Tirzepatide

Abstract

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Generic Name: Tirzepatide

Proprietary Name:Mounjaro (Eli Lilly and Company)

Approval Rating: 1P

Therapeutic Class: Glucose-Dependent Insulinotropic Polypeptide/Glucagon-Like Peptide 1 Receptor Agonist

Similar Drugs: Dulaglutide, Exenatide ER (Bydureon BCise), Semaglutide Injection

Sound-/Look-Alike Names:Monjuvi, Monoferric, Tizanidine, Tolazamide

Indications

Tirzepatide is approved by the Food and Drug Administration (FDA) as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The prescribing information notes that tirzepatide has not been studied in patients with a history of pancreatitis and is not indicated for use in patients with type 1 diabetes mellitus. ¹

Tirzepatide has also been evaluated for effects on weight in adults with diabetes or with obesity/overweight with or without diabetes, and for the treatment of nonalcoholic steatohepatitis.^2-4

Similar agents with FDA approval for type 2 diabetes mellitus (eg, semaglutide) are not generally recommended for first-line treatment in patients inadequately controlled on diet and exercise; metformin is the preferred initial pharmacologic agent for most patients based on safety, efficacy, and cost. However, the choice of first-line therapy should be based on comorbidities, patient-centered treatment factors, and management needs. ⁵

Table 1 provides a comparison of tirzepatide and select glucagon-like peptide 1 (GLP-1) receptor agonists approved for the treatment of type 2 diabetes mellitus.^1,6-12

Table 1.

Comparison of the GIP ^a /GLP-1 Receptor Agonist Tirzepatide with Select GLP-1 Receptor Agonists FDA Approved for the Treatment of Type 2 Diabetes Mellitus.^1,6-12

	Tirzepatide	Dulaglutide	Exenatide ER	Semaglutide
Brand name (manufacturer)	Mounjaro (Eli Lilly and Company)	Trulicity (Eli Lilly and Company)	Bydureon Bcise (AstraZeneca)	Ozempic (Novo Nordisk)
				Rybelsus (Novo Nordisk)
				Wegovy (Novo Nordisk)
Indications
As an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus	X	X	X	X (Ozempic, Rybelsus)
To reduce risk of major adverse cardiovascular events in patients with type 2 diabetes mellitus who have cardiovascular disease or multiple cardiovascular risk factors		X		X (Ozempic)
As an adjunct to diet and exercise for chronic weight management in patients who are obese or overweight with ≥1 weight-related comorbidity (eg, hypertension, type 2 diabetes mellitus, dyslipidemia)				X (Wegovy)
Approved population	Adults	Adults	Adults and pediatric patients ≥10 year	Adults
Mechanism of action	GIP/GLP-1 receptor agonist	GLP-1 receptor agonist	GLP-1 receptor agonist	GLP-1 receptor agonist
Route of administration	Subcutaneous injection	Subcutaneous injection	Subcutaneous injection	Subcutaneous injection (Ozempic, Wegovy); oral (Rybelsus)
Dosing frequency	Once weekly	Once weekly	Once weekly	Once weekly (subcutaneous injection); once daily (oral tablet)
Dosage form	Single-dose pen	Single-dose pen	Single-dose autoinjector	Single-dose pen (Ozempic, Wegovy); Tablets (Rybelsus)

^aGIP = glucose-dependent insulinotropic polypeptide.

Clinical Pharmacology

Tirzepatide is a dual GIP and GLP-1 receptor agonist, a novel combination drug class that has been referred to as “twincretin.”^1,13-16 GLP-1 and GIP are the main hormones involved in the incretin effect, which occurs following food consumption. Both hormones stimulate the production of insulin in response to a meal, but GIP has the additional functions of increasing glucagon secretion in a hypoglycemic state and affecting lipid homeostasis. In patients with type 2 diabetes mellitus, the incretin effect is greatly reduced due to a decreased response to nutrients and a decreased insulinotropic effect on pancreatic beta cells. The dual incretin agonism provided by administration of GIP and GLP-1 receptor agonists results in an additive effect that significantly improves beta cell function and increases insulin sensitivity.^8,15-17

Tirzepatide enhances first- and second-phase insulin secretion and reduces glucagon levels, both in a glucose-dependent manner. It also increases insulin sensitivity and delays gastric emptying. These actions result in decreased fasting and postprandial glucose concentrations, decreased food intake, and reduced body weight in patients with type 2 diabetes mellitus. ¹

Pharmacokinetics

Following subcutaneous injection of tirzepatide, T_max ranged from 8 to 72 hours. Mean absolute bioavailability following subcutaneous administration is 80% and is not influenced by the site of administration (abdomen, thigh, or upper arm). Tirzepatide is highly protein bound to plasma albumin (99%) and has a steady-state volume of distribution of approximately 10.3 L. Mean elimination half-life was approximately 5 days, and mean clearance was 0.061 L/hour.^1,13

Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety, and amide hydrolysis. The primary routes for excretion of tirzepatide metabolites are via urine and feces. No intact tirzepatide was found in urine or feces. ¹

Age, gender, race, ethnicity, body weight, and renal or hepatic impairment do not have a clinically relevant effect on the pharmacokinetics of tirzepatide. ¹

Comparative Efficacy

Indication: Type 2 Diabetes Mellitus

The approval of tirzepatide for treatment of type 2 diabetes was supported by a series of studies referred to as SURPASS.^7,18-25

Summaries of ongoing and completed trials of the SURPASS program (including some conducted in Japan) are included below:

• SURPASS-6 compares the safety and efficacy of tirzepatide with insulin lispro in patients with type 2 diabetes inadequately controlled on insulin glargine with or without metformin. ¹⁹

• SURPASS-J-mono study compares the safety and efficacy of tirzepatide with dulaglutide in patients with type 2 diabetes inadequately controlled with oral antihyperglycemic medications in Japan. ²¹

• SURPASS-J-combo study evaluates the long-term safety of adding tirzepatide to existing oral antihyperglycemic medication (sulfonylurea, biguanide, thiazolidinedione, alpha-glucosidase inhibitor, glinide, or sodium glucose cotransporter 2 [SGLT2] inhibitor) in patients with type 2 diabetes in Japan. ²⁰

• SURPASS-AP-Combo study compares tirzepatide with insulin glargine in patients with type 2 diabetes inadequately controlled on metformin with or without a sulfonylurea. Results have not been reported. ¹⁸

• SURPASS-CVOT compares the effects of tirzepatide versus dulaglutide on major adverse cardiovascular events in patients with type 2 diabetes. ²⁶

