Body mass index (BMI) is the most widely used tool for diagnosing obesity. Due to its simplistic nature, it fails to provide a more granular estimate of total body composition, a key metric for calculating obesity-associated cardiometabolic risk. Moreover, the interracial phenotypic variations in stature and body fat distribution are not accounted for by BMI.³³ Alternative measure of adiposity have been proposed, including waist circumference. A comprehensive account of obesity-related diagnostic modalities is listed in Table 1.

Individuals living with obesity experience discriminatory behaviors and scrutiny due to excess body weight, a phenomenon termed ‘weight stigma’.³⁴ Research has shown that the internalization of weight stigma is associated with significantly worse weight loss outcomes³⁵ secondary to a lack of confidence, anxiety, depression, and a reduced sense of self-esteem.³⁶ Healthcare workers should ascertain the extent of the patient's willingness to discuss weight management, ask openended questions, and use non-judgmental language during patient encounters (e.g. replacing phrases such as, ‘obese individuals’ or ‘morbid obesity’ with ‘individuals with obesity’ results in better discussion outcomes).

The 5As framework (ask, assess, advise, agree, and assist) provides the foundation for initiating and conducting motivational interviewing for weight management in individuals living with obesity.³⁷

Body mass index (BMI), calculated as weight /height² (reported in kg/m²), is a useful first-line screening tool for identifying patients with obesity. The standard BMI cut-offs for overweight and obesity recommended by the World Health Organization (WHO) are 25-29.9 kg/m² and ≥30.0 kg/m², respectively. Despite its widespread adoption, BMI is limited in its ability to discern lean body mass from body fat, thus providing a poor estimation of the total body fat percentage an important clinical marker for obesity-related cardiovascular disease (CVD) risk prognosis.³⁸ BMI fails to adjust for age, sex, and race-based differences in body fat composition, especially in adults. Wang et al. demonstrated that Asians recorded higher total body fat percentages at lower BMI values than their Caucasian counterparts.³⁹

Anthropometric measurements namely, higher waist circumference (males: ≥102 cm [40 inches]; females: ≥88 cm [35 inches] with lower cut-offs for Asian men [³90 cm] and women [³80 cm]) and higher waist-to-hip ratio (normal limits: <0.90 for males; <0.85 for females),⁴⁰ or higher waist-to-height ratio (≥0.50)^41,42 indicate increased cardiometabolic risk. DEXA and computed tomography (CT) scans provide more comprehensive measures of body fat distribution. Combining BMI with anthropometric measures of central obesity, which have demonstrated superior sensitivity and specificity in CVD risk prognostication, allows for a more robust evaluation of obesity-related complications. To date, however, BMI remains the primary obesity metric used in many countries, and more work is needed to determine if other measures can aid clinical practice and improve outcomes.

For a given level of body fat, age, and sex, individuals of Asian descent generally exhibit a lower BMI (by approximately 2-3 kg/m²) compared to their White counterparts, likely attributable to variations in body composition and muscularity, mandating the need for using different BMI cut-offs for this cohort for severity and risk estimation.⁴³

In 2004, a WHO Expert Consultation panel analyzed metabolic risk data from Asian countries and recommended lowering BMI thresholds for public health interventions in Asian populations. They proposed defining BMI ranges of 23.0-27.5 kg/m² as overweight and BMI ≥27.5 kg/m² as obese for this subset.¹ However, it is important to acknowledge that different Asian countries may have established their own BMI cut-offs for the diagnosis of overweight and obesity based on local epidemiological data. Where such country-specific thresholds exist, they should be used in place of the generalized WHO recommendations to ensure contextually appropriate risk stratification and intervention. Using the standard cut-offs in the United States, Asian Americans have low rates of overweight/obesity compared to the Non-Hispanic White (NH-White), African American, and Hispanic ethnic groups, yet they suffer from a disproportionately high burden of type 2 diabetes and associated metabolic abnormalities despite normal body weight profiles.⁴⁴

BIA utilizes impedance to electric conduction as a surrogate for estimating total body fat percentage and fat-free mass.⁴⁵ The accuracy and precision of this approximation are affected by hydration status, body geometry, and body water distribution.⁴⁶ The most accurate methods for estimating total body fat percentage are densitometry-based modalities, namely, underwater plethysmography and DEXA scanning.⁴⁷ However, none of these more costly measures are ripe for widespread use.

Calorie-restriction through dietary regulation can achieve a net-negative energy balance required for triggering weight loss but may also be associated with increases in hunger. Energy intake reduction of 500-750 Kcal per day can manifest in an initial weight loss of 0.5-1.0 kg (1.0-2.2 lbs) per week, or 2-3 kg (4.4-6.6 lbs) a month, not accounting for interpersonal variability.⁴⁹ Weight loss does not continue indefinitely despite continuous calorie restriction.

