Effect of semaglutide 2.4 mg on physical functioning and weight- and health-related quality of life in adults with overweight or obesity: Patient-reported outcomes from the STEP 1-4 trials.

AIMS: To summarize the effects of semaglutide 2.4 mg on weight-related quality of life (WRQOL) and health-related quality of life (HRQOL), focusing on the confirmatory secondary endpoint of physical functioning. MATERIALS AND METHODS: The STEP 1-4 Phase 3a, 68-week, double-blind, randomized controlled trials assessed the efficacy and safety of semaglutide 2.4 mg versus placebo in individuals with overweight/obesity. WRQOL and HRQOL were assessed by change from baseline to Week 68 in two different but complementary measures, the Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT; STEP 1 and 2) and the SF-36v2 Health Survey Acute (SF-36v2; STEP 1-4). RESULTS: Superiority for semaglutide 2.4 mg over placebo based on IWQOL-Lite-CT and SF-36v2 physical functioning scores was confirmed in STEP 1 and 2 and in STEP 1, 2 and 4, respectively. At Week 68, a greater proportion of participants treated with semaglutide 2.4 mg than with placebo reached meaningful within-person change (MWPC) thresholds for IWQOL-Lite-CT Physical Function scores in STEP 1 (51.8% vs. 28.3%; p < 0.0001) and STEP 2 (39.6% vs. 29.5%; p = 0.0083) and the MWPC threshold for SF-36v2 Physical Functioning in STEP 1 (39.8% vs. 24.1%; p < 0.0001), STEP 2 (41.0% vs. 27.3%; p = 0.0001) and STEP 4 (18.0% vs. 6.6%; p < 0.0001). All other IWQOL-Lite-CT and SF-36v2 scale scores in STEP 1-4 were numerically improved with semaglutide 2.4 mg versus placebo, except for SF-36v2 Role Emotional in STEP 2. CONCLUSIONS: Semaglutide 2.4 mg significantly improved physical functioning, with greater proportions of participants achieving MWPC compared with placebo, and showed beneficial effects on WRQOL and HRQOL beyond physical functioning.

Review of an international pilot project to adapt the Canadian Adult Obesity Clinical Practice Guideline.

Background: The evidence-based Canadian Adult Obesity Clinical Practice Guideline (CPG) released in August 2020 were developed through a systematic literature review and patient-oriented research process. This CPG is considered a paradigm shift for obesity care as it introduced a new obesity definition that is based on health not body size, incorporates lived experiences of people affected by obesity, and addresses the pervasive weight bias and stigma that patients face in healthcare systems. The purpose of this pilot project was to assess the feasibility of adapting the Canadian CPG in Chile and Ireland. Methods: An International Clinical Practice Guideline Adaptation Committee was established to oversee the project. The project was conducted through four interrelated phases: 1) planning and preparation; 2) pilot project application process; 3) adaptation; and 4) launch, dissemination, and implementation. Ireland used the GRADE-ADAPTE framework and Chile used the GRADE-ADOLOPMENT approach. Results: Chile and Ireland developed their adapted guidelines in one third of the time it took to develop the Canadian guidelines. In Ireland, 18 chapters, which underpin the 80 key recommendations, were contextually adapted. Chile adopted 18 chapters and 76 recommendations, adapted one recommendation, and developed 12 new recommendations.. Conclusion: The pilot project demonstrated it is feasible to adapt the Canadian CPG for use in other countries with different healthcare systems, languages, and cultural contexts, while retaining the Canadian CPG's key principles and values such as the treatment of obesity as a chronic disease, adoption of new clinical assessment approaches that go beyond anthropometric measurements, elimination of weight bias and stigma, shifting obesity care outcomes to improved health and well-being rather than weight loss alone, and the use of patient-centred, collaborative and shared-decision clinical care approaches.

Impact of a Powdered Meal Replacement on Metabolism and Gut Microbiota (PREMIUM) in individuals with excessive body weight: a study protocol for a randomised controlled trial.

