New Drug Monographs

New Drug

Camzyos (Mavacamten)

By: Rana Oueijan, PharmD Candidate

CamzyosTM (Mavacamten) is manufactured by Bristol Myers Squibb, MyoKardia Inc., and was approved by the FDA on April 28th, 2022 Classification Inhibitor 1: Cardiac Myosin

Indication1: Approved for the treatment of symptomatic New York Heart Association (NYHA) Class II-III obstructive hypertrophic cardiomyopathy (HCM) to improve functional capacity and symptoms.

US Boxed Warning1: Mavacamten can reduce the left ventricular ejection fraction (LVEF), leading to heart failure due to systolic dysfunction. Mavacamten should not be initiated in patients with an LVEF <55% and requires dispensing through the Risk Evaluation and Mitigation Strategy (REMS) program due to its potential to cause heart failure.

Contraindications1: Concomitant use with moderate to strong CYP2C19 and CYP3A4 inhibitors and inducers.

Pharmacology1: Mavacamten is a selective, reversible inhibitor of cardiac myosin. A hallmark of hypertrophic cardiomyopathy is a thickening of the heart muscles due to excess myosin-actin cross-bridging, making it difficult for the heart to function properly. Mavacamten modulates the number of myosin heads interacting with actin, reducing left ventricular outflow tract (LVOT) obstruction and improving cardiac function.

Pharmacokinetics1:

Absorption - Mavacamten is orally absorbed and reaches peak plasma concentrations within 1 hour. Mavacamten may be taken without regard to food since no clinically significant differences in pharmacokinetics were observed following mavacamten’s administration with a high-fat meal. Distribution - Mavacamten is 9798% protein bound.

Metabolism - Mavacamten is primarily metabolized by CYP2C19 (74%) but is also metabolized by CYP3A4 and CYP2C9.

Elimination - Mavacamten has a half-life of approximately 6-9 days in normal CYP2C19 metabolizers. This agent is primarily excreted in the urine (85%).

Clinical Efficacy2-4: The MAVERICK-HCM trial was a phase 2 trial that assessed the safety and tolerability of mavacamten in patients with symptomatic non-obstructive HCM. In the study, 59 subjects were randomized into 3 separate groups: a placebo group (n=19), a group targeting drug serum levels of 200 ng/ mL (n=19), and a group targeting 500 ng/mL (n=21). Patients achieved a target of 200 ng/mL after 4 weeks of treatment with patient-specific mavacamten daily dosing and a target of 500 ng/ mL after 8 weeks of patient-specific mavacamten daily dosing with a dose titration occurring at week 6. More patients in the 500 ng/mL target group experienced adverse effects. Overall, serious adverse events occurred at a rate of 10.3% in the experimental group and 21% in placebo. Patients receiving mavacamten had a 53% mean reduction of NT-proBNP (p=0.0005) and a 34% geometric mean of cardiac

troponin I compared to placebo (p=0.009), marking the effectiveness of this drug.2

Mavacamten then proceeded to its phase 3 trial testing, beginning with EXPLORER-HCM. This trial covered 13 different countries and was conducted to assess efficacy and safety on a larger scale than the MAVERICK-HCM trial. In this double-blind, placebo-controlled trial, 251 participants were randomized 1:1 and received either mavacamten 5 mg by mouth once daily (the starting dose) or a placebo for 30 weeks. Participants were included if they were at least 18 years of age with diagnosed obstructive HCM (maximal left ventricular wall thickness of greater than or equal to 15 mm), had a peak LVOT gradient of at least 50 mm Hg, had an LVEF of at least 55%, and NYHA Class II-III symptoms. Due to safety, patients were not included if they had a prior history of syncope or sustained ventricular tachyarrhythmia with exercise 6 months before screening, an extended QT interval (greater than 500 ms), paroxysmal or intermittent atrial fibrillation, or permanent atrial fibrillation that is uncontrolled and/or untreated. Patients previously taking standard HCM medications (including beta-blockers or calcium channel blockers) were allowed to continue them during the trial, with the exception of disopyramide for safety reasons.

