In 1997, the WHO formally recognised obesity as a complex, chronic disease requiring prevention and management strategies at individual and societal levels. 1 This coincided with its rapidly rising global prevalence across all age groups, prompting intensified research into its pathophysiology, barriers to treatment in healthcare systems and use of treatments including weight-lowering pharmacotherapy. 2 Historically, obesity was defined as a BMI ≥30 kg/m², reflecting steep increases in morbidity and mortality, particularly from cardiometabolic disease, above this threshold. However, BMI alone inadequately captures adiposity or health risk, given sex-, age- and ethnicity-related differences. 3 Accordingly, The Lancet Diabetes & Endocrinology Commission proposed redefining obesity based on the presence of adiposity-related organ or tissue dysfunction, distinguishing preclinical obesity from clinical obesity ( Figure 1 ) and recommending direct (imaging) or anthropometric measures, such as waist circumference or waist-to-height ratio. 4
This redefinition positions obesity as a multisystem disease rather than merely a risk factor, and is largely consistent with recommendations from other organisations, such as the European Association for the Study of Obesity. 5 Expectedly, the incidence of non-communicable diseases (NCDs) has risen in parallel sharing mechanisms including chronic inflammation, insulin resistance, adipokine dysregulation, ectopic fat deposition and neurohormonal activation. 6 – 9
Cardiovascular disease (CVD), notably MI, stroke and heart failure (HF), remains the leading cause of morbidity and mortality in individuals with obesity, while other major NCDs include chronic kidney disease (CKD), type 2 diabetes (T2D), metabolic dysfunction–associated steatotic liver disease (MASLD), chronic respiratory diseases, such as obesity-hypoventilation syndrome (OHS) and obstructive sleep apnea (OSA), adiposity-related cancers and mental health disorders, such as depression and anxiety. 10 , 11 Combined with weight stigma, obesity-related organ damage substantially impairs health-related quality of life (HRQL) and contributes to major economic losses, with 2022 costs ranging from US$15 million in Brazil to US$126 billion in the US, representing 0.7–17.8% of total health spending and 0.05–2.42% of GDP. 12
The complex, multifactorial aetiology of obesity, spanning genetic, environmental, behavioural, hormonal and socio-economic factors, poses a major challenge for prevention and treatment. 13 Lifestyle modification remains the cornerstone of therapy but often produces modest, unsustained weight loss. 14 Metabolic bariatric surgery (MBS) induces substantial, durable weight loss and rapid improvement in obesity-related disease, though it is invasive, carries (small) procedural risk and incurs high cost. 15 More recently, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists (RAs) have transformed obesity pharmacotherapy by targeting central and peripheral appetite-regulating pathways. 14 These agents also improve obesity-related organ dysfunction independently of weight loss, representing a major advance in obesity management. 16
This review summarises the global burden of obesity, focusing on trends in prevalence, associated end-organ damage across sex, age and ethnicity, and the resulting societal and economic implications.
