Weight regain after discontinuation (revision 5)

Weight regain after discontinuation is the return of body weight towards its pre-treatment value when incretin therapy stops. It has been documented in randomised withdrawal trials, which are the design capable of distinguishing it from the natural course of weight in a treated population.^[1]

In STEP 4, participants who had reached the maintenance dose during a 20-week run-in were randomised to continue or to switch to placebo. Those continuing lost further weight; those switched regained steadily over the following 48 weeks.^[1]

The finding is unsurprising given the mechanism. These agents act by producing a sustained pharmacological signal in the appetite-regulating system; removing the signal removes the effect, and the circuits return to their prior state rather than being reset by the period of treatment.^[2]

A randomised withdrawal design is necessary because an observational comparison of people who stop with people who continue is confounded: those who stop differ systematically, often having stopped because of intolerance or lack of response.^[1]

STEP 4 and SURMOUNT-4 both randomised after a lead-in on active treatment, so both groups had already lost weight and differed only in what followed. Regain in the withdrawn groups was substantial and progressive; neither trial ran long enough to establish whether weight returns fully to baseline.^[1]

Cardiometabolic markers moved with weight. Improvements in blood pressure, lipids and glycaemia during the lead-in reversed on withdrawal, which argues that the benefits were weight-mediated rather than persistent effects of the exposure.^[3]