Tirzepatide (MounjaroTM)

Monograph
Approval1: 2022
Generic (Trade name)1: Tirzepatide (MounjaroTM)
Manufacturer1: Eli Lilly and Company, LLC
Dosage Form1: 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, or 15
mg/0.5mL single-dose pens for subcutaneous injection

FDA-approved Indication1:
An adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus

Disease State Background

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by improper response to endogenous
insulin leading to chronically elevated blood glucose levels (hyperglycemia). T2DM is also associated with
altered metabolism of protein, lipids, and carbohydrates as well as increased risk of complications from
vascular disease.2,3 It is estimated that more than 37 million people have diabetes and T2DM accounts for 90-
95% of all diabetes.4 T2DM is associated with various modifiable risk factors, such as obesity, older age,
certain races/ethnic groups, genetic predisposition, hypertension, dyslipidemia, and lack of physical activity.2,3
T2DM is mostly diagnosed in patients over 40 years old and this age group accounts for more than 80% of the
total patient population with T2DM.4 The incidence and prevalence of T2DM are generally higher in minority
groups.4 The prevalence of T2DM in these demographic groups can be linked to possible factors such as
stationary lifestyle, increased likelihood of comorbidities, lower socioeconomic status, and inherited genetic
risk factors.5

Although the exact etiology of T2DM is unclear, the development of T2DM is often accompanied by
malfunctioning insulin production of pancreatic β-cells and insulin resistance, which describes the decreased
insulin sensitivity of tissue cells.2 T2DM is diagnosed by elevation in one of the following tests: fasting blood
glucose reading, 2-hour post-prandial reading, and A1c level.2,3 Despite the relatively convenient diagnosing
procedures, patients with T2DM can go undiagnosed for many years due to its subtle and nonspecific clinical
presentations. Alarming symptoms are often associated with complications caused by chronically elevated
blood glucose level. Long-term uncontrolled T2DM can cause chronic kidney disease (CKD), vision damage,
peripheral vascular disease (i.e. diabetic foot syndrome), coronary artery disease (i.e. myocardial infarction),
and cerebrovascular disease (i.e. stroke).2 As the result, patients with T2DM have a 15% increased risk of all-
cause mortality compared with people without diabetes.5

Table 1. Current FDA-approved drugs indicated for type 2 diabetes mellitus

Trade Drug Route of
Generic Indication Approval
Name Class Administration
Glucophage Metformin Biguanide T2DM, Oral 1994

T2DM,
SGLT2
Farxiga Dapagliflozin CKD, Oral 2014
inhibitor
HFrEF
Ozempic
GLP-1 SubQ
Rybelsus Semaglutide T2DM, 2017
agonist Oral

Management of type 2 diabetes mellitus

The clinical guidelines developed by the American Diabetes Association are generally used by clinicians as
primary source for diagnosis and treatment. The treatment goal is to maintain laboratory values within goal
range: fasting glucose reading ≤130 mg/dL, post-prandial glucose reading ≤180 mg/dL, and glycated
hemoglobin (A1c) < 7%.2 The A1c goal can be more or less stringent depending on patient-specific factors,

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such as disease duration, age, comorbidities, life expectancy, risk factors for hypoglycemia or drug adverse
effects.2,3 Non-pharmacological lifestyle modification is recommended as part of the first line treatment for
patients with T2DM. This includes eating a healthy diet, engaging in regular physical activity, maintaining a
healthy body weight, getting regular and sufficient sleep, and tobacco cessation.6

A first-line therapy option for T2DM is metformin which decreases hepatic glucose production, decreases
intestinal absorption of glucose, and improves insulin sensitivity.7 The recommended maintenance dose for
metformin is 2000 mg/day if patient tolerated. Second-line add-on therapies may be considered for patients
whose A1c is not at goal with metformin and lifestyle modifications alone. The selection of these therapies is
largely directed by comorbidities or co-existing risk factors. For patients with high ASCVD risk, heart failure
or chronic kidney diseases, either Sodium-glucose Cotransporter-2 (SGLT-2) inhibitors or Glucagon-like
Peptide-1 Receptor (GLP-1) agonists are the preferred options. SGLT-2 inhibitors are generally approved to
be used in patients with eGFR between 25-45 mL/min/1.73 m2 with depending on the specific agent.3 All
SGLT-2 inhibitors are contraindicated in patients receiving dialysis.8 Majority of GLP-1 agonists do not
require renal dosing adjustments with the exception of exendin-4 or incretin-mimetic analogs (daily
exenatide, weekly exenatide, and lixisenatide).3 In addition, a recent study found exendin-4 agents have not
been able to demonstrate superiority in cardioprotective property compared to human GLP-1 receptor agonists
(liraglutide, semaglutide, albiglutide, dulaglutide).9 Another benefit of these two drug classes is that SGLT-2
inhibitors are weight neutral and GLP-1 agonists can lead to weight loss.2

