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Effects of once-weekly semaglutide 2.4 mg on C-reactive protein in adults with overweight or obesity (STEP 1, 2, and 3): Exploratory analyses of three randomised, double-blind, placebo-controlled, phase 3 trials.
Verma, S, Bhatta, M, Davies, M, Deanfield, JE, Garvey, WT, Jensen, C, Kandler, K, Kushner, RF, Rubino, DM, Kosiborod, MN
EClinicalMedicine. 2023;:101737
Abstract
BACKGROUND Inflammation is a key driver of atherosclerotic cardiovascular disease. C-reactive protein (CRP), an established biomarker of inflammation, is commonly elevated in people with overweight/obesity. METHODS STEP 1, 2, and 3 were 68-week, placebo-controlled trials of semaglutide for weight management in participants with overweight/obesity, with (STEP 2) or without (STEP 1 and 3) type 2 diabetes. Change in serum CRP from baseline to week 68 was assessed as a prespecified secondary endpoint for semaglutide 2.4 mg versus placebo (STEP 1, 2, and 3) and versus semaglutide 1.0 mg (STEP 2). Post hoc assessments included change in CRP by baseline characteristics (bodyweight, body mass index [BMI], glycaemic status, CRP concentration); change in CRP-defined cardiovascular risk category (<1 [low], 1-3 [intermediate], and >3 mg/L [high]); and correlation between change in CRP and change in bodyweight, waist circumference, fasting serum insulin (STEP 1 and 3), fasting plasma glucose, and homeostatic model assessment of insulin resistance (HOMA-IR). FINDINGS The trials took place from June through November 2018 (STEP 1 and 2) and from August 2018 to April 2020 (STEP 3). In all trials, semaglutide 2.4 mg reduced CRP at week 68 versus placebo (estimated treatment difference [ETD; 95% CI] -44% [-49 to -39] in STEP 1, -39% [-46 to -30] in STEP 2, and -48% [-55 to -39] in STEP 3; all p < 0.05). In STEP 2, CRP reductions were greater with semaglutide 2.4 mg (-49%) than with 1.0 mg (-42%) but the difference did not reach statistical significance (ETD [95% CI] -12% [-23 to 1]; p = 0.06). Reductions in CRP occurred in parallel with bodyweight loss and were consistent regardless of baseline BMI/bodyweight/glycaemic status. More semaglutide-treated participants had reductions in CRP-defined cardiovascular risk versus those on placebo. Reductions in CRP were positively correlated with reductions in bodyweight, waist circumference, fasting plasma glucose, fasting serum insulin, and HOMA-IR (data not shown). INTERPRETATION In people with overweight/obesity, once-weekly semaglutide 2.4 mg and 1.0 mg reduced CRP concentration irrespective of baseline BMI/bodyweight/glycaemic status compared with placebo. These data suggest a potential anti-inflammatory role of semaglutide in obesity. FUNDING Novo Nordisk.
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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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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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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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Effects of Plant-Based Diets on Weight Status: A Systematic Review.
Tran, E, Dale, HF, Jensen, C, Lied, GA
Diabetes, metabolic syndrome and obesity : targets and therapy. 2020;13:3433-3448
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Being overweight or obese is a huge risk factor for many detrimental conditions. It is estimated that around one-third of the world’s population will be overweight or obese by 2025. Hence there is a need to look at dietary strategies in the prevention and treatment of overweight and obesity. Plant-based diets have always existed, however interest in the topic has increased recently and more research is being done on the health-related effects of different plant-based diets. There are many reasons why someone might convert to a plant-based diet, possible health benefits such as weight management are among the most common. The purpose of this review was to evaluate intervention studies assessing the effects of different plant-based diets on body mass index and weight. The results suggest that plant-based diets may improve weight status in some patient groups. It should be noted that only one study out of the 19 included in the review had normal weight, clinically healthy participants. The study populations for the rest were overweight, obese or had type 2 diabetes. Future research should aim to include a representative study population and apply study diets without dietary restrictions.
Abstract
There is an increasing number of people who convert to a plant-based diet. The desire for health benefits, including weight management, is often a contributing factor behind this dietary choice. The purpose of this review was to evaluate intervention studies assessing the effects of different plant-based diets on body mass index and weight. A literature search was conducted in PubMed until December 2019. Twenty-two publications from 19 studies were included. The majority of them were randomized controlled trials comparing a low-fat vegan diet to an omnivore diet in participants with overweight, type 2 diabetes mellitus and/or cardiovascular disease. All studies reported weight reductions, of which seven revealed significant differences, and four revealed non-significant differences between the intervention and the control groups. The results suggest that plant-based diets may improve weight status in some patient groups. Due to restrictions in fat intake in many studies, followed by reduced energy intake, the effects of the different interventions differ depending on the specific plant-based diets investigated. Future research should aim to include a representative study population and apply study diets without dietary restrictions.
