Which factors predict better outcomes with GLP-1 RAs and their successors

New obesity drugs have generated a wave of optimism in the battle against this pervasive health issue. Medications like semaglutide, marketed as Ozempic and Wegovy, and tirzepatide, known as Mounjaro, have shown remarkable weight-loss benefits in clinical trials.

“These new anti-obesity drugs represent a transformative breakthrough, as for the first time in the history of medicine, it is pharmacologically possible to normalise body weight in obesity,” says Professor Matthias Tschöp, physician and scientist CEO and scientific director of Helmholtz Zentrum München, Germany. “That also means prevention of type 2 diabetes, heart attacks, strokes, and several cancers. They will save tens of millions of lives and represent a preferred alternative to the highly invasive and irreversible gastric surgery.”

These drugs, however, do not work equally well for everyone.

“Current obesity treatments have enormous variability in outcome because obesity is a very complex disease,” says John Dixon, Adjunct Professor at the Iverson Health Innovation Research Institute, Swinburne University of Technology, Melbourne. “But we can make some forecasts.”

Search for predictors

Genetics plays a significant role in determining an individual’s response to obesity drugs. Genetic makeup can influence food preferences, satiety signals, and metabolic rate. Numerous genes are at play, but scientists have yet to identify a specific genetic profile to guide the selection of a particular medication, Professor Dixon explains.

Studies in people with type 2 diabetes have shown that some gene mutations related to GLP-1 receptor activation can alter how much people’s insulin and blood glucose levels change in response to these medications. However, these mutations don’t appear linked to weight changes during treatment.

Factors such as lack of sleep, poor mental health, poor nutrition and a sedentary lifestyle, also contribute to metabolism rate and weight. In one study, individuals with obesity were classified based on various factors, including their metabolic rate, food required to experience a sense of fullness, and lifestyle. Scientists found that liraglutide, an older GLP-1 receptor agonist (GLP-1 RA), was twice as effective in those who felt hungry soon after a meal.

Comorbidities, gender and starting weight

Other predictors include comorbidities, gender and starting weight.

GLP-1 RAs tend to be less effective in helping people with type 2 diabetes lose weight, says Professor Dixon. One study that evaluated the weight-loss power of semaglutide on type 2 diabetes patients showed that people lost 10% of their weight on average. In contrast, other clinical trials showed that once-weekly semaglutide led to an average 16% body weight loss in obese people without type 2 diabetes.

Gender may also affect a person’s response, as seen in the phase 2 trial for Eli Lilly’s triple hormone-receptor-agonist retatrutide, but “nobody really knows why,” says Professor Tschöp.

At the same time, studies in female mice have shown a correlation between starting weight and weight loss with triple agonists like retatrutide. “Patterns indicate that some of these drugs work better, the higher the BMI, which is the better bias because we want to treat morbid obesity, we don’t want to create a lifestyle drug,” Professor Tschöp says.

When people hit a plateau

While these hormone mimics are demonstrating significant promise, not everyone responds to them in the same way. Some people experience slower and less substantial weight loss than others, and a minority don’t lose much weight at all.

Once a person has achieved substantial weight loss, reaching a plateau is not a cause for concern, Professor Tschöp says.

As BMI decreases, the efficacy of these drugs diminishes, and they eventually stop reducing body weight. This leads to whether it makes sense to continue using these potent double and triple agonists for a lifetime. “Any of the gut hormone based obesity drugs are working to normalise body weight and body fat while present in the body of the patient. If treatment stops, body weight will increase again. They are not curing obesity,” Professor Tschöp says. “A less potent maintenance therapy which might help keep body fat from going back up once treatment with dual or triple agonists is stopped could be helpful in the interim.”

Professor Dixon explains that clinicians can try different combinations of drugs and lifestyle changes to tailor treatments to each patient. “If people haven’t had around a 5% weight loss within three months, we stop and try something else,” he says. While for the minority who don’t respond to any pharmaceutical treatment, bariatric surgery remains an option.

“We are treating a chronic disease and as for all other chronic conditions effective management is ongoing and scaled up as needed,” he sums up. “We do not have a cure.”