For patients without the comorbidities described above, treatment options will be guided based on patient’s
preferences and management needs.3 For patients who require greater glycemic control, GLP-1 agonists,
insulin, or a treatment plan containing multiple agents are recommended.3,7 In patients at higher risk for
hypoglycemic, dipeptidyl peptidase-4 (DPP-4) inhibitor, and thiazolidinediones (TZDs) are recommended in
addition to SGLT-2 inhibitors, GLP-1 agonists as they are less likely to cause hypoglycemia.3,7 Lastly, if cost
is a major concern, TZDs or sulfonylureas (SUs) are available as multi-brand generics at low prices.7 Last-
line options, include α-glucosidase inhibitors, meglitinides (glinides), bile acid sequestrants, dopamine-2
agonists, and amylin mimetics. These therapies are available as a last resort if patients cannot achieve target
A1c goal with the preferred anti-diabetic agents or was unable to tolerate preferable anti-diabetic agents.2

Pharmacology1
Tirzepatide is a selective GIP receptor and GLP-1 receptor agonist and enhances first- and second-phase
insulin secretion, and reduces glucagon levels, both in a glucose-dependent manner. It is a 39-amino-acid
modified peptide with a C20 fatty diacid moiety that enables albumin binding and prolongs the half-life.

Dosage and Administration1

The recommended starting dosage is 2.5 mg injected subcutaneously once weekly followed by an increase to
5 mg/week after 4 weeks. If additional glycemic control is needed, increase the dosage in 2.5 mg increments
after at least 4 weeks on the current dose (max dose: 15 mg/week).
Administer once weekly at any time of day, with or without meals. Inject subcutaneously in the abdomen,
thigh, or upper arm. Rotate injection sites with each dose.

Pharmacokinetics1
Table 2. Pharmacokinetics of tirzepatide
Parameter
Onset (minutes) 5 – 10 mins
Vd (L) ~ 10.3 L
Tmax (hours) 8 – 72 hrs
Metabolism proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty
diacid moiety and amide hydrolysis

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Half-life (hours) ~ 120 hrs (5 days)
Vd: volume of distribution; Cmax: maximum concentration at steady state; Tmax: time to maximum
concentration; AUC: area under the curve

Adverse reactions1
Table 3. Adverse reactions of tirzepatide
Adverse Reactions Observed in >5% of Patients Treated with Tirzepatide
Adverse Reaction Placebo 5 mg 10 mg 15 mg
(N=235) (N=237) (N=240) (N=241)
n (%) n (%) n (%) n (%)
Nausea 4 12 15 18
Diarrhea 9 12 13 17
Decreased Appetite 1 5 10 11
Vomiting 2 5 5 9
Constipation 1 6 6 7
Dyspepsia 3 8 8 5
Abdominal Pain 4 6 5 5
Sinus Tachycardia* 4.3 4.6 5.9 10
N: number of patients; n: number of patients experiencing the event
*Concomitant increase from baseline in HR of ≥15 beats/min

Hypoglycemia Adverse Reactions

Placebo 5 mg 10 mg 15 mg
(N=235) (N=237) (N=240) (N=241)
n (%) n (%) n (%) n (%)
Monotherapy
(40 weeks) N=115 N=121 N=119 N=120
Blood glucose <54 mg/dL 1 0 0 0
Severe hypoglycemia* 0 0 0 0
Add-on to Basal Insulin with or
without Metformin
(40 weeks) N=120 N=116 N=119 N=120
Blood glucose <54 mg/dL 13 16 19 14
Severe hypoglycemia* 0 0 2 1
N: number of patients; n: number of patients experiencing the event
* Episodes requiring the assistance of another person to actively administer carbohydrate, glucagon, or
other resuscitative actions.

Other Adverse Reactions1

Placebo Tirzepatide
n (%) n (%)
Hypersensitivity Reaction* 1.7 3.2
Injection Site Reaction 0.4 3.2
Acute Gallbladder Disease** 0 0.6
* Urticaria and eczema
** Cholelithiasis, biliary colic and cholecystectomy

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Contraindications1
Tirzepatide is contraindicated in patients with:
• A personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple
Endocrine Neoplasia syndrome type 2 (MEN 2).
• Known serious hypersensitivity to tirzepatide or any of the excipients in tirzepatide

Warnings and Precautions1

Pancreatitis
Has been reported in clinical trials. Discontinue promptly if pancreatitis is suspected.

