December 2023 – Tirzepatide

NEW DRUGS - Tirzepatide (Mounjaro®)

Metro Toronto Hospitals Drug Information Service (MetroDIS)
December 2023
Sunnybrook Health Sciences Centre
University of Toronto
Editor: Raea Dobson, BSc, BScPharm, ACPR, PharmD
Telephone: 416-451-7186, Email: metrodis@sunnybrook.ca

Generic Name Tirzepatide1

Brand Name (Manufacturer)
Drug Class
Dosage Forms
Dosing Recommendations
Special Patient Populations
Mounjaro® (Eli Lilly) - available in Canada as of 2-Nov-2023
Zepbound® (Eli Lilly) - not yet available in Canada
“Twincretin” – GLP1-receptor agonist and GIP-receptor agonist
Anti-hyperglycemic
Anti-obesity medication
Subcutaneous injection
Available as: single-dose prefilled pens (4 pack), single-dose vials
Per 0.5mL solution: 2.5mg, 5mg, 7.5mg, 10mg, 12.5mg, 15mg
2.5mg subcut once weekly
Increase by 2.5mg subcut once weekly every 4 weeks as tolerated
Maximum dose is 15mg subcut once weekly
1) Renal impairment: no dose adjustment required, though no
data for use in end-stage renal disease
2) Hepatic impairment: no dose adjustment recommended
3) Geriatrics (65+): no dose adjustment required, no differences
in safety or efficacy
4) Pediatrics (<18 yrs): not studied, but trial in progress2

Indications
 Treatment of Type 2 Diabetes (T2DM), either alone or in combo with other anti-hyperglycemics
 Weight loss in obesity (not yet an approved indication in Canada)

Benefits
Future FAQ to review benefits and their evidence. In brief:
 Reduction in weight (up to 22% of body weight), maintained for 88 weeks with continued use3
 HbA1c reduction (~2%)4-9
 Reduced blood pressure10
 Improved cholesterol: reduced total cholesterol, LDL, and triglycerides, and increased HDL10
 Multiple trials in progress, including a cardiovascular outcome trial11
Mechanism of Action1, 12
 Incretin hormones are released after food intake (i.e. they are nutrient-stimulated hormones).
 Incretin hormones work synergistically and have many effects:
o ↑: insulin production, lipolysis
o ↓: gut motility (leads to earlier satiety), appetite (via central action), glucagon release
 Tirzepatide has been termed a “twincretin” as it mimics two incretin hormones, acting as an
agonist at glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) receptors.
 Overall: results in lower fasting and post-prandial blood glucose, increased insulin sensitivity,
reduced food intake, and weight loss.4

Pharmacokinetics1
Bioavailability 80%
Tmax 8 to 72 hours
Protein Binding 99%, unlikely to be removed by dialysis
Volume of Distribution 10.3L
Metabolism Proteolytic cleavage, beta-oxidation, and amide hydrolysis
Excretion8 Urine and feces as inactive components
Half-life of Elimination ~5 days, steady state after 4 weeks
Effect of Food Can be given at any time of day, with or without meals
Drug Interactions1
 May impact absorption of oral drugs: due to delayed gastric emptying.
 Contraceptive medications: tirzepatide may reduce Cmax of ethanyl estradiol by over 50%. It is
recommended those on hormonal oral contraceptives switch to non-oral methods or add a
barrier method for 4 weeks after initiation and 4 weeks after each dose increase of tirzepatide.
 DPP4-inhibitors: avoid concomitant use as mechanisms of action are on similar pathways.
 Additive hypoglycemia: risk with sulfonylureas and insulins. Consider dose reductions. In trials,
pre-emptive dose reductions in basal insulin of 20% have been used.

Adverse Effects1
Future FAQ to review adverse effects and their evidence. In brief:
- Gastrointestinal (dose-related): nausea (12 to 22%), vomiting (5 to 10%) diarrhea (12 to 17%),
constipation (6 to 7%), anorexia (>5%), dyspepsia (>5%), abdominal pain (>5%).
o Contribute to weight loss.
o Can lead to dehydration resulting in hypotension and acute kidney injury.
o Rare complications of gastroparesis and intestinal obstruction.
o Increases the risk of aspiration during anesthesia.
- Injection site reactions (2 to 4%).
- Acute pancreatitis (0.2%): monitor for severe abdominal pain +/- vomiting.
- Acute gallbladder disease: e.g. cholelithiasis, cholecystitis, biliary colic, need for
cholecystectomy (0.6%). Note that this risk is increased for any scenario with rapid weight loss.
- Potential risk of thyroid cancer: patients should be monitored for masses in neck, dysphagia,
dyspnea, and persistent hoarse voice.
- Diabetic retinopathy worsening (temporary): occurs with rapid improvement in glucose.
- Hypersensitivity reactions including anaphylaxis and angioedema.