Individualized dose titrations for mavacamten occurred at weeks 8 and 14 to achieve a target LVOT gradient reduction of less than 30 mm Hg. Of the 251 participants, 5 patients discontinued treatment early due to either adverse effects or simply choosing to withdraw from the study.

The primary endpoint was a composite clinical response from baseline to week 30 and was defined as a 1.5 mL/kg/min or greater increase in peak oxygen consumption plus at least one NYHA class reduction or a 3.0 mL/kg/min or greater increase in peak oxygen consumption without NYHA class worsening. It was found that 37% (45 of 123 patients) of the experimental group met the primary composite endpoint (p=0.0005) compared to 17% (22 of 128 patients) of the placebo group (p=0.0005). Based on these percentages, the NNT for the primary outcome is 5, meaning 5 patients would have to be treated with mavacamten for one patient to achieve the outcome. All secondary endpoints were significantly improved with the use of mavacamten: post-exercise LVOT gradient (p<0.0001), pVO change from baseline to week 30 (p=0.0006), NYHA class improvement from baseline (p<0.0001), and others. In addition, a reduction in certain cardiac biomarkers, including serum NT-proBNP, added to the clinical benefit of mavacamten.

Assessments such as the KCCQ-CSS and the HCMSQ-SoB, which are specifically designed to evaluate symptomatic patients with HCM, were used to support the clinical benefit of mavacamten. These patient-reported assessments showed more symptomatic improvement and more improvement in functional class with mavacamten than with placebo. In addition to providing symptomatic relief, patients also reported that mavacamten was well-tolerated when taken either with a beta blocker, calcium channel blocker or as monotherapy.

The most recent phase 3 trial, VALOR-HCM, is set to identify if the use of mavacamten could reduce the need for septal reduction therapy and focuses on patients with severely symptomatic, drug-refractory hypertrophic cardiomyopathy. This trial is currently active (no longer recruiting) and includes patients who are taking concurrent disopyramide therapy as well as patients with NYHA class IV symptoms, of which both populations were excluded from EXPLORER-HCM.

Drug Interactions1:

Moderate or Strong CYP2C19 inhibitors - Concomitant use of mavacamten with a moderate to strong CYP2C19 inhibitor is contraindicated as concentrations of mavacamten may be increased, increasing the risk of developing heart failure. This information is also true for strong CYP3A4 inhibitors. Moderate or Strong CYP2C19 inducers - Concomitant use of mavacamten with a moderate to strong CYP2C19 inducer is contraindicated as concentrations of mavacamten may be decreased, reducing the efficacy of this medication. This information is also true for strong CYP3A4 inducers.

Negative Inotropes - Mavacamten will produce additive negative inotropic effects if used in combi-

nation with other agents that reduce cardiac contractility, such as beta blockers or verapamil (both of which were studied as concomitant therapy with mavacamten in EXPLORER-HCM) Monitor LVEF if concomitant therapy with a negative inotrope is initiated or the dose is increased. Monitoring should occur until clinical response has been achieved and dosing is stabilized.

Adverse Effects1-3: Dizziness (27%) and syncope (6%) were the most common adverse effects observed in clinical trials. Other reported adverse effects include reduced LVEF; however, these values normalized or returned to baseline in all patients after temporary treatment discontinuation or a washout period.

Dosing1: Proper dosing of mavacamten consists of a 12-week initiation phase followed by maintenance therapy. Dosing is individualized based upon clinical status and echocardiographic results. The recommended starting dose in most patients is 5 mg by mouth once daily without regard to food. Dosage may be titrated to a maximally tolerated dose providing the LVEF is greater than or equal to 55%.

A baseline echocardiogram must be done before starting mavacamten, and reassessment of ejection fraction and LVOT gradient should occur every 12 weeks before additional dosage modifications occur.

