Anti-obesity drug discovery: advances and challenges.
Nature reviews. Drug discovery
Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut-brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.
10.1038/s41573-021-00337-8
Epidemiology and determinants of obesity in China.
Pan Xiong-Fei,Wang Limin,Pan An
The lancet. Diabetes & endocrinology
Obesity has become a major public health issue in China. Overweight and obesity have increased rapidly in the past four decades, and the latest national prevalence estimates for 2015-19, based on Chinese criteria, were 6·8% for overweight and 3·6% for obesity in children younger than 6 years, 11·1% for overweight and 7·9% for obesity in children and adolescents aged 6-17 years, and 34·3% for overweight and 16·4% for obesity in adults (≥18 years). Prevalence differed by sex, age group, and geographical location, but was substantial in all subpopulations. Strong evidence from prospective cohort studies has linked overweight and obesity to increased risks of major non-communicable diseases and premature mortality in Chinese populations. The growing burden of overweight and obesity could be driven by economic developments, sociocultural norms, and policies that have shaped individual-level risk factors for obesity through urbanisation, urban planning and built environments, and food systems and environments. Substantial changes in dietary patterns have occurred in China, with increased consumption of animal-source foods, refined grains, and highly processed, high-sugar, and high-fat foods, while physical activity levels in all major domains have decreased with increasing sedentary behaviours. The effects of dietary factors and physical inactivity intersect with other individual-level risk factors such as genetic susceptibility, psychosocial factors, obesogens, and in-utero and early-life exposures. In view of the scarcity of research around the individual and collective roles of these upstream and downstream factors, multidisciplinary and transdisciplinary studies are urgently needed to identify systemic approaches that target both the population-level determinants and individual-level risk factors for obesity in China.
10.1016/S2213-8587(21)00045-0
Child and adolescent obesity.
Nature reviews. Disease primers
The prevalence of child and adolescent obesity has plateaued at high levels in most high-income countries and is increasing in many low-income and middle-income countries. Obesity arises when a mix of genetic and epigenetic factors, behavioural risk patterns and broader environmental and sociocultural influences affect the two body weight regulation systems: energy homeostasis, including leptin and gastrointestinal tract signals, operating predominantly at an unconscious level, and cognitive-emotional control that is regulated by higher brain centres, operating at a conscious level. Health-related quality of life is reduced in those with obesity. Comorbidities of obesity, including type 2 diabetes mellitus, fatty liver disease and depression, are more likely in adolescents and in those with severe obesity. Treatment incorporates a respectful, stigma-free and family-based approach involving multiple components, and addresses dietary, physical activity, sedentary and sleep behaviours. In adolescents in particular, adjunctive therapies can be valuable, such as more intensive dietary therapies, pharmacotherapy and bariatric surgery. Prevention of obesity requires a whole-system approach and joined-up policy initiatives across government departments. Development and implementation of interventions to prevent paediatric obesity in children should focus on interventions that are feasible, effective and likely to reduce gaps in health inequalities.
10.1038/s41572-023-00435-4
Obesity in children and adolescents: epidemiology, causes, assessment, and management.
The lancet. Diabetes & endocrinology
This Review describes current knowledge on the epidemiology and causes of child and adolescent obesity, considerations for assessment, and current management approaches. Before the COVID-19 pandemic, obesity prevalence in children and adolescents had plateaued in many high-income countries despite levels of severe obesity having increased. However, in low-income and middle-income countries, obesity prevalence had risen. During the pandemic, weight gain among children and adolescents has increased in several jurisdictions. Obesity is associated with cardiometabolic and psychosocial comorbidity as well as premature adult mortality. The development and perpetuation of obesity is largely explained by a bio-socioecological framework, whereby biological predisposition, socioeconomic, and environmental factors interact together to promote deposition and proliferation of adipose tissue. First-line treatment approaches include family-based behavioural obesity interventions addressing diet, physical activity, sedentary behaviours, and sleep quality, underpinned by behaviour change strategies. Evidence for intensive dietary approaches, pharmacotherapy, and metabolic and bariatric surgery as supplemental therapies are emerging; however, access to these therapies is scarce in most jurisdictions. Research is still needed to inform the personalisation of treatment approaches of obesity in children and adolescents and their translation to clinical practice.
