Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus

Statin therapy modestly increases new-onset diabetes risk. The effect of proprotein convertase subtilisin/kexin type 9 inhibition on new-onset diabetes, glycemia, and weight remains unclear. We studied the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on fasting plasma glucose, glycated hemoglobin, weight, and new-onset diabetes mellitus. We pooled 1-year (48-week) data for participants who had completed an evolocumab parent study before entering an open-label extension (OLE) trial. Data were available for 4,802 participants (1,602 on standard of care [SOC]; 3,200 on evolocumab plus SOC) in 2 OLE trials. Evolocumab lowered low-density lipoprotein cholesterol by approximately 60% compared with SOC alone. Over the first year of the OLE trials, there was no difference in median (Q1, Q3) change in glycated hemoglobin (0.1% [-0.1, 0.2] for both SOC and evolocumab plus SOC) and fasting plasma glucose (0.06 mmol/L [-0.28, 0.38 mmol/L] for SOC and 0.06 mmol/L [-0.28, 0.44 mmol/L] for evolocumab plus SOC). Mean weight change (standard error) at 1 year was -0.1 kg (0.2) on SOC compared with 0.3 kg (0.1) on evolocumab plus SOC. The exposure-adjusted incidence rate (95% confidence intervals) for new-onset diabetes per 100 patient years was 3.7 (2.9 to 4.7) on control/SOC alone and 3.9 (3.2 to 4.6) on evolocumab/evolocumab plus SOC treatment. Glycemic changes observed in 6,430 participants at week 12 in the parent studies were comparable with OLE trial findings. In conclusion, evolocumab therapy has no effect on glucose homeostasis over 1 year of open-label treatment

Development and validation of the Crohn’s disease patient-reported outcomes signs and symptoms (CD-PRO/SS) diary

Abstract Background The clinical course of Crohn’s disease (CD) and the effect of its treatment are monitored through patient-reported signs and symptoms (S&S), and endoscopic evidence of inflammation. The Crohn’s Disease Patient-reported Outcomes Signs and Symptoms (CD-PRO/SS) measure was developed to standardize the quantification of gastrointestinal S&S of CD through direct report from patient ratings. Methods The CD-PRO/SS was developed based on data from concept elicitation (focus groups, interviews; n = 29), then refined through cognitive interviews of CD patients (n = 20). Measurement properties, including item-level statistics, scaling structure, reliability, and validity, were examined using secondary analyses of baseline and two-week clinical trial data of adults with moderate-to-severe CD (n = 238). Results Findings from qualitative interviews identified nine S&S items covering bowel and abdominal symptoms. The final CD-PRO/SS daily diary includes two scales: Bowel S&S (three items) and Abdominal Symptoms (three items), each scored separately. Each scale showed evidence of adequate reliability (α = 0.74 and 0.67, respectively); reproducibility (intraclass correlation coefficient > 0.80), and validity, with the last including moderate correlations with the Inflammatory Bowel Disease Questionnaire bowel symptom score and select items (ranging from r = 0.43–0.54). Scores distinguished patients categorized by patient global ratings of disease severity (p < 0.0001). Conclusions Results suggest the CD-PRO/SS is a reliable and valid measure of gastrointestinal symptom severity in CD patients. Additional longitudinal data are needed to evaluate the ability of the CD-PRO/SS scores to detect responsiveness and inform the selection of responder definitions.https://deepblue.lib.umich.edu/bitstream/2027.42/143542/1/41687_2018_Article_44.pd

Long-term effects of evolocumab in participants with HIV and dyslipidemia: results from the open-label extension period

Objectives: People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52\u200aweeks in PWH. Design: This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420\u200amg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24\u200aweeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART. Methods: Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined. Results: Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4\u200ayears, 82.5% male, mean duration with HIV of 17.4\u200ayears). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP. Conclusion: Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events. Trail registration: NCT02833844. Video abstract: http://links.lww.com/QAD/C441

Evolocumab treatment in patients with HIV and hypercholesterolemia/mixed dyslipidemia: BEIJERINCK study design and baseline characteristics

