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Effect of Ziltivekimab on Determinants of Hemoglobin in Patients with CKD Stage 3-5: An Analysis of a Randomized Trial (RESCUE).
Pergola, PE, Davidson, M, Jensen, C, Mohseni Zonoozi, AA, Raj, DS, Andreas Schytz, P, Tuttle, KR, Perkovic, V
Journal of the American Society of Nephrology : JASN. 2024;(1):74-84
Abstract
SIGNIFICANCE STATEMENT Systemic inflammation in CKD can lead to anemia. Ziltivekimab, a fully human monoclonal antibody targeting the IL-6 ligand, has been shown to reduce systemic inflammation in patients with CKD. It has also been shown to increase serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to treatment with erythropoiesis-stimulating agents. This exploratory analysis of the RESCUE clinical trial found that among patients with CKD stage 3-5 and systemic inflammation, ziltivekimab treatment significantly increased hemoglobin (Hb) levels after 12 weeks compared with placebo. Ziltivekimab was also associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation. No major safety concerns were reported. Further clinical trials are warranted to study ziltivekimab's potential for anemia management in patients with CKD. BACKGROUND In the phase 2 RESCUE clinical trial, ziltivekimab, a fully human monoclonal antibody against the IL-6 ligand, significantly reduced the biomarkers of inflammation compared with placebo, in patients with CKD and systemic inflammation (high-sensitivity C-reactive protein ≥2 mg/L). The aim of this subanalysis of RESCUE trial data was to assess the effect of ziltivekimab on Hb and iron homeostasis in this patient population. METHODS This was an analysis of exploratory end points from the RESCUE trial ( NCT03926117 ), which included 264 adults with CKD stage 3-5 and high-sensitivity C-reactive protein ≥2 mg/L. Participants received placebo or subcutaneous ziltivekimab (7.5, 15, or 30 mg) (1:1:1:1) once every 4 weeks, up to 24 weeks. End points for this analysis were changes in Hb and biomarkers of iron homeostasis from baseline to week 12. RESULTS The trial was terminated early due to the coronavirus disease 2019 pandemic, and thus, data up to week 12 are presented. Hb levels significantly increased from baseline to week 12 with ziltivekimab 7.5, 15, and 30 mg (treatment differences versus placebo: +0.57 g/dl [95% confidence interval, 0.27 to 0.86], +1.05 g/dl [0.76 to 1.33], and +0.99 g/dl [0.70 to 1.28], respectively, all P < 0.001). Ziltivekimab was associated with significant increases in serum iron levels, total iron-binding capacity, and transferrin saturation from baseline to week 12 ( P < 0.05 versus placebo for all doses and comparisons). Cases of sustained thrombocytopenia, sustained neutropenia, anemia, and iron deficiency anemia were infrequent and similar across all groups. CONCLUSIONS Anti-inflammatory therapy with ziltivekimab improved the markers of anemia and iron homeostasis in people with stage 3-5 CKD and systemic inflammation, suggesting a possible role in anemia management.
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Efficacy and safety of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan (RESCUE-2): A randomized, double-blind, placebo-controlled, phase 2 trial.
Wada, Y, Jensen, C, Meyer, ASP, Zonoozi, AAM, Honda, H
Journal of cardiology. 2023;(4):279-285
Abstract
BACKGROUND Despite optimal treatment, a residual inflammatory risk often remains in patients with atherosclerotic cardiovascular disease. In a US-based phase 2 trial, ziltivekimab, a fully human monoclonal antibody targeting the interleukin-6 ligand, significantly reduced biomarkers of inflammation compared with placebo in patients at high atherosclerotic risk. Here, we report the efficacy and safety of ziltivekimab in Japanese patients. METHODS RESCUE-2 was a randomized, double-blind, 12-week, phase 2 trial. Participants aged ≥20 years with stage 3-5 non-dialysis-dependent chronic kidney disease and high-sensitivity C-reactive protein (hsCRP) ≥2 mg/L were randomized to receive placebo (n = 13) or subcutaneous ziltivekimab 15 mg (n = 11) or 30 mg (n = 12) at Weeks 0, 4, and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT; mean of Week 10 and Week 12 values). RESULTS At EOT, median hsCRP levels were reduced by 96.2 % in the 15 mg group (p < 0.0001 versus placebo), by 93.4 % in the 30 mg group (p = 0.002 versus placebo), and by 27.0 % in the placebo group. Serum amyloid A and fibrinogen levels were also reduced significantly. Ziltivekimab was well tolerated and did not affect total cholesterol to high-density lipoprotein cholesterol ratios. There was a small, but statistically significant increase in triglyceride levels with ziltivekimab 15 mg and 30 mg compared with placebo. CONCLUSIONS The efficacy and safety results support the development of ziltivekimab for secondary prevention and the treatment of patients at high atherosclerotic risk. CLINICALTRIALS gov identifier, NCT04626505.
