Liraglutide after diet-induced weight loss for pain and weight control in knee osteoarthritis: a randomized controlled trial.
The American journal of clinical nutrition. 2021;(2):314-323
BACKGROUND Weight loss is critical for preventing and managing obesity-related diseases. There is a notable lack of valid and reliable means to manage patients with overweight/obesity and knee osteoarthritis (KOA). OBJECTIVE To determine the efficacy and safety of liraglutide in a 30 mg/d dosing in patients with overweight/obesity and KOA. METHODS The trial was designed as a randomized controlled trial including patients between the age of 18 and 74 y with KOA and a BMI ≥27 (measured in kg/m2).Patients underwent a pre-random assignment diet intervention (week -8 to 0). At week 0, patients having lost >5% of their body weight were randomly assigned to liraglutide 3 mg/d or placebo for 52 wk. The coprimary outcomes were changes in body weight and the Knee injury and Osteoarthritis Outcome Score (KOOS) pain subscale from week 0 to 52. RESULTS In total, 168 patients enrolled and 156 were randomly assigned to receive liraglutide or placebo. Patients experienced a significant reduction in body weight and KOOS pain during the pre-random assignment dietary intervention period (week -8 to 0). From week 0 to 52 there was a significant difference in body weight between the liraglutide and placebo group (mean changes: -2.8 and +1.2 kg, respectively; group difference, 3.9 kg; 95% CI: -6.9, -1.0; P = 0.008). There was, however, no group difference in KOOS pain (mean changes: 0.4 and -0.6 points, respectively; group difference, 0.9 points; 95% CI: -3.9, 5.7; P = 0.71). Treatment-emergent adverse events related to the gastrointestinal system were experienced by 50.2% and 39.2% of patients in the liraglutide and placebo groups, respectively. CONCLUSIONS In patients with KOA and overweight/obesity liraglutide added after an 8-wk pre-random assignment diet induced a significant weight loss at >52 wk but did not reduce knee pain compared to placebo. This trial was registered at clinicaltrials.gov as NCT02905864.
Comprehensive treatment of microvascular angina in overweight women - a randomized controlled pilot trial.
PloS one. 2020;(11):e0240722
AIMS: Coronary microvascular dysfunction (CMD) carries a poor cardiovascular prognosis and may explain angina in women without obstructive coronary artery disease (CAD). Currently, no evidence-based treatment for CMD exists. We investigated whether reducing cardiovascular risk factors improves symptoms and microvascular function in women with non-endothelial dependent CMD and no obstructive CAD. METHODS We randomized 62 women aged 40-75, with body mass index (BMI) >25 kg/m2, angina ≥monthly, and coronary flow velocity reserve (CFVR) ≤2.5 to a 24-week intervention comprising low energy diet, exercise training, and optimized treatment of hypertension, dyslipidemia and diabetes or to control. Patients were assessed before randomization and after 24 weeks. Primary outcomes were CFVR assessed by transthoracic Doppler stress-echocardiography and angina burden by Seattle Angina Questionnaire (SAQ). Secondary outcomes were exercise capacity, body composition, glycemic control, myocardial function, and anxiety and depression symptoms. RESULTS Fifty-six participants (90%) completed the study. Median (IQR) age was 65.2 (57.1;70.7) years, BMI was 30.1 (28.4;32.7) kg/m2. The intervention resulted in relevant improvement in angina symptoms (9-21-point increase on SAQ-scales (all p<0.01)) but had no effect on CFVR (p = 0.468). Mean (CI) weight loss was 9.6 (7.80;11.48) kg, (p<0.0001). There was a significant mean (CI) decrease in depression symptoms = 1.16 (0.22;2.12), triglycerides = 0.52 (0.25;0.78) mmol/L, total cholesterol = 0.55 (0.12;0.98) mmol/L, and HbA1c in diabetics = 27.1 (1.60;52.6) mmol/mol but no effect on other secondary outcomes. CONCLUSION A major weight loss and intensified risk factor control resulted in significantly improved angina burden but no improvement of coronary microvascular function among women with microvascular angina.
Associations between the proportion of fat-free mass loss during weight loss, changes in appetite, and subsequent weight change: results from a randomized 2-stage dietary intervention trial.