People living with human immunodeficiency virus (PLHIV) are at higher risk of atherosclerotic cardiovascular disease (ASCVD) due to traditional and HIV- or antiretroviral treatment (ART)-related risk factors. The use of high-intensity statin therapy is often limited by comorbidities and drug–drug interactions with ART. Herein, we present the design and baseline characteristics of the BEIJERINCK study, which will assess the safety and efficacy of evolocumab in PLHIV and hypercholesterolemia/mixed dyslipidemia

Evolocumab in HIV-Infected Patients With Dyslipidemia: Primary Results of the Randomized, Double-Blind BEIJERINCK Study

Background: People living with human immunodeficiency virus (PLHIV) are at increased risk of atherosclerotic cardiovascular disease (ASCVD) and are prone to statin-related adverse events from drug-drug interactions with certain antiretroviral regimens.Objectives: This study sought to evaluate the efficacy and safety of evolocumab in dyslipidemic PLHIV.Methods: BEIJERINCK (EvolocumaB Effect on LDL-C Lowering in SubJEcts with Human Immunodeficiency VirRus and INcreased Cardiovascular RisK) is a randomized, double-blind, multinational trial comparing monthly subcutaneous evolocumab 420 mg with placebo in PLHIV with hypercholesterolemia/mixed dyslipidemia taking maximally-tolerated statin therapy. The primary endpoint was the percent change (baseline to week 24) in low-density lipoprotein cholesterol (LDL-C); secondary endpoints included achievement of LDL-C &lt;70 mg/dl and percent change in other plasma lipid and lipoprotein levels. Treatment-emergent adverse events were also examined.Results: A total of 464 patients were analyzed (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). ASCVD was documented in 35.6% of patients, and statin intolerance/contraindications to statin use were present in 20.7% of patients. Evolocumab reduced LDL-C by 56.9% (95% confidence interval: 61.6% to 52.3%) from baseline to week 24 versus placebo. An LDL-C level of &lt;70 mg/dl was achieved in 73.3% of patients in the evolocumab group versus 7.9% in the placebo group. Evolocumab also significantly reduced other atherogenic lipid levels, including non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) (all p &lt; 0.0001). Evolocumab was well tolerated, and treatment-emergent adverse events patient incidence was similar among evolocumab and placebo groups.Conclusions: Evolocumab was safe and significantly reduced lipid levels in dyslipidemic PLHIV on maximally-tolerated statin therapy. Evolocumab is an effective therapy for lowering atherogenic lipoproteins in PLHIV with high cardiovascular risk. (Safety, Tolerability & Efficacy on LDL-C of Evolocumab in Subjects With HIV & Hyperlipidemia/Mixed Dyslipidemia; NCT02833844).</p

Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate-to-Severe Ulcerative Colitis

BACKGROUND & AIMS: The α4β7 integrin is a validated target in inflammatory bowel disease. This randomized, phase 2b, placebo-controlled, double-blind study evaluated the efficacy and safety of the anti-α4β7 antibody abrilumab in patients with moderate-to-severe ulcerative colitis despite treatment with conventional therapies. METHODS: Patients (total Mayo Score 6-12, recto-sigmoidoscopy score ≥2) with inadequate response or intolerance to conventional therapies were randomized to receive subcutaneous abrilumab (7, 21, or 70 mg) on day 1, weeks 2 and 4, and every 4 weeks; abrilumab 210 mg on day 1; or placebo. The primary end point was remission (total Mayo Score ≤2 points, no individual sub-score >1 point) for the 2 highest dosages at week 8. Key secondary end points were response and mucosal healing (centrally read) at week 8. RESULTS: For 354 patients who received ≥1 dose of investigational product (placebo, n = 116; 7 mg, n = 21; 21 mg, n = 40; 70 mg, n = 98; 210 mg, n = 79), non-adjusted remission rates at week 8 were 4.3%, 13.3%, and 12.7% for the placebo and abrilumab 70-mg and 210-mg groups, respectively (P < .05 for 70 and 210 mg vs placebo); odds of achieving remission were significantly greater with abrilumab 70 mg (odds ratio 3.35; 90% CI 1.41-7.95; P = .021) and 210 mg (odds ratio 3.33; 90% confidence interval 1.34-8.26; P = .030) than with placebo. Response and mucosal healing rates with these dosages also were significantly greater than with placebo. Higher baseline α4β7 levels on naïve CD4+ T cells were a prognostic indicator for overall outcome, but not a predictive biomarker of abrilumab response. There were no cases of progressive multifocal leukoencephalopathy or deaths. CONCLUSIONS: Abrilumab treatment for 8 weeks induced remission, clinical response, and mucosal healing in patients with moderate-to-severe ulcerative colitis. ClinicalTrials.gov, number NCT01694485