Hypoglycemia with concomitant use of insulin secretagogues or insulin

Concomitant use with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including
severe hypoglycemia. Reducing dose of insulin secretagogue or insulin may be necessary.

Hypersensitivity Reactions
Hypersensitivity reactions have been reported. Discontinue tirzepatide if suspected.

Acute Kidney Injury

Monitor renal function in patients with renal impairment reporting severe adverse gastrointestinal reactions.

Severe Gastrointestinal Disease

Use may be associated with gastrointestinal adverse reactions, sometimes severe. Has not been studied in
patients with severe gastrointestinal disease and is not recommended in these patients.

Diabetic retinopathy complications in patients with a history of diabetic retinopathy

Has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy,
proliferative diabetic retinopathy, or diabetic macular edema. Monitor patients with a history of diabetic
retinopathy for progression.

Acute Gallbladder Disease

Has occurred in clinical trials. If cholelithiasis is suspected, gallbladder studies and clinical follow-up are
indicated.

Drug Abuse and Dependence1

No clinically significant risks for abuse or dependence

Drug Interactions1
Tirzepatide delays gastric emptying and has the potential to impact the absorption of concomitantly
administered oral medications. Use of tirzepatide in combination with an insulin secretagogue (e.g.,
sulfonylurea) or insulin may increase risk of hypoglycemia, including severe hypoglycemic events.

Table 4. Clinically Important Drug Interactions with tirzepatide

Clinical Impact Intervention
Oral hormonal Tirzepatide may decrease the serum Patients should switch to a non-oral
contraceptives concentration of Hormonal Contraceptives. contraceptive method, or add a barrier
method of contraception, for 4 weeks after
initiation of tirzepatide and for 4 weeks
after each dose escalation of tirzepatide.

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Insulins May enhance the hypoglycemic effect of Consider insulin dose reductions when used
Insulins. in combination with tirzepatide.
Sulfonylureas May enhance the hypoglycemic effect of Consider sulfonylurea dose reductions
Sulfonylureas. when used in combination with tirzepatide.
Sincalide May diminish the therapeutic effect of Consider discontinuing tirzepatide that may
Sincalide due to effects on gallbladder affect gallbladder motility prior to the use
function. of sincalide to stimulate gallbladder
contraction.

Hepatic Impairment1
No dosage adjustment of tirzepatide is recommended for patients with hepatic impairment.

Renal Impairment1
No dosage adjustment of tirzepatide is recommended for patients with renal impairment. Monitoring of renal
function is advised when initiating or escalating doses of tirzepatide in patients with renal impairment due to
increased risk of severe adverse gastrointestinal reactions.

Pregnancy and Lactation1

There are insufficient available data with tirzepatide use in pregnant women evaluate for a drug-related risk of
major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother
and fetus associated with poorly controlled diabetes in pregnancy. Based on animal reproduction studies,
there may be risks to the fetus from exposure to tirzepatide during pregnancy. In both pregnant rats and
rabbits, fetal growth reductions and fetal abnormalities were observed when tirzepatide was administered at
clinically relevant exposures based on AUC during organogenesis. These adverse embryo/fetal effects in
animals coincided with pharmacological effects on decreased maternal weight and food consumption.

There are no data on the presence of tirzepatide in animal or human milk, the effects on the breastfed infant,
or the effects on milk production.

Pediatric Use1
Safety and effectiveness of tirzepatide have not been established in pediatric patients (younger than 18 years
of age).

Geriatric Use1
No overall differences in safety or efficacy were detected between these patients and younger patients, but
greater sensitivity of some older individuals cannot be ruled out.
Number of geriatric patients included in clinical trials: 1539 (30.1%) tirzepatide-treated patients were 65 years
of age or older, and 212 (4.1%) tirzepatide-treated patients were 75 years of age or older at baseline.

Carcinogenesis, Mutagenesis, Impairment of Fertility1

In a 2-year carcinogenicity animal study in male and female rats, doses of 0.15, 0.5, and 1.5 mg/kg (0.1-, 0.4-,
and 1-fold the maximum human recommended dose (MRHD) of 15 mg once weekly based on AUC) were
administered by subcutaneous injection twice weekly. Statistically significant increase in thyroid C-cell
adenomas was observed in males (≥0.5 mg/kg) and females (≥0.15 mg/kg), and a statistically significant
increase in thyroid C-cell adenomas and carcinomas combined was observed in males and females at all doses
examined. In a 6-month carcinogenicity study in rasH2 transgenic mice, tirzepatide at doses of 1, 3, and 10
mg/kg administered by subcutaneous injection twice weekly was not tumorigenic.