Guidelines

Guideline: 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2022

Reference: American Diabetes Association, 2022 ⁵

Comments: The American Diabetes Association (ADA) guidelines recommend all glycemic-lowering agents be used in conjunction with lifestyle modifications, including weight management and physical activity. Metformin has been the preferred first-line pharmacologic agent for patients with type 2 diabetes inadequately controlled by diet and exercise alone and should be used if tolerated and if no contraindications are present. However, the updated guidelines now state that first-line therapy should be selected based on comorbidities, patient-centered treatment factors, and management needs. Considerations include effect on cardiovascular and renal comorbidities, efficacy, hypoglycemia risk, impact on weight, cost, risk for side effects, and patient preferences. Among patients with type 2 diabetes who have established atherosclerotic cardiovascular disease or indicators of high risk, established kidney disease, or heart failure, an SGLT2 inhibitor or GLP-1 receptor agonist with demonstrated cardiovascular disease benefit is recommended as part of the glucose-lowering regimen independent of hemoglobin A_1c (HbA_1c) and in consideration of patient-specific factors. A GLP-1 receptor agonist is preferred to insulin when possible. Recommendation for treatment intensification for patients not meeting treatment goals should not be delayed. Tirzepatide was not available at the time this guideline was prepared. However, because tirzepatide has activity as a GLP-1 receptor agonist and trials indicate similar safety and efficacy profiles, tirzepatide will likely join other FDA-approved injectable GLP-1 agents recommended for reduction of HbA_1c in type 2 diabetes.

Studies

Drug: Tirzepatide vs Semaglutide

Reference: Frías J, et al, 2021 (SURPASS-2 trial)^25,27,28

Study Design: Phase 3, randomized, open-label, multicenter, active-controlled, parallel-group, noninferiority and superiority study

Study Funding: Eli Lilly and Company

Patients: 1879 adult patients (at least 18 years of age) with type 2 diabetes mellitus inadequately controlled on metformin (at least 1500 mg/day). Patients had an HbA_1c between 7% and 10.5%, body mass index (BMI) of 25 kg/m² or greater, and a stable weight (no change beyond ±5% for at least 3 months prior to the study). Exclusion criteria included type 1 diabetes diagnosis; chronic or acute pancreatitis at any time prior to study; proliferative diabetic retinopathy or maculopathy or nonproliferative diabetic retinopathy requiring acute treatment; slowed gastric emptying disorders or weight loss stomach surgery; chronic or acute hepatitis; estimated glomerular filtration rate (eGFR) less than 45 mL/minute/1.73 m²; myocardial infarction (MI)/stroke/hospitalization for congestive heart failure (CHF) in past 2 months; personal or family history of medullary thyroid cancer (MTC) or personal history of multiple endocrine neoplasia type 2 (MEN2); and use of weight loss drugs (including over-the-counter) or of other oral antihyperglycemic medications aside from metformin during prior 3 months. Mean patient age was 56.6 years; 53% were female; 82.6% were White, 11.1% were American Indian/Alaska Native, 4.2% were Black, and 1.3% were Asian; and 70.1% were Hispanic and 29.9% were non-Hispanic. Baseline average duration of diabetes was 8.6 years, mean HbA_1c was 8.28%, and average BMI was 34.2 kg/m².

Intervention: Patients were randomly assigned (1:1:1:1) to receive tirzepatide 5, 10, or 15 mg or semaglutide 1 mg administered subcutaneously once weekly for 40 weeks, followed by a 4-week safety follow-up period. Tirzepatide was initiated at 2.5 mg once weekly and increased incrementally by 2.5 mg every 4 weeks until maintenance dose of 5, 10, or 15 mg was achieved (at 4, 12, and 20 weeks, respectively). Semaglutide was initiated at 0.25 mg once weekly and doubled every 4 weeks until 1 mg maintenance dose was reached. Patients were stratified based on country and baseline HbA_1c level (less than or equal to 8.5% vs greater than 8.5%).

Results:

Primary End Point(s):

• Change from baseline in HbA_1c at 40 weeks for tirzepatide 10 and 15 mg versus semaglutide: Least squares mean (LSM) change was −2.24% for tirzepatide 10 mg and −2.3% for tirzepatide 15 mg versus −1.86% with semaglutide. Mean treatment differences versus semaglutide were −0.39% (95% CI, −0.51% to −0.26%; P < .001) with tirzepatide 10 mg and −0.45% (95% CI, −0.57% to −0.32%; P < .001) with tirzepatide 15 mg.

Secondary End Point(s):

• Change from baseline in HbA_1c at 40 weeks for tirzepatide 5 mg versus semaglutide: LSM change was −2.01% versus −1.86% with semaglutide. Mean treatment difference was −0.15% (95% CI, −0.28% to −0.03%; P = .02); odds ratio (OR) was −0.23 (95% CI, −0.36 to −0.1; P < .001).

• Change from baseline in body weight at 40 weeks was dose dependent with tirzepatide: LSM change was −7.6, −9.3, and −11.2 kg with tirzepatide 5, 10, and 15 mg, respectively, compared with −5.7 kg with semaglutide. Treatment difference versus semaglutide was −1.9 kg (95% CI, −2.8 to −1) with tirzepatide 5 mg, −3.6 kg (95% CI, −4.5 to −2.7) with tirzepatide 10 mg, and −5.5 kg (95% CI, −6.4 to −4.6) with tirzepatide 15 mg.

• Percentage of patients achieving HbA_1c target value at 40 weeks:

  • Target value less than 7%: 82% to 86% of patients receiving tirzepatide versus 79% receiving semaglutide; OR was 1.54 (95% CI, 1.06-2.23) for tirzepatide 5 mg (P = .023), 2.14 (95% CI, 1.44-3.17) for tirzepatide 10 mg (P < .001), and 3.03 (95% CI, 1.97-4.66) for tirzepatide 15 mg (P < .001).
  • Target value less than 5.7%: 27% to 46% of patients receiving tirzepatide versus 19% receiving semaglutide; OR was 1.86 (95% CI, 1.35-2.57) for tirzepatide 5 mg, 3.94 (95% CI, 2.88-5.39) for tirzepatide 10 mg (P < .001), and 5.1 (95% CI, 3.73-6.97) for tirzepatide 15 mg (P < .001).

Other End Point(s):

• Percentage of patients achieving HbA_1c target value less than or equal to 6.5% at 40 weeks: 69% to 80% of patients receiving tirzepatide versus 64% receiving semaglutide; OR was 1.63 (95% CI, 1.2-2.21) for tirzepatide 5 mg, 2.75 (95% CI, 1.98-3.82) for tirzepatide 10 mg, and 3.95 (95% CI, 2.78-5.61) for tirzepatide 15 mg.