The American journal of clinical nutrition. 2020;(3):536-544
BACKGROUND Dynamic changes in body composition which occur during weight loss may have an influential role on subsequent energy balance behaviors and weight. OBJECTIVES The aim of this article is to consider the effect of proportionate changes in body composition during weight loss on subsequent changes in appetite and weight outcomes at 26 wk in individuals engaged in a weight loss maintenance intervention. METHODS A subgroup of the Diet, Obesity, and Genes (DiOGenes) study (n = 209) was recruited from 3 European countries. Participants underwent an 8-wk low-calorie diet (LCD) resulting in ≥8% body weight loss, during which changes in body composition (by DXA) and appetite (by visual analog scale appetite perceptions in response to a fixed test meal) were measured. Participants were randomly assigned into 5 weight loss maintenance diets based on protein and glycemic index content and followed up for 26 wk. We investigated associations between proportionate fat-free mass (FFM) loss (%FFML) during weight loss and 1) weight outcomes at 26 wk and 2) changes in appetite perceptions. RESULTS During the LCD, participants lost a mean ± SD of 11.2 ± 3.5 kg, of which 30.4% was FFM. After adjustment, there was a tendency for %FFML to predict weight regain in the whole group (β: 0.041; 95% CI: -0.001, 0.08; P = 0.055), which was significant in men (β: 0.09; 95% CI: 0.02, 0.15; P = 0.009) but not women (β: 0.01; 95% CI: -0.04, 0.07; P = 0.69). Associations between %FFML and change in appetite perceptions during weight loss were inconsistent. The strongest observations were in men for hunger (r = 0.69, P = 0.002) and desire to eat (r = 0.61, P = 0.009), with some tendencies in the whole group and no associations in women. CONCLUSIONS Our results suggest that composition of weight loss may have functional importance for energy balance regulation, with greater losses of FFM potentially being associated with increased weight regain and appetite. This trial was registered at clinicaltrials.gov as NCT00390637.
Pretreatment Prevotella-to-Bacteroides ratio and salivary amylase gene copy number as prognostic markers for dietary weight loss.
The American journal of clinical nutrition. 2020;(5):1079-1086
BACKGROUND The inconsistent link observed between salivary amylase gene copy number (AMY1 CN) and weight management is likely modified by diet and microbiome. OBJECTIVE Based on analysis of a previously published study, we investigated the hypothesis that interaction between diet, Prevotella-to-Bacteriodes ratio (P/B ratio), and AMY1 CN influence weight change. METHODS Sixty-two people with increased waist circumference were randomly assigned to receive an ad libitum New Nordic Diet (NND) high in dietary fiber, whole grain, intrinsic sugars, and starch or an Average Danish (Western) Diet (ADD) for 26 weeks. All foods were provided free of charge. Before subjects were randomly assigned to receive the NND or ADD diet, blood and fecal samples were collected, from which AMY1 CN and P/B ratio, respectively, were determined. Body weight change was described by using linear mixed models, including biomarker [log10(P/B ratio) and/or AMY1 CN] diet-group interactions. RESULTS Baseline means ± SDs of log10(P/B ratio) and AMY1 CN were -2.1 ± 1.8 and 6.6 ± 2.4, respectively. Baseline P/B ratio predicted a 0.99-kg/unit (95% CI: 0.40, 1.57; n = 54; P < 0.001) higher weight loss for those subjects on the NND compared with those on the ADD diet, whereas AMY1 CN was not found to predict weight loss differences between the NND and ADD groups [0.05 kg/CN (95% CI: -0.40, 0.51; n = 54; P = 0.83)]. However, among subjects with low AMY1 CN (<6.5 copies), baseline P/B ratio predicted a 2.12-kg/unit (95% CI: 1.37, 2.88; n = 30; P < 0.001) higher weight loss for the NND group than the ADD group. No such differences in weight loss were found among subjects in both groups with high AMY1 CN [-0.17 kg/unit (95% CI: -1.01, 0.66; n = 24; P = 0.68)]. CONCLUSIONS The combined use of low AMY1 CN and pretreatment P/B ratio for weight loss prediction led to highly individualized weight loss results with the introduction of more fiber, whole grain, intrinsic sugars, and starch in the diet. These preliminary observations suggest that more undigested starch reaches the colon in individuals with low AMY1 CN, and that the fate of this starch depends on the gut microbiota composition. This trial was registered at clinicaltrials.gov as NCT01195610.
Arabinoxylan oligosaccharides and polyunsaturated fatty acid effects on gut microbiota and metabolic markers in overweight individuals with signs of metabolic syndrome: A randomized cross-over trial.