Tirzepatide was not genotoxic in a rat bone marrow micronucleus assay.

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In fertility and early embryonic development studies, male and female rats were administered 0.3-, 1-, and 2-
fold and 0.3-, 0.9-, and 2-fold, respectively, the MRHD of 15 mg once weekly based on AUC. In male rats, no
effects of tirzepatide were observed on sperm morphology, mating, fertility, and conception. In female rats, an
increase in the number of females with prolonged diestrus and a decrease in the mean number of corpora lutea
resulting in a decrease in the mean number of implantation sites and viable embryos was observed at all dose
levels. These effects were considered secondary to the pharmacological effects of tirzepatide on food
consumption and body weight.

Efficacy

Study 1 (SURPASS-1)

SURPASS-1 is a randomized, double-blind, placebo-controlled, phase 3 trial conducted to evaluate the

efficacy of tirzepatide in improving glycemic control in adults with inadequately controlled T2DM. Patients
were included if they were naïve to injectable diabetic therapy, had a level of HbA1c between 7.0% - 9.5% at
screening, body mass index (BMI) ≥ 23 kg/m2, stable weight (no change outside of 5%) during the previous 3
months and agreed not to attempt weight loss. Patients who were excluded if they met one of the following
criteria: T1DM, history of pancreatitis, history of proliferative diabetic retinopathy, diabetic maculopathy, or
non-proliferative diabetic retinopathy that requires acute treatment, eGFR<30 mL/min/1.73m2, use of any oral
antihyperglycemic medication for 3 months before screening. After the initial 3-week of screening and lead-in
phase, 478 patients were randomly assigned via computer-generated random sequence into one of the 4
treatment groups: 5 mg, 10 mg, 15 mg, and placebo (n=121, 121, 120, and 113, respectively) in a double-
blind fashion and received weekly injections. Participants in the 3 tirzepatide treatment groups followed a
slow dose escalation regimen fixed at 2.5 mg-dose increments of tirzepatide every 4 weeks until the desired
maintenance dose was reached. Therefore, the maintenance doses of 5, 10, and 15 mg were achieved at weeks
4, 12, and 20, respectively.

The primary endpoint was the mean change from baseline in hemoglobin A1c (HbA1c) level at week 40, the
end of trial. The secondary endpoints were mean change from baseline in fasting serum glucose (FSG), mean
change from baseline in bodyweight and proportion of participants with HbA1c < 7.0%, ≤6.5% or <5.7%. All
primary and secondary outcome markers exhibited statistically significant reduction in hyperglycemic
readings compared to baseline readings in all tirzepatide groups. In addition, meaningful body weight
reductions were also observed in all tirzepatide groups. These results indicated both statistically and clinically
significant efficacy of tirzepatide in comparison to placebo for controlling T2DM in adult patients. The most
frequent adverse events with tirzepatide were mild to moderate gastrointestinal adverse events. Injection-site
reactions were reported by 2-3% of patients in tirzepatide groups compared to none in placebo group. And
hypoglycemic events with BG <70 mg/dL were reported in 6-7% of patients in tirzepatide groups and only
1% of placebo group. Patients were followed for another 4 weeks for safety monitoring.

Study 2 (SURPASS-5)
In the same vein of SURPASS-1 trial, SURPASS-5 trial followed a similar study design protocol. Adult
patients with uncontrolled T2DM were included if they had a baseline HbA1c of 7.0% – 10.5%, BMI ≥ 23
kg/m2, were receiving stable doses of once-daily insulin glargine (>20 IU/day or >0.25 IU/kg/day) with or
without metformin (≥1500 mg/day), and stable weight (no change outside of 5%) during the previous 3
months with agreement to not initiate attempts to lose weight other than those for diabetes treatment. Patients
were excluded if they had T1DM, history of pancreatitis, non-proliferative diabetic retinopathy, diabetic
maculopathy, hepatitis, hypoglycemia unawareness, gastroparesis, eGFR<30 mL/min/1.73m2, or used of any
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oral antihyperglycemic medication for 3 months before screening. After the initial 3-week of screening and
lead-in phase, 475 patients who were on long-term insulin glargine with or without metformin were randomly
assigned into one of the 4 treatment groups: 5 mg, 10 mg, 15 mg, and placebo (n=116, 119, 120, and 120,
respectively) by a computer-generated random sequence using an interactive web response system. The study
was conducted as a double-blind trial. All patients went through a stabilization period during the first 4 weeks
after randomization with restricted insulin dose adjustments to ensure safety and minimize hypoglycemic risk.
Following the initial stabilization period, patients entered the treatment period in which a titration schedule
was followed until the desired maintenance dose was reached. The maintenance period was estimated to be
weeks 24 to 40.