10.1016/S2213-8587(22)00047-X
General and abdominal adiposity and hypertension in eight world regions: a pooled analysis of 837 population-based studies with 7·5 million participants.
Lancet (London, England)
BACKGROUND:Adiposity can be measured using BMI (which is based on weight and height) as well as indices of abdominal adiposity. We examined the association between BMI and waist-to-height ratio (WHtR) within and across populations of different world regions and quantified how well these two metrics discriminate between people with and without hypertension. METHODS:We used data from studies carried out from 1990 to 2023 on BMI, WHtR and hypertension in people aged 20-64 years in representative samples of the general population in eight world regions. We graphically compared the regional distributions of BMI and WHtR, and calculated Pearson's correlation coefficients between BMI and WHtR within each region. We used mixed-effects linear regression to estimate the extent to which WHtR varies across regions at the same BMI. We graphically examined the prevalence of hypertension and the distribution of people who have hypertension both in relation to BMI and WHtR, and we assessed how closely BMI and WHtR discriminate between participants with and without hypertension using C-statistic and net reclassification improvement (NRI). FINDINGS:The correlation between BMI and WHtR ranged from 0·76 to 0·89 within different regions. After adjusting for age and BMI, mean WHtR was highest in south Asia for both sexes, followed by Latin America and the Caribbean and the region of central Asia, Middle East and north Africa. Mean WHtR was lowest in central and eastern Europe for both sexes, in the high-income western region for women, and in Oceania for men. Conversely, to achieve an equivalent WHtR, the BMI of the population of south Asia would need to be, on average, 2·79 kg/m (95% CI 2·31-3·28) lower for women and 1·28 kg/m (1·02-1·54) lower for men than in the high-income western region. In every region, hypertension prevalence increased with both BMI and WHtR. Models with either of these two adiposity metrics had virtually identical C-statistics and NRIs for every region and sex, with C-statistics ranging from 0·72 to 0·81 and NRIs ranging from 0·34 to 0·57 in different region and sex combinations. When both BMI and WHtR were used, performance improved only slightly compared with using either adiposity measure alone. INTERPRETATION:BMI can distinguish young and middle-aged adults with higher versus lower amounts of abdominal adiposity with moderate-to-high accuracy, and both BMI and WHtR distinguish people with or without hypertension. However, at the same BMI level, people in south Asia, Latin America and the Caribbean, and the region of central Asia, Middle East and north Africa, have higher WHtR than in the other regions. FUNDING:UK Medical Research Council and UK Research and Innovation (Innovate UK).
10.1016/S0140-6736(24)01405-3
Contemporary medical, device, and surgical therapies for obesity in adults.
Lancet (London, England)
The goal of obesity management is to improve health. Sustained weight loss of more than 10% overall bodyweight improves many of the complications associated with obesity (eg, prevention and control of type 2 diabetes, hypertension, fatty liver disease, and obstructive sleep apnoea), as well as quality of life. Maintenance of weight loss is the major challenge of obesity management. Like all chronic diseases, managing obesity requires a long-term, multimodal approach, taking into account each individual's treatment goals, and the benefit and risk of different therapies. In conjunction with lifestyle interventions, anti-obesity medications and bariatric surgery improve the maintenance of weight loss and associated health gains. Most available anti-obesity medications act on central appetite pathways to reduce hunger and food reward. In the past 5 years, therapeutic advances have seen the development of targeted treatments for monogenic obesities and a new generation of anti-obesity medications. These highly effective anti-obesity medications are associated with weight losses of more than 10% of overall bodyweight in more than two-thirds of clinical trial participants. Long-term data on safety, efficacy, and cardiovascular outcomes are awaited. Long-term studies have shown that bariatric surgical procedures typically lead to a durable weight loss of 25% and rapid, sustained improvements in complications of obesity, although they have not yet been compared with new-generation highly effective anti-obesity medications. Further work is required to determine optimal patient-specific treatment strategies, including combinations of lifestyle interventions, anti-obesity medications, endoscopic and bariatric surgical procedures, and to ensure equitable access to effective treatments.
