Will the Weight-Loss Results for Tirzepatide Shrink the Field for Future Anti-Obesity Treatments?

At the 2022 European Congress on Obesity, which I attended over the last few days, there was much buzz about the rather spectacular 22% average weight loss achieved with the dual GIP-GLP-1 agonist tirzepatide – a degree of weight loss that is not far from matching the weight-loss outcomes of patients undergoing metabolic surgery.

Clearly these results  are shifting the benchmark for what we can expect from future anti-obesity medications. 

While we await the full publication of these results and the outcomes of the other trials in the SURMOUNT program, it may be prudent to speculate what these results mean for compounds and treatment options for obesity currently in the pipeline. 

At last count, there were over twenty different anti-obesity compounds across a range of modes of action at various stages of clinical development. 

Some may well have the capacity to match the degree of weight loss seen with tirzepatide, but matching or even exceeding the 20% mark is likely to be a tall order for most. 

Thus, no doubt many anti-obesity medication development programs may now be seriously reconsidering or even abandoning current candidates.  

This would be unfortunate! 

For one, given the heterogeneity of pharmacodynamics responses, there will always be individuals for whom tirzepatide may either not work or not be well tolerated, leaving ample room for less effective medications that may do the job for these patients. 

More importantly, it may well be that, although these compounds may not be effective enough when used alone, they may be ideal candidates for add-on or combination treatments. 

An example that comes to mind would be the combination of the long-acting amylin analogue cagrilinitide with the long-acting GLP-1 analogue semaglutide, for which we have early data suggesting that it may well match or even exceed the weight loss seen with tirzepatide. 

Given that combination treatment is now the most common approach to treating a host of chronic diseases including hypertension, diabetes, heart or kidney disease, there is no reason why this would not be the case for obesity.  

While each component of these combinations may only be moderately effective on their own, they may well have synergistic effects that more than add up (as seen for buproprion plus naltrexone) or allow the use of lower doses, thus improving safety and tolerability (as with the combination of low-dose phentermine and low-dose topiramate). 

Thus, rather than abandoning compounds currently in the pipelines just because they promise less than 20% weight loss on their own, it may be time to consider developing these compounds as add-on or as combination therapies. 

Indeed, given that we now already have several effective medications for obesity, it will only be a matter of time before ethic committees decide that it is no longer ethical to test new anti-obesity compounds against a placebo. 

As in trials of medications for type 2 diabetes, hypertension, or dyslipidemia, the control arm (and likely even the intervention arm) of future studies would need to include baseline or standard medications. 

Although, at this time, none of the available anti-obesity medications would be considered “standard care”, this is largely because anti-obesity medications are currently not widely used in clinical practice, not because they lack efficacy. Thus, in the setting of a clinical trial, this argument as justification for having a placebo arm may no longer satisfy an ethics committee.  

Also, knowing that effective medications for obesity are already approved and available may make individuals seeking obesity treatments less likely to participate in lengthy trials that have placebo arms. 

The finding of “surgery-strength” weight-loss with tirzepatide may also be the benchmark against which future devices or surgical techniques would have to measure up. 

In fact, we may well reach the point where any novel obesity treatment will have to establish its superiority (or at a minimum non-inferiority) to approved anti-obesity medications. 

I certainly look forward to seeing how this plays out in the future. 

It would certainly be a shame if the rather spectacular results reported for tirzapetide leads to the premature abandoning of compounds that may well be perfect candidates for combination or add-on treatments for obesity. 

@DrSharma
Berlin, D