Primary outcome endpoint was the mean change from baseline in hemoglobin A1c (HbA1c) level at week 40,
same as in SURPASS-1 trial. The secondary endpoints were also similar, including mean change from
baseline in fasting serum glucose (FSG), mean change from baseline in bodyweight and proportion of
participants with HbA1c < 7.0%, ≤6.5% or <5.7%. The results echoed the conclusion of SURPASS-1 trial
and all primary and secondary outcomes markers showed both statistically and clinically significant results in
glycemic control. Significant body weight reductions were also observed across all tirzepatide treatment
groups. These results further supported the efficacy of tirzepatide in patients with more advanced T2DM.
Adverse events were reported at a similar rate by all groups with the most frequent adverse event being
gastrointestinal events in tirzepatide groups. Injection-site reactions were reported by 2.5-6.7% of patients in
tirzepatide groups compared with 0.8% in placebo group. And incidence of severe hypoglycemia with BG<54
mg/dL were reported by 14.2-19.3% in the tirzepatide groups compared with 12.5% in the placebo group.
Incidence rates of moderate hypoglycemia with BG<70 mg/dL were similar across all groups. And
participants were followed for another 4 weeks to ensure their safety.

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Trial Arms N Duration Eligibility Design and Endpoints Results
Demographics
Rosenstock J, • Placebo 478 40-week Inclusion: Multicenter, Primary endpoint:
et al. 10 (n=113) study • ≥18 yrs randomized, double- • Mean change Primary Outcome*
period • Inadequate T2DM control blind, placebo- from baseline in 5 mg 10 mg 15 mg Placebo
Efficacy and • Tirzepatide with diet and exercise controlled, parallel HbA1c at 40 (n=121) (n=121) (n=120) (n=113)
safety of a 5 mg 4-week alone group phase 3 trial weeks HbA1c (%)
novel dual GIP (n=121) safety • Naïve to injectable Baseline (mean) 8.0 7.9 7.9 8.1
and GLP-1 follow-up diabetic therapy Baseline Key secondary
Change at week 40 -1.87 -1.89 -2.07 0.04
receptor • Tirzepatide period • HbA1c of 7.0% - 9.5% at demographics endpoints:
(p=0.72)
agonist 10 mg screening • Mean age: 54.1 • Mean change
tirzepatide in Key Secondary Outcomes*
(n=121) • Body mass index (BMI) ≥ years old from baseline in
patients with FSG (mg/dL)
23 kg/m2 • Mean duration of fasting serum
type 2 diabetes • Tirzepatide Baseline (mean) 154 153 154 155
• Stable weight (no change T2DM: 4.7 years glucose (FSG)
(SURPASS-1): 15 mg Change at week 40 -43.6 -45.9 -49.3 12.9
outside of 5%) during the • Women: 48% • Mean change
(p=0.0014)
A double- (n=120) previous 3 months and (40% in 10 mg from baseline in
blind, group) bodyweight Body weight (kg)
agreed not to attempt
randomized, Modified • Caucasian: 36% • Proportion of Baseline (mean) 87.0 86.2 85.5 84.5
weight loss
phase 3 trial intend-to- participants with Change at week 40 -7.0 -7.8 -9.5 -0.7
Exclusion: • Asian: 35%
treat HbA1c < 7.0% (p=0.22)
• T1DM • American Indian/
population or <5.7% Number of participants 105 108 102 22
• History of pancreatitis Alaska Native:
reaching HbA1c<7.0% (n=87%) (n=92%) (n=88%) (n=19%)
• History of proliferative 25%
Number of participants 99 96 100 11
diabetic retinopathy, • Black: 5%
reaching HbA1c≤6.5% (n=82%) (n=81%) (n=86%) (n=10%)
diabetic maculopathy, or • Hispanic/Latino:
Number of participants 41 36 60 1
non-proliferative diabetic 43%
reaching HbA1c<5.7% (n=34%) (n=31%) (n=52%) (n=1%)
retinopathy that requires
*p value <0.001 unless specifically noted
acute treatment
• eGFR<30 mL/min/1.73m2
Conclusion:
• Use of any oral In conclusion, tirzepatide once a week administration at all doses showed robust
antihyperglycemic
reductions compared with placebo in glycemic markers and meaningful body weight
medication for 3 months reductions in patients with T2DM with diet and exercise alone. Tirzepatide resulted
before screening in robust reductions in HbA1c, fasting serum glucose levels, as well as patient-
recorded self-monitoring of blood glucose levels.
Limitations • Relatively shorty duration of trial (40 weeks) to see full weight loss effects
• Self-reported gastrointestinal adverse events: can lead to over- or under-estimation of true treatment-related adverse events
• Black or African American patient population was significantly underrepresented considering the prevalence of T2DM in this population
• Relatively small study population (N=478)

