By: Zarin Chowdhury, PharmD Candidate c/o 2023 and Lauren Merkovich, PharmD Candidate c/o 2023

              Type 2 diabetes (T2D) is a long-term medical condition in which the body is unable to use insulin properly, resulting in abnormal blood glucose levels.¹ More than 37 million Americans have diabetes (about 1 in 10); approximately 90 to 95% of these patients have T2D. T2D will most often develop in people over the age of 45, however, more children, teenagers, and young adults are also developing T2D.² Despite the variety of medications to treat diabetes, many patients have difficulty achieving their recommended blood glucose goals.

Blood glucose levels are monitored via glucose monitors and by following a patient’s Hemoglobin A1c (HbA1c) level. Glucose adheres to hemoglobin, a protein in red blood cells. As blood glucose levels increase, the hemoglobin becomes more saturated with glucose. An HbA1c test measures the percentage of red blood cells that have glucose-coated hemoglobin, indicating the average blood glucose level over the past two to three months. An HbA1c below 5.7% is normal, between 5.7 to 6.4% indicates prediabetes, and 6.5% or higher indicates diabetes. Target HbA1c varies by patient, but averages at 6.5 or below. First line treatment of T2D is metformin combined with lifestyle modifications, including meal planning and exercise. If targeted HbA1c is not reached with first-line treatment, additional medications may be added based on the patients’ compelling indication, including sulfonylureas, sodium-glucose transporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors, thiazolidinediones, or insulin. Factors to consider when prescribing medication regimens for patients include health goals, insurance, medical history, and ease of usage.³

On May 13, 2022, the Food and Drug Administration (FDA) approved Mounjaro (tirzepatide) injection to improve glycemic control in patients with T2D, along with diet and exercise.⁴ GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) are two incretin hormones released by the gut to aid in blood glucose control. Increases in these hormones lead to insulin release, increased satiety, and decreased glucose production.⁵ These mechanisms happen in a glucose-dependent manner, meaning GLP-1 and GIP receptor agonists are unlikely to cause severe hypoglycemia. Tirzepatide is a first-in-class medication that activates both the GLP-1 and GIP receptors.⁴

The FDA’s approval of tirzepatide was based on positive outcomes from the Phase III SURPASS program that included five clinical trials.⁶ The findings from each trial are summarized in the table below. In SURPASS-1, tirzepatide was studied as monotherapy. In SURPASS-2, SURPASS-3, and SURPASS-4, tirzepatide was studied as an add-on to other diabetes medications. For SURPASS-5, tirzepatide was evaluated in combination with basal insulin, with or without metformin. Three doses of tirzepatide (5 mg, 10 mg, and 15 mg) administered subcutaneously once weekly were evaluated. Patients with T2D who participated in the SURPASS program achieved average reductions in HbA1c levels between 1.8 to 2.1% for tirzepatide 5 mg, and between 1.7 to 2.4% for both 10 mg and 15 mg doses of tirzepatide.⁷ Tirzepatide delivered superior HbA1c level reductions against all comparators in the SURPASS trials. Additionally, patients given tirzepatide experienced significantly greater weight loss (p < 0.001 for all trials) than patients given comparator treatments. On average, patients treated with the 5 mg dose of tirzepatide lost 12 lbs of weight, while those treated with the 15 mg dose saw their weight reduced by 25 lbs.⁷

Tirzepatide comes as a single-dose prefilled pen that needs to be refrigerated. It is administered once weekly by subcutaneous injection.⁹ The recommended starting dose of tirzepatide is 2.5 mg. After 4 weeks, doses may be increased in 2.5 mg increments, as tolerated, up to a maximum of 15 mg a week. Injection sites include the abdomen, thigh, and upper arm. Patients should rotate injection sites with each dose. Administration can be at any time of the day, with or without food. If patients miss a dose of tirzepatide, they should administer it as soon as possible. If a missed dose is not administered within 4 days (96 hours), the dose should be skipped and the patient should inject their next dose as normally scheduled. Changing the day of weekly administration is possible if the time between 2 doses is at least 3 days (72 hours) apart. When tirzepatide is used in combination with insulin, the injections are administered as separate injections; they cannot be mixed. Patients may administer tirzepatide and insulin in the same body region as long as the injections are not adjacent.⁹