Contraindications & Precautions1

Contraindications:
- Hypersensitivity to any components of the formulation
- Thyroid: personal or family history of medullary thyroid cancer or those with Multiple
Endocrine Neoplasia (MEN) syndrome type 2
o In rats, tirzepatide and other GLP-1RAs have caused a dose-related and therapy-
dose-related increase in thyroid C-cell tumors (adenomas and carcinomas, including
medullary thyroid carcinoma). It is unknown if this risk extends to humans, though
has not yet been seen in clinical trials.
- Type 1 diabetes: not studied.
- Pregnancy and lactation: not studied, animal studies suggest harm to fetal development,
and maternal weight loss. Recommended to stop at least 4 weeks before planned
pregnancy.
Precautions: severe GI disease including gastroparesis, history of pancreatitis, diabetic retinopathy.

Administration1
- Do not mix with inulin in the same injection. Air bubbles are normal.
- Remove from fridge. Ensure pen is in Locked position, pull off and discard the gray base cap,
place the clear base against the injection site on the abdomen, thigh, or upper arm (purple
button facing away from the body), unlock, press the purple button, hold for 10 seconds, listen
 for 2 loud clicks (1st = injection started, 2nd = injection complete), remove and place unit in
sharps container.
- If pen is unlocked before removing gray base cap, discard pen.
- It is not necessary to hold the purple button during injection, but helps keep pen steady
- Sometimes a soft click can be heard before the 2nd loud click – do not remove pen until
the 2nd loud click is heard.
- If gray plunger is visible, the dose was delivered.
- Rotate injection sites.
- If dose missed within 4 days (96 hours), take missed dose. The day of weekly dose can be
adjusted as long as there are at least 3 days (72 hours) between injections.

Storage & Stability1

 Store in original package to protect from light.
 Stored in the fridge up to the expiration date. Do not freeze – discard any frozen product.
 Can be stored unrefrigerated for up to 12 days as long as temperature does not exceed 30C.
 All open vials should be discarded immediately after use.
 Liquid should appear clear, free of particulate matter, and colorless to slightly yellow.

Comparison With Existing Agents13

Future FAQ to review comparative evidence with other agents. In brief:
 A network meta-analysis of 38 trials including 34,166 patients found that tirzepatide had:
 No increase in GI-related adverse effects vs semaglutide 1mg subcut weekly.
 Increased GI-related adverse effects vs semaglutide 7mg po daily (nausea & vomiting)

Note that efficacy data below is not all-inclusive of every option compared in this study, but focuses
on the major existing options. See the Supplemental Appendix of this study for further details.

For HbA1c Reduction: For Weight Reduction:

(from best to worst)
tirzepatide 15mg subcut weekly
> tirzepatide 10mg subcut weekly
> tirzepatide 5mg subcut weekly
> semaglutide 1mg subcut weekly
≈ semaglutide 2.4mg subcut weekly
≈ semaglutide 40mg po daily
> semaglutide 20mg po daily
>semaglutide 10mg po daily
≈ semaglutide 0.5mg subcut weekly
>dulaglutide 0.5mg subcut weekly
>semaglutide 14mg po daily
>luraglutide 1.8mg subcut daily
> canagliflozin 300mg po daily
> insulin
> empagliflozin 25mg po daily
>semaglutide 0.25mg subcut weekly
> sitagliptin 100mg po daily
(from best to worst)
tirzepatide 15mg subcut weekly
> tirzepatide 10mg subcut weekly
>semaglutide 2.4mg subcut weekly
> tirzepatide 5mg subcut weekly
> semaglutide 40mg po daily
> semaglutide 20mg po daily
> semaglutide 1mg subcut weekly
>semaglutide 10mg po daily
≈ insulin
> canagliflozin 300mg po daily
≈ semaglutide 14mg po daily
> semaglutide 0.5mg subcut weekly
> empagliflozin 25mg po daily
> liraglutide 1.8mg subcut daily
> dulaglutide 1.5mg subcut weekly
>dulaglutide 0.75mg subcut weekly
> sitagliptin 100mg po daily
Place in Therapy
 Due to its recent release, tirzepatide is not consistently included in many guidelines.
o For example, while it is mentioned in the most recent Canadian Obesity Guidelines, it is
not included in the Canadian Diabetes Association Guidelines.
o Tirzepatide has convincing outcome data for both T2DM and obesity, and given other
similar GLP1-RAs are included in major guidelines, it is expected tirzepatide addition is
only a matter of time.20, 21
 The American Diabetes Association Standards of Care in Diabetes guidelines were updated in
2023 and include tirzepatide. They recommend:
o Considering the effect on weight when considering starting antihyperglycemic drugs.
o “In general, higher-efficacy approaches have greater likelihood of achieving glycemic
goals, with the following considered to have “very high” efficacy for glucose lowering:
the GLP-1 RAs dulaglutide (high dose) and semaglutide, the gastric inhibitory peptide
(GIP) and GLP-1RA tirzepatide, insulin, combination oral therapy, and combination
injectable therapy.”
o For those with both glycemic and weight-based goals (achieving or maintaining goal
weight), glucose-lowering therapies with “very high” efficacy for weight loss include
exclusively semaglutide and tirzepatide.
 NICE published recommendations for tirzepatide in T2DM on 25-Oct-2023.22 They state:
o “Tirzepatide is recommended for treating type 2 diabetes alongside diet and exercise in
adults when it is insufficiently controlled only if:
 triple therapy with metformin and 2 other oral antidiabetic drugs is ineffective,
not tolerated or contraindicated, and
 they have a body mass index (BMI) of 35 kg/m2 or more, and specific
psychological or other medical problems associated with obesity, or
 they have a BMI of less than 35 kg/m2, and:
 insulin therapy would have significant occupational implications, or
 weight loss would benefit other significant obesity-related
complications.”
Literature Review – Landmark Trials
Future FAQ to review evidence for efficacy. In brief:

SURPASS trials: T2DM

 SURPASS 1 to 64-11:
 A series of randomized trials (with variable blinding) of 5627 patients with inadequately
controlled T2DM given either tirzepatide or one of the following: placebo, semaglutide (all
patients on metformin), titrated insulin degludec (all on metformin +/- SGLT2i), insulin
glargine (open-label), insulin glargine (double-blind), or insulin lispro TID (all patients on
insulin glargine).
 Tirzepatide had statistically significant reduction in HbA1c and weight vs all of the
above interventions. It also reduced hepatic steatosis vs insulin degludec.
 SURPASS-CVOT (a large CV outcome trial of tirzepatide vs dulaglutide) is anticipated to be
complete in Oct 2024.11
 SURPASS-J-mono: a double-blind RCT of 636 Japanese patients with T2DM receiving no
antihyperglycemics were given tirzepatide or dulaglutide and found larger reductions in
HbA1c and weight with tirzepatide, along with increased nausea and constipation.14
 SURPASS-J-combo: a randomized, open-label trial of 443 Japanese patients with
inadequately controlled T2DM on a single oral drug for at least 3 months were given
tirzepatide (no active comparator or placebo was used) found reduced weight and HbA1c in
the tirzepatide group regardless of background therapy used.15
 SURPASS-AP-Combo: a randomized, open-label trial of 917 Asian-Pacific (predominantly
Chinese) patients with inadequately controlled non-insulin-dependent T2DM taking
metformin (+/- a sulfonylurea) were given tirzepatide or insulin glargine found tirzepatide
was non-inferior or superior to insulin glargine (depending on the dose of tirzepatide) for
reduction in HbA1c and proportion of patients achieving target HbA1c, and was superior for
body weight reduction at all doses.16

SURMOUNT trials: Obesity

 SURMOUNT-1 to 417-19,3:
 Randomized, double-blind, placebo-controlled trials of tirzepatide in variable groups:
 1: 2539 obese patients without diabetes
 2: 1514 obese patients with diabetes
 3: 579 obese patients without diabetes, with ≥1 obesity-related complication
 4: 670 overweight or obese patients without diabetes
 Tirzepatide reduced weight significantly more vs placebo in all patient groups
 SURMOUNT-523
 Not yet completed. Will assess tirzepatide vs semaglutide for overweight and
obese patients with weight-related comorbidities but without T2DM.
 SUMMIT24
 A trial of tirzepatide use in preserved-ejection fraction heart failure.

Cost Implications in Canada

 Per the most recent CADTH review: “Although the price of tirzepatide is currently not available,
future cost-effectiveness studies will be necessary to determine if tirzepatide adds value to the
existing drug classes already available in Canada.”25
 Per “PrescribeSmart,” the cost in Ontario is currently $80 to $92 per prefilled pen.26
Conclusions
 Tirzepatide has demonstrated superior efficacy for reductions in HbA1c and weight in diabetic
patients, and obese patients, when compared to multiple other standard treatments.
 High-dose tirzepatide has higher risk of nausea and constipation vs other comparators.
 As further outcome data becomes available, the patient populations for approved use are likely
to expand.

References
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