INTRODUCTION: Excess body weight is associated with a state of low-grade chronic inflammation and alterations of the gut microbiome. Powdered meal replacements (PMR) have been shown to be an effective strategy for weight management; however, their effect on inflammation and the gut microbiome remains unclear. The aim of this 12-week randomised control clinical trial is to investigate the effects of PMR consumption, here given as a soy-yoghurt-honey formula, on inflammation, gut microbiome and overall metabolism in individuals with excessive body weight. METHODS AND ANALYSIS: Healthy adults with excess body weight (n=88) are being recruited and randomly assigned to one of the following groups: (1) Control group (CON): maintaining usual diet for 12 weeks, or (2) PMR group: replacing morning and afternoon snacks daily with a PMR for 12 weeks. Participants are asked to maintain body weight throughout the study and fill out a journal with information about PMR consumption, body weight, food intake, appetite sensations and medications. Three study visits are required: baseline, week 6 and week 12. Outcome measures include systemic inflammatory biomarkers, gut microbiome composition, metabolic blood markers, host energy metabolism, body composition, appetite sensations and host gene expression profile. ETHICS AND DISSEMINATION: This research protocol was approved by the University of Alberta Ethics Board (Pro00070712) and adheres to the Canadian Tri-Council Policy statement on the use of human participants in research. Procedures and potential risks are fully discussed with participants. Study findings will be disseminated in peer-reviewed journals, conference presentations and social media. TRIAL REGISTRATION NUMBER: NCT03235804.

Evaluation of Autonomic Nervous System Dysfunction in Childhood Obesity and Prader-Willi Syndrome.

The autonomic nervous system (ANS) may play a role in the distribution of body fat and the development of obesity and its complications. Features of individuals with Prader-Willi syndrome (PWS) impacted by PWS molecular genetic classes suggest alterations in ANS function; however, these have been rarely studied and presented with conflicting results. The aim of this study was to investigate if the ANS function is altered in PWS. In this case-control study, we assessed ANS function in 20 subjects with PWS (6 males/14 females; median age 10.5 years) and 27 body mass index (BMI) z-score-matched controls (19 males/8 females; median age 12.8 years). Standardized non-invasive measures of cardiac baroreflex function, heart rate, blood pressure, heart rate variability, quantitative sudomotor axon reflex tests, and a symptom questionnaire were completed. The increase in heart rate in response to head-up tilt testing was blunted (p < 0.01) in PWS compared to controls. Besides a lower heart rate ratio with Valsalva in PWS (p < 0.01), no significant differences were observed in other measures of cardiac function or sweat production. Findings suggest possible altered sympathetic function in PWS.

Parents as Agents of Change in Managing Pediatric Obesity: A Randomized Controlled Trial Comparing Cognitive Behavioral Therapy versus Psychoeducation Interventions.

Background: Obesity interventions for parents of children with obesity can improve children's weight and health. This randomized controlled trial (RCT) evaluated whether a parent-based intervention based on cognitive behavioral therapy (CBT) principles was superior to a parent-based intervention based on a psychoeducation program (PEP) in improving children's obesity. Methods: This study was a pragmatic, two-armed, parallel, superiority RCT. Conducted at a Canadian outpatient pediatric obesity management clinic (September 2010-January 2014), this trial included families with children 8-12 years with an age- and sex-specific BMI ≥85th percentile. The 16-week manualized interventions were similar in content and delivered to parents exclusively, with different theoretical underpinnings. The primary outcome was children's BMI z-score at postintervention (4 months). Secondary outcomes included anthropometric, lifestyle, psychosocial, and cardiometabolic variables. Data were collected at preintervention (0 months), postintervention (4 months), 10, and 16 months. Intention-to-treat analysis using linear mixed models was used to assess outcomes. Results: Among 52 randomly assigned children, the mean age (standard deviation) was 9.8 (1.7) years and BMI z-score was 2.2 (0.3). Mean differences in BMI z-score were not significantly different between the CBT (n = 27) and PEP (n = 25) groups from 0 to 4-, 10-, and 16-month follow-up. At 4 months, the mean difference in BMI z-score from preintervention between the CBT (-0.05, 95% CI = -0.09 to 0.00) and PEP (-0.04, 95% CI = -0.09 to 0.01) groups was -0.01 (95% CI = -0.08 to 0.06, p = 0.80). Similar results were found across all secondary outcomes. Conclusions: Our CBT-based intervention for parents of children with obesity was not superior in reducing BMI z-score vs. our PEP-based intervention.