The Mediterranean Diet (MD) inspired by traditional eating habits in Mediterranean countries, emphasizes plant-based foods (fruits, vegetables, legumes, whole grains, nuts, and extra virgin olive oil), moderate intake of fish and dairy, and limited consumption of red meat. It is deemed as most effective at not only inducing weight loss,⁵⁰ but at maintaining 5-10% weight loss over prolonged periods, with or without physical activity.⁵¹ Poulimeneas and colleagues recruited participants from the MedWeight study and adherence to MD was assessed among them. The study reported that the participants adherent to the MD were two-times more likely to maintain weight loss of 5-10% than their non-adherent counterparts.⁵¹

The dietary approaches to stop hypertension (DASH) diet has demonstrated efficacy in inducing and maintaining weight loss as well, and is recommended as one of the first-line interventions for individuals with obesity suffering from hypertension. A meta-analysis underscored an additional −1.4 kg weight loss among the cohort consuming the DASH diet over other low-energy diets.⁵²

Intermittent Fasting (IF) diets entail alternating between 12-20 hours long periods of fasting and unrestricted eating. The 16:8 method (fasting 16 hours a day followed by an 8-hour eating window) and fasting for 24 hours twice a week (the 5:2 method) are some of the most commonly adopted approaches for dieters practicing IF. In a meta-analysis conducted by Almabruk and colleagues,⁵³ the IF fasting group experienced weight reductions ranging from 2 to 6 kg, and BMI decreased between 1 and 4 kg/m² over 1.5 and six months, respectively.

High­protein (HP) diets include consuming ≥1.6 g of protein per kg of body weight or obtaining ≥25% of calories from protein.⁵⁴

Low­fat (LF) diets prescribe deriving less than 30% of daily calorie requirement from fats. Evidence on using LF-diets as a standalone therapy for weight loss is sparse. Astrup et al.⁵⁵ reported a mean weight loss of 3.2 kg (95% CI: 1.9-4.5 kg) in the LF-diet group compared to the control in their meta-analysis of 16 RCTs. On the contrary, the DIRECT trial⁵⁶ comparing low-carbohydrate, Mediterranean, and LF diets reported higher weight loss in the low-carbohydrate and Mediterranean groups (-4.7 kg and −4.4 kg, respectively). The PREDIMED trial⁵⁷ demonstrated better cardiovascular outcomes in the group on the Mediterranean diet supplemented with extra-virgin olive oil or nuts compared to the LF-diet group.

Low­carb diets (LCDs) and calorie­restricted diets (CRDs): Low-carb diets are further classified into very low, low, moderate, or high-carb diets based on per diem carbohydrate load (very low; 20-50 g/day, low; ≤130 g/day). Ketogenic diets are a type of very low-carb diet. They work by depleting the body's glycogen stores to use fat stores as the primary source for energy production through the generation of ketones. Although effective at inducing weight loss and improving glycemic control in diabetics, the LCDs have been linked to greater odds of cardiovascular morbidity and mortality.⁵⁸ Thus, warranting caution and careful patient selection when identifying candidates for LCD-based weight loss intervention. Calorie-restricted diets are an effective recourse for achieving 5-10% weight loss. Combined with increased proportions of protein and dairy intake, they may reduce body fat percentage, total cholesterol (TC), and low-density lipoprotein-cholesterol (LDL-c) levels. However, statins remain the mainstay of pharmacologic therapy for lowering LDL-c in patients with obesity due to their robust evidence in reducing atherosclerotic cardiovascular risk. Intermittent fasting has gained traction as a potent means for achieving calorie restriction. In a randomized controlled trial (RCT), Sun and colleagues uncovered the synergistic weight loss effect achieved by combining LCDs with CRDs. Compared to those in the calorie-restricted (CR) only group, participants in the LCD plus CR group lost 55% more body mass index (BMI).⁵⁹ Wycherly et al.⁶⁰ performed a meta-analysis of 95 studies, wherein they established modest decreases in body weight (-0.79 kg; 95% CI, −1.50 to −0.08) and body fat mass (-0.87 kg; 95% CI, −1.26 to −0.48 kg) in the group consuming HP diets in comparison to the low-fat, low-carbohydrate, energy-restricted standard protein diet group.

In conclusion, this consensus statement recognizes that there is no universally superior dietary strategy for the management of obesity and that the average effects are modest. Rather, the optimal dietary approach is one that is tailored to the individual's preferences, cultural context, and lifestyle, and that supports long-term adherence. Notably, the limited long-term success of most diets is less often due to the specific macronutrient composition or structure of the diet itself, and more commonly attributable to challenges with sustained adherence over time.

