GLP-1 Agonists and Medication Absorption - Part 1
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One of the questions I’ve been getting a lot is about how the new GLP-1 weight loss drugs (Novo’s Semaglutide Wegovy) and GLP-1/GIP co-agonist weight loss drugs (Lilly’s Tirzepatide/Zepbound) can interfere with the absorption of other medications. In part 1 we’ll look at the information around this and in part 2 we’ll have a personal story of someone who experienced it.
One of the mechanisms by which these drugs work is by slowing the digestion of food by slowing gut motility as well as, in the case of the GLP-1/GIP co-agonists, reducing stomach acid. Part of the concern is that impairing the natural food digestion process may also impair the medication absorption process.
This is part of Wegovy’s FDA-approved prescribing guidelines: “WEGOVY delays gastric emptying. May impact absorption of concomitantly administered oral medications.”
That refers you to 7.2 which says:
“7.2 Oral Medications WEGOVY causes a delay of gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. In clinical pharmacology trials with semaglutide 1 mg, semaglutide did not affect the absorption of orally administered medications [see Clinical Pharmacology (12.3)]. Nonetheless, monitor the effects of oral medications concomitantly administered with WEGOVY.”
If you look at 12.3 you find “The delay of gastric emptying with semaglutide may influence the absorption of concomitantly administered oral medications [see Drug Interactions (7.2)]. The potential effect of semaglutide on the absorption of co-administered oral medications was studied in trials at semaglutide 1 mg steady-state exposure. No clinically relevant drug-drug interactions with semaglutide (Figure 3) were observed based on the evaluated medications.”
Figure 3 shows that they only tested 7 drugs: Metformin, S-warfarin, R-warfarin, Digoxin, Atorvastatin [Lipitor], Ethinylestradiol [used as a contraceptive in multiple brands), Levonorgestrel [Plan B]. It also only shows the impact at 1mg. The problem is that Information about the impact on drug absorption at 1mg may not be that helpful for someone taking 2.4 times, or even 1.7 times, that amount as in the case of Wegovy.
The last sentence is odd “In a separate study, no apparent effect on the rate of gastric emptying was observed with semaglutide 2.4 mg.” The study isn’t cited so I’m not clear if they mean that no apparent effect of delayed gastric emptying on the absorption of concomitantly taken drugs was observed, or if they are saying that taking semaglutide 2.4mg did not have an effect on the rate of gastric emptying which doesn’t make sense since delayed gastric emptying is a well-studied effect of the drug.
Zepbound’s FDA-approved prescribing information are a bit more detailed:
First the eerily familiar “ZEPBOUND delays gastric emptying and has the potential to impact the absorption of concomitantly administered oral medications.”
It sends you to (7.2). That says:
7.2 Oral Medications
ZEPBOUND delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with ZEPBOUND.
Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with ZEPBOUND.
Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception, for 4 weeks after initiation with ZEPBOUND and for 4 weeks after each dose escalation. Hormonal contraceptives that are not administered orally should not be affected...”
I wanted to dig deeper into three concepts here: concomitantly administered, medications dependent on threshold concentrations for efficacy, and those with narrow therapeutic index.
Concomitantly administered means that the two drugs are taken at, or nearly at, the same time. This becomes complicated a bit because most of these drugs are administered as weekly injections, but the “concomitant” drugs may be taken daily, or weekly at different times.
The other two terms wander pretty far from anything resembling an area of expertise for me, so I reached out to Dr. Lisa Erlanger and asked her for a plain-language explanation, which she was kind enough to provide:
“Narrow therapeutic window is a medication that doesn’t work until it’s at a certain blood level, and is toxic above a level that isn’t much higher than that. I think of chemotherapy as an obvious example. Warfarin. Lithium. Certain heart medications like digoxin.
Threshold would be a medicine that doesn’t have any of its intended effect below a certain blood level, and so keeping a constant blood level is important. Typically, dosing interval and dispersion characteristics of the pill would work together to make this happen (for example, extended release blood pressure medication can be taken once a day, but some antibiotics have to be taken three times a day). Intuitively, erratic digestion would interfere with these calculations for medicines. For threshold, I think of seizure medications, warfarin, and ADHD meds as well as some psychotropics. For example, some people feel really awful if their Effexor is even an hour late. I don’t think it has as significant a threshold effect for efficacy, but definitely for withdrawal for some people. Other psychotropics like SSRIs and anti-psychotics can be toxic at levels you wouldn’t ordinarily reach in usual dosing and lose efficacy with erratic dosing. I guess we don’t really know what happens with GLP-1 digestion and so that could happen. And if that’s happening then I imagine all sorts of medications could be a problem. Especially if it’s erratic rather than just slow- for example you don’t want too much blood pressure medication.”
So the bottom line is that very little is known about the way that these drugs, in the large doses that are recommended to increase their weight loss side effect, impact the absorption of other medications.
In part 2 we’ll learn about how this impacted one patient.
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More research and resources:
https://haeshealthsheets.com/resources/
*Note on language: I use “fat” as a neutral descriptor as used by the fat activist community, I use “ob*se” and “overw*ight” to acknowledge that these are terms that were created to medicalize and pathologize fat bodies, with roots in racism and specifically anti-Blackness. Please read Sabrina Strings’ Fearing the Black Body – the Racial Origins of Fat Phobia and Da’Shaun Harrison’s Belly of the Beast: The Politics of Anti-Fatness as Anti-Blackness for more on this.
Once again, Novo and Lilly are providing studies that don't begin to address real life-and-death concerns as they market the hell out of these meds. I wish your analyses of these studies were broadcast far and wide to counteract the outsized media hype these meds are getting.
I saw a pain doctor last week for five minutes to discuss a cortisone injection in my lumbar region. Two minutes into the appointment he asked if I was taking Mounjaro, "the GLP with the best reported results." I told him no. When he asked why I said it was complicated, as I wanted to shut down this conversation without having my blood pressure go through the roof. He backed off. But how the hell does he think it's at all appropriate to bring up weight loss in this context?
Needless to say, I left there with a very low opinion of this MD, who, in a couple of weeks, is going to stick big needles in my spine,
Ragen, thanks for the great work, as always.
Oh damn, this is so disappointing.
I’ve noticed that my allergy and asthma pills don’t work half as well if I take an acid reducer of some kind within an hour… I can’t imagine how bad off I’d be if I were taking it on top of one of these GLP1’s.
So now in 5-10 years, when we see that people on weight-loss-level doses of these meds are dying early of preventable things related to blood pressure, blood sugar, asthma, heart disease, seizures, (the list goes on), I bet that means the headlines will say we were simply too fat to be helped and died of our fatness, so we better start putting people on these drugs younger and sooner!