Epidemiology and Global Trends Across Age, Sex, Ethnicity and Geography
As of 2021, an estimated 342 million men and 496 million women worldwide were living with obesity, affecting 13–14% of adult men and 19–20% of adult women. Obesity is also increasingly prevalent in young people, with 93 million children and young adolescents (<12 years) and 81 million older adolescents (12–18 years) affected, nearly double the rates observed in 1990. Projections suggest that by 2050, obesity will affect 838 million men, 1.11 billion women and over 360 million children and adolescents, representing a 145% rise in men, 124% in women and approximately a twofold increase in younger populations. 17
Obesity remains most prevalent in high-income settings, where rising economic status increases the likelihood of obesity by 14%. 18 The largest numbers of adults with overweight or obesity currently reside in China (402 million), India (180 million) and the US (172 million). 2 Traditionally, obesity has been viewed as a problem related to urbanisation in high-income countries, with BMI increasing steadily in parallel with a rise in the proportion of the global population who live in cities. However, obesity is now spreading fastest in rural and low- to middle-income settings. Data from more than 2,000 population-based studies (112 million adults, 1985–2017) reveal that over half of the global rise in BMI originates from rural areas, with >80% of BMI increases in low- and middle-income regions occurring outside cities, effectively reversing the traditional urban–rural BMI gap. 19 Similarly, projections from the NCD Risk Factor Collaboration database show the share of global obesity in countries with the lowest GDP per capita increasing from 6% to 26% by 2040, with the steepest rises expected in east Asia, south Asia and sub-Saharan Africa. 20 Specifically, sub-Saharan Africa is forecast to see a 255% increase in obesity prevalence by 2050, with Nigeria projected to become the fourth-largest population of adults with overweight and obesity ( Figure 2 ). 2 As with global trends, childhood and adolescent obesity in low-middle socio-economic deprivation index countries are experiencing the fastest increases, reflecting a unified global shift across age groups. 21
This rural shift likely reflects the urbanisation of rural life, rapid lifestyle and dietary transitions characterised by lower physical activity (mechanisation, motorised transport) and greater intake of ultra-processed foods (UPFs). 19 , 22 Randomised trials show that UPF-rich diets lead to chronic excess caloric intake, while fiscal modelling studies from Brazil demonstrate their policy relevance: a 1% increase in UPF price was associated with a 0.59% decrease in obesity prevalence, with stronger effects in lower-income groups. 23 , 24 National projections suggest that a 20–30% excise tax on UPFs could reduce obesity prevalence by 6.7–9.1% over a decade, equivalent to 2.8–3.8 million fewer obesity cases and substantial healthcare cost savings. 25
Importantly, most global epidemiological estimates rely on BMI, which substantially underestimates true adiposity-related disease burden. Under the 2025 Lancet Diabetes & Endocrinology Commission framework, defining obesity by adiposity-related tissue or organ dysfunction rather than BMI alone, obesity prevalence is significantly higher. In the All of Us cohort, which has approximately 250,000 participants, 29% met criteria for preclinical and 36% for clinical obesity. Notably, >20% of individuals with a normal BMI and one-third of those classified as overweight were reclassified as having obesity, suggesting that nearly two-thirds of US adults have clinically significant adiposity when metabolic and functional criteria are applied. Clinical obesity was disproportionately common among Black and Hispanic populations, older adults and lower-income groups, underscoring persistent socio-demographic disparities. 26 Similarly, a retrospective cohort analysis of 502,233 adults enrolled in the UK Biobank demonstrated that the prevalence of preclinical and clinical obesity was 31.2% and 36.6%, respectively; most were in the WHO overweight category. Clinical obesity was more prevalent in men, the elderly, south Asians and lower education or income level groups. 27
This redefinition has major implications for clinical practice, public health surveillance and resource planning. It broadens the population eligible for early intervention, but also highlights the need for standardised operational criteria to ensure equitable access and consistent reporting across countries.
Health Consequences of Obesity: Cardiometabolic Disease, Chronic Respiratory and Kidney Disease, Cancer and Mental Health Disorders
The WHO identifies obesity prevention as the top global priority for reducing non-communicable diseases (NCDs). Under the 25×25 Global Prevention Plan, the aim is to reverse the rising trend of obesity, which is projected to become the leading preventable risk factor for NCDs by 2035, surpassing smoking and alcohol, with over 70% of NCDs linked to excess adiposity. 11 , 28 NCDs already represent the leading cause of death and disability worldwide, and curbing their impact is critical to improving global public health. 18 In 2019, elevated BMI was responsible for approximately 5 million deaths globally from CVD, metabolic disorders, including metabolic syndrome (MetS), T2D, MASLD and polycystic ovarian syndrome, CKD, chronic respiratory diseases (OSA, OHS), adiposity-related cancers and mental health disorders such as depression and anxiety ( Figure 3 ).