Targeted Deletion of Integrin-Linked Kinase Reveals a Role in T-Cell Chemotaxis and Survival

Integrin-linked kinase (ILK) is a serine/threonine kinase that is important in cell-matrix interactions and cell signaling. To examine the role of ILK in leukocyte trafficking and survival, we generated T cell-specific ILK knockouts by breeding ILK(flox/flox) mice to transgenic mice expressing Cre recombinase under control of the Lck proximal promoter. Thymic T cells from Lck-Cre(+)/ILK(flox/flox) mice had a marked reduction (>95%) in ILK protein levels. Thymic cellularity was comparable in 3- to 4-week-old mice, but a threefold diminution of thymic T cells became evident by 6 to 8 weeks of age in the T cell-specific ILK knockout mice due to increased cell death of double-positive (DP) T cells. Analysis of peripheral T cells by quantitative PCR and by breeding Lck-Cre(+)/ILK(flox/flox) mice to a YFP-transgenic reporter strain demonstrated an approximate 20-fold enrichment of ILK-competent cells, suggesting these cells have a competitive advantage in trafficking to and/or survival in peripheral lymphatic organs. We explored mechanisms related to altered cell trafficking and survival that might explain the decreases in thymic cellularity and enrichment for ILK-competent cells in the spleen and lymph nodes. We observed a >50% reduction in chemotaxis of ILK-deficient T cells to the chemokines CXCL12 (stromal cell-derived factor [SDF]-1α) and CCL19 (macrophage inflammatory protein [MIP]-3β), as well as enhanced apoptosis of ILK-deficient cells upon stress. Signaling studies in ILK-deficient T cells demonstrated diminished phosphorylation of Akt on the activating phosphorylation site, Ser 473, and a concordant decrease in Akt kinase activity following stimulation with the chemokine SDF-1. Rac1 activation was also markedly diminished in ILK-deficient T cells following chemokine stimulation. These data extend the role of ILK to immune-cell trafficking and survival via modulation of Akt- and Rac-dependent substrates, and have implications for cell recruitment in both homeostatic and pathological processes

Long-term effects of evolocumab in participants with HIV and dyslipidemia: results from the open-label extension period

International audienceObjectives: People with HIV (PWH) are at an increased risk of atherosclerotic cardiovascular disease. Suboptimal responses to statin therapy in PWH may result from antiretroviral therapies (ARTs). This open-label extension study aimed to evaluate the long-term safety and efficacy of evolocumab up to 52 weeks in PWH.Design: This final analysis of a multinational, placebo-controlled, double-blind, randomized phase 3 trial evaluated the effect of monthly subcutaneous evolocumab 420 mg on low-density lipoprotein cholesterol (LDL-C) during the open-label period (OLP) following 24 weeks of double-blind period in PWH with hypercholesterolemia/mixed dyslipidemia. All participants enrolled had elevated LDL-C or nonhigh-density lipoprotein cholesterol (non-HDL-C) and were on stable maximally tolerated statin and stable ART.Methods: Efficacy was assessed by percentage change from baseline in LDL-C, triglycerides, and atherogenic lipoproteins. Treatment-emergent adverse events (TEAEs) were examined.Results: Of the 467 participants randomized in the double-blind period, 451 (96.6%) received at least one dose of evolocumab during the OLP (mean age of 56.4 years, 82.5% male, mean duration with HIV of 17.4 years). By the end of the 52-week OLP, the overall mean (SD) percentage change in LDL-C from baseline was -57.8% (22.8%). Evolocumab also reduced triglycerides, atherogenic lipid parameters (non-HDL-C, apolipoprotein B, total cholesterol, very-low-density lipoprotein cholesterol, and lipoprotein[a]), and increased HDL-C. TEAEs were similar between placebo and evolocumab during the OLP.Conclusion: Long-term administration of evolocumab lowered LDL-C and non-HDL-C, allowing more PWH to achieve recommended lipid goals with no serious adverse events.Trail registration: NCT02833844. Video abstract: http://links.lww.com/QAD/C441