The need for dose adjustments based on severe renal impairment/kidney failure (eGFR less than 30 mL/min/1.73 m2) or

Pregnancy and Lactation1:

Mavacamten may be harmful to the fetus when administered to a patient who is pregnant according to data from animal studies. It is recommended that female patients have a negative pregnancy test before initiating mavacamten to prevent fetal harm. Additionally, it is important for a woman of childbearing age to use effective contraception (meaning contraception not induced by CYP450 enzyme induction, such as an intrauterine system, and/ or non-hormonal contraception) during treatment and for four months after the last dose, as mavacamten can reduce the effectiveness of combined hormonal contraceptives.

For patients who are breastfeeding, there is not enough data to determine if mavacamten passes into the breastmilk. Prescribers should consider the benefit of mavacamten versus the potential risks that may occur.

Storage1: Store between 20°C and 25°C (68°F and 77°F), with excursions permitted between 15°C and 30°C (59°F and 86°F).

Cost1,5: Mavacamten is supplied as 2.5 mg, 5 mg, 10 mg and 15 mg oral gelatin capsules. Capsules are priced at around $245.20, which places the annual cost at approximately $89,500.

Summary/Use in Clinical Prac-

tice1-6: Mavacamten is the first disease-specific agent that can be used to treat HCM and is FDA approved for treating patients with symptomatic NYHA Class II-III HCM. However, the most recent American Heart Association/ American College of Cardiology guidelines have not been updated to specify mavacamten’s place in therapy for patients with HCM.

Currently, for patients with symptomatic obstructive HCM without heart failure, the guidelines recommend pharmacologic therapy with either beta-blockers or calcium channel blockers (specifically verapamil or diltiazem). From there, if symptoms persist, therapy should progress to either disopyramide, procedural septal reduction therapy, or ablation. Through phase III clinical trials, mavacamten has been shown to provide symptomatic relief and reductions in LVOT gradient in patients with HCM showing NYHA class II-III symptoms. While mavacamten is not currently recommended as a firstline treatment option for this population, it may be considered in patients with HCM with preserved ejection fraction and an LVEF greater than 55% who are experiencing persistent symptoms after beta blocker or calcium channel blocker therapy or are intolerant to these therapies. As for patients with HCM plus heart failure with reduced ejection fraction, guideline-directed medication therapy should be implemented, and mavacamten is not recommended in this population due to its boxed warning for inducing or worsening heart failure.

A baseline echocardiogram is recommended before initiating mavacamten to determine LVEF. If the patient’s LVEF is greater

than 55%, the recommended starting dose for mavacamten is 5 mg by mouth daily. Up-titration is patient-specific and dependent upon the patient’s LVEF worsening and LVOT gradient. Echocardiogram monitoring is recommended every 12 weeks throughout therapy with this medication, and treatment interruption is required if LVEF becomes less than 50%. An echocardiogram should be repeated every 4 weeks, and therapy may be restarted if the LVEF reaches above 50%; however, permanent discontinuation is recommended if the LVEF remains below 50% after frequent echocardiogram monitoring.

Patients should have a negative pregnancy test before initiating mavacamten, as fetal harm may be possible with this agent. Patients of childbearing potential should also be on reliable and effective contraception during therapy with mavacamten. Lactating mothers should avoid mavacamten due to the lack of data regarding its presence in breast milk. Mavacamten has not been investigated in pediatric populations.

The cost of treatment and continuous monitoring might also impact mavacamten’s place in therapy.

The most common adverse effects are dizziness and syncope. The VALOR-HCM study is ongoing and will determine mavacamtem’s efficacy in patients with severely symptomatic (NYHA Class IV symptoms), treatment-refractory obstructive HCM to provide a non-invasive treatment option Author: Rana Oueijan is a 2023 PharmD Candidate at the Campbell University College of Pharmacy and Health Sciences. rioueijan1024@email.campbell.edu

References:

1. Mavacamten. [package insert online]. Bristol Myers Squibb,

Inc. Brisbane, CA. Issued April 2022. https://www.accessdata. fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf.

