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As blogged previously, we should not gauge weight management success solely on weight nor body mass index (BMI), and the goal should not be a ‘normal weight’. The primary target of weight management should be on improving health and quality of life.
With new and emerging evidence for the benefits of weight management medication far beyond simply weight loss, should we reframe and fine tune our targets further?
As extensively reviewed in our 2022 Canadian Obesity Guidelines Pharmacotherapy chapter (disclosure: I am the lead author), we have data for liraglutide 3mg (Saxenda), semaglutide 2.4mg (Wegovy), naltrexone/bupropion (Contrave) and orlistat (Xenical) showing that they improve diabetes control. Liraglutide, orlistat, and semaglutide have also demonstrated that they can provent progression of prediabetes to type 2 diabetes, and/or revert prediabetes to normal sugars. Liraglutide and semaglutide improve fatty liver disease, and liraglutide has evidence for some benefit to improve obstructive sleep apnea.
We now also have the STEP HFpEF study, demonstrating the impressive capacity of semaglutide 2.4mg to improve symptoms of heart failure with preserved ejection fraction (HFpEF) and exercise function (blogged here).
And most recently (blogged here), the golden crown: the SELECT study, which was the first study of a weight management medication in the world (semaglutide 2.4mg) to show that it reduces cardiovascular events in people with overweight/obesity with preexisting cardiovascular disease (disclosure: I was an investigator in this study).
Tirzepatide (Zepbound), recently approved in USA for weight management, has likewise shown that it can markedly improve control of type 2 diabetes, revert prediabetes to normal sugars, and has several studies underway for other weight-related health issues including cardiovascular disease (disclosure: I am an investigator in this study). (Note: tirzepatide is approved for type 2 diabetes in Canada (Mounjaro), not yet approved for weight management).
In establishing targets for weight management, I will draw an analogy to our approach in type 2 diabetes. In diabetes, treatment targets include good blood sugar control, weight management, and importantly, cardiorenal protection (protection against heart attacks, strokes, heart failure, and kidney protection). These organ protection goals have become central features of our type 2 diabetes treatment paradigm following the development of diabetes medications that provide these heart and kidney benefits (namely, the GLP1 receptor agonists and the SGLT2 inhibitors).
Similarly, as our evidence evolves in obesity management, we need to continually reframe and broaden our treatment targets towards goals that include improvement of coexisting health parameters. For example, for a person with overweight/obesity and a prior heart attack, we should include ‘prevention of another heart attack’ in our treatment targets, with semaglutide 2.4mg as a first line treatment consideration (based on the SELECT study). If we have a patient with prediabetes, then a treatment target should be preventing diabetes or reverting prediabetes to normal range sugars, in which case we should consider liraglutide, semaglutide, or tirzepatide (where approved for weight management), or perhaps orlistat (though noting that orlistat is not very effective for weight management).
As always, treating to targets must include goals that are important to the individual. This usually includes improvement in health parameters as above, but can also include things like ‘I want to be more active with my kids’, or ‘I want to have less knee pain’ (note: weight management medications are currently under study for this!), or ‘I just want to feel better’. Numbers on the scale remain important for many people, and this can be a goal as well.
It is also important to note that maximum dose of medication (especially the newer/emerging more effective medications like semaglutide and tirzepatide) will not be needed by every person. In fact, for some people, the maximum dose may be too much (more on this here). We must think of these medications as ‘titrate to target’ – in other words, use the dose needed for each individual to achieve the targets. We must also remember that not all health issues that are seemingly weight-related will improve or resolve with weight loss. For example, while sleep apnea is often related to obesity, there are lean people who have it too. Same goes for osteoarthritis, diabetes, hypertension, heartburn, and so on. So, as a person with obesity loses weight, these health issues may well improve, but that isn’t always the case. We must not fall into the trap of driving weight too low because the health issue we are trying to improve hasn’t improved to our ‘treatment target’. If weight loss is becoming excessive, we need to back off on the dose of medication, and we must accept that other health issues may require other treatment strategies.
Regarding the treatment goal of reducing cardiovascular events (as seen with semaglutide 2.4mg in the SELECT trial) – we don’t have data for lower doses of semaglutide to know if a lower dose provides cardiovascular benefit, and the benefit (eg not having a heart attack) is not one that we can see or feel. So in the case of a person with overweight/obesity with cardiovascular disease, the evidence supports using the full dose (2.4mg weekly), provided that the person is not losing excessive weight, and provided that they tolerate it well.
BOTTOM LINE: ‘Treating to target’ with weight management medication is taking on an increasingly broadened definition as we develop new evidence for improvement in weight-related health parameters. Targets/goals that are important to the person being treated, weight-related health parameters, and organ protection should be incorporated into a holistic, individualized set of targets, while avoiding excessive weight loss.
Disclaimer: I am/have been an investigator in clinical trials of semaglutide, tirzepatide, and liraglutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide and liraglutide (Novo Nordisk) and Eli Lilly (tirzepatide).
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