This week, I’m sleuthing out yet another common question about weight loss medication. Patients will sometimes tell me that, after having been on weight loss medication for say a year or so, when weight has come down and plateaued, that they feel less reduction in appetite than they did in the first months on treatment.  I advise my patients that the existing research shows that weight loss is sustained as long as a weight management medication is continued, so we believe that the effect on appetite does not wear off or fade.  (in medicalese – there is no known tachyphylaxis to the appetite suppressing effect).


A recent study, at first blush, would seem to suggest that the effect of the obesity medication semaglutide 2.4mg (Wegovy) to suppress appetite does wear off over time  – read on to find out if this is actually the case!



As part of the two year STEP5 trial of semaglutide 2.4mg weekly, the effect on appetite and cravings over time was assessed, and these results have just been published.  These parameters were assessed using the Control of Eating questionnaire, which was administered at several time points in the study [baseline, week 20, week 52 (1 year), and week 104 (2 years)].  The questionnaire was adminstered to the 174 US and Canadian participants in STEP5.  The weight loss in the people who completed this questionnaire was -14.8% with semaglutide 2.4mg, vs -2.4% with placebo.  In the STEP5 study, the weight plateaued after about week 60 (just over a year), and was maintained through the remainder of the 2 year study.


With semaglutide 2.4mg, compared to placebo:

  • the effect of semaglutide to reduce hunger and increase fullness was noted from the first time point of assessment (week 20), but were not significantly different at week 52 (1 year) or week 104 (2 years)
  • reduction in overall cravings and cravings for savory food were seen at week 20, and continued at 1 year and 2 years
  • cravings for sweets were reduced at week 20 and 1 year, but not at 2 years
  • better craving control was seen at week 20, and persisted out to 2 years
  • there was a positive correlation between weight loss and changes in cravings


The waning of the effect of semaglutide on hunger and fullness occurred over time seems to contradict what we have always believed about weight loss medication – but this finding stands in contrast to the study also showing that weight reduction plateaus at 1 year and is sustained at 2 years.  If the effect on hunger and fullness truly waned, why doesn’t the lost weight get regained? (noting that while some aspects of craving were still improved at 2 years, this would be unlikely to be able to hold the weight stable without continued effects on appetite)


The key here, is that the effect of weight loss medication on appetite continues, setting a lower set point (weight) balance of hunger and fullness.  There are many, redundant, powerful defenses in our natural human biology that vigorously defend weight.  When we lose weight, there are many fullness hormones that decrease, ghrelin (our hunger hormone) which increases, and a drop in our resting metabolism.  One singular weight loss medication is not able to stave off all of these defenses – nor would we want it to, because then theoretically weight would just continue to decrease and decrease without plateauing, which is of course not desired and would in fact be dangerous to human health.     So once a person reaches and plateaus at a lower weight with weight loss medication, these defenses will become stronger, and can offset the perceived feeling of satiety from the weight loss medication.  If that person were to stop weight loss medication, studies consistently show that weight is regained, and this makes sense – the lower set point held in place by the weight management medication is lost, and the prior set point is reestablished (which is usually the person’s lifetime highest weight).


Similarly, in a 1 year trial of liraglutide 3mg (trade name Saxenda), weight loss at 1 year with intensive behavioral therapy (IBT) was superior to weight loss with IBT alone.  People in the liraglutide group reported greater improvements in hunger, fullness and food preoccupation at 6 months, but at 1 year, there was no difference in hunger nor fullness, but weight loss differences were sustained and stable from 6 months to 1 year (as published here).


Note that potential gastrointestial side effects of the GLP1 receptor agonist class of obesity medication [semaglutide (trade name Wegovy) and liraglutide (trade name Saxenda)] are temporary for most people.  These can include nausea, diarrhea, constipation, heartburn, and/or vomiting, and are due to a slowing of the gastrointestinal tract which is temporary for most people.


Naltrexone/bupropion (trade name Contrave) is a weight management medication that reduces appetite and cravings.  Interestingly, its effect on hunger, fullness, and some aspects of cravings persists out to 1 year (this is the longest duration of study).  So, perhaps the nuances of how various weight management medications support weight maintenance after weight loss are different.   But the principle remains: weight management medication facilitates weight loss and maintaining that weight loss, which is why we recommend continuing weight management medications long term. 


And remember: if you (or your patient) feel that the effect of weight loss medication on appetite may be waning, it is so important to explore this in depth.  Is there something else that has changed?  A new medication that may be contributing to weight gain? A difference in how you feel about changes in your body shape/size?  A stressor in life that is driving emotional eating?  Looking at the weight management journey holistically and individually is always of crucial importance.


Disclaimer:  I receive honoraria as a continuing medical education speaker and consultant from the maker of semaglutide and liraglutide (Novo Nordisk) and naltrexone/bupropion (Contrave). I am/have been an investigator in clinical trials of liraglutide and semaglutide.


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