Not just weight loss, but optimal body composition and function should be our target

A presentation at this year’s International Congress on Obesity in Sao Paulo, Brazil (26-29 June) looked beyond the function of the new generation of obesity drugs in losing weight, to ask: what should our goal be in weight loss? “The obvious answer is not just bringing weight to some ideal level, but rather to achieve optimal body composition and body function,” says presenter Professor Donna Ryan, Pennington Biomedical Research Centre, New Orleans, USA.

Professor Ryan, who has carried out multiple studies of obesity treatments including the SELECT trial into semaglutide, says: “The desirable profile for an obesity medication would be to achieve weight loss efficacy in those who don’t respond to or don’t tolerate existing incretin-based medications; to achieve weight loss with body composition improvement; to achieve other health benefits not related to weight loss per se; and maintenance of weight loss when the medication is stopped.”

For some patients, preservation of lean mass can be as vital an aim as weight loss – so Professor Ryan introduces the concept of drug development beyond those targeting incretins (GLP-1,GIP and PYY) and other Nutrient Stimulated Hormones or NuSH (amylin, and glucagon) and discusses the non-incretin, non-NUSH medications in active development, including those targeting lean mass preservation (activin and myostatin inhibitors and enobosarm); targeting GDF-15 and the peripheral cannabinoid 1 receptor.

Ensobarm is a selective androgen receptor modulator that avoids the virilizing properties of androgens but selectively improves muscle mass and a phase 2b trial in combination with GLP-1 drugs has just been announced. This work is based on a meta-analysis of 3 prior ensobarm trials showing it increases lean muscle mass as well as decreasing fat mass.

Professor Ryan concludes: “While we are in an undeniably exciting time with new generation obesity medications, we have to keep expanding our horizons to further enhance therapeutic options for patients.  It is not enough to copy the initial success of the incretins and NuSH medications.”

Her talk gave some of the reasons why:

• Not all persons respond to existing medications (~16% don’t achieve 10% weight loss with 15 mg tirzepatide)
• Some persons need more weight loss in addition to weight loss achieved with existing medications (43% don’t achieve 20% weight loss with 15 mg tirzepatide)
• There are tolerability issues with existing medications – ~10% of discontinued semaglutide for gastrointestinal adverse events in SELECT.
• Some persons have safety issues with existing medications (allergy, pancreatitis, achalasia)
• Some people need to maintain or increase muscle mass along with fat loss.
• It would be good for some people to have weight loss with dual benefits in addition to those achieved with existing meds.
• It would be good to have weight loss sustained after stopping a drug.
• It would be good to use a less expensive medication to sustain weight loss.

Professor Donna Ryan, Pennington Biomedical Research Centre, New Orleans, USA. Please e-mail with questions / interview requests. E) ryandh@pbrc.edu