Phenotyping, genetics hold keys to precision medicine in obesity treatment
Click Here to Manage Email Alerts
From bariatric surgery to lifestyle interventions to medications, there are several options available for treating obesity. However, determining the treatment plan that works best for each person remains a challenge.
Researchers today realize that obesity is a disease that includes many subtypes, and that each person with obesity responds differently to treatment. One example of this variability can be found when analyzing the weight reduction of individual participants taking tirzepatide (Mounjaro, Eli Lilly) in the SURMOUNT-1 clinical trial.
“The average weight reduction was 52 lb with the 15 mg dose, but as with all potential therapies for obesity, variability was demonstrated in the trial. Most people lost a significant amount of weight, but there were some people who lost just a little bit of weight,” Ania M. Jastreboff, MD, PhD, associate professor of medicine and pediatrics (endocrinology) at Yale University School of Medicine, director of weight management and obesity prevention at the Yale Stress Center, and co-director of the Yale Center for Weight Management, told Endocrine Today. “There could be some types of obesity that respond more, while there are other types of obesity that respond less.”
Identifying which people will be the best responders to an obesity treatment is the goal of precision medicine, an area of research that is relatively new and quickly evolving.
“We are very much at the threshold of precision medicine for obesity,” Sadaf Farooqi, PhD, FRCP, FMedSci, FRS, a Wellcome Trust principal research fellow and professor of metabolism and medicine at the University of Cambridge, U.K., told Endocrine Today. “It hasn’t even been a concept until recently. We’ve known for a long time that people are clearly different in terms of their body weight, fat mass and fat distribution. But we don’t have a good enough understanding of what drives those differences and, as a result, how we might treat people differently.”
Researchers are trying to advance precision medicine for obesity in several ways. One involves using genetics to predict who may have a greater risk for obesity and identifying common genetic traits to allow subtyping.
“We know that there is enormous heterogeneity of response to every type of therapy,” Lee M. Kaplan, MD, PhD, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital, told Endocrine Today. “We know that there are different characteristics of obesity in different people. And we now know there’s a strong genetic component to how you respond to bariatric surgery. We therefore suspect there is a strong genetic component to obesity.”
Photo by Elizabeth Kaplan. Printed with permission.
Researchers are also trying to identify obesity subtypes through commonality in eating behavior questionnaires, body composition and energy expenditure. Andres Acosta, MD, PhD, assistant professor of medicine and co-director of the Nutrition Obesity Research Center at Mayo Clinic, has led the way with research on phenotyping and how specific phenotypes can be linked to certain medications and interventions to maximize weight-loss benefits.
“When we started seeing the outcomes of the phenotypes, we started building a biobank to develop a biomarker,” Acosta told Endocrine Today. “We decided to go back and identify unique genetic, hormonal and metabolic patterns or signatures that will be unique in our phenotypes and allow us to separate them from one another.”
Identifying obesity subtypes
Multiple studies have revealed that different individuals with obesity respond to medications, interventions and bariatric surgery differently. In findings from the SURMOUNT-1 trial published in 2022, nearly 90% of adults receiving 5 mg, 10 mg or 15 mg tirzepatide weekly lost 5% or more of their body weight at 72 weeks. However, response to the agent varied greatly between individuals, and 2.3% of participants assigned tirzepatide gained weight at 72 weeks.
“There’s variability, but there is variability and heterogeneity in response to all therapies for obesity,” Jastreboff said. “Variability is the same for bariatric surgery and medications. The degree of average weight reduction is different with each one of those interventions.”
This variability in responses serves as evidence that polygenic obesity is made up of many different subtypes. Acosta said physicians have been subtyping conditions such as cancer, cardiovascular disease and diabetes for many years and that it is only natural to extend subtyping to obesity.
In a study published in Gastroenterology in 2014, Acosta and colleagues measured gastric emptying, fasting and postprandial gastric volume; satiety; gastrointestinal hormones; and psychological traits for adults with normal weight, overweight or obesity. A principal component analysis was conducted with 231 adults who had all quantitative and psychological traits measured to analyze variations between them. The researchers identified four variables — satiety, gastric motility, psychological factors and gastric sensorimotor factors — that accounted for about 81% of body weight variation.
