Super responders are pervasive throughout medicine. They are patients who respond exceptionally well to medical treatment and often exceed the average results seen in clinical trials. In obesity medicine, clinicians have observed some patients using GLP-1 receptor agonists (GLP-1s) achieve 15%-20% total weight loss in the first 6-12 months, outcomes that rival those historically associated with bariatric surgery.

Predicting who will be a super responder is a bit more complicated. Weight loss in patients taking GLP-1s varies, and longitudinal follow-up has been limited because these agents in obesity medicine are still relatively new. Researchers and clinicians point to several clues that may ultimately support more targeted, precision prescribing in the future and, importantly, help guide management considerations in today’s clinical settings.

“We know that one of the predictors of a strong response is an early response. So if a patient started on GLP-1s and lost weight quickly or had a significant response early on, that predicts a very good response long-term,” said Eduardo Grunvald, MD, obesity medicine specialist, medical director of the Weight Management Program at UC San Diego Health, and professor of medicine at UC San Diego School of Medicine.

Grunvald explained that although lifestyle factors like diet, physical activity, stress, and sleep form the foundation of obesity treatment, larger factors are likely at play in super responders.

“Whether you’re a normal responder or strong responder is more dependent on biology than it is about behavior,” he said.

Gitanjali Srivastava, MD, professor of medicine in the Division of Diabetes, Endocrinology and Metabolism, medical director of Clinical Obesity Medicine, and co-director of the Vanderbilt Weight Loss Center at Vanderbilt University Medical Center in Nashville, Tennessee, agreed.

“There’s ongoing research looking at biomarkers, body composition, and maybe MRI scans to better understand what is going on inside these patients, both biologically and genetically,” said Srivastava, who is also a spokesperson for The Obesity Society.

Genetics, a Factor?

At the lab of Andres J. Acosta, MD, PhD, at the Mayo Clinic in Rochester, Minnesota, researchers have been studying obesity biology, including genetic polymorphisms associated with gastrointestinal traits and obesity therapy.

The team recently published a study in Gastroenterology examining gastric emptying and GLP-1 levels across three clusters in patients with obesity (n = 483). Findings showed patients with rapid response to tirzepatide shared several traits, including rapid gastric emptying and increased postprandial hunger with discordant low GLP-1 levels. When the researchers delved deeper, they found that 26.9% of patients (n = 130) also had reduced secretion of enteroendocrine satiety hormones (including GLP-1, plasma peptide YY [PYY], and cholecystokinin [CCK]).

“We were surprised to see that despite feeling hungry between meals and faster stomach emptying, we saw two different populations: a population of people with high levels of GLP-1 and a population with low GLP-1 levels,” said Acosta, who is a professor of medicine, gastroenterologist, and obesity researcher at Mayo Clinic.

“The problem was these patients were not making enough GLP-1, PYY, and CKK,” said Acosta. Twenty-seven percentage had enteroendocrine cell dysfunction. “If we can identify patients with this subphenotype (he is working to develop a surrogate biomarker making identification clinic-ready), they might need GLP-1 replacement therapy,” he said, noting it would be similar to hormone replacement therapy.

Acosta co-developed a precision genetic test — MyPhenome — which predicts how patients will respond to specific antiobesity medications. It is currently being used in roughly 360 clinical settings to help primary care doctors select the right obesity medication for their patients. He said that as of October 1, insurance will cover the test (although coverage might vary).

Super Response: A Risky Proposition?

Yuval Pinto, MD, is an obesity medicine/family medicine clinician at Johns Hopkins Medicine’s Johns Hopkins Healthful Eating, Activity, and Weight Program, and assistant professor of medicine at Johns Hopkins School of Medicine in Baltimore.

Pinto said he worries that patients who lose weight too fast are often unaware of the associated health risks, especially those who might not be receiving regular follow-up.

“Weight loss and weight management should follow guidelines. When weight loss is too fast, your body can go into shock. This is not healthy, especially for patients who are in an age group that is already prone to issues,” said Pinto.

“Let’s say you’re a 65-year-old woman and are not working out. Your muscle mass is low to begin with, so you lose more muscle, which is protective of longevity. You want to lose weight to live longer, and you’re losing muscle.”

He added that rapid weight loss can precipitate gallstones, cause dehydration, kidney damage, nutritional deficiencies, precipitate potential gastrointestinal side effects, and even affect reproductive health.

“The cornerstone of our program is that we see our patients every month and a half to 2 months,” he said, noting that his schedule is often very full. He recalled a recent patient who was scheduled 3.5 months out as a result.

“My patient, a young woman, a mother of two, a lawyer in Baltimore, started a GLP-1 on a very low dose and lost almost 22% of her body weight in 3 months. This is what people lose when they go to jail,” said Pinto.

Clinical Considerations

Like any treatment, GLP-1s carry a risk/benefit ratio that must be weighed consistently, especially in the over 65 age group. Grunvald emphasized the need for individualization. 

“In my younger and middle-aged patients, I am not as concerned,” she said.

Among her older patients, however, Grunvald said, she wants a baseline bone density scan or, if the patient already has osteoporosis, “consider what we are doing to mitigate further bone loss (eg, physical activity, adequate diet including adequate intake of calcium and vitamin D). And in patients who are already immobile due to some sort of orthopedic problem, consider interventions to prevent further loss of muscle,” said Grunvald.

When asked about dosing changes among super responders, Pinto said he considered numerous factors, for example, rate of weight loss, the list of obesity complications, age, sex, level of sedentary behavior, gym-going habits, and sleep quality.

“For most people, I slow down when the rate of weight loss exceeds 1.5 pounds a week, especially for the elderly. If someone comes in and they’re losing 3 pounds a week, I am going to slow down and taper the medication.” His concern, he said, is that some patients think losing too much weight too fast is a good thing.

Grunvald agreed.

“These are the patients I struggle with the most,” he said. “If they’re losing weight more rapidly or lose more weight than is common, I may take them off the drugs and then reintroduce a low dose again,” said Grunvald, pointing to the resurgence of food noise, which becomes a quality-of-life issue for many.

Education is key, said Srivastava, noting the wide variability in response among patients taking GLP-1s.

“It’s important that our patients understand that weight loss needs to be healthy weight loss. Patients see they’ve lost weight but don’t understand if they’ve lost fat, muscle mass, or a combination. We want to make sure our patients are feeling healthy and have energy. What good is weight loss if the patient is fatigued and doesn’t have an appetite and motivation to engage in life?” said Srivastava.

It’s a signal, she said, to scale down, step back, and address these patients’ needs individually, comprehensively, and holistically.

Pinto and Grunvald reported no disclosures. Srivastava reported serving as a consultant for Novo Nordisk, Eli Lilly, Madrigal, and Quest Diagnostics. Acosta reported being co-founder and co-inventor of intellectual property licensed to Phenomix Sciences Inc.; serving as a consultant to Rhythm Pharmaceuticals, Gila Therapeutics, Amgen, General Mills, Boehringer Ingelheim, Currax Pharmaceuticals, Nestlé, Busch Health, and RareDiseases; and receiving research support or contracts from Vivus Inc, Satiogen Pharmaceuticals, and Boehringer Ingelheim.

Liz Scherer is an independent health/medical journalist. She frequently writes about obesity and GLP-1s.