Tirzepatide: The next new weight loss medication
SUPER BRIEF SUMMARY
Tirzepatide is a new GIP/GLP-1 receptor agonist that has up to a 21% total body weight loss over 72 weeks. It is already approved for treatment of Type 2 Diabetes under the trade name “Mounjaro”. The data for weight loss alone is from an industry sponsored phase 3 trial so grain of salt, especially given the large magnitude of effect. However, this is promising data for a new injectable medication that will likely be FDA approved for weight loss alone.
Keep in mind, like Wegovy and Saxenda (the two other GLP-1 agonists), this will likely be very expensive (more than $1,400 a month) and unlikely covered by your insurance. So, though potentially impressive results, cost will likely prohibit many from using this medication. Regardless, these advancements are certainly exciting and bode well for the field of obesity medicine.
THE WHOLE TALK
There has been a large focus in recent decades to build upon the bodies own hormonal signaling pathways to help control hunger and weight for patients suffering from obesity. You may have already heard of Wegovy (Semaglutide) and Saxenda (Liraglutide). These are both injectable medications approved for weight loss alone. There are multiple others approved for the treatment of Type 2 Diabetes.
Both Wegovy and Saxenda are GLP-1 agonists, meaning the imitate the function of the hormone GLP-1. There is another gastrointestinal hormone (these are specifically know as “incretins”) called GIP that exerts an effect on our body. Interestingly, GIP was the first to be discovered, though it seems may be latter to be marketed and distributed¹. Although outside the scope of this particular blog post, the physiology of these to hormones exert effects across multiple areas of the body from bone to brain to gut and even heart². The excellent graft below demonstrates these wide ranging effects with thanks to Samms et al for their excellent summary paper on this topic³.
Now, you may notice that the GIP as an up arrow next to fat accumulation. While this is true no need to be discouraged. It seems that it actually helps with “healthy fat accumulation”. The idea is that the actual number of fat cells is increased and not the size. This helps with the buffering of fatty acids after a meal and can actually decrease lipid levels which theoretically could improve other health outcomes such as cardiovascular disease³.
However, it seems that the majority of the affect of GIP comes from the appetite suppressing or anorexigenic properties within the central nervous system (aka brain and spinal cord). Furthermore, GIP has been demonstrated to have a synergistic effect on appetite suppression when in combination with GLP-1. Though there also appears to be an independent affect.
So yes, there does appear to be a bit of a conundrum when it comes to GIP. There has been a longstanding debate regarding GIP and its ability to either increase fat mass versus decrease based off of its other mechanisms. Regardless, at this time the human data certainly supports that the total affect is toward weight reduction³.
An additional benefit is that GIP stimulation can help combat the nausea and other GI symptoms seen with higher levels of GLP one of stimulation³. These side effects have traditionally limited dose escalation in the use of GLP-1 agonists such as Semaglutide and Liraglutide.
Okay, so it seems as if the GIP and GLP-1 can have a synergistic effect to help patients lose weight, largely mediated through a appetite suppressing affect. Now with actually talk about the new medication in the title, Tirzepatide.
Adapted from Echemi⁴
As stated above in the initial summary, Tirzepatide manufacture, Eli Lilly, recently released the results SURMOUNT-1 phase three trial with some impressive results. The figures below from the paper itself demonstrate the impressive weight loss of 21% total body mass at the higher dose of Tirzepatide. This was a multicenter, double-blind, randomized, placebo-controlled trial was conducted at 119 sites in nine countries. A total of 2539 participants were randomized in a 1:1:1:1 ratio to Tirzpeatide 5mg, 10mg, 15mg or placebo⁵.
As a quick refresher regarding clinical trials…
While the primary endpoint was weight loss there was multiple secondary endpoints that demonstrated improvement as well compared to placebo. This included cardiovascular benefits such as glycemic control, cholesterol, waist circumference, diastolic blood pressure, in addition others.
Main side effects were largely limited to gastrointestinal such as nausea, diarrhea, constipation. These appear to be fairly time limited and improved with continued use.
Even the authors themselves recognize the large effect of this medication. Stating, “This is an unusually substantial degree of weight reduction in response to an antiobesity medication as compared with findings reported in other phase 3 clinical trials. Given that tirzepatide is both a GIP receptor and GLP-1 receptor agonist, we speculate that there may be additive benefit in targeting multiple endogenous nutrient-stimulated hormone pathways that have been implicated in energy homeostasis.”
I anticipate Tirzepatide will obtain FDA clearance for the treatment of obesity without comorbidities such as type 2 diabetes. However, it remains to be seen what barriers to utilizing this novel therapy will manifest. I have significant concern regarding the cost of the medication as Semaglutide is infrequently covered by insurance for the treatment of obesity and can cause up to $1,400 dollars a month. I certainly hope there will be cost effective options for Tirzepatide and that insurers will begin to recognize the importance of weight management as a preventative measure for nearly all other aspects of health and life.
In summary, my fingers are certainly cross though my expectations for real world use are low at the moment. This apprehension is largely related to cost concerns. Regardless I am excited by the continued advancements in the field of obesity medicine and look forward to more high quality data in the future.
SOURCES
Brown JC, Mutt V, Pederson RA. Further purification of a polypeptide demonstrating enterogastrone activity. JPhysiol 1970; 209: 57–64.
Seino, Yutaka, Mitsuo Fukushima, and Daisuke Yabe. “GIP and GLP-1, the Two Incretin Hormones: Similarities and Differences.” Journal of Diabetes Investigation 1, no. 1–2 (2010): 8–23. https://doi.org/10.1111/j.2040-1124.2010.00022.x.
Samms, Ricardo J., Matthew P. Coghlan, and Kyle W. Sloop. “How May GIP Enhance the Therapeutic Efficacy of GLP-1?” Trends in Endocrinology & Metabolism 31, no. 6 (June 2020): 410–21. https://doi.org/10.1016/j.tem.2020.02.006.
Echemi. Lilly’s GLP-1 and Tirzepatide initiates phase III clini cal trial [Internet]. Echemi; 2020 [cited 2021 Sep 17]. Available from: https://www.echemi.com/cms/110494.html
Jastreboff, Ania M., Louis J. Aronne, Nadia N. Ahmad, Sean Wharton, Lisa Connery, Breno Alves, Arihiro Kiyosue, et al. “Tirzepatide Once Weekly for the Treatment of Obesity.” New England Journal of Medicine 387, no. 3 (July 21, 2022): 205–16. https://doi.org/10.1056/NEJMoa2206038.
csilva. “Clinical Trials Part 3 - Phases of Clinical Trials and What Happens in Each.” Acromegaly Support - Rare Disease Awareness, Education, and Support, August 26, 2021. https://acromegalysupport.com/phases-of-clinical-trials/.