• Percentage of patients who achieved weight loss 5% or greater, 10% or greater, and 15% or greater at 40 weeks:

  • At least 5% weight loss: 65% to 80% of patients receiving tirzepatide and 54% receiving semaglutide; OR was 1.58 (95% CI, 1.2-2.08) for tirzepatide 5 mg, 3.49 (95% CI, 2.57-4.75) for tirzepatide 10 mg, and 4.6 (95% CI, 3.32-6.38) for tirzepatide 15 mg.
  • At least 10% weight loss: 34% to 57% of patients receiving tirzepatide versus 24% receiving semaglutide; OR was 1.68 (95% CI, 1.26-2.25) for tirzepatide 5 mg, 3.58 (95% CI, 2.69-4.77) for tirzepatide 10 mg, and 5.85 (95% CI, 4.37-7.82) for tirzepatide 15 mg.
  • At least 15% weight loss: 15% to 36% with tirzepatide versus 8% with semaglutide; OR was 1.92 (95% CI, 1.27-2.9) for tirzepatide 5 mg, 4.27 (95% CI, 2.9-6.29) for tirzepatide 10 mg, and 7.44 (95% CI, 5.09-10.87) for tirzepatide 15 mg.

• Change from baseline in fasting serum glucose at 40 weeks: Greater reductions were observed with all tirzepatide groups versus semaglutide.

• Mean change from baseline in daily 2-hour 7-point self-monitored blood glucose (SMBG) values: Reductions were greater in the tirzepatide groups versus semaglutide.

• Mean changes from baseline in BMI and waist circumference at 40 weeks were greater in the tirzepatide groups than with semaglutide.

• Mean change from baseline in lipid levels at 40 weeks: Greater improvements were observed in patients receiving tirzepatide than semaglutide for triglycerides, very low-density lipoprotein, and high-density lipoprotein levels. Total cholesterol and low-density lipoprotein levels were not significantly different between groups.

• Change in updated homeostasis model assessment-insulin resistance (HOMA2-IR) values from baseline: −0.31 for tirzepatide 5 mg, −0.39 for tirzepatide 10 mg, −0.48 for tirzepatide 15 mg, and −0.1 for semaglutide.

• Change in fasting glucagon (pmol/L × mmol/L) levels from baseline: −49.5 for tirzepatide 5 mg, −53.8 for tirzepatide 10 mg, −56.1 for tirzepatide 15 mg, and −48.5 for semaglutide.

• Proportion of patients achieving composite end point of HbA_1c of 6.5% or less with at least 10% weight loss and without clinically significant hypoglycemia or severe hypoglycemia events: 32% to 60% with tirzepatide versus 22% with semaglutide; OR was 1.76 (95% CI, 1.3-2.39) for tirzepatide 5 mg, 4.12 (95% CI, 3.06-5.55) for tirzepatide 10 mg, and 5.97 (95% CI, 4.43-8.06) for tirzepatide 15 mg.

• Mean change from baseline in pulse rate at 40 weeks: Mean pulse rate increased by 2.3, 2.2, and 2.6 beats per minute (bpm) with tirzepatide 5, 10, and 15 mg, respectively, compared to an increase of 2.5 bpm with semaglutide. Systolic and diastolic blood pressure decreased with tirzepatide (−4.8 and −1.9 mmHg, respectively, with 5 mg; −5.3 and −2.5 mmHg with 10 mg; and −6.5 and −2.9 mmHg with 15 mg) compared with semaglutide (−3.6 and −1 mmHg, respectively).

• Incidence of hypoglycemia events (blood glucose less than 54 mg/dL) was 0.2% to 1.7% in patients receiving tirzepatide and 0.4% in those receiving semaglutide. Severe hypoglycemia occurred in 2 patients receiving tirzepatide (1 each in 5 and 15 mg groups).

• Rescue antihyperglycemic therapy was required in 1.3% to 1.5% of patients receiving tirzepatide versus 2.8% receiving semaglutide.

Comments: The study was conducted across 128 sites in the United States, Argentina, Australia, Brazil, Canada, Israel, Mexico, and the United Kingdom. Efficacy and safety analyses were conducted in the modified intention-to-treat (mITT) population (all patients who underwent randomization and received at least 1 dose of study drug). The study was designed to provide at least 90% power to show noninferiority of tirzepatide at a dose of 10 mg or 15 mg compared with semaglutide at a dose of 1 mg with respect to change from baseline in HbA_1c level at 40 weeks, with a margin of 0.3%. If inferiority was demonstrated, then the outcomes were evaluated for superiority. Study results met noninferiority and were then evaluated for superiority.

All 3 tirzepatide doses were noninferior and superior to semaglutide for reduction in HbA_1c. Superiority of tirzepatide for body weight reduction was also demonstrated. Weight reduction was reported to double for patients receiving tirzepatide 15 mg versus semaglutide 1 mg, and results did not plateau at 40 weeks. Secondary end points showed trending toward improvement, and longer trials will allow for conclusions to be applied. Compared with approved GLP-1 receptor agonists, the improvements in lipid profile, blood pressure, and liver enzymes observed with tirzepatide suggest the benefits of dual agonism can lead to long-term clinical advantages.

Limitations: The study was of open-label design; treatment could not be blinded due to difference between the device and dose-escalation schematics. The trial duration was short, and the majority of patients were White.

Drug: Tirzepatide vs Insulin Degludec

Reference: Ludvik B, et al, 2021 (SURPASS-3 trial)^8,23,29

Study Design: Phase 3, randomized, open-label, parallel-group, active-controlled, multicenter study

Study Funding: Eli Lilly and Company

Patients: 1444 adult patients (at least 18 years of age) with type 2 diabetes mellitus inadequately controlled on stable metformin treatment alone or in combination with an SGLT2 inhibitor for at least 3 months before screening. Patients were insulin naive and had HbA_1c between 7% and 10.5%, BMI of at least 25 kg/m², and a stable weight (ie, no change beyond 5% for at least 3 months before screening). Key exclusion criteria included diagnosis of type 1 diabetes; history of pancreatitis; proliferative diabetic retinopathy or maculopathy or nonproliferative diabetic retinopathy requiring acute treatment; and an eGFR less than 45 mL/minute/1.73 m². Mean patient age was 57.4 years; 44% were women; 91% were White, 5% were Asian, and 3% were Black or African American; mean HbA_1c was 8.17%; body weight was 94.3 kg; BMI was 33.5 kg/m²; and eGFR was 94.1 mL/minute/1.73 m². At randomization, 68% were receiving metformin alone and 32% were receiving metformin plus an SGLT2 inhibitor.

Intervention: Patients were randomized (1:1:1:1) to receive tirzepatide 5, 10, or 15 mg administered subcutaneously once a week (using a single-dose pen) or insulin degludec administered subcutaneously once daily for 52 weeks, followed by a 4-week safety follow-up period. Tirzepatide was initiated at 2.5 mg once weekly and incrementally increased by 2.5 mg every 4 weeks until maintenance dose was achieved. Insulin degludec was initiated at a dose of 10 units/day and was titrated weekly to a fasting blood glucose level below 90 mg/dL, following a treat-to-target algorithm based on median value of last 3 SMBG values. Patients were stratified based on country, baseline HbA_1c (less than or equal to 8.5% vs greater than 8.5%), and current use of concomitant oral antihyperglycemic medication (metformin alone or metformin plus an SGLT2 inhibitor).