Accessed May 4, 2022. 2. Ho CY, Mealiffe ME, Bach RJ, et al. “Evaluation of Mavacamten in

Symptomatic Patients with Nonobstructive Hypertrophic Cardiomyopathy.” Journal of the American

College of Cardiology, vol. 75, no. 21,

June 2020, pp. 2649–2660., https:// doi.org/10.1016/j.jacc.2020.03.064. 3. Olivotto I, Oreziac A, Barriales-Villa

R, et al. “Mavacamten for Treatment of Symptomatic Obstructive

Hypertrophic Cardiomyopathy (EXPLORER-HCM): a Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial.” The Lancet,

vol. 396, no. 10253, Sept. 2020, pp. 759–769., https://doi.org/ https://doi.org/10.1016/S01406736(20)31792-X. 4. Desai MY, Wolski K, Owens A, et al. “Study Design and Rationale of

Valor-HCM: Evaluation of Mavacamten in Adults with Symptomatic Obstructive Hypertrophic Cardiomyopathy Who Are Eligible for Septal

Reduction Therapy.” American Heart

Journal, vol. 239, Sept. 2021, pp. 80–89., https://doi.org/10.1016/j. ahj.2021.05.007. 5. Satija B. “FDA Approves Bristol

Myers’ Oral Heart Disease Drug.”

Reuters.com, Reuters, 29 Apr. 2022, https://www.reuters.com/business/healthcare-pharmaceuticals/ fda-approves-bristol-myers-heartdisease-drug-2022-04-29/. 6. Ommen SR, Mital S, Burke MA, et al. “2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients with Hypertrophic

Cardiomyopathy.” Circulation, vol. 142, no. 25, 20 Nov. 2020, https://doi.org/10.1161/ cir.0000000000000937.

New Drug

MounjaroTM (tirzepatide)

By: Dr. Gloria Lo and Linda Nguyen, PharmD Candidate

MounjaroTM (tirzepatide) is manufactured by Lilly USA, LLC, and was FDA-approved on May 13, 2022.

Classification: Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist.

Indication1: Approved as an adjunct to diet & exercise in adult patients with type 2 diabetes mellitus (T2DM) to improve blood glucose control.

Contraindications1: History or family history of medullary thyroid carcinoma or patients with Multiple Endocrine Neoplasia Syndrome (MENS) type 2. Contraindicated in patients with known hypersensitivity to any of the components in tirzepatide. GLP-1 and GIP receptor agonist. The structure contains a modified peptide with a diacid moiety that allows albumin to bind and prolongs the half-life. Tirzepatide binds selectively to GIP and GLP1 receptors, which enhances both insulin secretion and sensitivity, lowers glucagon levels and slows gastric emptying.

Pharmacokinetics1:

Absorption After subcutaneous administration, tirzepatide reaches peak plasma concentrations after 8-72 hours. Following subcutaneous administration, the bioavailability of tirzepatide is 80%, regardless of whether it was administered in the abdomen, thigh, or upper arm.

Distribution Tirzepatide is highly protein bound, with 99% of it found bound to albumin. The volume of distribution after subcutaneous administration was approximately 10.3 L. Metabolism Tirzepatide is primarily metabolized by amide hydrolysis, beta-oxidation of the C20 fatty acid moiety, and proteolytic cleavage of its peptide backbone.

Elimination Metabolites of tirzepatide are excreted mainly via urine and feces, while non-metabolized tirzepaptide is not. Clearance of tirzepatide is 0.061 L/h, and its elimination half-life is around 5 days.

Clinical Efficacy: In four SURPASS-trials, the safety, tolerability, and efficacy of tirzepatide versus several comparators were assessed for the management of type 2 diabetes in lowering A1c and weight lowering capabilities:

SURPASS-1: tirzepatide vs placebo3 SURPASS-1 was a multi-center (US, Mexico, Japan, India), randomized, double-blind, parallel, placebo-controlled study with 478 adult patients randomized to receive once-weekly subcutaneous tirzepatide 5 mg, 10 mg, 15 mg, or placebo in a 1:1:1:1 ratio. All study participants in the tirzepatide arm were initiated at a dose of 2.5 mg once weekly and then increased in a stepwise approach at 4 weeks. The primary endpoint was a change in A1c from baseline at 40 weeks. Baseline characteristics of study participants had a mean A1c of 7.9%, type 2 diabetes for a duration of 4.7 years, and a mean weight of 85.9 kg. Participants were included if they were naïve to diabetes injectable therapies, had an A1c between ≥ 7.0% and