Clinical nutrition (Edinburgh, Scotland). 2020;(1):67-79
BACKGROUND & AIMS Gut microbiota composition is linked to obesity and metabolic syndrome. The nutrients and doses required to modulate the gut microbiota towards beneficially influence components of the metabolic syndrome are unclear. This study aimed to investigate diet-induced effects on the gut microbiota and metabolic markers in overweight individuals with indices of the metabolic syndrome. METHODS A twelve-week randomized cross-over trial was conducted with two intervention periods separated by a washout period. The dietary intakes of interest were wheat bran extract, rich in arabinoxylan oligosaccharides (AXOS) (10.4 g/d AXOS) and polyunsaturated fatty acids (PUFA) (3.6 g/d n-3 PUFA). Dietary records, fecal and blood samples, as well as anthropometric data, were collected before and after intervention. Anthropometry and gastrointestinal symptoms were evaluated weekly. Gut microbiota composition was analyzed by massive sequencing of 16S ribosomal RNA gene V3V4 amplicons. RESULTS Twenty-seven participants completed the study (90%). Intake of AXOS induced an expected bifidogenic effect on gut microbiota (p < 0.01) and increased butyrate-producing bacterial species as well (p < 0.05). Beta-diversity analysis indicated that the structure of the gut microbiota only changed as a result of the AXOS intervention (Permanova = 1.90, p < 0.02) and no changes in metabolic markers were observed after any of the interventions. CONCLUSIONS AXOS intake has a bifidogenic effect and also increases butyrate producers in the gut microbiota; even though this type of dietary fiber did not modulate lipid or glucose metabolic parameters related to metabolic syndrome. Four-week PUFA intake did not induce any notable effect on the gut microbiota composition or metabolic risk markers. REGISTRATION Registered under ClinicalTrials.gov Identifier no. NCT02215343. CLINICAL TRIAL REGISTRATION Registered at https://www.clinicaltrials.gov/ (NCT02215343). ETHICAL COMMITTEE H-4-2014-052. THE DANISH DATA PROTECTION AGENCY 2013-54-0522.
Integrative phenotyping of glycemic responders upon clinical weight loss using multi-omics.
Scientific reports. 2020;(1):9236
Weight loss aims to improve glycemic control in obese but strong variability is observed. Using a multi-omics approach, we investigated differences between 174 responders and 201 non-responders, that had lost >8% body weight following a low-caloric diet (LCD, 800 kcal/d for 8 weeks). The two groups were comparable at baseline for body composition, glycemic control, adipose tissue transcriptomics and plasma ketone bodies. But they differed significantly in their response to LCD, including improvements in visceral fat, overall insulin resistance (IR) and tissue-specific IR. Transcriptomics analyses found down-regulation in key lipogenic genes (e.g. SCD, ELOVL5) in responders relative to non-responders; metabolomics showed increase in ketone bodies; while proteomics revealed differences in lipoproteins. Findings were consistent between genders; with women displaying smaller improvements owing to a better baseline metabolic condition. Integrative analyses identified a plasma omics model that was able to predict non-responders with strong performance (on a testing dataset, the Receiving Operating Curve Area Under the Curve (ROC AUC) was 75% with 95% Confidence Intervals (CI) [67%, 83%]). This model was based on baseline parameters without the need for intrusive measurements and outperformed clinical models (p = 0.00075, with a +14% difference on the ROC AUCs). Our approach document differences between responders and non-responders, with strong contributions from liver and adipose tissues. Differences may be due to de novo lipogenesis, keto-metabolism and lipoprotein metabolism. These findings are useful for clinical practice to better characterize non-responders both prior and during weight loss.
Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans.
Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases.
Plasma lipid profiling of tissue-specific insulin resistance in human obesity.
International journal of obesity (2005). 2019;(5):989-998
BACKGROUND/OBJECTIVES Obesity-associated insulin resistance (IR) may develop in multiple organs, representing different aetiologies towards cardiometabolic diseases. This study aimed to identify distinct plasma lipid profiles in overweight/obese individuals who show muscle-IR and/or liver-IR. SUBJECTS/METHODS Baseline data of the European multicenter DiOGenes project were used (n = 640; 401 women, nondiabetic BMI: 27-45 kg/m2). Muscle insulin sensitivity index (MISI) and hepatic insulin resistance index (HIRI) were derived from a 5-point oral glucose tolerance test. The 140 plasma lipids were quantified by liquid chromatography-mass spectrometry. Linear mixed models were used to evaluate associations between MISI, HIRI and plasma lipids. RESULTS MISI was comparable between sexes while HIRI and triacylglycerol (TAG) levels were lower in women than in men. MISI was associated with higher lysophosphatidylcholine (LPC) levels (standardized (std)β = 0.126; FDR-p = 0.032). Sex interactions were observed for associations between HIRI, TAG and diacylglycerol (DAG) lipid classes. In women, but not in men, HIRI was associated with higher levels of TAG (44 out of 55 species) and both DAG species (stdβ: 0.139-0.313; FDR-p < 0.05), a lower odd-chain/even-chain TAG ratio (stdβ = -0.182; FDR-p = 0.005) and a lower very-long-chain/long-chain TAG ratio (stdβ = -0.156; FDR-p = 0.037). CONCLUSIONS In overweight/obese individuals, muscle insulin sensitivity is associated with higher plasma LPC concentrations. Women have less hepatic IR and lower TAG than men. Nevertheless, hepatic IR is associated with higher plasma TAG and DAG concentrations and a lower abundance of odd-chain and very-long-chain TAG in women, but not in men. This suggests a more pronounced worsening of plasma lipid profile in women with the progression of hepatic IR.
