obesity medication trials look beyond the plateau to new wave of treatment options
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when one hormone is altered via medication, others step in to compensate for the change, restoring what the body perceives as balance. when that happens, it can lead to people reaching plateaus when taking weight loss medications or not responding at all.
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in canada, there are roughly nine million adults living with obesity. there are currently fewer than a handful of medications available to help with management, leaving many people with the condition unable to find proper care if none of those medications provide the desired results or tolerability.
now, two new studies examining both the commonly used semaglutide and cagrisema, a new experimental weight loss drug, have found that both can usher in a new era of obesity treatment.
the semaglutide trial
semaglutide, commonly known by the names wegovy or ozempic, has shown great promise in obesity management thus far; however, not everyone responds to the medication. for those people, options are slim if the medication doesn’t work.
the phase 3b step up trial has now found that it may all be a matter of dosage when it comes to those who don’t achieve the desired results.
dr. sean wharton, medical director of the wharton medical clinic for weight loss, an expert in obesity medicine and trial research, notes that the trial aimed to determine if the current maximum dose was indeed the ceiling for semaglutide, or if a higher dose could be used in people who do not see any improvement at the current dose.
“that’s what this study was, to see whether we get good efficacy and a good safety profile by increasing the dose by three times the upper level of what we thought was the upper level,” he said. “and it turns out, it is possible, and it did work.”
the current maximum dose of semaglutide sits at 2.4 milligrams, whereas the study had participants take 7.2 milligrams. those in the group who took the higher dose saw almost a 21 per cent weight change, compared to 15 per cent on the lower dose. this was considered average weight loss.
comparatively, the study also examined categorical weight loss, which is the number of people who reached 20 per cent or more weight loss while taking the higher dose. close to 50 per cent of participants reached that point, which, as dr. wharton points out, “is a lot” of weight loss.
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“that’s where we really see the impressive difference,” said dr. wharton, when noting the amount of weight loss achieved in people taking the higher dose.
the safety profile was also tolerable enough to give the new dosage legs.
“when you have a three times increase in dose, you think, oh boy, this could be bad in terms of the severity of the side effect profile,” said dr. wharton. “but we did not see a significant increase, and the severe gi side effects and number of severe gi side effects were at the exact point in the 2.4 (group) as in the 7.2 milligram (group).”
while dr. wharton notes that mild and moderate side effects were a bit higher with the higher dose, that much is to be expected when introducing a larger amount of a new medication into the body. but they were “all transient, so they weren’t problematic.”
while the new dosing is a positive thing for patients, it won’t become the baseline because people do still respond to the lower dosage of 2.4. all it does is provide people who don’t respond with another avenue of treating their obesity.
“a lot of people are going to do very well on 2.4 milligrams, so if you’re doing great on 2.4, you don’t need more,” said dr. wharton. “but if you’re not and you’d like to move up, you have the option to now, and that’s what was important.”
the cagrisema trial
in another trial known as the phase 3 redefine 1, a different type of drug was investigated for its effects on obesity: cagrisema. the combination weight loss drug uses semaglutide mixed with cagrilintide, an amylin analog. the dual-agonist strategy was administered to participants in a 68-week trial, with some participants receiving a placebo to gauge results.
from baseline, or the starting point for participants, people taking cagrisema achieved an average weight reduction of over 20 per cent, showing that the drug can be just as effective as the commonly used semaglutide.
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“the combination was, in a way, synergistic, so people got more benefit on weight loss, the percentage of weight loss was much better, there was more reduction in the waist circumference or central obesity,” said dr. harpreet bajaj, medical director of endocrine and metabolic research as lmc healthcare/centricity research and clinical investigator on the trial.
participants in the redefine 1 trial had obesity, as well as a weight-related medical complication that wasn’t diabetes.
in a prior redefine 2 trial, however, the drug was given to people with both obesity and diabetes, and it showed promise as well for being effective at reducing both weight and managing blood sugar levels.
“we are seeing benefits which go much beyond what we have for semaglutide in the current form and in our country, and so this molecule, which is in research right now, in the future, may herald a new era of even better weight reduction and glucose control medications by targeting two different hormones rather than just one,” said dr. bajaj.
by creating a medication that can tackle various hormones at the same time, it’s thought that cagrisema can be a viable approach for people who are living with comorbid conditions.
“there are other hormone systems in the body that compensate in a way. hormones control our metabolic rate. they control our body functions,” said dr. bajaj. “many of them control our appetite as well, and hunger signals or cravings for certain foods, and so when you target one hormone with semaglutide, there are compensatory mechanisms that are built in the body that compensate.”
essentially, when one hormone is altered via medication, others step in to compensate for the change, restoring what the body perceives as balance. when that happens, it can lead to people reaching plateaus when taking weight loss medications or not responding at all.
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for individuals who experience compensatory actions in the body and don’t achieve the desired result, cagrisema is another option.
“people who are doing well with semaglutide and they’re happy with their weight, they may not need this,” said dr. bajaj. “but for those people who are not happy with the weight that they’ve maintained or wish for more, this may be a good drug.”
what this means for patients living with obesity
no two people are alike, and while the body can react to medicine in a more broad sense, what works for one person may not work for another. that’s why both trials are so important for the future of obesity medicine.
one gives people the chance to simply up the dose of a medication that’s worked for them in the past but hasn’t yet helped them reach their desired weight, whereas another provides a different option altogether, allowing for a more personalized approach to obesity treatment, as opposed to the one-size-fits-all therapies currently available.
“we need multiple options for multiple different people,” said dr. bajaj. “everybody’s different.”
tolerability can also be an issue, so for those who have obesity, one medication’s side effects could put them out of commission, whereas another could be non-existent, or mild enough to allow them to continue living their lives while their body adjusts.
for dr. wharton, the initiation of higher doses of semaglutide and more options for people is about helping obesity patients who have done everything they’ve needed to do while taking the medication and are still not seeing results.
“there’s a struggle and a frustration,” he said. “they’re like, ‘i’m doing all the right things. i’m at the right dose, and i’m still not where i need to (be). i could be better.’ here, they have an option … a lot of times, we’re kind of stacked, like that’s all i’ve got for you. you have to do a little bit more exercise and eating better … but now, we can say that there is something more.”
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