Zepbound/Mounjaro (Tirzepatide) for Weight Loss - Part 1

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Zepbound (one of the brand names for Tirzepatide) is a newly approved “weight loss medication” (more on that in a moment) delivered by weekly injection. Today we’ll talk about the basics of the drug, and over the next two parts we’ll do a deep dive into the latest research.

Let’s start here: Tirzepatide is not actually a weight loss medication, it is a Type 2 diabetes medication from Eli Lilly. It was approved under the brand name Mounjaro for Type 2 diabetes in May of 2022. The drug has a side effect of weight loss which, like Novo Nordisk did with Semaglutide, Eli Lilly decided to exploit. In November of 2023 the drug received FDA  approval for weight loss under the brand name Zepbound.

It is being compared to Semaglutide (Ozempic/Wegovy,) but there are some differences. In their weight loss applications, both medications work by interfering with normal digestion processes and hunger signals.  Semaglutide is a GLP-1 (glucagon-like peptide 1) receptor agonist. Tirzeptide, on the other hand, is a GIP (Glucose-dependent insulinotropic peptide)/GLP-1 receptor co-agonist.

Both GIP and GLP-1 agonists interfere with normal hunger signals and digestion. GLP-1 agonists slow gut motility causing food to stay in the body longer. GIP’s reduce the amount of stomach acid which further slows the breakdown and digestion of food.

This is a lot of names so here’s a key:

Semaglutide
Manufacturer: NovoNordisk
Type 2 Diabetes Brand Name: Ozempic
Weight Loss Brand Name: Wegovy

Tirzepatide
Manufacturer: Eli Lilly
Type 2 Diabetes Brand Name: Mounjaro
Weight Loss Brand Name: Zepbound

Dosing Differences

Remember that Tirzepatide is a type 2 diabetes drug with a side effect of weight loss. Dosing/titration is different between Mounjaro and Zepbound because the Type 2 Diabetes (T2D) application seeks to achieve the desired glycemic management while minimizing side effects, while the weight loss application’s sole focus is to maximize side effects that can create weight loss (which, of course is likely to maximize any and all side effects that are dose dependent.)  

Unlike semaglutide, in which the required dose of Wegovy is more than the maximum dose of Ozempic, Mounjaro and Zepbound have the same dose options and maximum (2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg). The difference is in titration. Both groups start at 2.5mg and increase to 5mg after 4 weeks. At that point, those taking Mounjaro for T2D  will only increase the dose if the desired glycemic management is not achieved (and, of course, they can/want to tolerate the side effects. ) On the other hand, those taking Zepbound for weight loss are encouraged to relentlessly increase the dose every four weeks to the maximum that is “tolerable.” This means that those on Zepbound are encouraged to simply take the highest dose they possibly can. (In fact, those who couldn’t tolerate at least 10mg were kicked out of the most recent study after 32 weeks.)  Beyond being exposed to side effects in general, another problem here is patients reporting that they are being pressured to tolerate side effects that significantly decrease their quality of life by doctors who believe that it’s worth the suffering and/or that their higher-weight patients deserve to suffer in order to lose weight.

EDIT: Reader Amanda emailed me with a great question, asking how my description above fits in with the FDA-approved materials prescribing instructions. Those state: “The recommended starting dosage is 2.5 mg injected subcutaneously once weekly. After 4 weeks, increase to 5 mg injected subcutaneously once weekly. Increase the dosage in 2.5 mg increments after at least 4 weeks on the current dose. The recommended maintenance dosages are 5 mg, 10 mg, or 15 mg injected subcutaneously once weekly. Consider treatment response and tolerability when selecting the maintenance dosage.”

That strategy comes from their first trial (SURMOUNT-1) which I wrote about here. In that trial, they tested the drug at 5mg, 10mg, and 15mg doses. People on the 5mg dose lost significantly less weight and their weight loss leveled off sooner than the 10mg and 15mg groups. Starting on the next study (SURMOUNT 2) Lilly dropped the 5gm test group completely, and in the most recent study (SURMOUNT 4, which we’ll look at in detail over the next two parts) they had very strict guidelines and limitations around reducing and then increasing the dose during the 32 week ramp-up period as well as the requirement that if patients couldn’t tolerate at least 10mg by 32 weeks they were removed from the study. While the current prescribing guidelines still stand, they, and particularly the phrase “consider treatment response and tolerability” can serve to obscure the way that new current trials are being conducted, and what patients are being encouraged to do by healthcare providers in order to maximize the intended effect of weight loss, which is as I described above, with apologies for any confusion I caused. I think it’s important to always keep in mind when talking about treatment response and tolerability, the T2D application seeks to minimize side effects in order to manage blood sugar, while the weight loss application simply seeks to maximize a side effect of the drug.

Side Effects

Like Semaglutide, the side effects of this drug range from unpleasant to potentially fatal.

The most common adverse reactions (which is to say, those reported by five or more percent of patients) are:

Nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia (upset stomach,) injection site reactions, fatigue, hypersensitivity reactions, eructation (belching,) hair loss, and gastroesophageal reflux disease.

The drug carries a Boxed Warning – the FDA’s strongest warning – for risk of thyroid C-Cell tumors.

Other serious side effects include:

·         Severe Gastrointestinal Disease

·         Acute Kidney Injury

·         Acute Gallbladder Disease

·         Acute Pancreatitis

·         Serious Hypersensitivity Reactions like anaphylaxis and angioedema

·         Hypoglycemia: Concomitant use with an insulin secretagogue or insulin may increase this risk

·         Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus

·         Suicidal Behavior and Ideation

Because the medication interferes with digestion, it can also interfere with the absorption of other medications.

The FDA-approved prescribing information recommends that those who can become pregnant who are using oral contraceptives switch to a non-oral contraceptive or add a barrier method for 4 weeks after initiation and four weeks after each dose increase.

The prescribing information states that “When pregnancy is recognized, discontinue ZEPBOUND.” However, it is not known if this is adequate to prevent fetal harm because “Available data with tirzepatide in pregnant patients are insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy.” These risks have been found in Semaglutide.

So those are the basics, in part 2 we’ll dig into the most recent research around this drug.

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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.