“In studying energy intake, we saw that obesity can be subclassified,” Acosta said. “Initially, we published that using unsupervised machine-learning-based classification, there were 11 groups, or clusters, of obesity.”
Acosta and colleagues built on those findings with a study, published in Obesity in 2021, that examined pharmacotherapy responses for adults with obesity grouped into four different phenotypes. The “hungry brain” phenotype included adults with abnormal satiation measured through kilocalories consumed at an ad libitum buffet meal and a visual analog scale measuring satisfaction after the meal. The “emotional hunger” phenotype included adults indicating less emotional restraint and higher anxiety on hedonic eating questionnaires. Adults with the “hungry gut” phenotype had abnormal postprandial satiety as determined through a visual analog scale measuring fullness 2 hours after a meal, and gastric emptying time. Adults with the “slow burn” phenotype had a decreased metabolic rate as determined through resting energy expenditure.
A series of validated and clinically available tests were used to measure homeostatic eating behaviors of hunger, satiation and satiety; hedonic eating behaviors; energy expenditure; and body composition. Participants with different phenotypes were then prescribed a specific therapy. Those with hungry brain received 7.5 mg/46 mg phentermine/topiramate extended-release (Qsymia, Vivus) daily. The emotional hunger group was prescribed 32 mg/360 mg oral naltrexone/bupropion sustained-release (Contrave, Currax Pharmaceuticals) twice daily. Those with the hungry gut phenotype received 3 mg liraglutide (Saxenda, Novo Nordisk) daily. And the slow burn group received 15 mg phentermine daily and participated in increased resistance training. At 12 months, adults receiving a phenotype-guided treatment approach lost a mean 15.9% of their body weight.
Using machine learning and multi-omics that incorporates data from genetics, hormones and metabolites, Acosta is developing an obesity phenotyping biomarker through Phenomix Sciences, where he serves as the scientific co-founder. The test would consist of a mouth swab to collect DNA and saliva samples that would then be processed through a lab and machine learning algorithms to determine a person’s obesity phenotype.
Aaron Kelly, PhD, co-director of the University of Minnesota Center for Pediatric Obesity Medicine, said the use of multi-omics could provide a platform for quickly identifying phenotypes in the future. However, some of the precision medicine work done in Acosta’s research, especially using eating behaviors to pinpoint therapy, is already being used in practice.
“There’s a lot of work going on in this area,” Kelly told Endocrine Today. “My group is doing it. In many of our studies, we are systematically and quantitatively trying to understand what these eating behavior phenotypes are and put them into bins to be able to help with decision-making. There is more to come.”
Using genetics to identify obesity risk
There are many factors that cause obesity, but some people have a greater risk based strictly on their genetic makeup. A review published in Obesity in 2021 estimated that genetics accounts for 60% to 80% of body weight variability.
“There are a whole bunch of genes in which you can get changes or variants,” Farooqi said. “These variants don’t cause severe obesity in everyone who gets them, but they increase your risk for obesity. Those variants often run in families, and that’s why people in certain families will have a higher risk for obesity.”
A small group of people with severe obesity have monogenic obesity caused by a single defective gene. One of these deficiencies takes place in the MC4R gene, which plays a role in regulating food intake and maintaining energy homeostasis. The identification of melanocortin4 receptor (MC4R) deficiency helped pave the way for development of the medication setmelanotide (Imcivree, Rhythm Pharmaceuticals), an MC4R agonist that targets impairment in the MC4R pathway.
Farooqi said the principles used to develop therapies for people with monogenic forms of obesity can also be applied to identify the best therapies for people with polygenic obesity.
“Most of the genes and pathways affect appetite, and so people with these genetic changes may benefit from drugs that suppress their appetite,” Farooqi said. “There are clearly some people who develop complications from obesity like type 2 diabetes and fatty liver disease early, perhaps even when their BMI is not that high, and they develop them because their fat tissue is not as good at storing lipids. For them, drugs which improve lipolysis are likely to be more effective.”
