Different varieties and doses of GLP-1 medications can have meaningful differences in how they address heart and metabolic health issues, according to new research led by the Perelman School of Medicine at the University of Pennsylvania. Through the analysis of data from 19 randomized controlled trials, the researchers believe their work points to possible precision medicine applications of GLP-1s beyond just weight loss. Their work was published in Diabetes, Obesity, and Metabolism .
“We hope that clinicians are encouraged by this study to take a more comprehensive and individual approach to treatment selection,” said senior author Yong Chen, PhD , a professor of Biostatistics at Penn. “For patients, the key message is that there may not be a single ‘best’ GLP-1 therapy for everyone, and it all could really depend on what their individual goals and needs are.”
A new measure showing individual differences
Conducted by researchers from Pennsylvania, the Yale School of Medicine, and UT Southwestern Medical Center, the analysis pulled information from trials totaling 13,117 overweight participants and used a measure the researchers developed for assessing heart and metabolic health called the Cardiometabolic Efficacy Index (CEI). Randing on a scale of 0 to 1—with values closer to 1 showing a greater treatment effect— the CEI factors in seven different data points: Body weight, waist circumference, HbA1c (blood sugar levels), systolic blood pressure, triglycerides, HDL cholesterol, and LDL cholesterol.
The researchers saw that, across all therapies, the higher-dose GLP-1 receptor agonists generally demonstrated greater cardiometabolic improvements. Semaglutide injections at 7.2mg achieved the highest CEI (0.86), followed by orforglipron 36mg (0.68), and injected semaglutide at 2.4mg (0.66). All of them delivered placebo-adjusted weight reductions of at least 10 percent of the participants body weight, on average.
But there were distinct differences across the therapies in individual datapoints in the CEI.
Orforglipron showed stronger effects on blood sugar control, HDL cholesterol, and systolic blood pressure, while semaglutide showed larger effects on total body weight, waist circumference, and LDL cholesterol.
Oral medications vs. injectables
GLP-1 therapies taken orally performed competitively against injectable ones. In adults without type 2 diabetes, orforglipron 36mg demonstrated a comparable cardiometabolic profile to oral semaglutide 25mg (CEI 0.67 vs. 0.63). In adults with type 2 diabetes, orforglipron ranked second overall, behind injected semaglutide 7.2mg and ahead of semaglutide 2.4mg.
“Oral options may expand access and offer more flexibility, which could play an important role in long-term treatment adherence and individualized care,” said Yu-Lun Liu, co-author of the study and Associate Professor of Biostatistics at UT Southwestern Medical Center.
On top of these findings, a dose-response relationship was observed for both semaglutide and orforglipron, suggesting that higher doses may deliver broader cardiometabolic effects.
Moving beyond weight loss
The analysis provides timely evidence for a field increasingly focused on the full metabolic burden of obesity rather than weight reduction alone.
“As obesity treatment becomes increasingly personalized, clinicians are often choosing among several highly effective therapies rather than deciding whether to treat at all,” said co-author Yuan Lu, Assistant Professor of Cardiology at Penn “Considering blood pressure, cholesterol, and glucose control together could be key to aligning with each patient’s overall, individualized cardiometabolic profile.”
Three focal points for the future
Chen identified a collection of priorities for the next phase of GLP-1 research and obesity care.
First, he said obesity treatment should increasingly focus on improving overall health—not just reducing weight alone. As the field evolves, evaluating therapies across broader cardiometabolic health domains—as well as other body systems—will be critical to understanding the full benefit of GLP-1s.
Second, Chen said the development of new multidimensional tools such as the Cardiometabolic Efficacy Index (CEI) may help move the field toward more personalized treatment selection.
Third, he noted that oral GLP-1 therapies are emerging as strong and competitive options that could expand treatment choice. As more oral agents enter clinical practice, they may improve accessibility, adherence, and flexibility for patients, making individualized obesity care more achievable in real-world settings. These options should be observed and analyzed, the researchers said.
Diabetes Obesity and Metabolism