Tirzepatide Clinical Breakdown

On May 13, 2022, the U.S. Food and Drug Administration (FDA) approved Eli Lilly and Company’s Mounjaro (tirzepatide), a once-weekly injection for the treatment of type 2 diabetes mellitus (T2DM). 

Pathophysiology of Type 2 Diabetes Mellitus

Incretins are the hormones that are released by the body in response to a meal. There are two key incretin hormones: glucose-dependent insulinotropic polypeptide (GIP; formally gastric inhibitory polypeptide) and glucagon-like peptide 1 (GLP-1). GIP and GLP-1 are both primarily produced by cells in the small intestine and stimulate insulin release upon binding of their specific receptors, GIPR and GLP-1R respectively. 

GIP and GLP-1 each carry out many functions, but both enhance insulin secretion and insulin sensitivity. GLP-1 also reduces appetite, food intake, GI motility, and gastric emptying, ultimately leading to weight loss and lowered A1c. Dual agonism of GIPR and GLP-1R lowers glucose levels, decreases food intake, and reduces body weight over time by increasing insulin sensitivity, reducing glucagon secretion, and delaying gastric emptying. 

GLP-1 agonists have now become a mainstay treatment for T2DM given their clinical efficacy, lower risk of hypoglycemia (compared to other antidiabetics alone), and favorable cardiovascular and renal outcomes. Where does tirzepatide fit in for the management of T2DM?

What is Tirzepatide & How Does it Work?

Tirzepatide (brand name Mounjaro) is a first-in-class dual incretin agonist indicated for adults living with T2DM. Activation of both GIP and GLP-1 receptors has an additive effect on insulin response and has demonstrated greater A1c reduction and weight loss over GLP-1 agonists alone. 

The SURPASS clinical trial program has assessed varying doses of tirzepatide across five different trials, each demonstrating significant A1c reduction and low rates of hypoglycemia compared to placebo, semaglutide (GLP-1R agonist), dulaglutide (GLP-1R agonist), and insulin (lispro, glargine, degludec). Weight loss has been observed in a dose-dependent effect. Those taking the lowest dose of tirzepatide losing 15% body weight on average and with higher dosing achieving as much as a 20% reduction in body weight. Adults also experienced greater glucose control using tirzepatide with approximately 73% achieving glucose within range (70-140 mg/dL) compared to 48% with dulaglutide. 

Safety of Tirzepatide 

Overall, tirzepatide is generally well tolerated. Its boxed warning, side effect profile, and safety precautions are comparable to that of a GLP-1 agonist. GI-related side effects are the most common and appear to be dose-related, but are generally mild to moderate in severity and diminish with time. A slower titration of tirzepatide (2.5 mg increments every 4 weeks) is recommended to improve the tolerability of side effects based on the SURPASS-3 study. 

Perhaps one of the most significant (and only clinically significant) differences between that of a GLP-1 agonist and tirzepatide concerns absorption of concurrent oral medications. Though both GLP-1 agonists and tirzepatide delay gastric emptying, studies have suggested that GLP-1 agonists do not significantly interfere with the pharmacokinetic properties of other medications. Contrastly, tirzepatide does not have significant data around this yet and will require additional monitoring of oral medications, especially those with narrow therapeutic indices or that are concentration-dependent. Additionally, it is recommended to switch individuals taking oral hormonal contraceptives to a non-oral contraceptive method if possible. Alternatively, an additional barrier method must be used for 4 weeks following initiation of tirzepatide and for an additional 4 weeks following any dose adjustments if oral contraceptives are continued. 

Dosing & Administration of Tirzepatide

Tirzepatide is a synthetic peptide that contains an albumin-binding moiety with a half-life of roughly 5 days, allowing for once-weekly dosing. It is available as a pre-filled single-dose pen containing 0.5 mL of solution. It varies in appearance anywhere from a clear, colorless liquid to slightly yellow in color. Each pen should be stored in the refrigerator but may be stored at room temperature for up to 21 days. 

Tirzepatide is available in a variety of doses from 2.5 mg to 15 mg per pen. It is administered subcutaneously with a starting dose of 2.5 mg weekly for 4 weeks and then titrated to a target dose of 5 mg once weekly. If glucose levels remain high after 4 weeks of stable dosing, dosing may be increased in 2.5 mg increments every 4 weeks to a maximum of 15 mg weekly. 

Similar to other subcutaneous injections, it may be injected into the abdomen, thigh, or upper arm. Sites should be rotated with each dose to avoid lipodystrophy and should be injected into a separate location from any other injectables (e.g. insulin). Tirzepatide may be administered at any time of day, with or without meals, though it should be administered the same day of every week. However, if a patient wishes to change their primary day of administration, tirzepatide may be given any other day of the week as long as it is at least 3 days (72 hours) from the previous dose.  

If a dose is missed and it is within 4 days (96 hours) from a normally scheduled dose, tirzepatide should be administered immediately. If a dose is missed and it has been longer than 4 days (>96 hours) from a normally scheduled dose, skip the dose and wait to administer the next dose as usual. 

Clinical Application

Tirzepatide is a GIP/GLP-1 agonist that is indicated in adults living with T2DM. GLP-1 agonists are regularly used in treatment of T2DM in those specifically with cardiovascular disease. Tirzepatide mimics current GLP-1 agonists but also exploits GIP agonism, effectively increasing its potency without sacrificing its tolerability. Specifically, tirzepatide has demonstrated greater reductions in body weight and A1c over 40 weeks. It achieved up to 11.3 kg reduction in body weight and up to 2.3% reduction of A1c depending on the dose. In comparison, semaglutide–one of the most potent GLP-1 agonists available–only demonstrated reductions of up to 1.8% and 6.5 kg for A1c and body weight respectively over the same 40 week period. Additionally, tirzeptide appears to reduce liver fat, which may contribute to its improved efficacy, insulin sensitivity, and beta cell function with long-term use. 

Up to this point, tirzepatide appears superior to GLP-1 agonists with respect to weight loss and A1C reduction. Current studies continue to assess the cardiovascular safety and reduction of liver fat associated with the use of tirzepatide. Though more studies are needed, tirzepatide may have a place in therapy for T1DM, nonalcoholic steatohepatitis (NASH), heart failure with reduced ejection fraction (HFrEF), and obesity. 

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Written by Alyssa Butterfield, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP

Written By Eric Christianson

May 25, 2022

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