Weight Loss Treatment: Should We Have Expected GLP-1 Agonists to Cause Gallstones ?

The short answer to this question is …Yes.

To explain this more fully, we first need a little background…

GLP-1 agonists are one of the most successful weight-loss inducing agents produced by big Pharma of recent times.

Originally designed and developed as anti-diabetic agents, their ability to suppress appetite soon became the main focus of drug developers, resulting in regulatory approval of the first in class Semaglutide (marketed by Novo Nordisk as Wegovy) and then Tirzepatide (Mounjaro; Ely-Lilly). {Note the parallel here with Viagra, which was originally developed as a heart drug, but quickly morphed into the world's most frequently used treatment of erectile dysfunction.}

The prevalence of obesity in most developed western nations has ensured that both of these new medications are in high demand, far exceeding that originally anticipated for their anti-diabetic indication. This has resulted in a ‘dash for the cash’ by manufacturers, and the resulting shortages have generated a sellers’ market for off-prescription supplies with many hundreds of thousands of overweight patients on one or other drug long-term in UK alone.   

Although both drugs are very effective in suppressing appetite, and can produce spectacular weight losses as part of controlled diets, they have one major disadvantage – they only work for as long as you continue taking them. Discontinuing treatment almost always results in rebound rapid weight gain in response to renewed appetite; indeed too rapid a rapid withdrawal can actually be dangerous. Hence there is, and always will be, a need for long-term or even lifelong treatment with these drugs to keep the weight off. Like virtually all drugs, there are also side-effects, particularly after prolonged use.

Thus any indication of unwelcome, and even life-altering, sequelae emerging in significant numbers of patients on long term treatment could be a bombshell for the supply industry, since these are by their nature long-term meds…..hence the interest of recent reports in the media.

Was this dilemma predictable for these new blockbuster drugs ? Sadly, yes….  

One of the known side effects of GLP-1 analogs is inhibition of gall-bladder contraction. and this was established well before the drugs were contemplated as weight loss therapies. This results in incomplete emptying of the gall-bladder (GB), and accumulation of high concentrations of bile components within it, resulting eventually in gallstones and damage to the gall bladder itself. The reduced secretion of bile also interferes with the digestive process, with possible long-term consequences for the health of the bowel. 

The fact that this adverse event is only being picked up now in significant numbers of patients is probably because the medications were approved too recently,  and the effects on the GB are cumulative and only manifest themselves in the longer term.

Is there any way round the problem ?

Possibly not for this class of compounds, if used as monotherapies – all GLP-1 analogs show this effect on the GB at the blood concentrations required for effective appetite suppression. 

One alternative approach might be to harness the power of another class of known gut-active compounds, the Cholesystokinin (CCK-8) analogues – these mimic endogenous CCK-8.

CCK-8 is another gut hormone controlling satiety, which is released in response to a fatty meal and suppresses appetite short-term, but which acts via a different mechanism. The key difference is that it does not suppress gallbladder contraction, but rather enhances it. Various attempts have been made to develop drug candidate CCK mimics over the past 30 years, but most have been abandoned as too short-acting or having too great an effect in enhancing GB contraction as a side effect. 

A more recent, and perhaps even more promising, option is to use hybrid GLP-1 and Exendin (i.e. GLP-1)-like peptides. These dual-moiety agents might be expected to be effectively neutral in their effects on the gallbladder, due to the competing and opposite effects of their moieties on its contraction. They might also be expected to enhance the overall effect on satiety by adding the short-term effect of CCK mimicry to the longer-acting GLP-1 effect.

Given what would be a huge unmet demand if GLP-1 does decline, we may yet see a revival of interest in developing this class of compounds, which has predictably fallen by the wayside somewhat as a result of the success of 'pure' GLP-1 agonists….it will be very interesting to see how this develops - the Regulators (MHRA in UK) will no doubt be keeping a close eye on post-marketing studies for all approved GLP-1 formulations, with a view to restricting, or even withdrawing product licences if the GB-related AEs appear to be widespread and/or severe. 

Will we see access to these hugely successful therapies restricted ?.....Time will tell.....

First published 30.1.26