Emerging weight loss medications: Is it (still) a numbers race?

This year’s American Diabetes Association (ADA) meeting has concluded, leaving researchers, scientists, clinicians, media and the general public in awe of the new data and developments in medications that powerfully reduce weight and/or improve blood sugar control.

Here are some of the biggest advances reported (buckle in, the list is long and impressive!):

Tirzepatide, an injectable GIP/GLP1 receptor dual agonist, as an obesity treatment in people with type 2 diabetes: The SURMOUNT2 phase 3 results were released, demostrating -14.7% weight loss and -2.2% A1c reduction with 15mg weekly at 72 weeks (published simultaneously in The Lancet).
The PIONEER PLUS phase 3 study oral (pill) semaglutide (a GLP1 receptor agonist) in people with type 2 diabetes, showing -2.0% A1C reduction and -8.5% weight loss with the 50mg daily dose at 52 weeks (as blogged previously, published in The Lancet. Disclosure: I am a co-author and investigator).
The OASIS 1 phase 3 results of oral semaglutide 50mg daily as an obesity treatment, demonstrating -15.1% weight loss at 68 weeks (as blogged previously, published in The Lancet).
A phase 2 trial of retatrutide, an injectable GLP/GLP-1/glucagon triple agonist, in people with obesity, demonstrating -24.2% mean weight loss at 48 weeks with the highest dose tested (12mg weekly), published in the New England Journal of Medicine.
A phase 2 trial of retatrutide in people with type 2 diabetes, demonstrating -16.9% weight loss at 36 weeks with 12mg weekly, and a robust A1C reduction of -2% at 24 weeks, published in The Lancet.
A phase 2 study of cagrisema (an injectable combination of cagrilintide (an amylin analog) 2.4mg with semaglutide 2.4mg) once weekly in people with type 2 diabetes, demostrating -15.6% weight loss and -2.2% A1C reduction at 32 weeks (published in The Lancet. Disclosure: I am a co-author.)
A phase 2 obesity trial of orfoglipron, a non peptide oral (pill) GLP1 receptor agonist, demonstrating -14.7% weight loss at the highest dose tested (45mg daily) at 36 weeks, published in the New England Journal of Medicine. (disclosure: I was an investigator)
A phase 2 study of orfoglipron in people with type 2 diabetes, showing up to -10% weight loss and -2.1% A1C reduction at 26 weeks, published in The Lancet.
A phase 2 obesity trial of survodutide (previously called BI456906), an injectable GLP1/glucagon receptor agonist, demonstrating -14.9% weight loss at the highest dose tested (4.8mg weekly) at 46 weeks.
And a short phase 1 study of a once-weekly injectable GIP monoagonist showing promise by inducing weight loss without nausea or vomiting (potential side effects that are a common theme with all of the above studies (and all currently approved GLP1 receptor agonists)).

[Note: In considering this long list of impressive results, remember that we should not compare the numbers from these trials, because there are differences between trials, such as duration, rate of dose escalation, dietary and physical activity counseling, the people/population being studied, and so forth. Comparisons between medications should only be drawn from head to head trials.]

[Note also that approvals for marketing of medications are based on efficacy and safety data from phase 3 trials. Phase 2 (and 1) are preliminary steps and not sufficient to fully evaluate any medication.]

Older generations of weight loss medications typically provide just 5-10% weight loss. We know that for many people, greater weight loss can provide greater health benefits, better physical function, and better quality of life, so a main goal had been to develop medications that provide greater weight loss.

With many new/emerging medications showing powerful effects on weight, is it really (still) a numbers race? In other words, is it really about which medication can give the very biggest amount of weight loss?

The answer to this question is no. What is going to differentiate these medications is not whether they result in an average of 24% or 27% or 29% weight loss, but whether they are proven to improve health issues related to obesity. For example, many of the medications above are being studied not just for weight management and diabetes, but also to see if they reduce cardiovascular events (eg heart attack and stroke), improve fatty liver disease, heart failure, sleep apnea, Alzheimer’s disease, and so on. In fact, for some people, the full dose of these medications will result in too much weight loss (more on this here). We must think of these highly effective medications as ‘titrate to effect’, meaning finding the right dose for each person that achieves their health and/or weight goals.

What will limit the broader use of these medications is cost and access. As blogged previously, having data demonstrating improvement in obesity-related health issues will hopefully convince insurance companies and governments to pay for treatment. As discussed extensively at the ADA this year, socioeconomic inequties render many new/emerging medications accessible to few, truly unacceptable in a world where obesity and diabetes knows no borders.

Disclaimer: I am an investigator in clinical trials of tirzepatide, semaglutide, retatrutide, cagrisema, orfoglipron, and survodutide. I receive honoraria as a continuing medical education speaker and consultant from the makers of semaglutide,liraglutide, and cagrisema (Novo Nordisk), tirzepatide, retatrutide, and orfoglipron (Eli Lilly), and survodutide (Boehringer Ingelheim).

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