage 4 or 5 CKD (estimated glomerular filtration rate [eGFR] ≤ 30 mL/min/1.73 m2) with each 1 point reduction in eGFR from 30 associated with an increase of $1,870 in all-cause total medical costs (p < 0.0001) and $1,805 of all-cause non-drug medical costs (p < 0.0001). Similarly, each point decline below 30 mL/min was associated annual cost increases of $1,701 for CKD-related total medical costs, $1,695 for CKD-related non-drug medical costs, $173 for diabetes-related medical costs, and $187 for diabetes-related non-drug medical costs (all p < 0.0001). LIMITATIONS: The investigation included only patients with medical insurance and laboratory test results, and results may not be generalizable to all T2D patients with CKD. The methodology allowed us to determine associations, not causation, and potential confounders, such as duration of diabetes, diet, exercise, or social support, could not be assessed. CONCLUSIONS: Results indicate there are sharp and significant increases in medical costs among T2D patients with Stage 4 and 5 CKD compared to those with earlier stages of CKD.

Glucagon-Like Peptide-1 Receptor Agonist Use and Renal Impairment: A Retrospective Analysis of an Electronic Health Records Database in the U.S. Population.

INTRODUCTION: The study characterizes the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) with and without renal impairment and examines the effects of such use on the clinical outcomes of estimated glomerular filtration rate (eGFR) and glycated hemoglobin (A1c). METHODS: Data from the Practice Fusion electronic health records database from 1 January 2012 through 30 April 2015 were used. Adults with T2D who received serum creatinine laboratory tests and initiated therapy with a GLP-1 RA (N = 3225) or other glucose-lowering agent (GLA) (N = 37,074) were included in the analysis. The GLP-1 RA cohort was matched to cohorts initiating therapy any other GLA, and multivariable analyses examined the association between GLP-1 RA use and changes in eGFR or A1c at 1 year after therapy initiation. RESULTS: In this study, only 5.7% of patients with an eGFR of < 30 and ≥ 15 mL/min/1.73 m2 and 3.6% of patients with an eGFR of  < 15 mL/min/1.73 m2 initiated therapy with a GLP-1 RA. Compared to other GLAs, at 1-year after initiation of therapy the use of a GLP-1 RA was associated with a significantly smaller decline in eGFR (- 0.80 vs. - 1.03 mL/min/1.73 m2; P = 0.0005), a significantly smaller likelihood of having a ≥ 30% reduction in eGFR (2.19 vs. 3.14%; P < 0.0001), and a significantly larger reduction in A1c (- 0.48 vs. - 0.43; P = 0.0064). CONCLUSION: In clinical practice, the use of GLP-1 RAs in patients with a higher degree of renal impairment disease was limited. Compared to other GLAs, the use of GLP-1 RAs was associated with a significantly smaller decline in eGFR and a larger reduction in A1c over the 1 year following therapy initiation. FUNDING: Eli Lilly and Company.