Results:

Primary End Point(s):

• Mean change in HbA_1c from baseline to week 52: −1.93% with tirzepatide 5 mg, −2.2% with tirzepatide 10 mg, −2.37% with tirzepatide 15 mg, and −1.34% with insulin degludec. The estimand treatment difference versus insulin degludec was −0.59% (95% CI, −0.73% to −0.45%) with tirzepatide 5 mg, −0.86% (95% CI, −1% to −0.72%) with tirzepatide 10 mg, and −1.04% (95% CI, −1.17% to −0.9%) with tirzepatide 15 mg. The upper limit of the CI for all tirzepatide doses was less than 0.3, thus meeting criteria for noninferiority. All tirzepatide doses also met criteria for superiority compared to insulin degludec (P < .001).

Secondary End Point(s):

• Percentage of patients achieving HbA_1c target value at week 52:

  • Target value less than 7%: 82% with tirzepatide 5 mg, 90% with tirzepatide 10 mg, 93% with tirzepatide 15 mg, and 61% with insulin degludec; OR was 3.45 (95% CI, 2.38-5.01) for tirzepatide 5 mg, 7.02 (95% CI, 4.55-10.84) for tirzepatide 10 mg, and 10.79 (95% CI, 6.65-17.48) for tirzepatide 15 mg (P < .001 for all vs insulin degludec).
  • Target value less than or equal to 6.5%: 71% with tirzepatide 5 mg, 80% with tirzepatide 10 mg, 85% with tirzepatide 15 mg, and 44% with insulin degludec; OR was 3.62 (95% CI, 2.59-5.06) for tirzepatide 5 mg, 6.36 (95% CI, 4.42-9.14) for tirzepatide 10 mg, and 9.59 (95% CI, 6.48-14.19) for tirzepatide 15 mg (P < .001 for all vs insulin degludec).
  • Target value less than 5.7%: 26% with tirzepatide 5 mg, 39% with tirzepatide 10 mg, 48% with tirzepatide 15 mg, and 5% with insulin degludec; OR was 7.11 (95% CI, 4.17-12.12) for tirzepatide 5 mg, 14.14 (95% CI, 8.34-23.96) for tirzepatide 10 mg, and 22.09 (95% CI, 13.02-37.47) for tirzepatide 15 mg (P < .001 for all vs insulin degludec).

• Change in body weight from baseline to week 52 was −7.5 kg with tirzepatide 5 mg, −10.7 kg with tirzepatide 10 mg, −12.9 kg with tirzepatide 15 mg, and 2.3 kg with insulin degludec. The estimand treatment difference versus insulin degludec was −9.8 kg (95% CI, −10.8 to −8.8) with tirzepatide 5 mg, −13 kg (95% CI, −14 to −11.9) with tirzepatide 10 mg, and −15.2 kg (95% CI, −16.2 to −14.2) with tirzepatide 15 mg (P < .001 for all).

• Proportion of patients achieving body weight loss targets at week 52:

  • 5% or greater weight loss: 66% of patients receiving tirzepatide 5 mg, 84% with tirzepatide 10 mg, 88% with tirzepatide 15 mg, and 6% with insulin degludec; OR was 29.78 (95% CI, 18.35-48.35) for tirzepatide 5 mg, 79.88 (95% CI, 47.56-134.17) for tirzepatide 10 mg, and 110.77 (95% CI, 64.73-189.55) for tirzepatide 15 mg (P < .001 for all vs insulin degludec).
  • 10% or greater weight loss: 37% of patients receiving tirzepatide 5 mg, 56% with tirzepatide 10 mg, 69% with tirzepatide 15 mg, and 3% with insulin degludec; OR was 20.61 (95% CI, 10.77-39.44) for tirzepatide 5 mg, 44.67 (95% CI, 23.34-85.51) for tirzepatide 10 mg, and 82.26 (95% CI, 42.7-158.48) for tirzepatide 15 mg (P < .001 for all vs insulin degludec).
  • 15% or greater weight loss: 13% with tirzepatide 5 mg, 28% with tirzepatide 10 mg, 43% with tirzepatide 15 mg, and 0% with insulin degludec; OR was 104.5 (95% CI, 6.73-1622.53) for tirzepatide 5 mg, 293.07 (95% CI, 19.02-4515.65) for tirzepatide 10 mg, and 564.49 (95% CI, 36.68-8686.39) for tirzepatide 15 mg (P < .001 for all vs insulin degludec).
• Incidence of hypoglycemic episodes:

  • Blood glucose less than 54 mg/dL: 1% with tirzepatide 5 mg, 1% with tirzepatide 10 mg, 2% with tirzepatide 15 mg, and 7% with insulin degludec.
  • Blood glucose 70 mg/dL or less: 8% with tirzepatide 5 mg, 14% with tirzepatide 10 mg, 14% with tirzepatide 15 mg, and 48% with insulin degludec.

Comments: The study was conducted at 122 sites in Argentina, Austria, Greece, Hungary, Italy, Poland, Puerto Pico, Republic of Korea, Romania, Spain, Taiwan, Ukraine, and the United States. Of the 1444 patients enrolled, 1437 received at least 1 dose of the study drug (mITT population), 1325 (92%) completed the study (whether or not they remained on treatment), and 1230 (85%) completed the study and treatment. The study was powered to assess both noninferiority and superiority of all doses of tirzepatide versus insulin degludec. The noninferiority margin was set at 0.3% difference for change from baseline in HbA_1c between tirzepatide and insulin degludec; the sample size calculation assumed at least a −0.35% difference for superiority. Primary and secondary end point results were obtained from the efficacy estimand, which was used for the treatment effect prior to discontinuation of study drug or initiation of rescue therapy for persistent hyperglycemia. The efficacy estimand evaluated the treatment effect between tirzepatide and insulin degludec among all randomized patients who continued to receive the study drug without rescue medication. The treatment-regimen estimand evaluated the treatment effect among all patients, including the effect of any additional antihyperglycemic medication, for all randomized patients regardless of premature study drug discontinuation and use of rescue medication. The mITT cohort was used for each estimand.

The results from 2 substudies (SURPASS-3 CGM and SURPASS-3 MRI) of SURPASS-3 have been published. In SURPASS-3 CGM, tirzepatide produced better glycemic control, based on continuous glucose monitoring, than insulin degludec. ³⁰ SURPASS-3 MRI showed a reduction in liver fat content, volume of visceral adipose tissue, and abdominal subcutaneous adipose tissue with tirzepatide compared to insulin degludec. ³¹

Limitations: The open-label design may have influenced study results, especially the incidence and severity of adverse reactions. The lack of ethnic diversity of the study population will influence application of these results to other patient populations.

