Overweight and Obesity — Capturing the Whole Picture

Overweight and obesity represent addressable proximal drivers of chronic disease. The prevalence of overweight and obesity is increasing around the world; by 2050, projections indicate that more than half the adult population worldwide will be living with overweight and obesity, most prominently in China (an estimated 627 million persons). In China, the numbers of persons with overweight and obesity have increased dramatically over the past four decades, contributing to major increases in the risks of noncommunicable diseases — including type 2 diabetes, cardiovascular disease, and cancer — and premature death. Dedicated interventional trials in Chinese populations are part of the multipronged strategy to increase evidence-supported obesity management in China.

Ji and colleagues5 now report in the Journal on the efficacy and safety of mazdutide, a once-weekly dual glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist, in 610 Chinese adults with overweight or obesity. This phase 3, double-blind, placebo-controlled trial explored the putative effects of multihormonal incretin-based therapy, which leverages the ability of GLP-1 to constrain the glycolytic effects of glucagon while exerting its effect on weight loss in a way that may specifically mobilize liver fat.6 It has become increasingly evident that glucagon agonism has highly divergent actions when delivered in combination with GLP-1, as compared with delivery on its own, yet the contribution of glucagon receptor agonism as compared with GLP-1 receptor agonism in the current trial cannot be dissociated.

The placebo-adjusted weight loss from baseline to week 32 was −13.00% (95% confidence interval [CI], −14.31 to −11.70) with mazdutide at a weekly dose of 6 mg and −10.54% (95% CI, −11.83 to −9.26) with a weekly mazdutide dose of 4 mg, from a mean body weight of 87.2 kg at baseline. More participants who received mazdutide (either dose) than who received placebo had a weight reduction of at least 5%, with higher magnitudes of weight loss with the higher dose (e.g., weight reduction of ≥15% in 44% of the participants in the mazdutide 6-mg group).

In addition to the fact that significance for the two primary end points (percentage change in body weight from baseline and a weight reduction of ≥5% at week 32) was met in this trial, comprehensive whole-body risk assessments were performed. These assessments showed meaningful improvements with regard to adiposity (body weight, body-mass index [BMI; the weight in kilograms divided by the square of the height in meters], total fat mass as assessed by dual-energy x-ray absorptiometry, and waist, hip, and neck circumferences), glycemia (glycated hemoglobin, fasting glucose, and fasting insulin levels and results on the HOMA2-IR [homeostasis model assessment–insulin resistance]), cardiovascular risk markers (systolic and diastolic blood pressure and high-sensitivity C-reactive protein, uric acid, and urinary albumin levels), liver markers (alanine aminotransferase and aspartate aminotransferase levels in the overall trial population and liver-fat content in a subpopulation of participants with liver steatosis), and physical function (according to the 36-Item Short Form Health Survey and the Quality of Life–Lite Clinical Trials Version questionnaire). The holistic data assessment provides compelling evidence that treatment with a dual GLP-1–glucagon receptor agonist in this population addressed more than just body weight and BMI alone but also comprehensively addressed the underlying whole-body health risk associated with excess adiposity.

The final population cohort that was enrolled in this trial also suggests either a shifting focus toward earlier preventive treatment for obesity or a phenotype representative of contemporary obesity in China. In a comparison of the Chinese cohort in the current trial (GLORY-1) with the population in the international SURMOUNT-1 clinical trial in obesity published in 2022,7 the population in the current trial was younger (mean age, 34.2 vs. 44.9 years), had a lower BMI consistent with Chinese criteria for overweight or obesity (mean BMI, 31.1 vs. 38.0), and a much lower prevalence of prediabetes (10.7% vs. 40.6%) and hypertension (22.8% vs. 32.3%) — findings consistent with a younger, metabolically healthier population than most participants in trials testing medications for obesity. Nevertheless, despite the lower enrollment of persons with prediabetes or hypertension in the current trial than in the earlier one, the population in GLORY-1 had a high prevalence of liver disease (48.9% with metabolic dysfunction–associated fatty liver disease vs. 7.1% with nonalcoholic fatty liver disease in SURMOUNT-1) and dyslipidemia (62.3% vs. 29.8%) and an overall high prevalence of weight-related coexisting conditions (88.9%).

This information serves to remind us that obesity-related conditions and complications may occur in different ethnic populations at different ages and with different manifestations that remain responsive to intervention. Furthermore, given the disproportionate number of years of life lost in persons in whom obesity develops at a younger age (at 20 to 30 years vs. >60 years), age may not be protective in the way that it is for cardiovascular disease. Although benefits were seen in the population as a whole, subgroup analyses and comprehensive longitudinal risk assessment may provide additional clarity regarding the risk–benefit ratio for pharmacologic treatment of obesity at this relatively younger age.

This trial also shows the importance of individual-level risk assessment, capturing with comprehensive clinical assessments various weight-associated risk factors and conditions that may be responsive to preventive treatment. Algorithms that attempt to generalize an approach to obesity into an “if–then” linear treatment sequence that is based on singular factors without considering the whole patient risk both overtreatment and undertreatment of the individual patient. With the unfolding of multiple new therapies and pathways to target the underlying biologic characteristics of obesity and related manifestations, future areas of research should also focus on comprehensive risk assessment at the individual-patient level to best understand effective timing and rationale for intervention. Although this trial highlights another stepping stone of progress regarding therapeutic agents for obesity, available, safe, and effective therapies are only one part of the expansive public health toolbox that will be required to curb obesity on a global scale.