In June 2024, the American Diabetes Association identified results from a few clinical trials — SELECT, FLOW, STEP-HFpEF and STEP-HFpEF-DM — as the main clinical advances of the year. Not surprisingly, all four trials evaluated glucagon-like peptide 1 receptor agonists (GLP-1RAs) as core interventions in populations with diabetes. GLP-1RAs, a class of medications that mimic the effects of the hormone GLP-1, aid in the regulation of blood sugar, weight loss and metabolic health improvement, which makes them effective for the treatment of diabetes and obesity. The National Health Service in the UK has proposed that providing weight-loss injections to unemployed individuals living with obesity could be beneficial for both the economy and public health. This decision was met with some criticism, including comments that the government was stigmatizing unemployed people and reducing them to their economic value1. Criticims aside, there are other shortcomings associated with making these drugs widely available, such as limited clinical trial data from heterogeneous populations that reflect the true make-up of the society. Although the safety and efficacy of a wide variety of GLP-1RAs have been assessed in large clinical trials, there is a deficit of good-quality data on young and older people, as well as people not of European ancestry. This raises the question of whether the time is right to shift from a generalized approach to a precision-based approach in obesity treatment.

In the SELECT trial involving a highly diverse pool of participants, treatment with the GLP-1RA semaglutide resulted in clinically meaningful weight loss over 208 weeks2. Despite the significant weight loss observed across all groups, subgroup analyses based on self-reported race, sex and body-mass index (BMI) cutoffs highlighted discrepancies in weight loss and other anthropometric parameters, with discontinuations increasing as BMI class decreased. On average, women experienced greater weight loss than men and people of self-reported Asian race recorded smaller weight reductions — both deviations potentially attributable to the distinct BMI classes to which the participants belonged. One limitation of the trial relates to the dataset, which, although large and diverse, lacked sufficient representation within racial subgroups, which can often produce misleading results.

The SURMOUNT-CN randomized clinical trial, assessing once-weekly treatment with tirzepatide in Chinese adults, demonstrated significant and clinically meaningful weight loss3, consistent with other SURMOUNT trials conducted predominantly in self-reported white populations. However, in the SURMOUNT-CN study, weight loss continued until week 44, when it reached a plateau3, whereas in the SURMOUNT-1 study, body weight continued to decrease for 72 weeks4. These variations were attributed to two main factors: distinct BMI cutoffs imposed as part of the respective inclusion criteria, and differences in the proportion of female participants recruited in the two trials. It is known that BMI thresholds are very different between populations on the basis of ethnicity — for example, Chinese adults generally have a lower BMI threshold for obesity than that of populations of European descent, which can in turn impact the efficacy of the same drug dose across diverse populations. These findings emphasize the need to design and implement GLP-1RA trials with outcomes tailored to address sex- and BMI-based differences in populations with diverse ethnicities.

Beyond sex and BMI, age-based tailoring of GLP-1RA treatment could improve clinical outcomes. Evidence suggests that among adolescents with obesity, the most rapid weight gain occurs between 2 and 6 years of age, which highlights the importance of reevaluating the appropriate timing of GLP-1RA treatment initiation and continuation throughout life5. However, few clinical options have been tested for children and adolescents facing the obesity crisis. A long-term weight-management trial conducted by the SCALE Kids Trial Group in children 6 to less than 12 years of age showed that liraglutide, a GLP-1RA, was superior to placebo in reducing body weight and BMI6. Although direct comparison across age groups is not ideal, a larger treatment difference of almost double the BMI standard-deviation score was observed in children than in adolescents, with both age groups experiencing an increase in BMI after discontinuing pharmacotherapy7. These differing observations alone justify further exploration of dose responses, treatment regimens and duration that each age group needs to achieve maximum efficacy with minimal side effects throughout the life course.

Major trials evaluating the effect of GLP-1RAs on cardiovascular, kidney and liver outcomes have shown that the benefits of these drugs might extend beyond weight loss. As the utility of this class of incretins expands to the treatment of diseases beyond obesity, factoring in comorbidities when prescribing these drugs for weight loss becomes a logical approach if the aim is to provide tailored healthcare for all. The risk of comorbidities varies on the basis of age, sex and ethnicity, which reinforces the need for trials designed specifically for distinct risk stratification, reducing the reliance on post hoc and underpowered subgroup analyses.

The potential of GLP-1RAs seems almost infinite. Although there is no doubt that these drugs can be efficacious in the treatment of various non-communicable diseases, there are limited data on their treatment benefits and adverse outcomes that reflect the real-world diversity of populations. These concerns can be addressed through well-designed clinical trials that prioritize diverse participants and include extended follow-up periods. Until these knowledge gaps are filled, large-scale homogeneous deployment of these drugs to treat weight loss needs to proceed with caution.