Drug: Tirzepatide vs Insulin Glargine

Reference: Del Prato S, et al, 2021 (SURPASS-4 trial)^22,32,33

Study Design: Phase 3, randomized, open-label, parallel-group, active-controlled, multicenter, efficacy and safety study

Study Funding: Eli Lilly and Company

Patients: 2002 adult patients (18 years and older) with inadequately controlled type 2 diabetes mellitus with increased cardiovascular risk (coronary, peripheral arterial, or cerebrovascular disease; or 50 years or older with either a history of chronic kidney disease and an estimated glomerular filtration rate [eGFR] of less than 60 mL/minute/1.73 m² or history of congestive heart failure [New York Heart Association class II or III]). Patients had HbA_1c between 7.5% and 10.5%, BMI of at least 25 kg/m², a stable weight (ie, no change beyond 5%), and were on a stable treatment with 1 to 3 types of oral antihyperglycemic drugs (metformin, SGLT2 inhibitors, and/or sulfonylureas at an unchanged dose for at least 3 months before screening). Exclusion criteria were diagnosis of type 1 diabetes; chronic or acute pancreatitis at any time prior to trial; proliferative diabetic retinopathy or maculopathy or nonproliferative diabetic retinopathy requiring immediate or urgent treatment; slowed gastric emptying disorders or stomach surgery for weight loss; acute or chronic hepatitis; MI/stroke/hospitalization for CHF in past 2 months; personal or family history of MTC or personal history of MEN2; and use of any other diabetes medication (other than those listed in inclusion criteria) or weight loss drugs (including over-the-counter medications) in prior 3 months. Mean patient age was 63.6 years; 62% were male; 82% were White; median duration of diabetes was 10.5 years; mean HbA_1c was 8.52%; mean weight was 90.3 kg; and more than 85% had a history of cardiovascular events.

Intervention: Patients were randomized (1:1:1:3) to receive tirzepatide 5, 10, or 15 mg administered subcutaneously once weekly or insulin glargine subcutaneously once daily for at least 52 weeks, with treatment continued for a maximum of 104 weeks. Stratification was based on country, baseline HbA_1c (8.5% or less vs more than 8.5% [69 mmol/mol]), and baseline SGLT2 inhibitor use. Tirzepatide was initiated at 2.5 mg once weekly and increased by 2.5 mg every 4 weeks until maintenance dose was achieved. Insulin glargine was initiated at 10 units/day and titrated up using a treat-to-target algorithm to target blood glucose less than 100 mg/dL; mean insulin glargine dose at 52 weeks was 43 units/day. Any background glucose-lowering medications were continued throughout the study; the dose could be reduced or the glucose-lowering drug discontinued if hypoglycemia occurred. Additional glucose-lowering medications (except for GLP-1 receptor agonists, dipeptidyl peptidase-4 [DPP-4] inhibitors, or pramlintide) could be used as rescue therapy for persistent hyperglycemia.

Results:

Primary End Point(s):

• Change in HbA_1c from baseline to week 52: −2.24% with tirzepatide 5 mg, −2.43% with tirzepatide 10 mg, −2.58% with tirzepatide 15 mg, and −1.44% with insulin glargine. Treatment difference from insulin glargine was −0.8% (95% CI, −0.92% to −0.68%; P < .001) with tirzepatide 5 mg, −0.99% (95% CI, −1.11% to −0.87%; P < .001) with tirzepatide 10 mg, and −1.14% (95% CI, −1.26% to −1.02%; P < .001) with tirzepatide 15 mg. The P-value is applicable to both noninferiority and superiority.

Secondary End Point(s):

• Change in body weight from baseline to week 52: −7.1 kg with tirzepatide 5 mg, −9.5 kg with tirzepatide 10 mg, −11.7 kg with tirzepatide 15 mg, and +1.9 kg with insulin glargine. The treatment difference from insulin glargine was −9 kg (95% CI, −9.8 to −8.3; P < .01) with tirzepatide 5 mg, −11.4 kg (95% CI, −12.1 to −10.6; P < .001) with tirzepatide 10 mg, and −13.5 kg (95% CI, −14.3 to −12.8; P < .001) with tirzepatide 15 mg.

• Percentage of patients achieving HbA_1c less than 7% at 52 weeks: 81% with tirzepatide 5 mg, 88% with tirzepatide 10 mg, 91% with tirzepatide 15 mg, and 51% with insulin glargine. The OR versus insulin glargine was 4.78 (95% CI, 3.47-6.58; P < .001) with tirzepatide 5 mg, 9.23 (95% CI, 6.31-13.49; P < .001) with tirzepatide 10 mg, and 11.87 (95% CI, 7.88-17.89; P < .001) with tirzepatide 15 mg.

• Percentage of patients achieving HbA_1c less than 6.5% at 52 weeks: 66% with tirzepatide 5 mg, 76% with tirzepatide 10 mg, 81% with tirzepatide 15 mg, and 32% with insulin glargine. The OR versus insulin glargine was 4.86 (95% CI, 3.66-6.45; P < .001) with tirzepatide 5 mg, 8.93 (95% CI, 6.53-12.21; P < .001) with tirzepatide 10 mg, and 11.84 (95% CI, 8.52-16.45; P < .001) with tirzepatide 15 mg.

• Percentage of patients achieving HbA_1c less than 5.7% at 52 weeks: 23% with tirzepatide 5 mg, 33% with tirzepatide 10 mg, 43% with tirzepatide 15 mg, and 3% with insulin glargine. The OR versus insulin glargine was 9.57 (95% CI, 6.16-14.86; P < .001) with tirzepatide 5 mg, 17.11 (95% CI, 11.12-26.35; P < .001) with tirzepatide 10 mg, and 26.53 (95% CI, 17.35-40.56; P < .001) with tirzepatide 15 mg.

• Percentage of patients achieving body weight loss of 5% or more at 52 weeks: 63% with tirzepatide 5 mg, 78% with tirzepatide 10 mg, 85% with tirzepatide 15 mg, and 8% with insulin glargine. The OR versus insulin glargine was 21.42 (95% CI, 15.35-29.89; P < .001) with tirzepatide 5 mg, 46.14 (95% CI, 32.05-66.42; P < .001) with tirzepatide 10 mg, and 76.93 (95% CI, 51.76-114.35; P < .001) with tirzepatide 15 mg.

• Percentage of patients achieving body weight loss of 10% or more at 52 weeks: 36% with tirzepatide 5 mg, 53% with tirzepatide 10 mg, 66% with tirzepatide 15 mg, and 2% with insulin glargine. The OR versus insulin glargine was 35.61 (95% CI, 20.61-61.55; P < .001) with tirzepatide 5 mg, 76.79 (95% CI, 44.42-132.75; P < .001) with tirzepatide 10 mg, and 127.51 (95% CI, 73.52-221.14; P < .001) with tirzepatide 15 mg.

