Tirzepatide Injection (Mounjaro)
By William Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California, San Francisco.
Dr. Chan is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
The FDA has approved a first-in-class polypeptide to treat type 2 diabetes mellitus (T2DM).1 Tirzepatide is an agonist for both glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors (“twincretin”). Tirzepatide (39 amino acids) is based on the native GIP sequence. It received a priority review designation and is marketed as Mounjaro.
INDICATIONS
Tirzepatide can be prescribed as an adjunct to diet and exercise to improve glycemic control in adults with T2DM.2 It is not indicated for patients with type 1 DM.
DOSAGE
The recommended starting dose is 2.5 mg, injected subcutaneously once weekly.2 After four weeks, increase the dose to 5 mg weekly. If additional glycemic control is needed, raise the dose in 2.5 mg increments after at least four weeks on the current dose. The maximum dose is 15 mg weekly. The dose should be administered in the abdomen, thigh, or upper arm. The injection site should rotate with each dose and can be given any time of day, regardless of meal. Tirzepatide is available in 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg single-dose pens.
POTENTIAL ADVANTAGES
The dual mechanism of action of tirzepatide demonstrated more effective glycemic control and weight loss than various comparators (e.g., semaglutide, insulin glargine, insulin degludec).1-4 Tirzepatide reported lower risk of hypoglycemia compared to insulin.4,5 The basic polypeptide unit is linked to a 20-carbon fatty diacid moiety to enable albumin binding and long elimination half-life (approximately five days), permitting once-weekly dosing.2
POTENTIAL DISADVANTAGES
Tirzepatide carries a boxed warning for the risk of thyroid C-cell tumors, including medullary thyroid carcinoma.2 Tirzepatide delays gastric emptying and may affect concomitantly administered oral medications.2 Patients on oral contraceptives should switch to a non-oral contraceptive method or add a barrier method for four weeks after dose initiation and each dose escalation.2 The most frequently reported adverse reactions (range, 5 mg to 15 mg vs. placebo) are nausea (12% to 18% vs. 4%), diarrhea (12% to 17% vs. 9%), and decreased appetite (5% to 11% vs. 1%).2 In pooled data, tirzepatide treatment resulted in a mean increase of serum pancreatic amylase concentrations of 33% to 38% and serum amylase of 31% to 42% vs. 4% and no change, respectively, for placebo treatment.2
COMMENTS
Tirzepatide enhances the activity of a GLP-1 agonist by simultaneously stimulating the GIP receptors. This enhances first and second phase insulin secretion and lowers glucagon levels in a glucose-dependent manner.2 Tirzepatide increases insulin sensitivity and reduces fasting and postprandial glucagon concentrations. The efficacy and safety were evaluated in five Phase III clinical trials.2,6 These included monotherapy vs. placebo (n = 478; 40 weeks); add-on to metformin vs. semaglutide (n = 1,879; 40 weeks); add-on to metformin ± a selective glucose transporter-2 inhibitor (SGLT2i) vs insulin degludec (n = 1,444; 52 weeks); add-on to metformin, sulfonylurea, or SGLT2i vs. insulin glargine (n = 2,002; 104 weeks); and in combination with basal insulin ± metformin vs. placebo (n = 475; 40 weeks). Each study included three different doses of tirzepatide (5 mg, 10 mg, and 15 mg) with changes from baseline in HbA1c, fasting serum glucose, and body weight as the key efficacy endpoints. All doses of tirzepatide were statistically better compared to active comparators in all endpoints (except no statistical differences in changes in serum glucose levels vs. insulin glargine, insulin degludec, and semaglutide).
CLINICAL IMPLICATIONS
Tirzepatide offers a new option for patients with T2DM inadequately controlled on currently marketed medications. In comparison to semaglutide, a selective GLP-1 receptor agonist, tirzepatide was superior in terms of helping patients lower HbA1c levels and lose weight.3 However, more subjects randomized to tirzepatide discontinued treatment (6% to 8.5% vs. 4.1%).3
The authors of a recent report suggested tirzepatide may provide renal protective benefit in patients with high vascular risk.7 The drug also is under investigation to treat obesity with substantial and sustained reductions in body weight seen with 5 mg, 10 mg, and 15 mg dosing.8 Another trial is in progress to assess the cardiovascular benefit of tirzepatide compared to dulaglutide, with results expected in 2025. The cost is $974.33 for a four-week supply.
REFERENCES
- U.S. Food & Drug Administration. FDA approves novel, dual-targeted treatment for type 2 diabetes. May 13, 2022.
- Eli Lilly and Company. Mounjaro prescribing information. May 2022.
- Frías JP, Davies MJ, Rosenstock J, et al. Tirzepatide versus semaglutide once weekly in patients with type 2 diabetes. N Engl J Med 2021;385:503-515.
- Ludvik B, Giorgino F, Jódar E, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3): A randomised, open-label, parallel-group, phase 3 trial. Lancet 2021;398:583-598.
- Del Prato S, Kahn SE, Pavo I, et al. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): A randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet 2021;398:1811-1824.
- Min T, Bain SC. The role of tirzepatide, dual GIP and GLP-1 receptor agonist, in the management of type 2 diabetes: The SURPASS clinical trials. Diabetes Ther 2021;12:143-157.
- Heerspink HL, Sattar N, Pavo I, et al. Effects of tirzepatide vs. insulin glargine 100 U/mL on kidney outcomes in participants with type 2 diabetes in SURPASS-4. Diabetes 2022.
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022; Jun 4. doi: 10.1056/NEJMoa2206038. [Online ahead of print].
Tirzepatide can be prescribed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
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