10.1016/S0140-6736(22)02403-5
Obesity Management in Adults: A Review.
JAMA
Importance:Obesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiovascular disease, sleep disorders, osteoarthritis, and premature death. Observations:A body mass index (BMI) of 25 or greater is commonly used to define overweight, and a BMI of 30 or greater to define obesity, with lower thresholds for Asian populations (BMI ≥25-27.5), although use of BMI alone is not recommended to determine individual risk. Individuals with obesity have higher rates of incident cardiovascular disease. In men with a BMI of 30 to 39, cardiovascular event rates are 20.21 per 1000 person-years compared with 13.72 per 1000 person-years in men with a normal BMI. In women with a BMI of 30 to 39.9, cardiovascular event rates are 9.97 per 1000 person-years compared with 6.37 per 1000 person-years in women with a normal BMI. Among people with obesity, 5% to 10% weight loss improves systolic blood pressure by about 3 mm Hg for those with hypertension, and may decrease hemoglobin A1c by 0.6% to 1% for those with type 2 diabetes. Evidence-based obesity treatment includes interventions addressing 5 major categories: behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures. Comprehensive obesity care plans combine appropriate interventions for individual patients. Multicomponent behavioral interventions, ideally consisting of at least 14 sessions in 6 months to promote lifestyle changes, including components such as weight self-monitoring, dietary and physical activity counseling, and problem solving, often produce 5% to 10% weight loss, although weight regain occurs in 25% or more of participants at 2-year follow-up. Effective nutritional approaches focus on reducing total caloric intake and dietary strategies based on patient preferences. Physical activity without calorie reduction typically causes less weight loss (2-3 kg) but is important for weight-loss maintenance. Commonly prescribed medications such as antidepressants (eg, mirtazapine, amitriptyline) and antihyperglycemics such as glyburide or insulin cause weight gain, and clinicians should review and consider alternatives. Antiobesity medications are recommended for nonpregnant patients with obesity or overweight and weight-related comorbidities in conjunction with lifestyle modifications. Six medications are currently approved by the US Food and Drug Administration for long-term use: glucagon-like peptide receptor 1 (GLP-1) agonists (semaglutide and liraglutide only), tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. Of these, tirzepatide has the greatest effect, with mean weight loss of 21% at 72 weeks. Endoscopic procedures (ie, intragastric balloon and endoscopic sleeve gastroplasty) can attain 10% to 13% weight loss at 6 months. Weight loss from metabolic and bariatric surgeries (ie, laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) ranges from 25% to 30% at 12 months. Maintaining long-term weight loss is difficult, and clinical guidelines support the use of long-term antiobesity medications when weight maintenance is inadequate with lifestyle interventions alone. Conclusion and Relevance:Obesity affects approximately 42% of adults in the US. Behavioral interventions can attain approximately 5% to 10% weight loss, GLP-1 agonists and glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists can attain approximately 8% to 21% weight loss, and bariatric surgery can attain approximately 25% to 30% weight loss. Comprehensive, evidence-based obesity treatment combines behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures as appropriate for individual patients.
10.1001/jama.2023.19897
Rehabilitation Nutrition in Patients with Chronic Kidney Disease and Cachexia.