≤ 9.5%, and had a BMI ≥ 23kg/ m2. They were excluded if they had type 1 diabetes, a history of a previous heart attack or stroke, or were hospitalized for heart failure in the past 2 months, acute or chronic pancreatitis, eGFR <30 mL/min/1.73 m2 , taking weight loss medications during the last 3 months, history or family history of thyroid carcinoma or have a personal history of multiple endocrine neoplasia syndrome type 2, and or required acute treatment for proliferative diabetic complications such as retinopathy or maculopathy. Results from SURPASS-1 were statistically significant, all with a p-value < 0.0001 showing that patients in the tirzepatide arm achieved significantly lower A1c [-1.75% (5 mg), -1.71% (10 mg), -1.69% (15 mg)] compared to placebo (-0.09%) and an overall weight reduction of -6.3 kg (5 mg), -7.0 kg (10 mg), -7.8 kg (15 mg) compared to -1.0 kg in the placebo group.

SURPASS-2: tirzepatide vs semaglutide4 SURPASS-2 was a multicenter (US, Argentina, Australia, Brazil, Canada, Mexico, UK, Israel), randomized, parallel, open-label trial comparing the efficacy and safety of tirzepatide to semaglutide in 1879 adults with type 2 diabetes inadequately controlled with ≥1500 mg/day metformin alone. Subjects were randomized in a 1:1:1:1 ratio to receive either tirzepatide 5 mg, 10 mg, or 15 mg or semaglutide 1mg. The primary endpoint was a change in A1c from baseline at 40 weeks. Inclusion and exclusion criteria are similar to SURPASS-1 with an additional exclusion to study participants if they have acute or chronic liver disease. Baseline characteristics of study participants had a mean A1c 8.3% and type 2 diabetes duration of 8.6 years. Results from SURPASS-2 showed that patients in the tirzepatide arm achieved an A1c lowering of up to -2.01% (5 mg), -2.24% (10 mg), -2.30% (15 mg) compared to -1.86% in the semaglutide arm. Furthermore, the percent of participants achieving an A1c <7% with tirzepatide was 82% (5 mg), 86% (10 mg), 86% (15 mg) compared to 79% of participants treated with semaglutide. Each tirzepatide dose was found to be superior to semaglutide, with estimated treatment differences of -0.15% [95% CI (-0.28 to -0.03, p=0.02)] with tirzepatide 15 mg, −0.39 percentage points [95% CI (−0.51 to −0.26 p<0.001)] with tirzepatide 10 mg, and −0.45% [95% CI (−0.57 to −0.32, p<0.001)] with tirzepatide 5 mg. Weight reduction with tirzepatide compared to semaglutide had the following results: 7.6 kg (5 mg), -9.3 kg (10 mg), -11.2 kg (15 mg), -5.7 kg (semaglutide), with p<0.001 for all comparisons made.

SURPASS-3: tirzepatide vs insulin degludec5 SURPASS-3 was a randomized, phase 3, open-label, active-controlled trial that included 1444 adult patients with inadequately controlled type 2 diabetes despite being on metformin with or without SGLT-2 inhibitor. Patients were randomized in a 1:1:1:1 ratio to take tirzepatide subcutaneous once weekly (at doses of 5 mg, 10 mg, or 15 mg) or insulin degludec in a 1:1:1:1 ratio. Initial dose of insulin degludec was 10-units/day and was titrated to a fasting blood glucose goal of < 90 mg/dL. Primary and secondary efficacy points included changes in A1c lowering and weight changes from baseline at 52 weeks, respectively. Inclusion and exclusion criteria were the same as in the SURPASS trials. Baseline characteristics of participants had a mean baseline A1c of 8.2%, type 2 diabetes duration of 8.4 years, and a mean weight of 94.3 kg. Results from SURPASS-3 demonstrated that tirzepatide was superior in reducing A1c and body weight across all 3 doses (5mg, 10mg, and 15mg) compared to insulin degludec (mean dose 48.8-units/day at 52 weeks). The mean A1c lowering seen with tirzepatide was -1.93% (5 mg), -2.20% (10 mg), -2.37% (15 mg) compared to -1.34% in the insulin degludec group, with p < 0.0001 for each group. Weight change from baseline at 52-weeks with tirzepatide was: -7.5 kg (5 mg), -10.7kg (10 mg), -12.9kg (15 mg) versus a mean weight gain of +2.3 kg in patients treated with insulin degludec, with p < 0.0001 for each group.

