As we discussed in the previous article, people are starting to use incretins as an adjunct therapy in the treatment of type 1 diabetes. All off label, of course.
Anyone familiar with these drugs will know that they are indicated to be injected once a week. A model that’s easy to follow, doesn’t involve too much onerous effort for those who are needle shy and presents no funny, off date reminders in the middle of the day.
With this in mind, here we’re going to take a look at the pharmacokinetics of the two big boys (WeGovy and Mounjaro) and think about the impact those may have on the expected effects with type 1, and potentially the corroloary effects when used for other conditions.
Pharmacokinetics
The data for the PK of both drugs is widely available. We’ll split it into absorption, decay and provide a graph of how these drugs add up in the body.
It’s worth noting that in the context of drug delivery, the starting point for decay is when the max concentration of the drug from a single dose is reached. It’s also worth mentioning that while the term “availability” is used for both, the data will be normalised to a maximum of 100% of available drug, as that’s what the user experiences. Availability is provided for information only.
Given the similarities in time to peak concentration that we’ll describe, for the purposes of the analysis undertaken, both have been set to 48 hours.
WeGovy
WeGovy, produced by Novo Nordisk, is the older of the second generation incretins containing Semaglutide.
According to the data, it has the following pharmacokinetics:
- Time to max concentration: 24-72 hours
- Max availability: 89%
- Half life: approximately 7 days
- Time to steady state of current dose: 4-5 weeks
With weekly dosing, the graph for Semaglutide is shown below.
Mounjaro
Mounjaro, produced by Lilly is a dual incretin containing GIP and GLP1 -RA. It contains Tirzepatide.
According to the data, it has the following pharmacokinetics:
- Time to max concentration: 8-72 hours
- Max availability: 80%
- Half life: 5 days
- Time to steady state: No details provided
With weekly dosing, the graph for Tirzepatide is shown below.
Pharmacokinetics commentary
What’s noticeable in both the graphs above is that there are significant swings from minimum to maximum availability of the drugs in the user’s body. Both graphs show a period rolling average which is significantly different from either peak or trough.
What’s also noticeable is that the steady state average for both drugs is really an amount that’s higher than the stated dose that’s being used.
Taking a look at that difference from the rolling average, the graph below shows how much the two incretins differ.
What we can see from this graph is that the variation for Mounjaro, as a result of the five day half life, is greater than that of WeGovy.
Typically in a steady state, Mounjaro moves between 40% more than the steady state average and roughly 30% less. WeGovy, on the other hand, goes between just under 30% more and around 20% less than the periodic average.
But what does this mean?
Essentially, on the standard weekly dosing model, the amount of incretin circulating on the last couple of days is quite a bit lower than the rest of the time. With less in circulation, you’d expect the effects to be reduced, and a quick search on social media suggests this is probably true, with people asking questions like “Why do I feel more hungry on day five to seven?”.
People report an increase in appetite, along with other reduced therapeutic outcomes. This thread on Reddit is one example. This suggests that amongst other things, the Ghrelin suppression we mentioned in the previous article is dropping as the “Incretin on board” (IOB) drops.
It also raises questions about the best way to move to a “maintenance dose” once desired weight loss is achieved.
The implications of this when using incretins for weight loss are somewhat different compared to use for managing hormones in type 1 diabetes.
Effects in a type 1 context
As we previously discussed, one of the benefits of using incretins in type 1 treatment is the opportunity to manage the effects of hormones that are under-regulated. Essentially, we’d be looking to down-regulate Ghrelin and Glucagon as smoothly and equally as possible over time.
The likely effect of the variation identified here is that towards the end of a weekly dosing period, those reduction effects will wear off. With the increase in gastric transit rate and Glucagon, measures used to determine insulin dose would change, alongside increasing total daily dose of insulin.
From a treatment perspective, the ups and downs associated with this could end up being hard to manage as, for example, insulin sensitivity may change in response to variation in Glucagon levels. Carb ratios may change in response to different rates of gastric transit.
This is where different approaches to dosing regimes might need to be considered.
Incretin dosing for type 1 management – suggestions
If the variation about the mean with the 7-day dosing period is likely to be problematic for hormone control, then perhaps a reduced dosing period at a smaller dose would make more sense.
The following two graphs show the effects of shorter periods between doses, using half the indicated dose.
What’s clear in both these graphs is the reduced steady state average, compared to seven days dosing. When you aim to achieve the same periodic average as the 7-day dosing, with the shorter period, each dose needs to be around 55%-60% of the normal 7-day dose. This achieves the same level of average drug concentration.
When we look at the variance from periodic mean, there’s a significant difference between 7-day and 3.5/4 day dosing.
The two graphs below demonstrate the difference for both Mounjaro and WeGovy.
By shrinking the period between doses, we can see that the peaks and troughs, as we would expect, have reduced in amplitude. With WeGovy we see roughly +/- 10% while with Mounjaro, it’s roughly +15%/-10%, compared to much larger swings with the 7-day dosing.
In theory, this suggests that there’d be fewer ups and downs over the dosing period and as a result, things like total daily dose and insulin sensitivity would be likely to remain within a range that would be much easier to manage.
It also raises questions as to what the most appropriate incretin to use with type 1 is?
Does the constitution of Tirzepatide block hormones better than Semaglutide, even though the variation about the mean of Semaglutide might make managing type 1 easier when using it?
Takeaways
There’s a lot to read into this.
Firstly, the way that the different drug concentration varies over time seems to play a part, for some people at least, in the short term effectiveness of it. Whether this carries over in to use in type 1 isn’t clear. It certainly appears from this data that titration may be an important consideration in incretin use.
Secondly, does the difference between the dual incretin make-up of Tirzepatide produce a different set of results to Semaglutide with type 1 users seeking to manage hormones?
Neither of these is easy to answer, and there’s little data available right now. Both are likely to require either significant real world observation in off-label use, or some form of RCT with careful observation.
And then there’s the question about interaction with Automated Insulin Delivery systems. That will come in the next article.
Very interesting – thank you!
Thank you for your excellent analysis. My concerns: 1) the doses are supra-physiological and long term risks are uncertain 2) side-effects such as slowing of gastro-intestinal transit may be troublesome – such as gastric fullness and burping to life-threatening such as intestinal paralysis. How many prescribers check to ensure someone with diabetes does not have gastro-paresis as a complication before prescribing?