Simple blood test could identify the most effective obesity drug

Why obesity drugs produce different patient responses

Obesity, characterized by excessive fat accumulation in the body, has become a global epidemic, with over 650 million affected adults worldwide. The condition is associated with significantly increased risk of cardiovascular disease, type 2 diabetes, certain cancers, and all-cause mortality.

Among pharmaceutical interventions, glucagon-like peptide-1 receptor agonists (GLP-1RAs), including semaglutide, and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor co-agonists, including tirzepatide, have shown immense promise in tackling this global epidemic. However, one major drawback of these therapeutics is inter-individual variability in treatment response, highlighting the need to identify the biological mechanisms driving this variation.

GLP-1 and GIP are the two principal incretin hormones, secreted by intestinal cells following food ingestion. GLP-1 suppresses appetite and promotes satiety through central nervous system pathways, whereas GIP regulates adipose tissue metabolism and energy expenditure. These incretin hormones act synergistically to regulate glucose metabolism and appetite, thereby playing a major role in the management of obesity and type 2 diabetes.

Given that the incretin system is frequently dysregulated in obesity, researchers at the University of Catania and MEDISAN, both located in Italy, designed this study to investigate whether fasting blood levels of GLP-1 and GIP can help identify individuals more likely to respond to semaglutide and tirzepatide.

Pilot study compared fasting hormone profiles and drugs

The study enrolled 90 adults with BMI >40 kg/m² (class III obesity). Fasting blood samples were collected from the participants to measure GLP-1 and GIP levels.

Each hormone was independently divided into low, intermediate, and high tertiles (a statistical division of a dataset into three equal parts) based on its distribution within the study population. The combination of GLP-1 and GIP tertiles yielded nine distinct profiles, each comprising 10 participants. Within each profile, participants were randomly assigned to receive either semaglutide or tirzepatide, with five participants receiving each drug per profile.

The pharmacological response of participants was assessed at six months. Body weight reductions of less than 5%, 5-15%, and more than 15% were considered low, intermediate, and optimal responses, respectively.

Low GLP-1 and GIP levels shaped treatment outcomes

The analysis of pharmacological response indicated that participants in the three profiles characterized by the low GIP tertile achieved optimal response to tirzepatide, irrespective of GLP-1 levels. These findings suggest that low fasting GIP levels were associated with greater responsiveness to exogenous GIP receptor agonists, such as tirzepatide.

Regarding semaglutide, the analysis indicated that participants in two profiles, characterized by low GLP-1 tertile and intermediate-to-high GIP tertile, exclusively achieved the optimal response. These findings may suggest that low endogenous GLP-1 availability leaves more GLP-1 receptors available for activation by exogenous semaglutide. The intermediate-to-high levels of endogenous GIP, on the other hand, may indicate intact or compensatory incretin secretory capacity that does not interfere with GLP-1 receptor agonist efficacy.

Participants in the profile characterized by high GLP-1 and high GIP tertiles achieved low response to both drugs. The authors suggest this may reflect a dysregulated incretin system that was not overcome by pharmacological doses of the drugs within six months. However, they note that fasting hormone measurements alone cannot distinguish between incretin secretory deficiency and receptor resistance, making this interpretation speculative.

Regarding clinical outcomes, the analysis showed that participants achieving an optimal response to semaglutide or tirzepatide experienced significant reductions in waist circumference and improvements in insulin sensitivity, changes that paralleled the weight-loss patterns observed across the response groups, indicating clinically meaningful improvements in central adiposity and metabolic health.

Blood biomarkers could personalize obesity drug selection

The study suggests that fasting blood levels of GLP-1 and GIP were associated with therapeutic response to semaglutide and tirzepatide in individuals with severe obesity and may help identify individuals more likely to respond to treatment. Specifically, the study finds that low GIP levels are associated with optimal tirzepatide response, whereas low GLP-1 levels and intermediate-to-high GIP levels are associated with optimal semaglutide response.

Since a single-timepoint measurement of GLP-1 and GIP levels cannot indicate receptor resistance, the researchers recommend treating these observations as hypothesis-generating and highlight the need for mechanistic validation of the observed associations through dynamic measurements of incretin levels and receptor activity.

The observed variations in therapeutic response may be explained through incretin receptor occupancy. Tirzepatide, as a dual GIP/GLP-1 receptor co-agonist, simultaneously activates both receptor systems. At low abundance (low fasting levels), GIP cannot fully occupy its receptor, potentially leaving the receptor available for exogenous tirzepatide. Upon binding and activating the receptor, tirzepatide may subsequently exert greater therapeutic effects by regulating adipose tissue metabolism, energy expenditure, and potentially central appetite regulation.

Semaglutide, which exclusively binds and activates the GLP-1 receptor, may exert its greatest therapeutic effects when GLP-1 receptors are relatively unoccupied due to low levels of endogenous GLP-1. In such conditions, semaglutide may more effectively restore GLP-1 receptor signaling and exert its anorectic, insulinotropic, and metabolic effects.

Overall, these findings provide preliminary clinical evidence for incretin-guided personalized pharmacotherapy that may improve treatment outcomes in obesity management. However, this was a small, single-center, open-label pilot study, with only five participants per treatment arm within each hormone profile. In addition, fasting hormone measurements cannot distinguish incretin secretory deficiency from receptor resistance. The authors therefore emphasize that the findings are preliminary and should not guide clinical practice until confirmed in larger, adequately powered randomized trials. 

Download your PDF copy now!