As with obesity itself, the burden of these conditions is rising fastest in low- and middle-income countries. 28 Modelled projections highlight the scale of impact: in Brazil, if current BMI trends persist, overweight and obesity could cause 5.26 million new NCD cases and over 800,000 deaths by 2030. Conversely, halting current trends could prevent 93,000 NCD cases and 12,000 deaths, while a 6.7% reduction in overweight and obesity prevalence could avert up to 182,000 cases and 34,000 deaths. 29
Cardiovascular Disease
CVD represents the greatest burden of all NCDs, accounting for one-third of global deaths, the leading cause of mortality both worldwide and among individuals with obesity and nearly 400 million disability-adjusted life years (DALYs). Obesity causally drives cardiovascular risk, predisposing to hypertension, dyslipidaemia and overt disease such as ischaemic heart disease (IHD), AF and HF. 30 These effects are mediated by structural, functional, humoral and haemodynamic alterations, arising from visceral and ectopic fat depots that secrete cytokines, growth factors and vasoactive peptides, leading to neurohormonal imbalance, insulin resistance, renin–angiotensin–aldosterone system (RAAS) activation, inflammation, cardiac fibrosis, microvascular dysfunction and autonomic dysregulation. 30
The relationship between obesity, CVD and mortality is complex and extends beyond traditional BMI-based definitions. BMI does not distinguish between fat distribution or muscle mass, meaning individuals with a ‘healthy’ BMI may still harbour excess visceral adiposity and low lean mass, so-called ‘normal-weight obesity’, which carries a higher risk of CVD and all-cause mortality than equivalent BMI without central adiposity. 31 Waist circumference and waist-to-hip ratio better reflect this risk, highlighting the role of fat distribution over total mass, though they still fail to differentiate between visceral and subcutaneous adipose tissue. 10
The obesity paradox, whereby overweight or mild obesity appears to have lower mortality in chronic CVDs such as heart failure, IHD and AF, is likely attributable to reverse causality, unintentional weight loss from chronic illness, or protective effects of greater lean mass, rather than genuine benefit from obesity. 21 Similarly, the notion of metabolically healthy obesity (MHO) (elevated BMI without metabolic abnormalities) appears transient, as most individuals progress to metabolic dysfunction and increased CVD risk over time. 32 Reflecting these nuances, obesity is now recognised as a chronic, systemic and heterogeneous disease comprising preclinical and clinical obesity. 4 Within this framework, the so-called obesity paradox likely reflects BMI misclassification rather than a true survival advantage of excess adiposity.
Ischaemic Heart Disease
IHD exemplifies the close interplay between obesity and cardiovascular risk. Around 70–80% of individuals with IHD are living with overweight or obesity, yet most cardiac rehabilitation programmes lack structured weight management interventions. 10 In a meta-analysis of 21 studies including 18,000 IHD events, after adjustment for demographic and lifestyle factors, moderate overweight and obesity were associated with 32% and 81% higher risks of IHD, respectively. After further adjustment for hypertension and dyslipidaemia, these risks attenuated to 17 and 49%, respectively. Each five-unit increase in BMI conferred a 29% higher IHD risk, or 16% when accounting for these mediators. 33 The results suggest that obesity is a significant risk factor for IHD, supported by Mendelian randomisation studies highlighting a causal link, although about 45% of the risk is mediated by obesity-induced hypertension and dyslipidaemia. 33 , 34 The remaining risk likely reflects atherosclerotic mechanisms shared between obesity and chronic overnutrition. Excess energy intake elevates triglyceride-rich lipoproteins, notably very low-density lipoproteins (VLDL) and chylomicrons, which increase atherogenic LDL and remnant particles that deposit cholesterol in the arterial intima, initiating inflammation and plaque formation. Elevated triglycerides enhance cholesteryl ester transfer protein activity, impairing reverse cholesterol transport and lowering high-density lipoprotein levels. In parallel, chronic exposure to high glucose and saturated fats promotes endothelial dysfunction and insulin resistance, reducing lipid and glucose clearance and further accelerating atherogenesis. 35