In the last decade, incretin-based medications with high efficiency of weight loss have emerged. These include liraglutide, semaglutide, and tirzepatide. They act on GLP-1 receptors in the pancreatic β-cells, increasing intracellular cyclic AMP (cAMP) and triggering endogenous insulin release and appetite suppression. Tirzepatide is a dual GLP-1RA / Glucose-dependent insulinotropic polypeptide (GIP) agonist that works by modulating insulin release and increasing adiponectin levels.

Liraglutide, a GLP-1 receptor agonist (RA) is approved for chronic weight management in adults with a BMI of 30 kg/m² or at least 27 kg/m², if at least one weight-related comorbid condition is present. Dosing begins at 0.6 mg daily for one week and is then titrated up weekly at 0.6 mg intervals until the recommended dose of 3 mg daily is reached. LEADER,⁶⁸ Satiety and Clinical Adiposity-Liraglutide Evidence in individuals with and without diabetes (SCALE),⁶⁹ SCALE Maintenance,⁷⁰ SCALE Diabetes,⁷¹ and SCALE Sleep Apnea⁷² were among the most prominent RCTs evaluating liraglutide's safety and efficacy profiles. A meta-analysis⁷³ revealed that liraglutide produced a mean 5.2 kg placebo-subtracted weight loss at 1 year, with 63% of participants achieving a ≥5% weight loss, inclusive of 34% of participants who lost ≥10% of initial weight. Weight loss of 7% was maintained for 3 years in the SCALE Prediabetes study.⁷⁴

The recent expiration of liraglutide's patent protection in multiple countries opens the door for generic versions, which may become a cost-effective GLP-1 RA option in resource-limited settings. This could enable broader pharmacologic implementation, particularly in LMICs where newer agents like semaglutide and tirzepatide remain cost-prohibitive.

Semaglutide, another GLP-1RA, works by up-regulating the downstream effects of GLP-1 receptor activation.⁷⁵ Once-weekly subcutaneous semaglutide 1.0 mg was approved by the FDA in 2017 and the European Medicines Association in 2018 for the treatment of type 2 diabetes.⁷⁶ In 2021, the FDA approved 2.4 mg once weekly semaglutide for treating obesity in adults. Ongoing trials of oral semaglutide may result in another option for the treatment of obesity, but at the time of publishing this guideline, oral semaglutide was not yet approved by any regulatory authorities, and hence it cannot be recommended. Higher dose (7.2 mg) once weekly semaglutide may also become available in the near future, but they are not yet approved for use.

Semaglutide Treatment Effect in People with obesity (STEP) was the first global program to evaluate semaglutide 2.4 mg once weekly for weight management.

STEP 1⁷⁷ The STEP 1 trial (Semaglutide Treatment Effect in People with obesity) was the first large-scale, double-blind, randomized controlled study to demonstrate that once-weekly subcutaneous semaglutide 2.4 mg led to significant weight loss in non-diabetic adults with overweight or obesity. Participants receiving semaglutide lost an average of 14.9% of body weight, compared to 2.4% in the placebo group over 68 weeks.

STEP 2⁷⁸ compared semaglutide 2.4 mg vs 1.0 mg with placebo. The 2.4 mg dose cohort had the highest 9.6% of baseline body weight loss compared to the 1.0 mg group that experienced 7% of baseline body weight loss.

STEP 3⁷⁹ showed that including intensive lifestyle therapy with semaglutide did not affect weight loss as the weight loss in the drug plus intensive lifestyle arm was 16%, the same as STEP 1, which did not have an intensive lifestyle component. STEP 4⁸⁰ revealed that discontinuing semaglutide resulted in weight regain, while continuing semaglutide beyond 20 weeks resulted in 16-18% weight loss.

STEP 5⁸¹ was the first long-term study that ran for 104 weeks and corroborated the findings of the previous studies, and showed how increased duration of treatment resulted in maintenance of the 16% weight loss achieved at 1 year. No weight regain was observed when the medication was continued.

STEP 8,⁸² a phase 3 trial, compared once-weekly subcutaneous semaglutide (2.4 mg) with once-daily liraglutide (3.0mg) in adults with overweight or obesity without diabetes mellitus. Semaglutide resulted in significantly greater weight loss (-15.8%) compared to liraglutide (-6.4%). Semaglutide also showed higher odds of achieving ≥10%,

≥15%, and ≥20% weight loss. Both treatments had similar rates of gastrointestinal adverse events.

