The current highly effective antiobesity medications approved for treating obesity (semaglutide), under review (tirzepatide), or in late-stage clinical trials “appear to lower the body’s target and defended fat mass [set point]” but do not permanently fix it at a lower point, Lee M. Kaplan, MD, PhD, explained in a lecture on October 15 at ObesityWeek.
It is very likely that patients with obesity will have to take these antiobesity medications “forever,” he said, “until we identify and can repair the cellular and molecular mechanisms that the body uses to regulate body fat mass throughout the life cycle and that are dysfunctional in obesity.”
“The body is able to regulate fat mass at multiple stages during development,” Kaplan, from Massachusetts General Hospital and Harvard Medical School, Boston, explained, “and when it doesn’t do it appropriately, that becomes the physiological basis of obesity.”
The loss of baby fat, as well as fat changes during puberty, menopause, aging, and, in particular, during and after pregnancy “all occur without conscious or purposeful input,” he noted.
The body uses food intake and energy expenditure to reach and defend its intended fat mass, and there is an evolutionary benefit to doing this.
For example, people recovering from an acute illness can regain the lost fat and weight. A woman can support a pregnancy and lactation by increasing fat mass.
However, “the idea that [with antiobesity medications] we should be aiming for a fixed lower amount of fat is probably not a good idea.” Kaplan cautioned. “These medications change [the defended fat mass] to something that is more normal, rather than ‘fixing’ it.”
People need the flexibility to recover lost fat and weight after an acute illness or injury, and pregnant women need to gain an appropriate amount of body fat to support pregnancy and lactation.
Intermittent Therapy: A Practical Strategy?
The long-term benefit of antiobesity medications requires continuous use, Kaplan noted. For example, in the STEP 1 trial of semaglutide in patients with obesity and without diabetes, when treatment was stopped at 68 weeks, average weight increased through 120 weeks, although it did not return to baseline levels.
Intermittent antiobesity therapy may be an effective, “very practical strategy” to maintain weight loss, which would also “address current challenges of high cost, limited drug availability, and inadequate access to care.”
“Until we have strategies for decreasing the cost of effective obesity treatment, and ensuring more equitable access to obesity care,” Kaplan said, “optimizing algorithms for the use of intermittent therapy may be an effective stopgap measure.”
Kaplan is or has recently been a paid consultant for Eli Lilly, Novo Nordisk, and multiple pharmaceutical companies developing antiobesity medications.
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