Atrial Fibrillation
AF is another major cardiovascular complication of obesity. In a meta-analysis of 16 studies including 123,249 individuals, obesity was associated with an 87% higher risk of AF compared with normal weight. 36 This risk arises partly through haemodynamic and metabolic disturbances, including elevated heart rate, stroke volume and blood pressure, that promote eccentric left ventricular hypertrophy, atrial dilation and increased blood volume. 37 Obesity commonly coexists with MetS, T2D and OSA, which further elevate AF risk via nocturnal hypoxia, autonomic instability and atrial remodelling. 38 Emerging evidence also suggests that direct cardiac lipotoxicity from excessive myocardial lipid deposition may contribute to atrial and ventricular remodelling. 39
Stroke
Stroke risk rises substantially with increasing adiposity. A meta-analysis of 25 studies involving 2.27 million individuals and 30,757 events showed that obesity increases the risk of ischaemic stroke by 64% and haemorrhagic stroke by 24% compared with healthy weight. 40 Moreover, evidence from the Northern Finland Birth Cohort 1966 underscores the long-term consequences of early onset obesity: higher BMI in adolescence and young adulthood (ages 14–31 years) was associated with greater stroke risk by midlife, particularly ischaemic stroke in young women and haemorrhagic stroke in both sexes. These findings parallel global data showing a 20–35% rise in stroke incidence among adults under 55 years across the US and Europe. 41 While obesity contributes to stroke risk indirectly through hypertension, diabetes and related metabolic complications, even metabolically healthy obesity confers a 17% higher risk of stroke compared with metabolically healthy lean individuals. 32 , 42 This suggests additional direct mechanisms, including cytokine-mediated sympathetic activation, RAAS stimulation, endothelial dysfunction and microvascular injury, which have been validated through Mendelian randomisation studies. 34 , 42 Of course, risk may also be mediated by the increased risk of AF in patients with obesity, as discussed earlier. 43
Heart Failure
HF is unequivocally linked to obesity, particularly HF with preserved ejection fraction (HFpEF; EF <50%), characterised by exercise intolerance, oedema and elevated B-type natriuretic peptide (BNP); although BNP thresholds should be adjusted downward in individuals with obesity. 10 In pooled data from 22,681 participants across four community cohorts followed for 12 years, each 1 SD increase in BMI was associated with a 34% higher risk of HFpEF and 18% higher risk of HF with reduced EF (HFrEF). Insulin resistance, measured by the homeostatic model assessment for insulin resistance, mediates part of this relationship, while sex differences are evident; obesity confers a greater HFpEF risk in women, potentially reflecting hormonal and cardiometabolic variation. 44 Chronic systemic inflammation and obesity-induced myocardial remodelling further contribute to HF pathogenesis. 45
Metabolic Dysfunction
Extensive preclinical and clinical evidence demonstrates that chronic low-grade inflammation of adipose tissue is a key mechanistic driver of metabolic dysfunction and obesity-related organ complications. Indeed, metabolic disorders such as hypertension, dyslipidaemia, MASLD and T2D, collectively components of metabolic syndrome (MetS), share overlapping pathophysiological pathways, including insulin resistance, adipokine imbalance and systemic inflammation. 46
Metabolic Syndrome
MetS is a cluster of interrelated conditions including central obesity, hypertension, dyslipidaemia and insulin resistance, which collectively increase the risk of CVD and T2D. 47 Although diagnostic criteria vary, most definitions require the presence of central obesity, which typically precedes dyslipidaemia, hypertension and ultimately insulin resistance. 47 In fact, the most frequent accumulation sequence starts with abdominal obesity, followed by dyslipidaemia, hypertension and finally, insulin resistance. 48 In a cohort of 19,328 adults, the number of MetS components rose linearly with both BMI and age, illustrating the cumulative metabolic burden of excess adiposity. 49 Notably, up to 80% of hypertension cases are attributable to obesity, mediated through renal compression, sympathetic and RAAS activation and increased cardiac output causing elevated pulse pressure. 11 Metabolically healthy obesity appears rare and is often short-lived. 49 Indeed, meta-analysis of 87 studies, involving 951,083 participants, demonstrated that MetS, even in the absence of T2D, markedly increases all-cause mortality by 58%, largely through higher rates of CVD (35%) and cardiovascular mortality (40%). 50