A high-protein total diet replacement alters the regulation of food intake and energy homeostasis in healthy, normal-weight adults.

PURPOSE: Dietary intake can affect energy homeostasis and influence body weight control. The aim of this study was to compare the impact of high-protein total diet replacement (HP-TDR) versus a control (CON) diet in the regulation of food intake and energy homeostasis in healthy, normal-weight adults. METHODS: In this acute randomized controlled, cross-over study, participants completed two isocaloric arms: a) HP-TDR: 35% carbohydrate, 40% protein, and 25% fat; b) CON: 55% carbohydrate, 15% protein, and 30% fat. The diets were provided for 32 h while inside a whole-body calorimetry unit. Appetite sensations, appetite-related hormones, and energy metabolism were assessed. RESULTS: Forty-three healthy, normal-weight adults (19 females) participated. Appetite sensations did not differ between diets (all p > 0.05). Compared to the CON diet, the change in fasting blood markers during the HP-TDR intervention was smaller for peptide tyrosine-tyrosine (PYY; - 18.9 ± 7.9 pg/mL, p = 0.02) and greater for leptin (1859 ± 652 pg/mL, p = 0.007). Moreover, postprandial levels of glucagon-like peptide 1 (1.62 ± 0.36 pM, p < 0.001) and PYY (31.37 ± 8.05 pg/mL, p < 0.001) were higher in the HP-TDR. Significant correlations were observed between energy balance and satiety (r = - 0.41, p = 0.007), and energy balance and PFC (r = 0.33, p = 0.033) in the HP-TDR. CONCLUSION: Compared to the CON diet, the HP-TDR increased blood levels of anorexigenic hormones. Moreover, females and males responded differently to the intervention in terms of appetite sensations and appetite-related hormones. TRIAL REGISTRATION: NCT02811276 (retrospectively registered on 16 June 2016) and NCT03565510 (retrospectively registered on 11 June 2018).

Using the Edmonton Obesity Staging System in the real world: a feasibility study based on cross-sectional data.

BACKGROUND: The Edmonton Obesity Staging System (EOSS) combined with body mass index (BMI) enables improved functional and prognostic assessment for patients. To facilitate application of the EOSS in practice, we aimed to create tools for capturing comorbidity assessments in electronic medical records and for automating the calculation of a patient's EOSS stage. METHODS: In this feasibility study, we used cross-sectional data to create a clinical dashboard to calculate and display the relation between BMI and EOSS and the prevalence of related comorbidities. We obtained data from the Northern Alberta Primary Care Research Network and the Canadian Primary Care Sentinel Surveillance Network (CPCSSN). We included patients at least 18 years of age with BMI between 30 and 60 who visited a network clinic between July 2016 and July 2019. We calculated descriptive statistics and used stepwise ordinary least squares regression to assess the contributions of age, sex and BMI to EOSS variation. RESULTS: We created a clinical dashboard using the CPCSSN data presentation tool. Of the total 31 496 patients included in the study, 23 460 had a BMI of at least 30; BMI was unavailable for 8036 patients. Within each EOSS disease severity stage, there were similar proportions of patients from each BMI class (e.g., patients with EOSS stage 2 included 51.8% of those with BMI class I, 55.3% of those with BMI class II and 58.8% of those with BMI class III). INTERPRETATION: Using data from primary care electronic medical records, it was feasible to create a clinical dashboard for obesity that highlighted the severity and stage of obesity. Making this information easily accessible for individual clinical care and practice-level quality improvement may advance obesity care.

The real-world cost-effectiveness of bariatric surgery for the treatment of severe obesity: a cost-utility analysis.