In the STEP 9⁸³ trial, semaglutide 2.4 mg administered once weekly resulted in significant improvements in knee pain, function, and stiffness, as well as weight loss, in individuals with obesity and symptomatic knee osteoarthritis. These findings suggest that semaglutide may have added musculoskeletal benefits, particularly in patients for whom joint pain limits mobility or exercise tolerance.

The recently concluded STEP UP⁸⁴ trial compared weekly 7.2 mg semaglutide to 2.4 mg semaglutide and placebo in adults with obesity without diabetes mellitus. People treated with semaglutide 7.2 mg achieved a superior weight loss of 20.7% after 72 weeks compared to a reduction of 17.5% with semaglutide 2.4 mg and 2.4% with placebo. In addition, 33.2% of those who received semaglutide 7.2 mg achieved a weight loss of 25% or more after 72 weeks, compared to 16.7% with semaglutide 2.4 mg and 0.0% with placebo. In the STEP UP T2D⁸⁵ trial results were largely confirmed in adults with obesity with diabetes mellitus using the same treatment approach. People treated with semaglutide 7.2 mg achieved a superior weight loss of 13.2% after 72 weeks compared to a reduction of 3.9% with placebo (p<0.0001). In patients with semaglutide 2.4 mg, weight loss amounted to 10.4%.

In all these trials, weight losses were generally less in people with type 2 diabetes than without, though recent evidence suggests that weight losses are substantially greater in type 2 diabetes when HbA1c levels are lower.⁸⁶ The lower weight losses seen with weight loss therapies at higher HbA1c levels may be partly due to correction of unintentional weight losses due to glucosuria. In SURMOUNT-2, weight losses in in people with type 2 diabetes was similar to that in people without when HbA1c <7.0%.⁸⁷

The SELECT study⁸⁸ showed weight maintenance for 4 years without any regain, provided the medication was continued. This is also the only RCT in patients with obesity without diabetes that has shown a reduction in major adverse cardiovascular events when an intentional weight loss strategy was used.⁸⁸

The SELECT⁸⁸ trial was a large, randomized, placebo-controlled cardiovascular outcomes trial (CVOT) that enrolled 17,604 patients with established atherosclerotic cardiovascular disease (ASCVD) and either obesity or overweight (BMI ≥27 kg/m²) but without diabetes. Over a mean follow-up of

39.8 months, subcutaneous semaglutide 2.4 mg once weekly significantly reduced the incidence of major adverse cardiovascular events (MACE), a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, by 20% compared to placebo (HR 0.80; 95% CI, 0.72-0.90; p<0.001). Although hazard ratios for cardiovascular death (HR 0.85; 95% CI, 0.71-1.01) and the composite of cardiovascular death or heart failure events (HR 0.82; 95% CI, 0.71-0.96) favored semaglutide, these endpoints did not meet the required significance thresholds in hierarchical testing.

STEP HFpEF⁸⁹ and STEP HFpEF DM⁹⁰ showed that treatment with semaglutide led to a reduction in heart failure events, NT-proBNP and CRP levels, as well as an improvement in 6-minute walking distance (6MWD) and Kansas City Cardiomyopathy (KCCQ) scores in patients with confirmed HFpEF and the obesity phenotype, over one year, compared to placebo.⁹¹

STRIDE,⁹² a phase 3b randomized placebo-controlled trial, studying the role of semaglutide in peripheral artery disease (PAD) reported that in patients with concomitant diabetes and PAD with intermittent claudication, semaglutide (1.0 mg weekly) significantly improved maximum walking distance at 52 weeks by a mean of 39.9 meters versus placebo, a 13% greater median improvement from baseline (estimated treatment ratio: 1.13; 95% CI: 1.06-1.21; p= 0.0004). It also reduced the composite risk of rescue therapy or all-cause death by 54% (HR 0.46; 95% CI: 0.24-0.85), and improved quality of life.

The ESSENCE trial⁹³ enrolled adults with metabolic dysfunction-associated steatohepatitis (MASH) and moderate to advanced fibrosis (stage 2-3). Treatment with weekly semaglutide 2.4 mg for 72 weeks achieved resolution of steatohepatitis with no worsening of fibrosis in ∼62.9% vs

∼34.3% with placebo, and improvement in fibrosis with no worsening of steatohepatitis in ∼36.8% vs ∼22.4%. Patients also lost an average of ∼10.5% of body weight vs ∼2.0% with placebo, with a safety profile consistent with prior semaglutide obesity trials.