Metabolic Dysfunction-associated Steatotic Liver Disease
MASLD is the most common chronic liver disease globally. It affects 30% of adults, increasing approximately 1% annually. 51 The updated MASLD definition requires hepatic steatosis plus at least one MetS component, in the absence of significant alcohol intake or other causes of liver injury. 52 MASLD spans a continuum from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis and cirrhosis, with an average fibrosis progression rate of 0.09/year. 51 The degree of end-organ damage in patients with MASLD, which includes CVD, T2D, CKD and hepatic and extra-hepatic cancers, is modulated by both incrementally increasing metabolic dysfunction and the severity of liver disease (with MASLD cirrhosis carrying the greatest risk). 53 – 55 While obesity as defined by BMI confers a more than sevenfold increased risk of MASLD, the condition also occurs in individuals with normal BMI (lean MASLD), the limitations of BMI as a marker of metabolic health and supporting The Lancet Diabetes & Endocrinology Commission’s framework distinguishing preclinical and clinical obesity. 4 , 56 Mechanistically, energy intake exceeding adipose tissue’s storage capacity leads to lipid spillover into non-adipose organs, promoting ectopic fat accumulation in the liver. 57 In lean MASLD, genetic variants such as patatin-like phospholipase domain-containing protein 3 predispose to hepatic steatosis, inflammation and fibrosis independent of adiposity. 58 Collectively, these findings underscore that ectopic fat deposition in the liver, muscle and viscera, rather than total body fat or BMI, is a stronger determinant of cardiometabolic and hepatic risk. Supporting this, each 1% increase in MRI-measured liver fat corresponds to a 4% higher risk of prediabetes and T2D. 59
Type 2 Diabetes
T2D prevalence will reach 643 million by 2030 and 783 million by 2045 according to the most recent estimates by the International Diabetes Federation. 60 Obesity, MASLD and T2D share a tri-directional pathophysiological relationship, reflecting a common basis in metabolic dysfunction. 61 Among these, obesity is the strongest and most consistent risk factor for T2D across all age groups, driven primarily by the twin cycle hypothesis, which posits that chronic energy surplus leads to hepatic fat accumulation, promoting insulin resistance and increased hepatic VLDL export, which in turn drives pancreatic fat deposition and β-cell failure. 60 , 62 Cross-sectional data highlights a positive correlation between BMI and HbA 1c (r=0.45; p<0.001), while higher BMI confers greater risk of diabetes-related complications. 63 In patients with T2D, the likelihood of insulin dependence rose by 77% for BMI 25–27.5 kg/m² and by 3.5-fold for BMI>40 kg/m² compared with BMI<25 kg/m². Similarly, risks for macrovascular and microvascular complications (CVD and nephropathy) increased by 34–150% and 31–200%, respectively. 64 However, ethnic variation in diabetes susceptibility further highlights BMI’s limitations. In a cohort of 1.47 million individuals, the BMI threshold conferring equivalent diabetes risk to 30 kg/m² in white adults was 23.9 kg/m² in south Asian, 26.6 kg/m² in Arab, 26.9 kg/m² in Chinese and 28.1 kg/m² in Black populations, underscoring substantial ethnic heterogeneity in metabolic risk. 3 Moreover, T2D can develop in individuals with a ‘healthy’ BMI. The ReTUNE trial demonstrated that people with T2D but BMI <27 kg/m² achieved 70% remission after only 6.5% weight loss, accompanied by normalisation of liver fat, hepatic fat export and fasting insulin. 65 Together, ReTUNE and the twin cycle hypothesis reinforce that ectopic fat accumulation, rather than total body weight or BMI, underpins T2D pathogenesis, and that clinical obesity defined by dysfunctional adipose distribution is the central therapeutic and public health target.
