Saw this pop up again today and figured it might be handy to have a post addressing the topic properly. It's commonly claimed that reta doesn't work differently from tirzepatide at doses lower than 4mg or that the glucagon agonist doesn't "kick in" until that level.
The 4mg thing is a myth that persists based on someone misinterpreting data from a phase 1 trial. In that trial participants were given single doses of reta and then had various things tracked following that single dose. The 3mg group was the lowest dosed group where serum glucagon levels fell significantly from their previous baseline and at some point that got rounded to 4mg, as a 3mg dosing wasn't maintained in phase 2 trials.
Here's why that's dubious logic:
1: A single 4mg dose is roughly equivalent to a weekly 2mg dose (due to how drugs build up in your system over time) in terms of peak level. A weekly 4mg dose would lead to blood levels that roughly fluctuated from 8mg total back down to 4mg right before shot day. Single dose vs weekly dose is not apples to apples.
2: There's no reason to think every person is going to see glucagon levels fall at the same dosing level, since insulin and glucagon levels vary quite a bit from person to person (and baseline levels can be quite high in an obese or diabetic person). Someone who is less insulin resistant would likely see that same result occur at lower reta dosing, while someone who is more insulin resistant would likely need a higher dosing before observing such a result. Also, as one progresses through treatment, this is all a moving target, as degree of insulin resistance is going to change too.
3: Serum glucagon level itself isn't an isolated metric. Your body regulates metabolism by balancing your insulin to glucagon ratio. A GLP is already slightly bumping up your baseline insulin level. That means before factoring in glucagon agonism your body is already going to naturally raise your glucagon level in response to any GLP. This is observed in that same phase 1 trial where glucagon level goes up at a very low reta dosing level. That means when we see glucagon "unchanged" at a low dosing level, that's not the full story. That result would be better explained as "balanced," since it represents the point where the action of the glucagon agonist is balancing the GLP-1 RA's effect in raising glucagon. The 4mg dosing is simply the level at which the glucagon agonist began to dominate.
Note:
It's also worth pointing out that 99% of influencers don't even understand what that change in glucagon level actually means. The goal with reta isn't to lower glucagon level. Just as a GLP-1 agonist can be thought of as counterfeit GLP-1, the glucagon agonist in reta could be thought of as "counterfeit glucagon." The reason we're interested in seeing a lower level of real glucagon in the blood is because that indicates that your body believes the glucagon level is too high (due to sensing all of the counterfeit glucagon) and is taking steps to scale back production of it. It's a sign that your body is both being "fooled" by the counterfeit glucagon and believes that current glucagon levels are excessive.
Conceptually, your body would normally increase your glucagon levels when you haven't eaten in several hours and scale it back after a meal containing carbs. A glucagon agonist is overriding that and fooling your body into thinking that those levels are perpetually raised. Empirically, this seems to maintain an elevated metabolism, as well as driving certain other processes that on the whole seem to benefit those with obesity and/or diabetes and help drive weight loss, although I'm not sure the specific biochemical rationale for that result is completely nailed down.
Of course, none of this is to say that 4mg isn't a "good level" or anything like that, just that there's nothing magical or unique about that particular level VS any other level.
The 4mg thing is a myth that persists based on someone misinterpreting data from a phase 1 trial. In that trial participants were given single doses of reta and then had various things tracked following that single dose. The 3mg group was the lowest dosed group where serum glucagon levels fell significantly from their previous baseline and at some point that got rounded to 4mg, as a 3mg dosing wasn't maintained in phase 2 trials.
Here's why that's dubious logic:
1: A single 4mg dose is roughly equivalent to a weekly 2mg dose (due to how drugs build up in your system over time) in terms of peak level. A weekly 4mg dose would lead to blood levels that roughly fluctuated from 8mg total back down to 4mg right before shot day. Single dose vs weekly dose is not apples to apples.
2: There's no reason to think every person is going to see glucagon levels fall at the same dosing level, since insulin and glucagon levels vary quite a bit from person to person (and baseline levels can be quite high in an obese or diabetic person). Someone who is less insulin resistant would likely see that same result occur at lower reta dosing, while someone who is more insulin resistant would likely need a higher dosing before observing such a result. Also, as one progresses through treatment, this is all a moving target, as degree of insulin resistance is going to change too.
3: Serum glucagon level itself isn't an isolated metric. Your body regulates metabolism by balancing your insulin to glucagon ratio. A GLP is already slightly bumping up your baseline insulin level. That means before factoring in glucagon agonism your body is already going to naturally raise your glucagon level in response to any GLP. This is observed in that same phase 1 trial where glucagon level goes up at a very low reta dosing level. That means when we see glucagon "unchanged" at a low dosing level, that's not the full story. That result would be better explained as "balanced," since it represents the point where the action of the glucagon agonist is balancing the GLP-1 RA's effect in raising glucagon. The 4mg dosing is simply the level at which the glucagon agonist began to dominate.
Note:
It's also worth pointing out that 99% of influencers don't even understand what that change in glucagon level actually means. The goal with reta isn't to lower glucagon level. Just as a GLP-1 agonist can be thought of as counterfeit GLP-1, the glucagon agonist in reta could be thought of as "counterfeit glucagon." The reason we're interested in seeing a lower level of real glucagon in the blood is because that indicates that your body believes the glucagon level is too high (due to sensing all of the counterfeit glucagon) and is taking steps to scale back production of it. It's a sign that your body is both being "fooled" by the counterfeit glucagon and believes that current glucagon levels are excessive.
Conceptually, your body would normally increase your glucagon levels when you haven't eaten in several hours and scale it back after a meal containing carbs. A glucagon agonist is overriding that and fooling your body into thinking that those levels are perpetually raised. Empirically, this seems to maintain an elevated metabolism, as well as driving certain other processes that on the whole seem to benefit those with obesity and/or diabetes and help drive weight loss, although I'm not sure the specific biochemical rationale for that result is completely nailed down.
Of course, none of this is to say that 4mg isn't a "good level" or anything like that, just that there's nothing magical or unique about that particular level VS any other level.
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