Few studies have been conducted on how people with similar genes respond to interventions, but one study published in 2011 found a genetic link to response from bariatric surgery. In the study, first-degree relatives had a mean difference in excess weight loss of 9% after Roux-en-Y gastric bypass surgery compared with a 25% mean difference between randomly matched people who were not genetically related.
The role of genetics could go beyond responses to therapies. In a study published in Cell in 2019, researchers created a genome-wide polygenic risk score that combined the average effect of more than 2 million genetic variants on BMI and weighed them in an algorithm. After dividing a cohort of 288,016 adults from the UK Biobank into deciles based on their risk score, researchers found 37.6% of adults in the highest decile had obesity compared with 9.2% in the lowest decile. Additionally, 5.6% of those in the top decile had severe obesity compared with 0.2% in the lowest decile and 1.5% in all remaining deciles.
Kaplan said polygenic risk scores currently do not have clinical relevance. However, several consortiums are currently working to identify genetic predictors to obesity interventions and the deconvolution of genome-wide polygenic obesity scoring systems is being performed to pinpoint genes associated with a higher obesity risk.
Precision medicine for children
Some researchers have found childhood to be a critical period when an individual’s obesity risk can be identified and treated early. A study published in 2018 tracked the trajectory of BMI in a cohort of 1,364 children from age 2 years through eighth grade. Researchers identified four common BMI trajectory types and found that two groups of children — those who have a high BMI at age 2 years that increases with time and those who have a low BMI at age 2 years that steeply rises through early childhood — had the highest BMI in grades five through eight. Additionally, birth weight and infant weight gain were significant predictors of BMI trajectory and were even stronger than sex or race and ethnicity.
Many of the same principles in practicing obesity precision medicine for adults are similar with children. However, there are certain considerations providers need to keep in mind when treating children, according to Kelly.
“For the younger kids, your treatment approach and plan would necessarily involve the parents or guardians, because that child is going to be highly influenced by the environment that is present at home and in their school setting,” Kelly said. “Whereas if you use the example of the 16-, 17- or 18-year-old, I would argue they are much more like adults in terms of how we view them from a physiologic, biological and social perspective. In terms of thinking about the precision approach in the younger child, it would involve much more readily the parents and the family in that type of decision-making process.”
Many studies have focused on precision medicine for adults with obesity, but Kelly said more studies need to be conducted with children and adolescents.
“We have a real opportunity to try to understand the right timing and the right treatment escalation for kids,” Kelly said. “If we get that right, we can get a lot of bang for our buck in terms of treatments and setting them up to live a longer, healthier life.”
Practicing precision medicine today
Research is still in its early stages, Kaplan said, but providers can practice precision medicine today by recognizing the heterogeneity in obesity and acting on it.
“What’s clear about obesity is that people who respond to one therapy don’t respond to another therapy, and people who don’t respond to one therapy do respond to another,” Kaplan said. “So even before we know the code, we know that we should be trying different therapies.”
The amount of research on precision medicine for obesity is poised to grow in the years ahead. Farooqi said the biggest challenge is integrating all of the genetic, environmental and societal factors that influence obesity. Although a lot of research will be required, Farooqi said, experts will be able to build off the principles that have already been established.
“We’re not starting from zero knowledge,” Farooqi said. “If you try to tap into everything, then it gets too complicated, and you would need huge numbers [of participants]. But if you start with the core variables that are going to be driving most of this disease, that’s the way to do it.”
Acosta noted that several different consortiums aside from his own group have formed to investigate obesity phenotyping. He said research will eventually lead to a place where adults will be able to be quickly diagnosed with a specific type of obesity and receive an appropriate intervention.
“It’s exciting that scientists are doing this,” Acosta said. “Government is supporting it, and pharmaceutical companies are doing it as well. Together, we’re going to change obesity like we saw a precision medicine change in cancer care.”
Click here to read the Point/Counter to the Cover Story.
- References:
-
-
-
-
-
-
-
Collapse
Read more about
Click Here to Manage Email Alerts