Kidney Disease
Worldwide, more than 850 million people are estimated to be living with CKD, with diabetes and CKD surpassing CVD as the leading contributors to DALYs (although CVD remains the main driver of BMI-related deaths) accounting for 82% of deaths and 73%, respectively. 2 , 66 Despite this, CKD prevalence is likely underestimated in many countries due to insufficient screening for functional and structural renal abnormalities. 66 Obesity contributes to CKD through three interrelated pathways:
Haemodynamic: obesity promotes hypertension via renal hyperfiltration, RAAS and autonomic activation, fluid overload and altered arteriolar tone, creating a self-perpetuating cycle of elevated blood pressure;
Adipose tissue–related: excess visceral fat induces renal injury through dysregulated adipokines (low adiponectin, high leptin), chronic inflammation and gut microbiota alterations;
Insulin resistance–hyperinsulinaemia: visceral fat–driven insulin resistance impairs podocyte function, GLUT4-mediated glucose uptake and nutrient sensing, promoting renal fibrosis and hypertension. 67
Indeed, meta-analysis demonstrate that elevated BMI, waist circumference and waist-to-height ratio are all independent predictors of declining glomerular filtration rate (GFR) and mortality, in individuals with or without pre-existing kidney disease. 68
Other Systemic Consequences
Obesity is independently associated with at least 13 cancers, including gastrointestinal (oesophageal, upper stomach, gallbladder, liver, pancreas, colorectal), genitourinary (breast, endometrial, ovarian, kidney), thyroid, meningioma and multiple myeloma. More recent evidence suggests an additional 31 cancers may be linked to obesity, spanning genitourinary (cervical, vulvar, penile), gastrointestinal (biliary tract, lower stomach, pancreatic islets, small intestine), endocrine (adrenal, pituitary, parathyroid), head and neck, connective tissue and hematologic cancers and malignant melanoma. 69
Obesity also drives fat mass disease, explaining its association with chronic respiratory conditions such as OSA and OHS, and musculoskeletal disorders, including osteoarthritis and chronic non-specific lower back pain. 70
Finally, obesity is linked to mental health disorders, notably depression and anxiety across all ages from adolescents with early-onset obesity to older adults. 71 , 72 Mechanisms include weight-related stigma, reduced physical function, sleep disturbance, chronic low-grade inflammation disrupting neurotransmitter function and hypothalamic–pituitary–adrenal axis dysregulation. 73
Societal and Economic Burden
The economic impact of overweight and obesity is substantial. In 2019, they accounted for 2.19% of global GDP, ranging from US$20 per capita in Africa to US$872 in the Americas, and are projected to rise to 3.29% by 2060, with the largest increases in low- and middle-income countries (12–25-fold) compared with a fourfold rise in high-income countries. Reducing prevalence by 5% annually could save US$429 billion–$2.2 trillion per year globally between 2020 and 2060. 74 Beyond macroeconomic impact, obesity drives higher healthcare costs and resource use. Across 32 studies, individuals with obesity incurred 1.1- to 3.3-fold higher annual healthcare costs than those of healthy weight, rising with obesity severity and up to fivefold in those with T2D and hypertension. A modest 5% weight loss over 1 year was associated with significant savings. 75 In a cohort of 1.4 million adults, costs and healthcare use rose progressively with BMI from 2015–2019, with the highest costs in individuals with CKD or CVD. In 2019, >72% of total costs were concentrated in the highest cost quintile, characterised by older age and more obesity-related complications. Similarly, patients hospitalised with COVID-19 and above-normal BMI had longer stays, higher numbers of intensive care unit admissions and greater hospital costs. 76
Therapeutic and Public Health Interventions
Given the vast societal and economic burden of obesity, effective treatment strategies and population-level initiatives are essential.
Lifestyle and Behavioural Interventions
Energy-restricted diets induce initial weight loss, but most patients regain weight due to robust evolutionary physiological mechanisms that resist a reduction in body fat stores below a personal fat threshold. 77 , 78 Meanwhile, physical activity is effective for prevention and maintaining weight loss, but alone is insufficient for significant weight loss in established obesity. 79
Metabolic Bariatric Surgery
Over the past 70 years, MBS has evolved from high risk to being among the safest surgical procedures, with laparoscopic Roux-en-Y gastric bypass and sleeve gastrectomy the most common form. Typically offered to patients with BMI ≥40, or ≥35 kg/m 2 with complications, MBS produces >30% weight loss at 1 year, remaining >25% at 10 years, while reducing T2D, CVD, cancer and mortality. 80 – 82 Beyond mechanical restriction and malabsorption, MBS induces complex biological changes promoting sustained weight loss that have formed the foundation of ongoing obesity pharmacotherapy ( Figure 4 ). 83 , 84 Despite economic benefits, MBS is resource-intensive, limiting accessibility. 85
Pharmacotherapy
Seven drugs are approved for obesity in the EU/UK: orlistat, naltrexone/bupropion, GLP-1 receptor agonists (liraglutide, semaglutide) and the dual GLP-1/GIP agonist tirzepatide. Setmelanotide and metreleptin target monogenic obesity. In the US, phentermine/topiramate are also approved.