In the SURPASS 1-5 trials, which evaluated glycemic lowering efficiency as an primary endpoint, different dosages of tirzepatide (5 mg, 10 mg, and 15 mg once weekly) demonstrated significant weight reduction as a secondary endpoint in patients with type 2 diabetes mellitus (T2DM), especially when compared to placebo (SURPASS 1),⁹⁴ semaglutide 1 mg (SURPASS 2),⁹⁵ insulin degludec as an add-on to metformin with or without SGLT2 inhibitor (SURPASS 3),⁹⁶ insulinglargine (SURPASS 4),⁹⁷ and placebo +insulin glargine (SURPASS 5).⁹⁸ The overall weight loss ranged from 7.6 kg, 10.7 kg, to 12.9 kg with tirzepatide 5 mg, 10 mg, and 15 mg, respectively.

The SURMOUNT 1-4 trials were specifically designed to evaluate the weight-lowering effectiveness and safety of tirzepatide as an adjunct to lifestyle interventions compared to a placebo in patients with obesity, with or without T2DM. SURMOUNT 1⁹⁹ compared tirzepatide 5 mg vs 10 mg vs 15 mg vs placebo in patients without diabetes. At the end of 72 weeks, 5 mg,10 mg, and 15 mg groups experienced a −15%, −19.5%, and −20.9% weight reduction vs −3.1% in those receiving placebo. In the 3-year extension of SURMOUNT-1 among participants with prediabetes, mean weight reductions at 176 weeks were −12.3% with tirzepatide 5 mg, − 18.7% with 10 mg, and −19.7% with 15 mg, compared with −1.3% in the placebo group.¹⁰⁰

SURMOUNT 2⁸⁷ included patients with concomitant obesity and type 2 diabetes mellitus. tirzepatide 10 mg, 15 mg, and placebo were compared for 72 weeks. The mean change in body weight at the end was −12.8%, −14.7%, and −3.2%, respectively.

SURMOUNT 3¹⁰¹ patients were subjected to an intensive lifestyle intervention, and only those who lost ³5% weight on it were randomized to either tirzepatide (10 or 15 mg) or placebo. Mean weight change at the end of 72 weeks was − 18.4% for tirzepatide, while the group treated with the intensive lifestyle intervention and placebo had a weight increase of 2.5%.

SURMOUNT 4¹⁰² started as an open-label trial. Participants experienced a 20.9% weight loss. Then they were randomized. Those who switched to the placebo experienced a 14% weight gain, whereas those who continued with tirzepatide lost an additional 5.5% of their initial weight.

SURMOUNT 5¹⁰³ trial demonstrated that maximally tolerated tirzepatide (10 mg or 15 mg once weekly) achieved significantly greater weight loss than maximally tolerated semaglutide (1.7 mg or 2.4 mg) over 72 weeks in adults with obesity or overweight and at least one comorbidity. Specifically, tirzepatide led to a 20.2 % mean reduction in body weight vs 13.7% with semaglutide (p<0.001), along with a greater mean decline in waist circumference (-18.4 cm vs − 13.0 cm).

For patients who plateau on GLP-1 receptor agonists, switching to an alternative GLP-1RA based drug could offer additional benefit in terms of weight loss. This statement reflects a consensus opinion based on available comparative trial data and clinical experience. However, it is important to note that no dedicated randomized «switch» study currently exists to formally evaluate this strategy. Until further studies are available, such an approach should be considered cautiously, considering safety, patient preference, and long-term goals. Drug accessibility, safety, and longterm adherence remain additional critical factors in therapy selection.

SURMOUNT-OSA¹⁰⁴ investigated the utility of tirzepatide in patients in two cohorts (Cohort 1 not using CPAP, Cohort 2 using CPAP) with obstructive sleep apnea (OSA). They found that among persons with moderate-to-severe obstructive sleep apnea and obesity, tirzepatide reduced the AHI, body weight, hypoxic burden, high-sensitivity C-reactive protein (hsCRP) concentration, and systolic blood pressure and improved sleep-related patient-reported outcomes.

SYNERGY-NASH¹⁰⁵ revealed that in patients with MASH and moderate or severe fibrosis, treatment with tirzepatide for 52 weeks was more effective than placebo with respect to the resolution of MASH without worsening of fibrosis.

In the SUMMIT trial,¹⁰⁶ weekly subcutaneous tirzepatide (up to 15mg) was compared with placebo over 104 weeks in adults with obesity and heart failure with preserved ejection fraction (HFpEF; LVEF ≥50%). Tirzepatide reduced the risk of cardiovascular death or worsening heart failure events by 38% compared to placebo (HR 0.62; 95% CI, 0.41-0.95; p=0.026), and improved patient-reported symptom burden and quality of life. Mean Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores increased by 19.5 points compared to 12.7 with placebo (mean difference 6.9; 95% CI, 3.3-10.6; p<0.001). These findings support tirzepatide's emerging role as a potential disease-modifying therapy for obesity-related cardiovascular comorbidities.