Nutrients
Rehabilitation nutrition is a proposed intervention strategy to improve nutritional status and physical function. However, rehabilitation nutrition in patients with cachexia and protein-energy wasting (PEW), which are the main nutrition-related problems in patients with chronic kidney disease (CKD), has not been fully clarified. Therefore, this review aimed to summarize the current evidence and interventions related to rehabilitation nutrition for cachexia and PEW in patients with CKD. CKD is a serious condition worldwide, with a significant impact on patient prognosis. In addition, CKD is easily complicated by nutrition-related problems such as cachexia and PEW owing to disease background- and treatment-related factors, which can further worsen the prognosis. Although nutritional management and exercise therapy are reportedly effective for cachexia and PEW, the effectiveness of combined nutrition and exercise interventions is less clear. In the future, rehabilitation nutrition addressing the nutritional problems associated with CKD will become more widespread as more scientific evidence accumulates. In clinical practice, early intervention in patients with CKD involving both nutrition and exercise after appropriate assessment may be necessary to improve patient outcomes.
10.3390/nu14224722
Dietary Behaviour and Nutrition in Patients with COPD Treated with Long-Term Oxygen Therapy.
International journal of environmental research and public health
BACKGROUND:It is the first study in Poland and one of the first in the world to assess the nutrition of patients with chronic obstructive pulmonary disease (COPD) treated with long-term oxygen therapy (LTOT). METHODS:The study group consisted of 110 COPD patients treated with LTOT. Anthropometric measurements and spirometry were performed. The diet of patients was assessed using a 3-day nutrition diary. RESULTS:When assessing the degree of airflow obstruction (FEV1% N) depending on the BMI in patients treated with LTOT, a statistically significant correlation was demonstrated between the BMI and the value of the FEV% N parameter ( = 0.0093). Patients with COPD with a BMI >30 had statistically significantly higher values of FEV1% N than patients with a BMI in the range of 20-24.9 ( = 0.0278). Intake of calcium, vitamins A, C, D, E and folates was lower than the recommended daily intake in more than 95% of COPD patients. CONCLUSIONS:The diet of COPD patients treated with long-term oxygen therapy was improperly balanced, with deficiencies of important nutrients. Airflow obstruction in the respiratory tract was significantly smaller in obese patients, and greater in patients with diagnosed malnutrition.
10.3390/ijerph182312793
The role of diet and nutrition in the management of COPD.
European respiratory review : an official journal of the European Respiratory Society
In 2014, the European Respiratory Society published a statement on nutritional assessment and therapy in COPD. Since then, increasing research has been performed on the role of diet and nutrition in the prevention and management of COPD. Here, we provide an overview of recent scientific advances and clinical implications. Evidence for a potential role of diet and nutrition as a risk factor in the development of COPD has been accumulating and is reflected in the dietary patterns of patients with COPD. Consuming a healthy diet should, therefore, be promoted in patients with COPD. Distinct COPD phenotypes have been identified incorporating nutritional status, ranging from cachexia and frailty to obesity. The importance of body composition assessment and the need for tailored nutritional screening instruments is further highlighted. Dietary interventions and targeted single or multi-nutrient supplementation can be beneficial when optimal timing is considered. The therapeutic window of opportunity for nutritional interventions during and recovering from an acute exacerbation and hospitalisation is underexplored.
10.1183/16000617.0003-2023
Managing malnutrition in COPD: A review.
Keogh Emma,Mark Williams E
Respiratory medicine
In the UK approximately 1.2 million people have COPD with around 25-40% being underweight and 35% have a severely low fat-free mass index. Measuring their body mass index is recommended and Health care professionals should endeavour to ensure that COPD patients are achieving their nutritional requirements. A narrative review summarizes evidence from 28 original articles identified through a systematic searches of databases, grey literature and hand searches covering 15 years, focusing on two themes, on the impact of malnutrition on COPD, and the management of malnutrition in COPD. Malnutrition causes negative effects on exercise and muscle function and lung function as well as increasing exacerbations, mortality and cost. Management options include nutritional supplementation which may increase weight and muscle function. Nutritional education has short-term improvements. Malnutrition affects multiple aspects of COPD, but treatment is of benefit. Clinical practice should include nutrition management.
10.1016/j.rmed.2020.106248