Weight loss
GLP-1 (+/- GIP) RAs approach MBS-level weight loss: tirzepatide (21% over 72 weeks), semaglutide (15% over 68 weeks at currently approved doses of 2.4 mg, increasing to 19% at higher doses of 7.2 mg) and liraglutide (8% over 56 weeks). 86 – 89 Phase two trials of retatrutide, a tri-agonist of GLP-1, GIP and glucagon receptors, demonstrate the greatest weight loss to date: 24% over 48 weeks, while co-administration of cagrilintide (a long-acting amylin analogue) and semaglutide produces 20% weight loss over 68 weeks. 90 , 91
Cardiometabolic Protection
GLP-1 (+/- GIP) RAs confer sustained cardiometabolic protection. The SELECT trial demonstrated 20% reduction in major adverse cardiovascular events (MACE) with semaglutide in patients with obesity and CVD, and these benefits are largely independent of weight change. 16 , 92 Meanwhile, tirzepatide also produces 38% risk reduction in CV death or decompensated heart failure in patients with obesity and HFpEF. 93 Moreover, GLP-1 (+/- GIP) RAs have demonstrated efficacy in reducing AF incidence and burden, as well as improving MASLD histology and reducing the risk of progression to major adverse liver outcomes. 94 – 97
Other Benefits
Observational data suggest that GLP-1 (+/- GIP) RAs may reduce the incidence of other NCDs, including cancer and dementia, as well as reducing incidence of infectious diseases including pneumonia and secondary sepsis and substance misuse disorders, but these effects have not yet been proven in clinical trials. 98 – 101
Policy and Prevention
Population-level measures target obesogenic environments including food systems, urban planning, taxation and marketing regulation. On an international level, the WHO’s Global Action Plan on NCDs and the 2022 Acceleration Plan to STOP Obesity promote systemic interventions, such as urban design for activity and subsidised healthy diets. 102 Taxes on sugar-sweetened beverages and UPFs, for example in the Philippines, are projected to avert thousands of T2D, IHD and stroke cases over 20 years, generate substantial health-adjusted life-years, and be cost-effective. 103
National programmes include the UK’s NHS Diabetes Prevention Programme, which reduced T2D incidence by 6–7% through diet, exercise and behavioural support, and the Better Health Campaign, which successfully increased awareness of obesity–cancer links without increasing stigma. 104 , 105
Practical Clinical Implications for Cardiovascular Practice
From a cardiovascular perspective, obesity should be recognised and managed as a chronic, multisystem disease and a modifiable driver of cardiovascular risk, rather than solely as a lifestyle issue or risk factor. The reclassification of obesity into preclinical and clinical disease reinforces the need for earlier identification of excess adiposity and ectopic fat-related organ dysfunction, even in individuals with BMI below traditional thresholds for defining obesity. Routine cardiovascular assessment should therefore incorporate measures of central adiposity, such as waist circumference or waist-to-height ratio, and systematic screening for obesity-related complications, including hypertension, AF, HF (particularly HFpEF) and metabolic dysfunction.
Effective obesity management in cardiovascular practice increasingly requires multidisciplinary working, with close collaboration between cardiologists, endocrinologists/obesity specialists, hepatologists and primary care teams. Integrated cardiometabolic clinics or shared-care pathways may facilitate timely initiation of evidence-based weight-lowering therapies, optimisation of cardiometabolic risk factors and coordinated monitoring of treatment response and adverse effects.