BACKGROUND: Severe obesity is associated with adverse health outcomes and increased risk of death. This study evaluates the real-world cost-utility of therapy for severe obesity, from the publicly funded health care system and societal perspectives. METHODS: We conducted a cost-utility analysis using primary data from a prospective observational cohort of adults living with severe obesity (BMI ≥ 35 kg/m2 and a major medical comorbidity or BMI ≥ 40 kg/m2) who were enrolled in a regional obesity program over 2 years. We extrapolated 10-year and lifetime Markov models, validated and supplemented with literature sources, to compare medical, surgical and standard care therapies. We performed deterministic and probabilistic sensitivity analyses. RESULTS: The cohort included 500 adults living with severe obesity, 150 of whom received laparoscopic surgical therapy. From a publicly funded health system perspective, at 2 years, surgical therapy had an incremental cost-effectiveness ratio (ICER) of $54 456 per quality-adjusted life-year (QALY) compared with standard care therapy. Over a lifetime, it had an ICER of $14 056 per QALY. From the societal perspective, at 2 years, surgical therapy had an ICER of $340 per QALY; over a lifetime, it was the dominant option. The results were robust to sensitivity analysis. INTERPRETATION: From a public health care perspective, surgery for severe obesity is cost effective, and when approached from a societal perspective, it becomes cost saving. Real-world data support using surgical therapy for severe obesity, and our results contribute to the health economic and clinical literature with regard to a robust analysis from a societal perspective.

Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial.

BACKGROUND: Accumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome. METHODS: This is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12-18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids. DISCUSSION: This study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT04578652 . Registered on 8 October 2020.

Consumption of a High-Protein Meal Replacement Leads to Higher Fat Oxidation, Suppression of Hunger, and Improved Metabolic Profile After an Exercise Session.

The aim of this study was to compare the impact of a high-protein meal replacement (HP-MR) versus a control (CON) breakfast on exercise metabolism. In this acute, randomized controlled, cross-over study, participants were allocated into two isocaloric arms: (a) HP-MR: 30% carbohydrate, 43% protein, and 27% fat; (b) CON: 55% carbohydrate, 15% protein, and 30% fat. Following breakfast, participants performed a moderate-intensity aerobic exercise while inside a whole-body calorimetry unit. Energy expenditure, macronutrient oxidation, appetite sensations, and metabolic blood markers were assessed. Forty-three healthy, normal-weight adults (24 males) participated. Compared to the CON breakfast, the HP-MR produced higher fat oxidation (1.07 ± 0.33 g/session; p = 0.003) and lower carbohydrate oxidation (-2.32 ± 0.98 g/session; p = 0.023) and respiratory exchange ratio (-0.01 ± 0.00; p = 0.003) during exercise. After exercise, increases in hunger were lower during the HP-MR condition. Changes in blood markers from the fasting state to post-exercise during the HP-MR condition were greater for insulin, peptide tyrosine-tyrosine, and glucagon-like peptide 1, and lower for low-density lipoprotein cholesterol, triglyceride, and glycerol. Our primary findings were that an HP-MR produced higher fat oxidation during the exercise session, suppression of hunger, and improved metabolic profile after it.

A high-protein total diet replacement increases energy expenditure and leads to negative fat balance in healthy, normal-weight adults.