• Percentage of patients achieving body weight loss of 15% or more at 52 weeks: 14% with tirzepatide 5 mg, 24% with tirzepatide 10 mg, 37% with tirzepatide 15 mg, and less than 1% with insulin glargine. The OR versus insulin glargine was 28.58 (95% CI, 11.88-68.75; P < .001) with tirzepatide 5 mg, 59.14 (95% CI, 25.01-139.86; P < .001) with tirzepatide 10 mg, and 105.74 (95% CI, 45.11-247.87; P < .001) with tirzepatide 15 mg.

• Incidence of hypoglycemia (less than 54 mg/dL) at 52 weeks: 9%, 6%, and 8% for tirzepatide 5, 10, and 15 mg, respectively, and 19% with insulin glargine. Hypoglycemia events were reported more often in patients who were also being treated with a sulfonylurea.

• The hazard ratio for major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina) was 0.74 (95% CI, 0.51-1.08).

Comments: The study was conducted at 187 sites in Argentina, Australia, Brazil, Canada, Greece, Israel, Mexico, Poland, Romania, Russia, Slovakia, Spain, Taiwan, and the United States. The primary efficacy assessment was conducted at week 52, but many participants continued treatment beyond 52 weeks (some for up to 2 years). Study completion was driven by the accrual of major adverse cardiovascular events in order to meet the regulatory submission requirements for evaluating cardiovascular risk for type 2 diabetes therapies, a key focus of the study. Primary and secondary end point results were obtained from the efficacy estimand, which was used for the treatment effect prior to discontinuation of study drug or initiation of rescue therapy for persistent hyperglycemia.

Limitations: The open-label design may have influenced study results, especially the incidence and severity of adverse reactions. The duration may not be sufficient to assess cardiovascular protective effects.

Drug: Tirzepatide vs Placebo

Reference: Rosenstock J, et al, 2021 (SURPASS-1 trial)^7,15,34

Study Design: Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study

Study Funding: Eli Lilly and Company

Patients: 478 adult patients (at least 18 years of age) with type 2 diabetes mellitus inadequately controlled with diet and exercise. Patients were naive to injectable diabetes therapy and had HbA_1c between 7% and 9.5%, BMI of 23 kg/m² or greater, and a stable weight (no change beyond ±5% for at least 3 months prior to enrollment). Exclusion criteria included type 1 diabetes diagnosis; chronic or acute pancreatitis at any time prior to study; proliferative diabetic retinopathy or maculopathy or nonproliferative diabetic retinopathy requiring acute treatment; any disorders of slowed gastric emptying or stomach surgery for weight loss; eGFR less than 30 mL/minute/1.73 m²; MI/stroke/hospitalization due to CHF in prior 2 months; personal or family history of MTC or personal history of MEN2; or use of weight loss medications (including over-the-counter) or of oral antihyperglycemic medication during the previous 3 months. Mean patient age was 54.1 years; 48% of patients were female; 36% were White, 35% were Asian, 25% were American Indian/Alaska Native, and 5% were Black/African American; 43% were Hispanic or Latino, 38% were not Hispanic/Latino, and ethnicity was not reported for 18%. Baseline average HbA_1c was 7.94%, BMI was 31.9 kg/m², and duration of type 2 diabetes was 4.7 years. A total of 46% of patients had previously used oral antihyperglycemic medications, with use distributed similarly among groups.

Intervention: Patients were randomly assigned (1:1:1:1) to receive tirzepatide 5, 10, or 15 mg or placebo once weekly via subcutaneous injection using a single-dose pen for 40 weeks, followed by a 4-week safety follow-up period. To decrease the risk of GI adverse reactions, the study used a slow dose escalation regimen fixed at 2.5 mg dose increments every 4 weeks until assigned maintenance dose of 5, 10, or 15 mg was reached in each group (at 4, 12, and 20 weeks, respectively). Patients were stratified based on country, baseline HbA_1c (less than or equal to 8.5% vs greater than 8.5%), and previous use of any oral antihyperglycemic medications (yes or no). If glucose control was inadequate or permanent discontinuation of study drug was required, a new antihyperglycemic drug could be added under the rescue protocol.

Results:

Primary End Point(s):

• Mean change from baseline in HbA_1c at 40 weeks: LSM change was −1.87% with tirzepatide 5 mg, −1.89% with tirzepatide 10 mg, and −2.07% with tirzepatide 15 mg versus +0.04% with placebo. These changes were noted at the first assessment at week 4. Mean treatment differences versus placebo were −1.91% (95% CI, −2.18% to −1.63%) with tirzepatide 5 mg, −1.93% (95% CI, −2.21% to −1.65%) with tirzepatide 10 mg, and −2.11% (95% CI, −2.39% to −1.83%) with tirzepatide 15 mg (all P < .001).

Secondary End Point(s):

• Mean change from baseline in fasting serum glucose at 40 weeks: LSM change was −43.6 mg/dL with tirzepatide 5 mg, −45.9 mg/dL with tirzepatide 10 mg, and −49.3 mg/dL with tirzepatide 15 mg versus +12.9 mg/dL with placebo. Mean treatment differences versus placebo were −56.5 mg/dL (95% CI, −66.8 to −46.1) with tirzepatide 5 mg, −58.8 mg/dL (95% CI, −69.2 to −48.4) with tirzepatide 10 mg, and −62.1 mg/dL (95% CI, −72.7 to −51.5) with tirzepatide 15 mg (all P < .001).

• Proportion of patients reaching HbA_1c target values at 40 weeks:

  • Target value less than 7%: 87% to 92% of patients receiving tirzepatide versus 19% with placebo; OR was 49 (21.1-113.7) for 5 mg, 80.4 (31.8-203.2) for 10 mg, and 52.9 (22.3-125.7) for 15 mg (all P < .001).
  • Target value less than or equal to 6.5%: 81% to 86% of patients receiving tirzepatide versus 10% with placebo; OR was 74.8 (30.6-183) for 5 mg, 69.1 (28.5-167.6) for 10 mg, and 105.8 (41.3-271.4) for 15 mg (all P < .001).
  • Target value less than 5.7%: 31% to 52% of patients receiving tirzepatide versus 1% with placebo; OR was 40.3 (7.7-209.7) for 5 mg, 34.1 (6.5-178.2) for 10 mg, and 85.1 (16.4-443.1) for 15 mg (all P < .001).

• Mean change from baseline in body weight at 40 weeks: LSM change was −7 kg with tirzepatide 5 mg, −7.8 kg with tirzepatide 10 mg, and −9.5 kg with tirzepatide 15 mg versus −0.7 kg with placebo. Mean treatment differences versus placebo were −6.3 kg (95% CI, −7.8 to −4.7) for tirzepatide 5 mg, −7.1 kg (95% CI, −8.6 to −5.5) for tirzepatide 10 mg, and −8.8 kg (95% CI, −10.3 to −7.2) for tirzepatide 15 mg (all P < .001). This weight reduction was seen at the 4-week assessment point and had not plateaued by week 40, indicating a progressive and dose-dependent effect.