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Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial.
Rubino, D, Abrahamsson, N, Davies, M, Hesse, D, Greenway, FL, Jensen, C, Lingvay, I, Mosenzon, O, Rosenstock, J, Rubio, MA, et al
JAMA. 2021;(14):1414-1425
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IMPORTANCE The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown. OBJECTIVE To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes. INTERVENTIONS A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups. MAIN OUTCOMES AND MEASURES The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]). RESULTS Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%). CONCLUSIONS AND RELEVANCE Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03548987.
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Vitamin E-doped total hip arthroplasty liners show similar head penetration to highly cross-linked polyethylene at five years: a multi-arm randomized controlled trial.
Kjærgaard, K, Ding, M, Jensen, C, Bragdon, C, Malchau, H, Andreasen, CM, Ovesen, O, Hofbauer, C, Overgaard, S
The bone & joint journal. 2020;(10):1303-1310
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AIMS: The most frequent indication for revision surgery in total hip arthroplasty (THA) is aseptic loosening. Aseptic loosening is associated with polyethylene liner wear, and wear may be reduced by using vitamin E-doped liners. The primary objective of this study was to compare proximal femoral head penetration into the liner between a) two cross-linked polyethylene (XLPE) liners (vitamin E-doped (vE-PE)) versus standard XLPE liners, and b) two modular femoral head diameters (32 mm and 36 mm). METHODS Patients scheduled for a THA were randomized to receive a vE-PE or XLPE liner with a 32 mm or 36 mm metal head (four intervention groups in a 2 × 2 factorial design). Head penetration and acetabular component migration were measured using radiostereometric analysis at baseline, three, 12, 24, and 60 months postoperatively. The Harris Hip Score, University of California, Los Angeles (UCLA) Activity Score, EuroQol five-dimension questionnaire (EQ-5D), and 36-Item Short-Form Health Survey questionnaire (SF-36) were assessed at baseline, three, 12, 36, and 60 months. RESULTS Of 220 screened patients, 127 were included in this study. In all, 116 received the allocated intervention, and 94 had their results analyzed at five years. Head penetration was similar between liner materials and head sizes at five years, vE-PE versus XLPE was -0.084 mm (95% confidence interval (CI) -0.173 to 0.005; p = 0.064), and 32 mm versus 36 mm was -0.020 mm (95% CI -0.110 to 0.071; p = 0.671), respectively. No differences were found in acetabular component migration or in the patient-reported outcome measures. CONCLUSION No significant difference in head penetration was found at five years between vE-PE and XLPE liners, nor between 32 mm and 36 mm heads. Cite this article: Bone Joint J 2020;102-B(10):1303-1310.
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Efficacy and Safety of Liraglutide 3.0 mg in Individuals With Overweight or Obesity and Type 2 Diabetes Treated With Basal Insulin: The SCALE Insulin Randomized Controlled Trial.