Importantly, not all anti-obesity therapies have equivalent cardiovascular evidence. The American Association of Clinical Endocrinology Consensus Statement 2025 highlights that, to date, semaglutide is the only approved agent that has demonstrated reduced incidence of MACE (by about 20%) in a pre-specified cardiovascular outcome trial in patients with obesity and established CVD, independent of baseline weight or weight change, and should therefore be currently recommended as a first-line treatment in this high-risk population; although post hoc 10-year predictions from clinical trial data suggest tirzepatide may confer additional cardioprotection. 16 , 92 , 106 , 107 Moreover, tirzepatide reduces cardiovascular death or decompensated HF by approaching 40% in patients with obesity and HFpEF. 93 These agents should therefore be considered cardioprotective therapies in people with obesity at elevated cardiovascular risk, rather than solely as weight-loss medications.
Therefore, for practising clinicians, a stepwise approach is recommended:
Recognise obesity as a significant cause of CVD
Assess central adiposity and obesity-related cardiovascular complications;
Provide advice to support appropriate lifestyle change and consider early initiation of evidence-based pharmacotherapy with agents demonstrating cardiovascular benefit; and
Escalate treatment through multidisciplinary pathways when targets are not achieved.
For practising clinicians, early referral, proactive treatment escalation and alignment of obesity management with cardiovascular prevention strategies represent critical opportunities to reduce downstream morbidity, mortality and healthcare usage.
Future Directions
Future efforts must focus on transitioning from a one-size-fits-all to a precision approach in obesity medicine. Advances in genomics, metabolomics and imaging now enable detailed phenotyping of individuals with obesity, facilitating the identification of distinct endotypes driven by differential patterns of adipose tissue distribution, hormonal responses and genetic predisposition. Integrating these multidimensional data into clinical practice could allow treatment stratification, matching patients to specific lifestyle, pharmacological or surgical interventions based on biological profiles and predicted response. This shift will be critical for optimising long-term efficacy, improving patient adherence and reducing treatment resistance.
Emerging digital health technologies and artificial intelligence (AI) are likely to play a central role in optimising and monitoring therapeutic interventions. Machine-learning models can integrate longitudinal clinical data, imaging-derived adiposity metrics, wearable sensor outputs, such as physical activity, heart rate variability and sleep, and biochemical markers to dynamically track treatment response, identify early non-response and prompt timely treatment escalation. 108 AI-driven analysis of imaging modalities, including MRI- and CT-derived fat depots, may enable automated quantification of visceral and ectopic fat changes, offering more sensitive markers of cardiometabolic risk modification than weight or BMI alone. 109 Similarly, digital platforms incorporating remote monitoring and adaptive feedback may improve adherence to pharmacotherapy and lifestyle interventions, while reducing healthcare usage. 108
In parallel, the reframing of obesity as a chronic, multisystem disease underscores the need to embed obesity management within cardiovascular, renal, hepatic and mental healthcare pathways, recognising shared risk mechanisms and treatment synergies. From a public health perspective, equity of access to evidence-based obesity care remains a major unmet need, particularly in low- and middle-income countries where prevalence is rising fastest but health system resources remain constrained. Future policy and research priorities should therefore focus on scalable, technology-enabled prevention strategies that modify obesogenic environments, ensure equitable access to pharmacotherapy and MBS and incorporate obesity as a vital sign in routine healthcare delivery. Only through this integrated, precision-based and globally inclusive approach can the growing burden of obesity and its downstream complications be effectively mitigated.
Conclusion
In conclusion, obesity has reached epidemic proportions globally, driving a rising burden of cardiometabolic, hepatic and psychological diseases with substantial societal and economic costs. The redefinition of obesity into preclinical and clinical stages highlights its pathophysiological complexity, recognising individuals with metabolic dysfunction or ectopic fat accumulation even at lower BMI thresholds, and will likely increase the estimated global prevalence. This shift underscores the urgent need for early detection and stratified, person-centred interventions that target the specific complications of obesity to reduce morbidity, mortality and health system strain.
The authors acknowledge the assistance of ChatGPT in the production of Figure 3 .
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