Other End Point(s):

• Proportion of patients reaching 5% or greater, 10% or greater, and 15% or greater weight loss at 40 weeks was higher in all tirzepatide groups versus placebo:

  • At least 5% weight loss: OR was 12.4 (95% CI, 6.4-23.9) for 5 mg, 21.1 (95% CI, 10.6-42.2) for 10 mg, and 20.1 (95% CI, 10.1-40) for 15 mg (P < .001 for all vs placebo).
  • At least 10% weight loss: OR was 34.9 (95% CI, 6.8-180.5) for 5 mg, 50.6 (95% CI, 9.8-260.4) for 10 mg, and 71.5 (95% CI, 13.9-368.4) for 15 mg (P < .001 for all vs placebo).
  • At least 15% weight loss: OR was 35.6 (95% CI, 2.2-565.3; P = .011) for 5 mg, 46.5 (95% CI, 3-733.2; P = .0063) for 10 mg, and 83.6 (95% CI, 5.4 to greater than 999; P = .0016) for 15 mg.

• Mean 7-point SMBG profiles at 40 weeks showed significant lowering of daily, premeal, and 2-hour postmeal glucose values with tirzepatide versus placebo (P < .001).

• Most common treatment-emergent adverse events were mild to moderate and included nausea (12% for tirzepatide 5 mg, 13% for tirzepatide 10 mg, and 18% for tirzepatide 15 mg versus 6% with placebo), diarrhea (12%, 14%, 12%, and 8%, respectively), and vomiting (3%, 2%, 6%, and 2%, respectively). Most cases of adverse events decreased over time.

• Incidence of adverse events leading to study drug discontinuation was highest in the tirzepatide 15 mg group.

• Allergic and hypersensitivity reactions occurred in 1% to 2% of tirzepatide patients and 1% of placebo patients; none of the participants who showed treatment-emergent antidrug antibody positivity had severe or serious hypersensitivity or injection-site reactions (data not given).

• Mean changes from baseline in pulse rate at 40 weeks: Increases of 1 to 2 bpm were observed with tirzepatide.

• Mean change from baseline in blood pressure at 40 weeks: A decrease in systolic blood pressure ranging from −4.7 to −5.2 mmHg occurred with tirzepatide versus −2 mmHg with placebo (difference from placebo was significant for tirzepatide 10 mg); decreases in diastolic blood pressure did not differ between tirzepatide and placebo groups.

• Hypoglycemia events (blood glucose less than 70 mg/dL) were reported in 6% of patients receiving tirzepatide 5 mg and in 7% of the tirzepatide 10 and 15 mg groups versus 1% receiving placebo. Severe hypoglycemia or clinically significant hypoglycemia (less than 54 mg/dL) was not reported by any patients receiving tirzepatide.

Comments: The study was conducted across 52 medical centers in India (15%), Japan (19%), Mexico (34%), and the United States (32%). Efficacy analyses were conducted in the mITT population (defined as all randomly assigned patients who received at least 1 dose of study drug). Improvements in HbA_1c and reduction in body weight were shown for all 3 tirzepatide doses versus placebo. Prior exposure to oral antihyperglycemic medications did not affect the observed changes in HbA_1c. Changes in HbA_1c were evident by the first assessment and plateaued around week 20, but weight loss continued through the entire 40-week study timeframe. Secondary end points showed trends toward improvement, and longer trials will allow for conclusions to be applied. Rescue therapy for persistent hyperglycemia was required in 8 patients in tirzepatide cohorts, with metformin being the most common antihyperglycemic medication used as rescue therapy.

This study confirmed results of the previously published 26-week phase 2, randomized, dose-ranging, placebo-controlled study. ³⁵

Limitations: The SURPASS-1 trial was of short duration, with no active comparator group; adverse events were self-reported, and the plateau effect observed for HbA_1c reductions was possibly due to dose-response limitations.

Reference: Dahl D, et al, 2022 (SURPASS-5 trial)^24,29,36

Study Design: Phase 3, randomized, double-blind, parallel-group, placebo-controlled, multicenter study

Study Funding: Eli Lilly and Company

Patients: 475 adult patients (at least 18 years of age) with type 2 diabetes mellitus inadequately controlled on insulin glargine (U100) with or without metformin. Patients had HbA_1c 7% to 10.5%, BMI at least 23 kg/m², and a stable weight (ie, no change beyond 5% for at least 3 months before screening), and had been receiving insulin glargine (greater than 20 units/day or greater than 0.25 units/kg/day) once daily with or without metformin (1500 mg/day or greater) for at least 3 months prior to study. Exclusion criteria were a diagnosis of type 1 diabetes; chronic or acute pancreatitis at any time prior to trial; proliferative diabetic retinopathy or maculopathy or nonproliferative diabetic retinopathy requiring acute treatment; slowed gastric emptying disorders or stomach surgery for weight loss; an eGFR less than 30 mL/minute/1.73 m²; MI/stroke/hospitalization for CHF in past 2 months; personal or family history of MTC or personal history of MEN2; and use of weight loss drugs (including over-the-counter medications) in the prior 3 months. Mean patient age was 61 years; duration of diabetes was 13.3 years; HbA_1c was 8.31%; BMI was 33.4 kg/m²; body weight was 95.2 kg; median insulin glargine dose was 30 units/day; and 82.9% were receiving metformin.

Intervention: Patients were randomized (1:1:1:1) to receive tirzepatide 5, 10, or 15 mg or placebo subcutaneously once a week in addition to existing therapy (basal insulin glargine with or without metformin) for 40 weeks. Tirzepatide was initiated at 2.5 mg and increased by 2.5 mg every 4 weeks until the assigned maintenance dose was achieved. If the patient was receiving metformin prior to enrollment, it was continued at the same dose and formulation for the entire study. Rescue therapy for inadequate glucose control was allowed; however, other basal insulin, GLP-1 receptor agonists, DPP-4 inhibitors, and pramlintide were not allowed.

Results:

Primary End Point(s):

• Change in HbA_1c from baseline to week 40: −2.11% with tirzepatide 5 mg, −2.4% with tirzepatide 10 mg, and −2.34% with tirzepatide 15 mg versus −0.86% with placebo. Difference versus placebo was −1.24% (95% CI, −1.48% to −1.01%) for tirzepatide 5 mg, −1.53% (95% CI, −1.77% to −1.3%) for tirzepatide 10 mg, and −1.47% (95% CI, −1.71% to −1.23%) for tirzepatide 15 mg (P < .001 for all).