Garvey, WT, Birkenfeld, AL, Dicker, D, Mingrone, G, Pedersen, SD, Satylganova, A, Skovgaard, D, Sugimoto, D, Jensen, C, Mosenzon, O
Diabetes care. 2020;(5):1085-1093
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OBJECTIVE Most individuals with type 2 diabetes also have obesity, and treatment with some diabetes medications, including insulin, can cause further weight gain. No approved chronic weight management medications have been prospectively investigated in individuals with overweight or obesity and insulin-treated type 2 diabetes. The primary objective of this study was to assess the effect of liraglutide 3.0 mg versus placebo on weight loss in this population. RESEARCH DESIGN AND METHODS Satiety and Clinical Adiposity-Liraglutide Evidence (SCALE) Insulin was a 56-week, randomized, double-blind, placebo-controlled, multinational, multicenter trial in individuals with overweight or obesity and type 2 diabetes treated with basal insulin and ≤2 oral antidiabetic drugs. RESULTS Individuals were randomized to liraglutide 3.0 mg (n = 198) or placebo (n = 198), combined with intensive behavioral therapy (IBT). At 56 weeks, mean weight change was -5.8% for liraglutide 3.0 mg versus -1.5% with placebo (estimated treatment difference -4.3% [95% CI -5.5; -3.2]; P < 0.0001). With liraglutide 3.0 mg, 51.8% of individuals achieved ≥5% weight loss versus 24.0% with placebo (odds ratio 3.41 [95% CI 2.19; 5.31]; P < 0.0001). Liraglutide 3.0 mg was associated with significantly greater reductions in mean HbA1c and mean daytime glucose values and less need for insulin versus placebo, despite a treat-to-glycemic-target protocol. More hypoglycemic events were observed with placebo than liraglutide 3.0 mg. No new safety or tolerability issues were observed. CONCLUSIONS In individuals with overweight or obesity and insulin-treated type 2 diabetes, liraglutide 3.0 mg as an adjunct to IBT was superior to placebo regarding weight loss and improved glycemic control despite lower doses of basal insulin and without increases in hypoglycemic events.
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Acute effects of whey protein on energy intake, appetite and gastric emptying in younger and older, obese men.
Oberoi, A, Giezenaar, C, Jensen, C, Lange, K, Hausken, T, Jones, KL, Horowitz, M, Chapman, I, Soenen, S
Nutrition & diabetes. 2020;(1):37
Abstract
BACKGROUND Obesity is becoming more prevalent in older people. A management strategy in obese, young adults is to increase dietary protein relative to other macronutrients. It is not clear if this is effective in obese, older individuals. Obesity may be associated with diminished sensitivity to nutrients. We have reported that a 30-g whey protein drink slows gastric emptying more, and suppresses energy intake less, in older, than younger, non-obese men. The aim of this study was to determine the effect of a 30 g whey protein drink on energy intake, GE and glycaemia in obese, older and younger men. METHODS In randomized, double-blind order, 10 younger (age: 27 ± 2 years; BMI: 36 ± 2 kg/m²), and 10 older (72 ± 1 years; 33 ± 1 kg/m²), obese men were studied twice. After an overnight fast, subjects ingested a test drink containing 30 g whey protein (120 kcal) or control (2 kcal). Postprandial gastric emptying (antral area, 2D Ultrasound) and blood glucose concentrations were measured for 180 min. At t = 180 min subjects were given a buffet meal and ad libitum energy intake was assessed. RESULTS Older subjects ate non-significantly less (~20%) that the younger subjects (effect of age, P = 0.16). Whey protein had no effect on subsequent energy intake (kcal) compared to control in either the younger (decrease 3 ± 8%) or older (decrease 2 ± 8%) obese men (age effect P > 0.05, protein effect P = 0.46, age × protein interaction effect P = 0.84). Whey protein slowed gastric emptying, to a similar degree in both age groups (50% emptying time: control vs. protein young men: 255 ± 5 min vs. 40 ± 7 min; older men: 16 ± 5 min vs. 50 ± 8 min; protein effect P = 0.001, age effect P = 0.93, age × protein interaction effect P = 0.13). CONCLUSIONS Our data suggest that obesity may blunt/abolish the age-related effect of whey protein on suppression of energy intake.
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Effects of Timing of Whey Protein Intake on Appetite and Energy Intake in Healthy Older Men.