In the SURPASS-CVOT trial,¹⁰⁷ in more than 13,000 patients with T2DM, weekly subcutaneous tirzepatide (up to 15 mg) as compared to weekly dulaglutide (1.5 mg) was non-inferior for rate of major adverse cardiovascular events (MACE- 3: hazard ratio 0.92, 95.3%CI: 0.83-1.01, p=0.086) and was found to nominally lower all-cause mortality by 16% (p=0.002). At the time of publication, the trial was not yet published.

Consider using biosimilar liraglutide, which is expected to be less expensive than semaglutide or tirzepatide in resource-limited settings. Hopefully, in a few years, biosimilar semaglutide may become available, as well as multiple small-molecule non-peptide GLP-1RAs currently in development, which may be easier to produce in a more scalable fashion, making them more affordable. Unfortunately, compounded products of GLP-1RAs of unknown origin are being increasingly used as lower-cost alternatives in some countries, despite a lack of data on manufacturing quality control and the absence of randomized controlled trials to properly assess their safety and efficacy.

The authors of this guideline recognize the need to address access to obesity medications in lower- and middle-income countries. However, in many parts of the world, these incretin-related compounded medications are either disallowed or illegal, or are subject to litigation in courts, as they are associated with significant safety and efficacy concerns. We cannot recommend the use of these compounded obesity medications, but recognize the fact that they are a reflection of a serious call to the pharmaceutical industry to address the need to improve access and affordability to larger populations of the currently approved, properly tested obesity drugs.

When selecting anti-obesity pharmacologic agents, both efficacy and cost-effectiveness must be considered. While GLP-1RAs demonstrate the greatest weight loss benefits, they are also among the most expensive options, with annual costs significantly higher than agents like orlistat or phentermine/topiramate. Economic analyses suggest that for populations with established cardiovascular disease or diabetes, semaglutide may be cost-effective due to associated reduction in adverse events. In contrast, orlistat and naltrexone/bupropion may offer more favorable cost-benefit profiles for primary obesity management in lower-income settings. However, for orlistat and naltrexone/bupropion as well as for phentermine/topiramate no cardiovascular outcome benefit has been documented.

Additionally, cold chain storage, injectable delivery routes, and limited drug approvals in certain countries further constrain accessibility. Health systems should evaluate all these issues when selecting pharmacological interventions.

SGLT2 inhibitors are not approved to treat obesity per se, i.e. they are not drugs for treatment "of obesity". However, they are very effective medicines for patients "with obesity" and cardio-renal-metabolic disease. SGLT2 inhibitors work by blocking the re-uptake of sodium and glucose in the proximal convoluted tubule- a mechanism that is thought to underlie its weight loss effects. Although they cause minimal weight loss and are not considered weight loss agents per se, they are very effective in improving outcomes in chronic conditions that commonly co-exist with obesity, including heart failure and chronic kidney disease. Mazidi and colleagues,⁸¹ in their meta-analysis of 43 RCTs evaluating the efficacy and safety profile of SGLT2 inhibitors in managing diabetes-related comorbidities, reported a weighted mean difference of −1.8 kg (95% CI: −2.1 to −1.6 kg) between the SGLT2 inhibitor group and those receiving placebo. In a meta-analysis of 15 randomized controlled trials, Usman and colleagues¹⁰⁸ demonstrated that SGLT2 inhibitors significantly reduced risks for HF-related hospitalization and cardiovascular mortality in patients with HF, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease.

Orlistat works by inhibiting the lipase mediated breakdown of fats, thus decreasing fatty uptake from the gut. One of the earliest investigations of Orlistat-mediated weight loss was conducted by Zavoral,¹⁰⁹ who performed a pooled analysis of data from five RCTs and reported that at the one year mark, patients taking orlistat 120 mg thrice daily, experienced significantly greater weight loss than those on a placebo, with an average reduction of 9.2% compared to 5.8% (p<0.001). Additionally, a higher percentage of orlistat-treated patients achieved weight loss of over 5% and over 10% of their initial body weight, compared to those on placebo (69.6% vs 51.9%; p<0.001 and 42.1% vs 22.7%; p<0.001, respectively). Since then, several RCTs^110-112 and prospective observational studies have detailed more comprehensive accounts of orlistat's efficacy in managing obesity and preventing the development of as well as treating its co-morbidities namely, dyslipidemias, MASLD and diabetes.

