Are We Entering a Golden Era of Anti-Obesity Medications?

I have been practicing medicine long enough to remember treating hypertension before there were ACE inhibitors or ARBs. I vividly remember training in a lipid clinic before the introduction of statins. Many will recall managing type 2 diabetes before we had TZDs, DPP4 inhibitors, SGLT2 blockers, or GLP-1 analogues. 

In all of these disease areas, prior to the introduction of the currently available effective medications, the focus was on dietary and other behavioural interventions.  Thus, I recall giving talks on sodium restriction, physical activity, or the DASH diet for managing hypertension or on the AHA Step I/II diets to manage dyslipidemia. While dietary and other behavioural interventions remain important pillars for managing these conditions, it would be quite uncommon today to see clinicians manage any of these entities with “lifestyle” interventions alone. 

However, the latter is still the case for treating obesity, which in itself remains the exception rather than the rule as far as clinical management is concerned.

This may be about to change. 

Thus, according to a paper by Timo Müller and colleagues, published in Nature Reviews Drug Discovery, there is much reason for hope that we will soon have a plethora of anti-obesity medications that may well drastically change obesity management.

The paper extensively reviews the rather sketchy past history of anti-obesity medication and provides a brief primer on the complex neuroendocrine systems that govern the energy homeostasis. 

The authors also highlight the important challenges in developing effective anti-obesity medications including heterogeneity of the disorder, the complexity of the neuroendocrine system, translating findings from animals to humans, and of course safety aspects. 

The authors then go on to discuss the various existing and potential targets with an update on the rather wide range of molecules currently under investigation. Broadly, these can be classified as incretin-based (mono-, dual- and even triple-agonists), leptin, leptin-sensitisers and MC4 receptor agonists, mitochondrial uncouplers, GDF15, amylin, PYY, and a few others. 

While no one expects all or even most of these molecules to ultimately meet the rather high bar of efficacy and safety, one would have to be rather pessimistic to think that none of these molecules will make it. 

Rather, as we are currently witnessing with the recent regulatory approval of semaglutide for obesity (in the US, UK, EU and Canada), which is promising to deliver weight-loss in the 15-20% range, and the emerging data for the dual agonist tirzepatide or the early data for the combination of semaglutide with the amylin analogue cagrilinitide, it is foreseeable that medical treatment of obesity will one-day routinely involve the use of anti-obesity medications, in the same way that medications are routinely used to manage hypertension, dyslipidemia or type 2 diabetes.

Obviously, much needs to happen before this becomes a reality. Not only do we need long-term outcome studies (some of which are already underway) but we also need payors to help make these medications accessible to those who need them. Finally, we need education of both health care providers and patients to fully understand why these medications are necessary in the first place and how they can be best used to reduce the burden of obesity related complications and impairments in quality of life in people living with obesity. 

@DrSharma

Berlin, D