Using a phenotype-guided approach for the treatment of obesity

June 18, 2021

Obesity is a chronic, relapsing disease and a primary cause of type 2 diabetes, fatty liver disease, cardiovascular disease and cancer. There are many obesity interventions, such as diets, devices, surgery and medications. However, not much is known about the predictors of response to these obesity interventions.

"Sustained weight loss with current treatment options remains a challenge in the clinical practice," says Andres J. Acosta, M.D., Ph.D., a Mayo Clinic gastroenterologist and obesity expert at Mayo Clinic in Rochester, Minnesota.

To address this, Dr. Acosta and a team of Mayo Clinic researchers set out to study anti-obesity medications based on obesity phenotypes to enhance weight loss. Their findings, published in the journal Obesity in 2021, show that a phenotype-guided approach was associated with 1.75-fold greater weight loss after one year and the proportion of patients who lost more than 10% at one year was 79%, compared with 34% whose treatment was not phenotype guided.

Why do phenotypes matter?

The team stratified obesity into four phenotypes:

  • Hungry brain — mainly controlled by the brain-gut axis, and abnormal calories needed to reach fullness
  • Emotional hunger — desire to eat to cope with positive or negative emotions
  • Hungry gut — abnormal duration of fullness
  • Slow burn — decreased metabolic rate

With regard to energy balance — intake versus expenditure — these four phenotypes regulate body weight. Key drivers for intake are fullness, duration of fullness and emotional eating. Key drivers for energy expenditure are resting energy expenditure, nonexercise physical activity, exercise and the thermogenic effect — increase in the metabolic rate that occurs after a meal — of food and exercise.

"It was essential to explain differences among patients in some of these measurable components of food intake and energy expenditure, and assess their potential for individualizing therapy for obesity," says Dr. Acosta. The team theorized that classifying phenotypes would reveal obesity subgroups and enhance response to obesity medications. "Our aim was to characterize the obesity phenotypes and to assess the effectiveness of phenotype-guided anti-obesity medications compared with nonphenotype-guided medication."

The Mayo team conducted a yearlong clinical trial performed in a weight management center where 312 patients were randomly assigned to phenotype-guided treatment or treatment that was not phenotype guided and included anti-obesity medications. In the era of individualized medicine, the proposed phenotype-guided stratification and treatment approach, in addition to the positive outcomes reported in previous randomized trials, represent a step toward a precision medicine approach to optimize obesity therapy.

"Biological and behavioral phenotypes clarify the complexities of human obesity and can be targeted with medications to enhance weight loss," says Dr. Acosta. "Our long-term goal is to develop a personalized approach to identify the right medication for the right patient, minimizing side effects to obesity management."

Dr. Acosta's team applies principles of pharmacogenomics in obesity to better understand how the disease develops, reduce treatment inconsistencies and decrease the treatment's side effects. His goal is to stratify obesity to support the development of personalized drugs to treat obesity and generate safer and more effective medications.

For more information

Acosta A, et al. Selection of antiobesity medications based on phenotypes enhances weight loss: A pragmatic trial in an obesity clinic. Obesity. 2021;29:662.