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Trial Arms N Duration Eligibility Design and Endpoints Results
Demographics
Dahl D, et • Placebo Inclusion: Multicenter, Primary endpoint: Primary Outcome*
al.11 (n=120) 475 4-week • ≥18 yrs with T2DM randomized, • Mean change 5 mg 10 mg 15 mg Placebo
insulin • Baseline HbA1c of 7.0% – double-blind, from baseline in (n=116) (n=119) (n=120) (n=120)
Effect of • Tirzepatide stabilization 10.5% placebo- HbA1c at week HbA1c (%)
Subcutaneo 5 mg period • BMI ≥ 23 kg/m2 controlled phase 40 Baseline (mean) 8.30 8.36 8.22 8.38
us (n=116) • Receiving stable doses of once- 3 trial Change at week 40 -2.11 -2.40 -2.34 -0.86
Tirzepatide 36-week daily insulin glargine (>20 Secondary Key Secondary Outcomes*
vs Placebo • Tirzepatide insulin IU/day or >0.25 IU/kg/day) with Baseline endpoints: FSG (mg/dL)
Added to 10 mg titration or without metformin (≥1500 demographics: • Proportion of Baseline (mean) 162.9 162.6 160.4 164.4
Titrated (n=119) period mg/day) • Mean age: 61 patients with Change at week 40 -58.2 -64.0 -62.6 -39.2
Insulin • Stable weight (no change outside years old HbA1c <7.0%, Body weight (kg)
Glargine on • Tirzepatide 4-week of 5%) during the previous 3 • Mean BMI: ≤6.5%, or Baseline (mean) 95.8 94.6 96.0 94.2
Glycemic 15 mg safety months with agreement to not 33.4 kg/m2 <5.7%
Control in follow-up Change at week 40 -5.4 -7.5 -8.8 1.6
(n=120) initiate attempts to lose weight • Mean duration • Mean change Number of participants 101 106 100 41
Patients other than those for diabetes of T2DM: 13.3 from baseline in
with Type 2 reaching HbA1c<7.0% (n=87%) (n=90%) (n=85%) (n=35%)
Modified treatment years fasting serum
Diabetes Number of participants 86 101 94 21
intend-to- • Mean HbA1c: glucose (FSB)
The reaching HbA1c ≤6.5% (n=74%) (n=86%) (n=80%) (n=17%)
treat Exclusion: 8.31% • Mean change
SURPASS- Number of participants 28 49 59 3
population • T1DM • Median insulin from baseline in reaching HbA1c<5.7%
5 (n=24%) (n=42%) (n=50%) (n=2.7%)
• History of pancreatitis glargine dose: body weight
Randomized *p value <0.001
• Non-proliferative diabetic 30.0 IU/day • Mean change
Clinical • Metformin use: from baseline in
retinopathy
Trial 82.9% daily insulin
• Diabetic maculopathy Conclusion:
• Hepatitis • Women: 44% glargine dose
Compared to placebo, the addition of subcutaneous tirzepatide to titrated insulin
• Hypoglycemia unawareness (39% in 10 mg glargine resulted in statistically significant improvements in glycemic control in
• Gastroparesis group) patient with inadequately controlled T2DM. Tirzepatide resulted in robust reductions
• eGFR<30 mL/min/1.73m2 • Caucasian: in HbA1c, fasting serum glucose levels, and body weight.
• Use of any oral 80%
antihyperglycemic medication • Asian: 18%
for 3 months before screening • American
Indian/ Alaska
Native: 0.4%
• Black: 1%
• Hispanic/
Latino: 5%
Limitations • Relatively small patient population (N=475) with only 1% of black/African American patients
• Participants were treated with insulin glargine with or without metformin which cause the results may not be directly extrapolated to other regimens using different oral antihyperglycemic drugs
• Lack of adjustment of insulin dose for the first 4 weeks of treatment may have initially favored patients receiving tirzepatide
• Self-reported gastrointestinal adverse events