Phentermine, an adrenergic stimulant, induces weight loss by appetite suppression. Although the exact mechanisms underlying Topiramate's role in inducing weight loss have not been elucidated, it is hypothesized to reduce total body fat content.¹¹³ The EQUIP-trial¹¹⁴ showed a significant decrease in body weight (10.9% of baseline weight) in the group receiving Phentermine/Topiramate (15 mg/92 mg) when compared to matched controls receiving placebo (1.6% of baseline weight). Phentermine/ Topiramate is FDA approved for use as a weight loss regimen in the U.S. since 2012. It is also approved in more than 10 European countries; however a Europe-wide general approval of EMA has not been granted. This combination is contraindicated in patients with a with glaucoma, and in hyperthyroidism.

Naltrexone / Bupropion induce weight loss by increasing signaling from the pro-opiomelanocortin (POMC) neurons in the hypothalamus. Consequently decreasing appetite by blunting the hyperphagia pathways in the mesolimbic system.¹¹⁵ The recommended dose for obesity treatment is a total of 32 mg naltrexone and 360 mg bupropion. ¹¹⁶ The Contrave Obesity Research program encompasses a series of four RCTs (COR-I,¹¹⁷ COR-II,¹¹⁸ COR-DM¹¹⁹ and COR-BMOD¹²⁰) that form the central body of literature depicting the efficacy of the naltrexone/ bupropion combination drug in obesity management. These phase III trials demonstrated that over approximately 56 weeks, naltrexone 32 mg/bupropion 360 mg plus lifestyle intervention led to mean weight loss of 8.1-8.2% in COR-I and COR-II (vs 1.3-1.7% with placebo), 3.7% in COR-DM (vs 1.7%), and 9.3% in COR-BMOD with intensive behavioral modification (vs 5.1%). A history of hypertension, depression, breastfeeding or active substance abuse precludes the use of naltrexone/ bupropion.¹²¹

A stimulant medication used very rarely for treating obesity in children and adolescents with underlying eating disorders. It is primarily approved for ADHS and binge eating. To avoid adverse effects (e.g., significant weight gain in a small subgroup of patients), close follow-up is needed when this treatment is applied.

Several novel dual and triple agonists built on a GLP-1RA backbone are in various stages of clinical trials. In the phase III REDEFINE 1 trial,¹²² weekly CagriSema (combination of amylin-based cagrilintide and incretin-based semaglutide) (2.4 mg each) produced a mean weight loss of 20.4 % vs 3.0 % with placebo at 68 weeks (difference −17.3 percentage points; p<0.001). In fully adherent participants, weight loss reached 22.7%, with over 40% achieving ≥25% reduction in body weight. Orforglipron, a once-daily oral nonpeptide GLP-1RA, demonstrated a placebo-adjusted weight reduction of up to 5.9% and HbA1c reduction of up to 1.07% over 40 weeks in the phase 3 ACHIEVE-1 trial.¹²³ Novel drug therapies acting centrally (setmelanotide; melanocortin 4 [MC4] receptor activator, velneperit; neuropeptide Y antagonist, zonisamide-bupropion; combination drug comprised of sodium and T-type calcium channel blocker as well as norepinephrine-dopamine reuptake inhibitor, and cannabinoid type-1 receptor blockers), and peripherally including amylin mimetics (davalintide), pramlintide-metreleptin (amylin and leptin analogues working by slowing gastric emptying and inducing early satiety), beloranib (methionine aminopeptidase 2 inhibitors), and novel anti-obesity vaccines (ghrelin, somatostatin, adenovirus36) are currently under investigation as emerging adjuncts in obesity pharmacotherapy.¹²⁴

This is the most widely adopted technique for performing bariatric surgery owing to its superior safety and efficacy profile.¹²⁷ Mechanisms are complex - amongst other things it induces weight loss by increasing signaling from the gut to the brain, including hampering ghrelin release, increasing satiety hormones, bile acids and altering the gut microbiota.¹²⁸ It should especially be considered in patients with BMI ≥30 kg/m² (or higher) with diabetes mellitus, hypertension, hyperlipidemia or other CVD risk factors (Table 5).¹²⁹

Sleeve gastrectomy is effective and comparable to slightly worse for weight loss, in comparison to the Roux-en-Y bypass,^130,131 but with a greater risk of developing gastroesophageal reflux disease (GERD) and Barrett's esophagus, and the irreversible nature of the procedure.¹³⁰

Abu Dayyeh et al.¹³² conducted an RCT to demonstrate that; when used in conjunction with lifestyle interventions, adjustable IGB resulted in significant weight loss (15% in the aIGB group vs 3% in the control group; p<0.0001) which maintained for 6 months following balloon removal. Most other studies suggested weight regain when the balloon is removed.

