Unsurprisingly, gene variants don’t tell the whole story. For example, the obesity-related genes we have identified to date are estimated to predict only 5% of obesity risk. This is where the role of environment, behavior, epigenetics, and other factors will likely come into play from individual to individual.
In fact, we already have clear signs that obesity is a heterogeneous disease. Lorcaserin, a 5HT2c agonist, produces a more than 3% weight loss when considering all randomized patients, but one-third respond well, losing more than 10% of body weight with accompanying substantial and clinically meaningful improvements in diabetes and CV risk.
Why do some respond and others don’t? We at the Translational Research Institute for Metabolism and Diabetes (TRI) believe that the tipping point in obesity pharmacotherapy will lie in the answer to that question and should be the focus of both academic and industry research.
Another route to accelerate obesity R&D will involve leveraging the known links between obesity and type 2 diabetes. While obesity and type 2 diabetes are distinct diseases, we are beginning to learn more about shared common pathways and underlying defects.
Obviously, we have had far more success in treating diabetes from a pharmacological perspective and in securing FDA approval for novel diabetes therapies. Some of today’s most effective diabetes therapies, such as GLP-1 agonists, also carry weight loss benefits. This presents an opportunity from a development and regulatory perspective to identify type 2 diabetes therapies with weight-loss potential and expand to an indication in obesity.
Examples of Early Progress
For extreme obesity, surgery is currently the preferred and only effective treatment modality. Exciting new data suggests that in addition to substantial weight loss, bariatric surgery is highly effective in controlling, and in some patients, completely eliminating, type 2 diabetes symptoms. It appears that bariatric surgery triggers massive changes in metabolic—specifically gut—hormones, which leads to a decrease in appetite and improved diabetes.
Preclinical and some early clinical efforts to replicate these hormonal changes without surgery are quite promising. While surgery is certainly an important option right now for people with extreme obesity, we need to focus in the long term on producing the same hormonal changes without surgery, eliciting the same substantial weight loss, and improving or resolving type 2 diabetes.
In fact, gut hormones present a plethora of opportunities for obesity drug development. And because they represent peripheral targets, they likely will have significantly fewer side effects than drugs targeting CNS pathways.
Another exciting area of research we are focused on at TRI employs a novel strategy to increase energy expenditure at the cellular level. Our partners at Sanford Burnham Medical Research Institute found that orexin, an appetite-producing hormone that is produced in the brain, activates brown adipose tissue, or brown fat.
Brown fat is a kind of “good fat” that burns high quantities of sugar and fat in a process that is designed by nature to moderate body temperature in babies, who have a large number of brown fat cells. By activating brown fat in adults, calories that otherwise would be stored as unwanted white fat can be burned.
Low levels of orexin are associated with obesity, while high levels are associated with leanness. At TRI, we have now advanced orexin research into the clinical phase, and are undertaking proof of concept experiments to validate this new drug target and evaluate its safety and efficacy.
The augmented focus on obesity has sparked heightened clinical research to better understand the complex pathophysiology of this disease. Exploring and beginning to define the heterogeneity of obesity will put us on a path toward more targeted, effective, and safe treatment strategies and, hopefully someday, prevention.
While we have made some progress, we have a long way to go. But dispelling the myth that the obesity problem can be resolved if people would simply just eat less and exercise more is a critical first step.