Obesity-related inflammation or inflammation-related obesity?

Zealand Pharma's decision to "pause" development of its dual GLP-1/GLP-2 receptor agonist dapiglutide due to a lack of clinical differentiation in a crowded obesity marketplace is notable and viewed largely in a positive light by investors (the stock is up slightly since the announcement and 16+% this week). Indeed, the company has a rich pipeline that will benefit from a reallocation of resources. And GLP-2 is a tough nut to crack even though it has many potential benefits, the main issue being the complexity and duration of studies required to prove efficacy for "obesity-related co-morbidities".

And that is what I had overlooked until now: in its description of dapiglutide, we read "People living with obesity have increased translocation of bacteria from the gut lumen into the bloodstream due to a reduced integrity of the intestinal barrier, or “leaky gut”, driving a state of low-grade inflammation. This obesity-related low-grade inflammation can result in comorbidities, such as cardiovascular disease, liver disease, and neu ro-inflammation."

It may be only tangentially related to Zealand's decision, but the implicit causal direction in this statement is problematic: there is ample evidence that low-grade inflammation and "leaky gut" are upstream factors in obesity, driven by gut dysbiosis and an excess of certain gram-negative bacteria. The concept of co-morbidity hides the causal pathways under the "correlation is not causation" banner, but "obesity-related inflammation" reintroduces causality in a sneaky way. If we could dampen inflammation and promote gut barrier integrity early, obesity may well be preventable.