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Table 5. Glossary of terms used in efficacy tables
Abbreviation Term
BMI Body mass index (kg/m2)
HbA1c Hemoglobin A1c, also known as glycated hemoglobin
T1DM Type I diabetes mellitus
T2DM Type II diabetes mellitus
Pricing and Utilization12,13,14,15
Table 6. Pricing for tirzepatide and competitors
Tirzepatide Semaglutide Dulaglutide (Trulicity)
(Ozempic/Rybelsus)
Administration SubQ injection SubQ injection / Oral SubQ injection
Dosing (lowest effective dose) 5 mg/week 0.5 mg injection/week or 0.75 mg/week
7 mg tablet/day
Cost per week (AWP) $263.58 Ozempic: $178.41 $265.97
Rybelsus: $249.76

Efficacy Comparison
SURPASS-2 trial16 was a phase 3, open-label, non-inferiority trial published in 2021 comparing efficacy of
tirzepatide and semaglutide in 1,879 adult patients with T2DM. Patients were randomly assigned to 4 groups:
tirzepatide 5 mg, 10 mg, 15 mg, and semaglutide 1 mg. Results were obtained at week 40 with the primary
efficacy endpoint being the mean change from baseline in HbA1c. HbA1c was reduced -2.01%, -2.24%, -
2.30%, in tirzepatide groups and -1.86% in semaglutide group. As for secondary outcomes, a total of 82%-
86% of patients in the tirzepatide groups and 79% of patients in semaglutide group had a HbA1c level <7.0%
at the end of trial. The percentage of patients reaching HbA1c goal of ≤6.5% were 69%, 77%, 80% in
tirzepatide groups, and 64% in semaglutide group. Whereas patients who were able to reach a level of HbA1c
<5.7% were 27%, 40%, 46% in tirzepatide groups, and 19% in semaglutide group. The mean change from
baseline in fasting serum glucose (FSB) were reported to be -56.0 mg/dL, -61.6 mg/dL, -63.4 mg/dL in
tirzepatide groups, and -48.6 mg/dL in semaglutide group. At week 40, mean body weight reductions are -7.6
kg, -9.3 kg, -11.2 kg in tirzepatide groups, and -1.9 kg in semaglutide group. Based on results obtained at
week 40, all three groups of patients on tirzepatide showed slightly greater reduction in HbA1c levels, FSB,
and body weight from baseline than semaglutide. Overall, the resulting data was statistically significant and
supported therapeutic non-inferiority but did not show significant superiority.

A trial conducted in Japan, the SURPASS J-mono trial was a randomized, double-blind trial comparing the
efficacy and safety of tirzepatide and dulaglutide in 636 adult patients with T2DM. Although it has not been
officially published yet, the study results are publicly available as of April, 2022.17. Patients were randomly
assigned to 4 groups: tirzepatide 5 mg, 10 mg, 15 mg, and dulaglutide 0.75 mg. The primary endpoint was the
mean change in HbA1c from baseline at week 52. HbA1c was reduced by -2.37%, -2.55%, -2.82% in
tirzepatide groups, and -1.29% in dulaglutide group. Secondary outcomes assessed for proportion of patients
with HbA1c <7.0% and reported the results to be 93.67%, 96.79%, 99.37% in tirzepatide groups, and 67.30%
in dulaglutide groups. Mean change from baseline in fasting serum glucose (FSB) was reported to be -57.9
mg/dL, -64.6 mg/dL, -67.6 mg/dL in tirzepatide groups, and -31.9 mg/dL in dulaglutide group. For reduction
in body weight from baseline, -5.8 kg, -8.5 kg, -10.7 kg in tirzepatide groups, and -0.5 kg in dulaglutide group
were reported. The data indicates a favorable outcome for all tirzepatide groups in reducing HbA1c, FBS, and
body weight from baseline values compared to dulaglutide 0.75 mg. Preliminary conclusion shows superiority
of tirzepatide to dulaglutide 0.75 mg. However, no conclusion can be drawn for higher doses of dulaglutide
due to lack of data and the study population only included Japanese patients.

Last reviewed: [06/28/2022]

Tirzepatide (MounjaroTM)
Monograph
Adverse Event Comparison
As SURPASS-2 trial16 concluded, adverse event profiles were similar across all four groups, tirzepatide 5 mg,
10 mg, 15 mg, and semaglutide 1 mg, with gastrointestinal adverse more prominent than others. These GI
adverse events were reported at a similar rate across all treatment groups, including nausea (17.4-22.1%),
diarrhea (13.2-16.4%), vomiting (5.7-9.8%) and constipation (4.5-6.8%). Serious adverse events that were
observed more in tirzepatide groups included acute cholecystitis, acute myocardial infraction, chest pain,
upper abdominal pain, atrial fibrillation, urinary tract infection, severe hypoglycemia, and syncope. These
serious adverse events were reported more frequently with 5.3-7.0% of patients in tirzepatide groups
compared to 2.8% of patients in semaglutide group. Clinically significant hypoglycemia, which is defined by
a blood glucose level <54 mg/dL, was observed in 0.6%, 0.2%, and 1.7% of patients in respective tirzepatide
groups compared with 0.4% in semaglutide group. Injection-site reactions were more frequently observed in
tirzepatide groups and occurred in 1.9 to 4.5% of the patients, whereas only 0.2% in semaglutide group
reported such reactions.