SURPASS-5: tirzepatide vs insulin glargine vs placebo6 SURPASS-5 was a 40-week, randomized, double-blind, placebo-controlled, phase-3 trial that randomized 475 adult patients with uncontrolled type 2 diabetes who were on insulin glargine with or without metformin. Participants were randomized to receive once-weekly subcutaneous tirzepatide 5 mg, 10 mg, 15 mg, or placebo in a 1:1:1:1 ratio. Similar exclusion and inclusion criteria as previous SURPASS trials. Study participants had a

baseline mean of 8.31% A1c, type 2 diabetes duration of 13.3 years, a baseline weight of 95.2 kg, and a baseline dose of 37.6-units/day insulin glargine. The mean A1c lowering seen with tirzepatide was -2.11% (5 mg), -2.40% (10 mg), -2.34% (15 mg) compared to -0.86% with placebo. Mean weight reduction achieved with tirzepatide was -5.4 kg (5 mg), -7.5 kg (10 mg), -8.8 kg (15 mg) compared to a mean weight gain of +1.6 kg in the placebo arm. The percentage of participants that were able to achieve an A1c <7% in the tirzepatide group was 87.3% (5 mg), 89.6% (10 mg), 84.7% (15 mg) compared to about 34.5% of participants in the placebo. Overall, tirzepatide demonstrated superior A1c lowering and weight reductions from baseline compared to various comparators. In placebo-controlled trials, the most common adverse effects seen with tirzepatide in placebo-controlled trials were gastrointestinal effects (nausea, diarrhea, vomiting) which were noticeable during dose-escalation.

Drug Interactions 1,2:

Hormonal Contraceptives: Tirzepatide may decrease serum concentrations of oral hormonal contraceptives. Patients on oral hormonal contraceptives should switch to non-oral contraceptive methods and use a barrier method for 4 weeks after initiating tirzepatide and for 4 weeks after each dose escalation.

GLP-1 Receptor Agonists and DP4-Inhibitors Increased risk of adverse/toxic effects of GLP-1 agonists. Avoid Sulfonylureas: Tirzepatide and other GLP-1 receptor agonists may enhance the hypoglycemic effects of sulfonylureas. Doses of sulfonylureas should be reduced when used in combination with GLP-1 receptor agonists.

Adverse Effects1,2: The most common adverse effects of tirzepatide observed in clinical trials were GI related (mild to moderate) and occurred mostly during the dose-escalation phase: nausea (12-18%), diarrhea (1217%), and vomiting (5-9%).

Dosing1,2: Tirzepatide titration in adult patients starts at 2.5 mg once weekly for 4 weeks. Increase dose by 2.5 mg/week increments every 4 weeks to achieve glycemic goals. The maximum dose weekly is 15 mg/ week. No renal or hepatic adjustments are necessary. The safety and effectiveness of tirzepatide have not been established in the pediatric population <18 years of age.

Pregnancy and Lactation1,2,4:

The safety of tirzepatide in pregnant and/or lactating women have not been assessed in human patients; however, based on animal studies, in utero exposure of tirzepatide may lead to fetal harm. There is no data regarding the presence of tirzepatide in human milk or the effects it may have on an infant.

Storage1,2: Store in the original carton and protect from light. Keep refrigerated between 2°C and 8°C (36°F and 46°F). If necessary, each single-dose pen may be stored unrefrigerated at temperatures ≤ 30°C (≤ 86°F) for up to 21 days. Do not freeze or use if frozen.

