New paradigm in obesity diagnosis & Tx: Look beyond BMI, treat to target to reduce complications

Obesity diagnosis should be based beyond BMI alone and include assessment of excess adiposity, organ dysfunction, daily activity limitations, and obesity-related diseases. A treat-to-target approach should be adopted to achieve disease-modifying effects and reduce obesity-related complications, according to Dr Samantha Hocking of the University of Sydney, Australia, who spoke at the 8^th Endocrinology, Diabetes & Metabolism Hong Kong Annual Meeting (EDM HK 2025).

Not just BMI

“The differences in international and Asian BMI cut-offs tell us there are limitations with using BMI alone in defining obesity,” said Hocking.

“Although BMI-based classification is useful, it does not tell us about body fat distribution, disease states or complications,” she continued. “Increased waist circumference is associated with increased risks of cardiovascular [CV] diseases and mortality, regardless of BMI.” [Lancet Diabetes Endocrinol 2025;13:221-262; Int J Obes (Lond) 2009;33:289-295; CMAJ 2011;183:E1059-E1066; BMJ 1984;288:1401-1404]

New diagnostic criteria

As current BMI-based measures of obesity can under- or over-estimate adiposity and provide inadequate information about an individual’s health, The Lancet Diabetes & Endocrinology Commission now recommends a three-step approach in diagnosis. Their consensus recommendations also pragmatically distinguish between preclinical obesity (ie, excess body fat associated with variable levels of health risk, but no ongoing illness) and clinical obesity (ie, a chronic disease due to obesity alone, characterized by signs and symptoms of ongoing organ dysfunction and/or reduced ability to conduct daily activities), which helps identify patients with different needs and urgency of care. [Lancet Diabetes Endocrinol 2025;13:221-262]

Step 1 in the diagnostic process is to confirm excess adiposity with ≥1 measurement of body size (ie, waist circumference, waist-to-hip ratio, or waist-to-height ratio) on top of BMI, or ≥2 measurements of body size regardless of BMI, or direct body fat measurement (eg, DEXA scan). “I prefer waist-to-height ratio as it is simple with no need for ethnicity-based adjustment,” said Hocking. “In those with BMI >40 kg/m², excess adiposity can pragmatically be assumed with no need for further confirmation.”

Step 2 involves medical history taking, physical examination, and standard blood tests to identify signs/symptoms of organ dysfunction and limitations of daily activities in individuals with excess adiposity. Preclinical obesity is characterized by preserved function of organs and other tissues, while clinical obesity is characterized by limitations of daily activities and/or obesity-related signs/symptoms of organ dysfunction.

“Step 3 is to assess obesity-related diseases and limitations. The Lancet Commission listed 18 conditions directly attributable to excess adiposity, involving the central nervous, respiratory, CV, reproductive, urinary, musculoskeletal and lymphatic systems, as well as metabolism, liver and kidneys,” said Hocking. “Obesity underpins most chronic conditions people now suffer from.”

“On top of these, we must not forget about the mental complications of living with obesity,” Hocking added. “Stigma against obesity is still very prevalent in societies and healthcare systems. There is a bidirectional relationship between obesity and depression.”

Treat to target to reduce complications

“A 16 percent weight loss produces disproportionately greater loss of intra-abdominal and liver adipose tissue, of 30 and 65 percent, respectively,” said Hocking. [Diabetes Spectrum 2020;33:117-124]

“There is a ‘dose-response’ relationship between weight loss and obesity-related complications. While 3–5 percent weight loss can improve insulin sensitivity and prevent progression from prediabetes to diabetes, ≥10–15 percent weight loss is needed to achieve diabetes remission. This highlights the importance of treating obesity to target to reduce complications,” Hocking emphasized. [Lancet 2022;399:394-405; J Clin Endol Metab 2022;107:e1339-e1347]

The difficulty of maintaining weight loss stems from underlying physiology: Weight loss leads to alterations in levels of hunger and satiety hormones. These changes are found to be maintained 1 year after initial weight loss. [Obes Rev 2020;21:e12949; N Engl J Med 2011;365:1597-1604]

“That’s why we need effective pharmacotherapy to achieve weight-loss targets,” Hocking pointed out.

GLP-1 RA and GIP/GLP-1 RA for obesity

Semaglutide (a glucagon-like peptide-1 [GLP-1] receptor agonist [RA]; 2.4 mg QW), as an adjunct to lifestyle intervention, demonstrated a mean weight loss of 14.9 percent at 68 weeks in its pivotal phase III, double-blind, randomized controlled trial on overweight/obesity. One in three patients in the semaglutide group achieved ≥20 percent weight loss. [N Engl J Med 2021;384:989-1002]

Tirzepatide (a dual glucose-dependent insulinotropic polypeptide [GIP] and GLP-1 RA; 5, 10 or 15 mg QW), as an adjunct to lifestyle intervention, demonstrated mean weight losses of 15–20.9 percent at 72 weeks in its pivotal phase III, double-blind, randomized controlled trial on overweight/obesity. Nearly 40 percent of patients on tirzepatide 15 mg QW achieved ≥25 percent weight loss. [N Engl J Med 2022;387:205-216]

“The weight-loss effects are impressive,” said Hocking. “To put this in context, weight loss at 1 year after bariatric surgery is 25–30 percent.”

Both trials also demonstrated improvements in cardiometabolic health parameters and physical function with semaglutide and tirzepatide. “With larger weight reductions seen with tirzepatide, we see better improvements in these health parameters,” noted Hocking.

In a phase IIIb, open-label, randomized controlled trial in patients with obesity, tirzepatide (maximum tolerated dose [MTD] of 10 or 15 mg) demonstrated greater mean body weight reduction vs semaglutide (MTD of 1.7 or 2.4 mg) at 72 weeks (20.2 vs 13.7 percent; p<0.001). Higher proportions of patients in the tirzepatide vs semaglutide group achieved ≥20 or ≥25 percent weight loss (48.4 vs 27.3 percent and 31.6 vs 16.1 percent, respectively). [N Engl J Med 2025;393:26-36]

“Greater improvements in important cardiometabolic risk factors were also seen with tirzepatide vs semaglutide,” said Hocking. “These included blood pressure, glycaemia, fasting insulin, and lipid levels.”

Choosing a medication: Practical considerations

“Apart from clinical trial data, patients’ preferences and cost should also be considered when choosing a medication for obesity,” said Hocking.

“Counselling should be provided on weekly injections, possible side effects, the need for long-term treatment, and the possibility of weight regain after treatment discontinuation,” she explained.

“Also, none of these newer therapies are reimbursed by our government. This may be related to stigma against obesity in the healthcare system. Advocacy on the important health outcomes from these medications is needed so that subsidized therapy is available for patients who need it most,” she continued.