BACKGROUND: High-protein diets and total diet replacements are becoming increasingly popular for weight loss; however, further research is needed to elucidate their impact on the mechanisms involved in weight regulation. OBJECTIVE: The aim of this inpatient metabolic balance study was to compare the impact of a high-protein total diet replacement (HP-TDR) versus a control diet (CON) on select components of energy metabolism in healthy adults of both sexes. METHODS: The acute intervention was a randomized, controlled, crossover design with participants allocated to 2 isocaloric arms: 1) HP-TDR: 35% carbohydrate, 40% protein, and 25% fat achieved through a nutritional supplement; 2) CON: 55% carbohydrate, 15% protein, and 30% fat. Participants received the prescribed diets for 32 h while inside a whole-body calorimetry unit (WBCU). The first dietary intervention randomly offered in the WBCU was designed to maintain energy balance and the second matched what was offered during the first stay. Energy expenditure, macronutrient oxidation rates and balances, and metabolic blood markers were assessed. Body composition was measured at baseline using DXA. RESULTS: Forty-three healthy, normal-weight adults (19 females and 24 males) were included. Compared with the CON diet, the HP-TDR produced higher total energy expenditure [(EE) 81 ± 82 kcal/d, P <0.001], protein and fat oxidation rates (38 ± 34 g/d, P <0.001; 8 ± 20 g/d, P = 0.013, respectively), and a lower carbohydrate oxidation rate (-38 ± 43 g/d, P <0.001). Moreover, a HP-TDR led to decreased energy (-112 ± 85 kcal/d; P <0.001), fat (-22 ± 20 g/d; P <0.001), and carbohydrate balances (-69 ± 44 g/d; P <0.001), and increased protein balance (90 ± 32 g/d; P <0.001). CONCLUSIONS: Our primary findings were that a HP-TDR led to higher total EE, increased fat oxidation, and negative fat balance. These results suggest that a HP-TDR may promote fat loss compared with a conventional isocaloric diet. These trials were registered at clinicaltrials.gov as NCT02811276 and NCT03565510.

Higher Edmonton Obesity Staging System scores are independently associated with postoperative complications and mortality following bariatric surgery: an analysis of the MBSAQIP.

INTRODUCTION: Bariatric surgery is an evidence-based approach for sustained weight loss in patients with severe obesity. The most common procedures in North America are the laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-en-Y gastric bypass (LRYGB). The Edmonton Obesity Staging System (EOSS) is a tool that assigns patients a score of 0 to 4 according to their obesity-related comorbidities and functional status. Previous research demonstrates that increasing EOSS score is associated with overall non-operative mortality risk. OBJECTIVE: We sought to assess the association of the EOSS with major 30-day postoperative complications following LSG or LRYGB. METHODS: Primary LSG or LRYGB patients were identified from the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program data registry. Patients were assigned EOSS scores according to their comorbidities and functional limitations extracted from the database. Multivariable logistic regression analysis was conducted to evaluate the relationship between EOSS score, age, sex, BMI, type of procedure, or operative time with 30-day major complications. RESULTS: From 2015 to 2017, 430,238 patients (79.4% female) who underwent primary LSG or LRYGB were identified. The relative frequencies of patients by EOSS score were: 0 and 1 (23.9%), 2 (62.8%), 3 (10.5%), and 4 (2.9%). Mean preoperative BMI was 45.4 (SD 7.9) kg/m2 and mean age was 44.6 (SD 12.0) years. The overall 30-day major complication rate was 3.5%. EOSS 2, 3, and 4 were significantly associated with major complications. The strongest associations with major complications were EOSS 4 (OR 2.30; 95% CI 2.11-2.51, p < 0.001) and LRYGB versus LSG (OR 2.03; 95% CI 1.97-2.11, p < 0.001). EOSS 3 and 4 were most strongly associated with death. CONCLUSION: Higher EOSS scores are independently associated with 30-day major postoperative complications and mortality. The EOSS provides utility in staging patients and identifying those at greater risk of postoperative complications.

Obesity in adults: a clinical practice guideline

Obesity is a complex chronic disease in which abnormal or excess body fat (adiposity) impairs health, increases the risk of long-term medical complications and reduces lifespan.1 Epidemiologic studies define obesity using the body mass index (BMI; weight/height2), which can stratify obesity-related health risks at the population level. Obesity is operationally defined as a BMI exceeding 30 kg/m2 and is subclassified into class 1 (30­34.9), class 2 (35­39.9) and class 3 (≥ 40). At the population level, health complications from excess body fat increase as BMI increases.2 At the individual level, complications occur because of excess adiposity, location and distribution of adiposity and many other factors, including environmental, genetic, biologic and socioeconomic factors.