Gastric banding utilizes laparoscopic approach to modulate gastric filling. The overall weight loss effect is achieved by invoking the early satiety mechanisms. There are a number of well conducted RCTs showing the safety and superior efficacy of gastric banding in comparison to lifestyle changes. The only long-term RCT comparing Roux-en-Y gastric bypass with gastric banding reported significantly superior weight loss outcomes for the former.¹³²

The BPD/DS is another effective bariatric surgery procedure, characterized by a sleeve gastrectomy followed by gastroileal and ileoileal anastomoses.¹³⁴ In a longitudinal analysis of the weight loss effects of this procedure by Sorribas and colleagues reported 15%, 18% and 18% initial body weight loss at 2, 5 and 10 year intervals.¹³⁵ In a meta-analysis estimating the efficacy of bariatric surgery procedures, Buchwald et al., reported that the percentage of extra body weight lost (calculated as [preoperative BMI−current BMI)/(preoperative BMI−25] × 100) at 2-years of follow-up was the highest (73%) for the BPD/DS subgroup, followed by the gastric bypass (63%), gastroplasty (56%), and gastric banding (49%) subgroups.¹³⁶

A forecasting study from the Global Burden of Disease Study 2021⁶ examined the prevalence, trends, and future projections of overweight and obesity in children and adolescents across 180 countries from 1990 to 2021, with projections extending to 2050. The study reported that between 1990 and 2021, the global prevalence of overweight and obesity in youth doubled, while obesity alone tripled. In 2021, an estimated 93.1 million children (5-14 years) and 80.6 million adolescents (15-24 years) were living with obesity. The highest prevalence was noted in North Africa, the Middle East, and parts of Oceania, with the greatest increases observed in Southeast Asia, East Asia, and Oceania. By 2050, obesity rates are expected to rise further, particularly in South Asia, surpassing historical trends globally. Routine screening for overweight and obesity should begin at age 6 years, using BMI-for-age percentiles based on WHO or CDC growth charts. Earlier screening may be warranted in children with risk factors such as a family history of obesity, rapid weight gain in infancy, or comorbid conditions such as sleep-disordered breathing or insulin resistance.¹³⁷ As with adults, effective weight management in children and adolescents requires more than dietary changes alone; it should include physical activity and psychosocial support, with dietary strategies tailored to the child's preferences, comorbidities, food restrictions, and personal context as part of a comprehensive care plan.¹³⁸

School-based interventions such as healthier meal offerings, physical activity programs, and culturally relevant nutrition awareness talks can help foster healthier habits at a young age and prevent obesity, especially in resource-limited settings with limited healthcare access.

Recent evidence supports the use of GLP-1RAs in children and adolescents with obesity. In children aged 6 to <12 years, liraglutide 3.0 mg daily reduced BMI by 7.3% at 52 weeks (vs 1.5% with placebo).¹³⁹ Among adolescents, semaglutide 2.4 mg weekly achieved a 16.1% BMI reduction at 68 weeks (vs 0.6%),¹⁴⁰ and liraglutide 3.0 mg daily reduced BMI by 4.6% at 56 weeks (vs a 1.6% increase).¹⁴¹ These trials support the adjunctive use of GLP-1RAs with lifestyle therapy in pediatric obesity (Table 6).

The detrimental impact of gestational obesity on both maternal and fetal well-being has been well documented in the literature, making adequate weight control both in the antenatal period and during pregnancy of paramount importance. A holistic approach consisting of nutritional support, physical activity guidance, and supervision can optimize obesity management during pregnancy, improving health outcomes for both the fetus and the mother.¹³⁸

The detrimental impact of gestational obesity on both maternal and fetal well-being has been well documented in the literature, making adequate weight control both in the antenatal period and during pregnancy of paramount importance. A holistic approach consisting of nutritional support, physical activity guidance, and supervision can optimize obesity management during pregnancy, improving health outcomes for both the fetus and the mother. Balanced dietary intake in line with gestational calorie requirements remains key. Restrictive or very-low-calorie diets are strongly discouraged.^142-145 Moderate-intensity physical activity, such as brisk walking or swimming, is generally safe and encouraged in the absence of contraindications and has been shown to be associated with better outcomes.^142,146,147 Early screening for gestational diabetes should be offered to all pregnant individuals with obesity, with repeat testing at 24 to 28 weeks where appropriate.^144,148 All obesity medications, including GLP-1 receptor agonists of any kind, orlistat and phentermine/topiramate etc., are contraindicated during pregnancy, and women of reproductive age on such therapies should receive counseling on contraception and medication discontinuation if pregnancy occurs^{143,144,148,149} (Table 7).

Recommendations pertaining to interventions for obesity in patients with psychiatric illnesses are listed in Table 8.