Effects of 1 year of exercise training versus combined exercise training and weight loss on body composition, low-grade inflammation and lipids in overweight patients with coronary artery disease: a randomized trial.
Cardiovascular diabetology. 2019;(1):127
BACKGROUND Dyslipidaemia and low-grade inflammation are central in atherogenesis and linked to overweight and physical inactivity. Lifestyle changes are important in secondary prevention of coronary artery disease (CAD). We compared the effects of combined weight loss and interval training with interval training alone on physical fitness, body composition, dyslipidaemia and low-grade inflammation in overweight, sedentary participants with CAD. METHODS Seventy CAD patients, BMI 28-40 kg/m2 and age 45-75 years were randomised to (1) 12 weeks' aerobic interval training (AIT) at 90% of peak heart rate three times/week followed by 40 weeks' AIT twice weekly or (2) a low energy diet (LED) (800-1000 kcal/day) for 8-10 weeks followed by 40 weeks' weight maintenance including AIT twice weekly and a high-protein/low-glycaemic load diet. Effects of the intervention were evaluated by physical fitness, body weight and composition. Dyslipidaemia was described using both biochemical analysis of lipid concentrations and lipoprotein particle subclass distribution determined by density profiling. Low-grade inflammation was determined by C-reactive protein, soluble urokinase-type plasminogen activator receptor and tumour necrosis factor α. Effects on continuous outcomes were tested by mixed-models analysis. RESULTS Twenty-six (74%) AIT and 29 (83%) LED + AIT participants completed the study. At baseline subject included 43 (78%) men; subjects averages were: age 63 years (6.2), body weight 95.9 kg (12.2) and VO2peak 20.7 mL O2/kg/min (4.9). Forty-six (84%) had pre-diabetes (i.e. impaired fasting glucose and/or impaired glucose tolerance). LED + AIT reduced body weight by 7.2 kg (- 8.4; - 6.1) and waist circumference by 6.6 cm (- 7.7; - 5.5) compared to 1.7 kg (- 0.7; - 2.6) and 3.3 cm (- 5.1; - 1.5) after AIT (within-group p < 0.001, between-group p < 0.001 and p = 0.018, respectively). Treatments caused similar changes in VO2peak and lowering of total cholesterol, triglycerides, non-HDL cholesterol and low-grade inflammation. A shift toward larger HDL particles was seen following LED + AIT while AIT elicited no change. CONCLUSIONS Both interventions were feasible. Both groups obtained improvements in VO2peak, serum-lipids and inflammation with superior weight loss and greater central fat loss following LED + AIT. Combined LED induced weight loss and exercise can be recommended to CAD patients. Trial registration NCT01724567, November 12, 2012, retrospectively registered (enrolment ended in April 2013).
A Randomized, Double-Blind, Placebo-Controlled Study of Gelesis100: A Novel Nonsystemic Oral Hydrogel for Weight Loss.
Obesity (Silver Spring, Md.). 2019;(2):205-216
OBJECTIVE This study aims to assess the efficacy and safety of Gelesis100, a novel, nonsystemic, superabsorbent hydrogel to treat overweight or obesity. METHODS The Gelesis Loss Of Weight (GLOW) study was a 24-week, multicenter, randomized, double-blind, placebo-controlled study in patients with BMI ≥ 27 and ≤ 40 kg/m2 and fasting plasma glucose ≥ 90 and ≤ 145 mg/dL. The co-primary end points were placebo-adjusted weight loss (superiority and 3% margin super-superiority) and at least 35% of patients in the Gelesis100 group achieving ≥ 5% weight loss. RESULTS Gelesis100 treatment caused greater weight loss over placebo (6.4% vs. 4.4%, P = 0.0007), achieving 2.1% superiority but not 3% super-superiority. Importantly, 59% of Gelesis100-treated patients achieved weight loss of ≥ 5%, and 27% achieved ≥ 10% versus 42% and 15% in the placebo group, respectively. Gelesis100-treated patients had twice the odds of achieving ≥ 5% and ≥ 10% weight loss versus placebo (adjusted OR: 2.0, P = 0.0008; OR: 2.1, P = 0.0107, respectively), with 5% responders having a mean weight loss of 10.2%. Patients with prediabetes or drug-naive type 2 diabetes had six times the odds of achieving ≥ 10% weight loss. Gelesis100 treatment had no apparent increased safety risks. CONCLUSIONS Gelesis100 is a promising new nonsystemic therapy for overweight and obesity with a highly desirable safety and tolerability profile.