Regarding its safety profile, tirzepatide has a black box warning for increased risk of thyroid cancer. It is important that patients examine themselves and inform their provider of any new lumps or swelling in the neck, sudden difficulty swallowing, or shortness of breath. Common adverse reactions reported in ≥ 5% of tirzepatide-treated patients include nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. Patients and providers should be aware that tirzepatide delays gastric emptying and has the potential to alter absorption of other oral medications.¹¹ This may impact narrow therapeutic index drugs or drugs that need a minimum blood level for efficacy. Patients taking oral contraceptives should be counseled to switch to a non-oral contraceptive method or add a barrier contraceptive method for 4 weeks after initiation of tirzepatide, and for 4 weeks after each dose escalation.¹¹ Based on animal reproduction studies in pregnant rats and rabbits, tirzepatide may cause fetal harm, but data is insufficient to evaluate the safety of tirzepatide in pregnant women.¹² There is no data on the presence of tirzepatide in human milk, the effects on breastfed infants, or the effects on milk production. Tirzepatide should only be used during pregnancy or lactation if the potential benefits outweigh the potential risks.¹² Furthermore, tirzepatide’s safety and efficacy are unknown for use in children under 18 years of age.¹¹

The increased prevalence of diabetes in the United States has lead to the introduction of new treatment options like tirzepatide into the market. These innovations in medicine are created to help achieve improved glucose control. As pharmacists, it is important to not only be aware of the current treatment guidelines but to also stay up to date with the emergence of new medications. Healthcare providers should provide patients with the best medication options, however, it is equally important to provide education on non-pharmacological options, such as lifestyle modifications, to help decrease the prevalence of diabetes. Keeping this mindset allows pharmacists and other healthcare providers to be the patient’s best advocates in maintaining a healthy lifestyle.  


References

1. Type 2 overview. Type 2 Diabetes – Symptoms, Causes, Treatment | ADA. https://www.diabetes.org/diabetes/type-2.  Accessed July 25, 2022.
2. Type 2 diabetes. Centers for Disease Control and Prevention. https://www.cdc.gov/diabetes/basics/type2.html.  Published December 16, 2021. Accessed July 25, 2022.
3. Davies, M. J., D’Alessio, D. A., Fradkin, J., Kernan, W. N., Mathieu, C., Mingrone, G., Rossing, P., Tsapas, A., Wexler, D. J., & Buse, J. B. (2018, October 5). Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). American Diabetes Association. Retrieved August 18, 2022, from https://diabetesjournals.org/care/article/41/12/2669/36544/Management-of-Hyperglycemia-in-Type-2-Diabetes
4. FDA approves novel, dual-targeted treatment for type 2 diabetes. U.S. Food and Drug Administration. https://www.fda.gov/news-events/press-announcements/fda-approves-novel-dual-targeted-treatment-type-2-diabetes.  Published May 13, 2022. Accessed July 25, 2022.
5. Seino Y. Glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1: Incretin actions beyond the pancreas. Journal of diabetes investigation. https://pubmed.ncbi.nlm.nih.gov/24843641/.  Published March 18, 2013. Accessed July 25, 2022.
6. Latest data from surpass trials demonstrate Tirzepatide provided meaningful blood sugar reductions. Latest Data From SURPASS Trials Demonstrate Tirzepatide Provided Meaningful Blood Sugar Reductions | ADA. https://www.diabetes.org/newsroom/press-releases/2021/latest-data-from-SURPASS-trials-demonstrate-tirzepatide-provided-blood-sugar-reductions-weight-loss. Published June 29, 2021. Accessed July 25, 2022.
7. Mounjaro (tirzepatide) for the treatment of type 2 diabetes. Clinical Trials Arena. https://www.clinicaltrialsarena.com/projects/mounjaro-tirzepatide-type-2-diabetes/. Published June 1, 2022. Accessed July 25, 2022.
8. McDermid E. A quick guide to the surpass and surmount trials. Diabetes. https://diabetes.medicinematters.com/Mounjaro/type-2-diabetes/a-quick-guide-to-the-surpass-and-surmount-trials/18478154. Published June 22, 2022. Accessed July 25, 2022.
9. Salvon J. Clinical overview: Tirzepatide (Mounjaro) for type 2 diabetes mellitus. Pharmacy Times. https://www.pharmacytimes.com/view/clinical-overview-tirzepatide-mounjaro-for-type-2-diabetes-mellitus. Published June 21, 2022. Accessed July 25, 2022.
10. New analyses of mounjaro™ (tirzepatide) injection for the treatment of adults with type 2 diabetes presented at the American Diabetes Association’s® 82nd scientific sessions®. Eli Lilly and Company. https://investor.lilly.com/news-releases/news-release-details/new-analyses-mounjarotm-tirzepatide-injection-treatment-adults.  Published June 6, 2022. Accessed July 25, 2022.
11. Mounjaro [Package Insert]. Indianapolis, IN: Lilly USA, LLC https://pi.lilly.com/us/mounjaro-uspi.pdf?s=pi Published April 2022. Accessed July 25, 2022.
12. Type 2 diabetes treatment to lower A1C: Mounjaro™ (tirzepatide). Mounjaro. https://www.mounjaro.com/.  Published May 2022. Accessed July 25, 2022.

Published by Rho Chi Post