Based on the data from the recently completed SURPASS J-mono trial17, incidence rates of serious adverse
events were similar among all groups with no death in any group. Gastrointestinal adverse events were the
predominant adverse events observed in all groups. However, more patients in the tirzepatide groups
experienced GI adverse events than dulaglutide group. Nausea was reported in 12.0-20.0% of patients in
tirzepatide groups compared with 7.6% in dulaglutide group. Diarrhea was reported in 8.9-17.0% of patients
in tirzepatide groups compared with 6.9% in dulaglutide group. Vomiting was reported in 5.1-11.9% of
patients in tirzepatide groups compared with 1.3% in dulaglutide group. And lastly, constipation was reported
in 13.8-17.7% of patients in tirzepatide groups compared with 10.7% in dulaglutide group. But the injection-
site reactions rates were lower in tirzepatide groups (1.3-5.6%) compared with the dulaglutide group (7.6%).
Future studies including higher doses of dulaglutide are needed to better compare the safety data of these two
drugs.

Summary
Tirzepatide is a novel anti-diabetic agent with two mechanisms of action. It acts as agonist for both GIP and
GLP-1 receptors to lower glycemic markers in patients with T2DM. The two clinical trials comparing
tirzepatide to placebo demonstrated the effectiveness and safety of tirzepatide in reducing HbA1c, fasting
serum glucose, and body weight. SURPASS-1 trial studied tirzepatide as mono therapy against placebo and
SURPASS-5 trial studied tirzepatide with the concomitant use of long-acting insulin glargine with or without
metformin. Both studies concluded the superiority of tirzepatide in reducing HbA1c, fasting serum glucose,
and body weight with no significant safety concerns.

Two additional trials were conducted to compare tirzepatide with two other GLP-1 agonist medications,
semaglutide and dulaglutide. Tirzepatide was found to be non-inferior to semaglutide and superior to
dulaglutide. However, the trial comparing tirzepatide with semaglutide was unblinded which may increase the
risk of the placebo effect. And the trial comparing tirzepatide with dulaglutide was conducted in Japan and
only included Japanese/Asian patients. Although the efficacy data of tirzepatide was significant, extrapolation
of it to patients of other racial groups may be questionable.

Possible utilization may be seen in patients with T2DM that are nonresponsive to current GLP-1 agonist
treatments. And we may likely see tirzepatide used off-label for weight loss. The cost of tirzepatide is similar
to dulaglutide and is about $350 more expensive than semaglutide per month.

Recommendation: Non-preferred brand

Last reviewed: [06/28/2022]

Tirzepatide (MounjaroTM)
Monograph
Rationale: Although tirzepatide is the first dual-MOA agent, current efficacy and safety data only supports its
non-inferiority in comparison with semaglutide in managing T2DM in adult patients. Yet tirzepatide was
shown to be more effective than dulaglutide. One of the major concerns is the lack of long-term data to
support the use of tirzepatide as chronic treatment. Another concern is the potential off-label use for weight
loss purposes. Therefore, the placement of a prior authorization is warranted but should include less restrictive
criteria to allow optimal access.

RECOMMENDED PRIOR AUTHORIZATION CRITERIA

1. Initial Therapy: Approve for 3 months if the patient meets the following criterion:
a. Diagnosis of Type 2 diabetes confirmed by patient chart and HbA1c ≥ 6.5%

2. Subsequent Therapy Requests:

a. Meaningful clinical response endorsed by provider, AND
b. Provider statement testifying for absence in symptoms of thyroid tumors (e.g., a mass in the neck,
dysphagia, dyspnea, persistent hoarseness)

CONDITIONS NOT RECOMMENDED FOR APPROVAL

There is lack of evidence in efficacy or potential safety concerns in using these agents in the following
conditions:
1. Treatment of Type 1 diabetes
2. Appetite suppression or treatment of obesity
3. Personal or family history of medullary thyroid carcinoma or personal history of multiple endocrine
neoplasia syndrome type 2
4. Pregnancy
5. History of pancreatitis

Prepared by: Haley Sun

Reviewed by: Courtney Reilly, PharmD

Last reviewed: [06/28/2022]

Tirzepatide (MounjaroTM)
Monograph
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