Giezenaar, C, Coudert, Z, Baqeri, A, Jensen, C, Hausken, T, Horowitz, M, Chapman, I, Soenen, S
Journal of the American Medical Directors Association. 2017;(10):898.e9-898.e13
Abstract
BACKGROUND Protein-rich supplements are used widely to prevent and manage malnutrition in older adults. We previously showed that 30 g whey protein ingestion, 3 hours before a buffet meal, suppressed energy intake in young, but not in older men. Information about the impact of the timing of ingestion of protein drinks on the suppression of energy intake in older adults is lacking. OBJECTIVE The aim of the study was to determine the effect of the timing of whey protein ingestion on appetite and subsequent ad libitum energy intake in healthy older men. DESIGN In a single blind, randomized design, 16 older men were studied on 5 occasions, on which they consumed a whey protein drink (30 g/120 kcal, 140 mL) 3, 2, 1 hour(s), or immediately before a buffet meal, from which ad libitum energy intake was quantified, and isopalatable noncaloric drinks (∼1 kcal) at the remaining time points. On the control day, noncaloric drinks were ingested at all time points. Perceptions of appetite and gastrointestinal symptoms were determined, by visual analog scales, throughout the study days. RESULTS There was no effect of the timing of protein ingestion on perceptions of appetite and gastrointestinal symptoms (P > .05) or energy intake at the buffet meal (3 hours: 888 ± 49 kcal, 2 hours: 879 ± 56 kcal, 1 hours: 909 ± 47 kcal, 0 hour: 892 ± 51 kcal, control: 930 ± 49 kcal, P = .94). Total energy intake (ie, preload + test meal) was higher on the protein days compared with control (82 ± 24 kcal increase, P = .003). CONCLUSIONS In older men, ingestion of 30 g protein increased total energy intake, irrespective of the time of intake in relation to the meal. These observations support the use of "pure" whey protein drinks to increase overall protein and energy intake in older adults at risk of undernutrition.
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Intraindividual variability of plasma antioxidants, markers of oxidative stress, C-reactive protein, cotinine, and other biomarkers.
Block, G, Dietrich, M, Norkus, E, Jensen, C, Benowitz, NL, Morrow, JD, Hudes, M, Packer, L
Epidemiology (Cambridge, Mass.). 2006;(4):404-12
Abstract
BACKGROUND Within-person variability in biomarkers results in random error that can attenuate estimates of association. Little information on such variability is available for a number of nutrition-related biomarkers. METHODS Blood samples obtained 2 to 4 weeks apart were analyzed for tocopherols, carotenoids, ascorbate, lipids, cotinine, C-reactive protein, and oxidative stress. Subjects (n = 206 men and women, mean age 45.4 years) were either smokers or passively exposed to smoke. We calculated intraindividual and interindividual variability and the number of measurements required to reduce attenuation. RESULTS For most biomarkers, 2 measurements would be required to limit the attenuation of correlation coefficients to no lower than 90% of the true correlation. If only one measurement were obtained, observed correlations would be approximately 80-88% of true correlations. For regression coefficients, 3 or 4 measures would be required. Exceptions were ascorbic acid and malondialdehyde, for which a single measure resulted in little attenuation. CONCLUSIONS For most serum markers, collection of 2 or more measurements per person is desirable to increase the ability to detect associations between biomarkers and health-related variables. If only one measure is possible, sample sizes should be planned to permit detection of associations that are likely to be observed, not the theoretical true associations. The results of this study, in which measurements were obtained 2 to 4 weeks apart, are relevant for epidemiologic research in which the exposure of interest is the subject's baseline or current status. It is likely that within-person variability would be greater over a period of months or years.
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Effect of orlistat on weight and body composition in obese adolescents: a randomized controlled trial.