Dosages and Cost2,4: Tirzepatide is available in 2.5 mg/0.5 mL, 5 mg/0.5 mL, 7.5 mg/0.5 mL, 10 mg/0.5 mL, 12.5 mg/0.5 mL, and 15 mg/0.5 mL solution pen-injector. Currently, each tirzepatide pen-injector costs around $300.00 for all strengths; however, manufacturer coupons may help patients pay as low as $25 a month for 4 pens.

Summary/Use in Clinical Prac-

tice1-7 When assessing which pharmacological agent should be used to treat Type 2 DM, a patient-centered approach should be used. Consideration should be given not only to patient preference but to which agent will best fit the patient’s comorbidities, the impact the medication may have on the patient’s weight, and medication cost. The American Diabetes Association (ADA) guidelines currently recommend metformin as the initial pharmacological agent (along with diet and exercise) for treating type 2 diabetes and should be continued as long as tolerated and no contraindications occur. The addition of other anti-diabetic agents should be added to metformin unless contraindicated. It is also recommended to consider the effects an agent has on weight when choosing any glucose-lowering medication for type 2 diabetics with overweight or obesity. The 2022 ADA guidelines recommend considering GLP-1 receptor agonists in most patients with diabetes before initiating insulin.

A GLP-1 receptor agonist is preferred over insulin for the management of type 2 diabetes due to decreased weight gain as well as a lower risk of hypoglycemia.

Similar agents to tirzepatide are agents in the GLP-1 receptor agonist class, which have also demonstrated A1c lowering and weight reduction [semaglutide (Ozempic), dulaglutide (Trulicity), and exenatide (Byetta)] are also administered subcutaneously once weekly. Unlike some of the other GLP-1 receptor agonists, tirzepatide has not been studied for CV morbidity or mortality benefit, although it is expected to exhibit similar effects based on its mechanism of action. For now, more studies are required to determine a CV benefit.

Patients should be counseled that the 2.5 mg dose is intended to reduce GI symptoms and does not provide effective glycemic control. Patients should be counseled to administer tirzepatide subcutaneously into the abdomen, thigh, or upper arm at any time of day on the same day of each week, with or without food. It is important not to mix tirzepatide with other injectable products such as insulin and rotate injection sites. The most common adverse effects of tirzepatide are nausea, diarrhea, and vomiting.

Authors: Gloria Lo, PharmD is currently a PGY-1 resident at UH Meds at Cleveland Medical Center. In Cleveland, OH. gplo1216@ email.campbell.edu. Linda Nguyen is a 2023 PharmD Candidate at the Campbell University College of Pharmacy in Buies Creek,

References

1. Tirzepatide (MounjaroTM).

Package insert. Lilly USA, LLC; 2022. 2. Lexi-Drugs. Lexicomp [database online]. Hudson, OH: Lexicomp,

Inc. http://online.lexi.com.

Updated 2022. Accessed May 19, 2022. 3. Rosenstock J, Wysham C, Frías

JP, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomized, phase 3 trial [published correction appears in Lancet. 2021 Jul 17;398(10296):212]. Lancet. 2021;398(10295):143155. doi:10.1016/S01406736(21)01324-6. 4. 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(6):503515. doi:10.1056/NEJ-

Moa2107519. 5. 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 randomized, open-label, parallel-group, phase 3 trial.

Lancet. 2021;398(10300):583598. doi:10.1016/S01406736(21)01443-4. 6. Dahl D, Onishi Y, Norwood P, et al. Effect of Subcutaneous

Tirzepatide vs Placebo Added to Titrated Insulin Glargine on

Glycemic Control in Patients with Type 2 Diabetes: The SUR-

PASS-5 Randomized Clinical

Trial. JAMA. 2022;327(6):534545. doi:10.1001/ jama.2022.0078 7. American Diabetes Association Professional Practice

Committee; 9. Pharmacologic

Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2022. Diabetes Care 1 January 2022; 45 (Supplement_1): S125–S143. https://doi.org/10.2337/ dc22-S009