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Effects of Plant-Based Diets on Outcomes Related to Glucose Metabolism: A Systematic Review.
Johannesen, CO, Dale, HF, Jensen, C, Lied, GA
Diabetes, metabolic syndrome and obesity : targets and therapy. 2020;13:2811-2822
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Research indicates that a reduction in the intake of animal products and an increase in plant-based foods have several positive health outcomes. The aim of this study was to evaluate the effect of a plant-based diet on outcomes related to glucose metabolism. This study is a systemic review of nine randomised controlled trials which focused on subjects with overweight/obesity, type 2 diabetes mellitus, or cardiovascular disease. Overall, the results of this study were inconsistent overall. Findings show that: - five of the nine studies (56%) showed that the plant-based intervention significantly improved markers of glycaemic control from baseline to end point. - four studies (44%) showed a significant improvement in markers of glycaemic control in the intervention group that differed from the control intervention. Additionally, they also did not reveal any significant improvements of a plant-based intervention on outcomes related to glucose metabolism. Authors outline that no clear conclusion regarding effects of different plant-based diets can be drawn based on the current findings.
Abstract
According to the rising prevalence of obesity and metabolic disorders leading to impaired glucose metabolism, effective strategies to prevent and/or delay the onset of disease are of great need. A plant-based diet has been suggested as an effective lifestyle change that may reduce the degree of obesity and improve outcomes related to glucose metabolism. This systematic review aimed to evaluate the effect of a plant-based diet on outcomes related to glucose metabolism. A literature search was conducted in the database PubMed until January 30, 2020. Randomized controlled trials investigating the effect of a plant-based dietary intervention on outcomes related to glucose metabolism in human subjects compared to an omnivorous diet were eligible for inclusion. Of 65 publications identified, nine trials on subjects with overweight/obesity, type 2 diabetes mellitus, or cardiovascular disease were included. Five studies reported that the plant-based intervention significantly improved markers of glycemic control from baseline to end point, of which four revealed a significant improvement in the intervention group compared to the control intervention. The remaining four studies did not observe a significant effect of a plant-based intervention on outcomes related to glucose metabolism. Our findings suggest that a shift to a plant-based diet may lead to favorable effects on glycemic control in individuals diagnosed with type 2 diabetes mellitus and/or obesity. The data were however somewhat conflicting, and the included trials reported results based on different intervention diets and study populations. Overall, no clear conclusions regarding effects of different plant-based diets can be drawn based on the current findings alone.
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Erratum: Effect of a cod protein hydrolysate on postprandial glucose metabolism in healthy subjects: a double-blind cross-over trial - CORRIGENDUM.
Dale, HF, Jensen, C, Hausken, T, Lied, E, Hatlebakk, JG, Brønstad, I, Hoff, DAL, Lied, GA
Journal of nutritional science. 2019;:e1
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[This corrects the article DOI: 10.1017/jns.2018.23.].
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Symptoms of common mental disorders and related stressors in Danish professional football and handball.
Kilic, Ö, Aoki, H, Haagensen, R, Jensen, C, Johnson, U, Kerkhoffs, GMMJ, Gouttebarge, V
European journal of sport science. 2017;(10):1328-1334
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The aim of the study was twofold, namely (i) to determine the prevalence of symptoms of common mental disorders (CMDs) among current and retired professional football and handball players and (ii) to explore the relationship of psychosocial stressors with the outcome measures under study. A total of 1155 players were enrolled in an observational study based on a cross-sectional design. Questionnaires based on validated scales were set up and distributed among current and retired professional football and handball players by the Danish football and handball players' union. In professional football, the highest prevalence (4 weeks) of symptoms of CMDs was 18% and 19% for anxiety/depression among current and retired players, respectively. In professional handball, the highest prevalence (4 weeks) of symptoms of CMDs was 26% and 16% for anxiety/depression among current and retired players, respectively. For both the current and retired professional football and handball players, a higher number of severe injuries and recent adverse life events (LE) were related to the presence of symptoms of CMD. Players exposed to severe injuries and/or recent adverse LE were 20-50% times more likely to report symptoms of CMD. The results suggest that it is possible to recognize the population of professional athletes that are more likely to develop symptoms of CMD. This could create the opportunity to intervene preventively on athletes that suffered from severe injury and/or recent adverse LE that could lead to a faster and safer recovery and psychological readiness to return to play.