Chanoine, JP, Hampl, S, Jensen, C, Boldrin, M, Hauptman, J
JAMA. 2005;(23):2873-83
Abstract
CONTEXT The prevalence of overweight and obesity in children and adolescents is increasing rapidly. In this population, behavioral therapy alone has had limited success in providing meaningful, sustained weight reduction, and pharmacological treatment has not been extensively studied. OBJECTIVE To determine the efficacy and safety of orlistat in weight management of adolescents. DESIGN, SETTING, AND PATIENTS Multicenter, 54-week (August 2000-October 2002), randomized, double-blind study of 539 obese adolescents (aged 12-16 years; body mass index [BMI] >or=2 units above the 95th percentile) at 32 centers in the United States and Canada. INTERVENTIONS A 120-mg dose of orlistat (n = 357) or placebo (n = 182) 3 times daily for 1 year, plus a mildly hypocaloric diet (30% fat calories), exercise, and behavioral therapy. MAIN OUTCOME MEASURES Change in BMI; secondary measures included changes in waist and hip circumference, weight loss, lipid measurements, and glucose and insulin responses to oral glucose challenge. RESULTS There was a decrease in BMI in both treatment groups up to week 12, thereafter stabilizing with orlistat but increasing beyond baseline with placebo. At the end of the study, BMI had decreased by 0.55 with orlistat but increased by 0.31 with placebo (P = .001). Compared with 15.7% of the placebo group, 26.5% of participants taking orlistat had a 5% or higher decrease in BMI (P = .005); 4.5% and 13.3%, respectively, had a 10% or higher decrease in BMI (P = .002). At study end, weight had increased 0.53 kg with orlistat and 3.14 kg with placebo (P<.001). Dual-energy x-ray absorptiometry showed that this difference was explained by changes in fat mass. Waist circumference decreased in the orlistat group but increased in the placebo group (-1.33 cm vs +0.12 cm; P<.05). Generally mild to moderate gastrointestinal tract adverse events occurred in 9% to 50% of the orlistat group and in 1% to 13% of the placebo group. CONCLUSIONS In combination with diet, exercise, and behavioral modification, orlistat statistically significantly improved weight management in obese adolescents compared with placebo. The use of orlistat for 1 year in this adolescent population did not raise major safety issues although gastrointestinal adverse events were more common in the orlistat group.
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Plasma C-reactive protein concentrations in active and passive smokers: influence of antioxidant supplementation.
Block, G, Jensen, C, Dietrich, M, Norkus, EP, Hudes, M, Packer, L
Journal of the American College of Nutrition. 2004;(2):141-7
Abstract
OBJECTIVE C-reactive protein (CRP) may directly affect the progression of atherosclerosis, and therefore, may be a target for reducing disease risk. The objective was to determine whether antioxidant supplementation reduces plasma CRP in active and passive smokers. DESIGN Randomized, double-blind, placebo-controlled, parallel group trial with 2 months exposure to study supplements. SETTING Berkeley and Oakland, California. SUBJECTS Healthy adult men and women, consuming <4 daily servings of fruits and vegetables, and who were actively or passively exposed to cigarette smoke. Analysis was limited to participants with detectable baseline CRP concentrations and no evidence of inflammation associated with acute illness at baseline or follow-up as reflected in CRP elevations (> or =10.0 mg/L). A total of 1393 individuals were screened, 216 randomized, 203 completed the study, and 160 were included in the analysis. INTERVENTIONS Participants were randomized to receive a placebo or vitamin C (515 mg/day) or antioxidant mixture (per day: 515 mg vitamin C, 371 mg alpha-tocopherol, 171 mg gamma-tocopherol, 252 mg mixed tocotrienols, and 95 mg alpha-lipoic acid). MEASURES OF OUTCOME Change in plasma CRP concentration. RESULTS Vitamin C supplementation yielded a 24.0% reduction (95% confidence interval, -38.9% to -5.5%, p = 0.036 compared to control) in plasma CRP, whereas the antioxidant mixture and placebo produced a nonsignificant 4.7% reduction (-23.9% to 19.3%) and 4.3% increase (-15.1% to 28.2%), respectively. Results were adjusted for baseline body mass index and CRP concentrations. CONCLUSIONS Plasma CRP itself may serve as a potential target for reducing the risk of atherosclerosis, and antioxidants, including vitamin C, should be investigated further to confirm their CRP-lowering and anti-inflammatory effects.