Secondary End Point(s):

• Percentage of patients achieving HbA_1c target values at week 40:

• Target value less than 7%: 87.3% with tirzepatide 5 mg, 89.6% with tirzepatide 10 mg, and 84.7% with tirzepatide 15 mg versus 34.5% with placebo. The OR versus placebo was 14.7 (95% CI, 7-30.6; P < .001) for tirzepatide 5 mg, 19.5 (95% CI, 9.2-41.3; P < .001) for tirzepatide 10 mg, and 11.5 (95% CI, 5.6-23.3; P < .001) for tirzepatide 15 mg.

• Target value less than or equal to 6.5%: 74.3% with tirzepatide 5 mg, 85.9% with tirzepatide 10 mg, and 79.5% with tirzepatide 15 mg versus 17.3% with placebo. The OR versus placebo was 13.7 (95% CI, 7.1-26.2; P < .001) for tirzepatide 5 mg, 29.5 (95% CI, 14.4-60.6; P < .001) for tirzepatide 10 mg, and 18.5 (95% CI, 9.3-36.6; P < .001) for tirzepatide 15 mg.

• Target value less than 5.7%: 24.4% with tirzepatide 5 mg, 41.6% with tirzepatide 10 mg, and 49.6% with tirzepatide 15 mg versus 2.7% with placebo. The OR versus placebo was 10.4 (95% CI, 3.3-32.1; P < .001) for tirzepatide 5 mg, 22.8 (95% CI, 7.5-69.5; P < .001) for tirzepatide 10 mg, and 30.7 (95% CI, 10.1-93.6; P < .001) for tirzepatide 15 mg.

• Change in body weight from baseline to week 40: −5.4 kg with tirzepatide 5 mg, −7.5 kg with tirzepatide 10 mg, and −8.8 kg with tirzepatide 15 mg versus 1.6 kg with placebo. Difference versus placebo was −7.1 kg (95% CI, −8.7 to −5.4) for tirzepatide 5 mg, −9.1 kg (95% CI, −10.7 to −7.5) for tirzepatide 10 mg, and −10.5 kg (95% CI, −12.1 to −8.8) for tirzepatide 15 mg (P < .001 for all).

• Change in fasting serum glucose from baseline to week 40: −58.2 mg/dL with tirzepatide 5 mg, −64 mg/dL with tirzepatide 10 mg, and −62.6 mg/dL with tirzepatide 15 mg versus −39.2 mg/dL with placebo. Difference versus placebo was −19 mg/dL (95% CI, −26.6 to −11.4) for tirzepatide 5 mg, −24.9 mg/dL (95% CI, −32.3 to −17.4) for tirzepatide 10 mg, and −23.4 (95% CI, −31 to −15.8) for tirzepatide 15 mg (P < .001 for all).

• Percentage of patients who achieved target weight loss at 40 weeks:

  • At least 5% weight loss: 47.9% with tirzepatide 5 mg, 57.9% with tirzepatide 10 mg, and 71.6% with tirzepatide 15 mg versus 6% with placebo. The OR versus placebo was 13.8 (95% CI, 6-31.4; P < .001) with tirzepatide 5 mg, 20.9 (95% CI, 9.2-47.8; P < .001) with tirzepatide 10 mg, and 38.5 (95% CI, 16.5-89.8; P < .001) with tirzepatide 15 mg.
  • At least 10% weight loss: 20.7% with tirzepatide 5 mg, 41.6% with tirzepatide 10 mg, and 40.7% with tirzepatide 15 mg versus 0.8% with placebo. The OR versus placebo was 21.5 (95% CI, 4.2-111.6; P < .001) with tirzepatide 5 mg, 65 (95% CI, 12.7-331.7; P < .001) with tirzepatide 10 mg, and 63.3 (95% CI, 12.4-323.3; P < .001) with tirzepatide 15 mg.
  • At least 15% weight loss: 6.9% with tirzepatide 5 mg, 23.7% with tirzepatide 10 mg, and 22.9% with tirzepatide 15 mg versus 0% with placebo. The OR versus placebo was 18.8 (95% CI, 1.2-298.6; P = .038) with tirzepatide 5 mg, 79.7 (95% CI, 5.3-1203.1; P = .002) with tirzepatide 10 mg, and 78 (95% CI, 5.2-1179.2; P = .002) with tirzepatide 15 mg.

• Change in daily mean insulin glargine dose from baseline to week 40 was 13% in the tirzepatide 5 mg group, 8.1% in the tirzepatide 10 mg group, −11.4% in the tirzepatide 15 mg group, and 75% in the placebo group. Difference versus placebo was −35.4% (95% CI, −46% to −22.8%; P < .001) with tirzepatide 5 mg, −38.2% (95% CI, −48.3% to −26.1%; P < .001) with tirzepatide 10 mg, and −49.3% (95% CI, −57.7% to −39.4%; P < .001) with tirzepatide 15 mg.

Other End Point(s):

• At week 40, all doses of tirzepatide produced improvements from baseline in total cholesterol, low-density lipoprotein cholesterol, very low–density lipoprotein cholesterol, and triglycerides compared to placebo.

• Incidence of hypoglycemia (blood glucose less than 54 mg/dL): 15.5% with tirzepatide 5 mg, 19.3% with tirzepatide 10 mg, and 14.2% with tirzepatide 15 mg versus 12.5% with placebo. Severe hypoglycemia (episodes with severe cognitive impairment requiring the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions) occurred in 0%, 1.6%, 0.8%, and 0%, respectively.

Comments: The study was conducted at 45 sites in the Czech Republic, Germany, Japan, Poland, Puerto Rico, Slovakia, Spain, and the United States. Primary and secondary end point results were obtained from the efficacy estimand, which was used for the treatment effect prior to discontinuation of study drug or initiation of rescue therapy for persistent hyperglycemia. The secondary outcomes were evaluated using hierarchical sequence.

Limitations: Maintenance of blinding may have been compromised because of GI adverse events, body weight loss, and glycemic improvement with little to no changes in insulin dose. Lack of racial diversity is another potential limitation.

Preliminary evidence indicates that tirzepatide improves cardiovascular risk biomarkers in patients with type 2 diabetes mellitus.^32,37,38

Contraindications, Warnings, and Precautions

Contraindications

The contraindications associated with tirzepatide are similar to those associated with other longer-acting GLP-1 receptor agonists (ie, semaglutide, dulaglutide, exenatide ER).^6,9-12 Tirzepatide is contraindicated in patients with a personal or family history of MTC or patients with MEN2, and in patients with prior serious hypersensitivity to the drug or any of its excipients (sodium chloride and sodium phosphate dibasic heptahydrate; hydrochloric acid solution and/or sodium hydroxide solution may also be added to adjust pH). ¹

Warnings and Precautions

The warnings and precautions associated with tirzepatide are similar to those associated with other longer-acting GLP-1 receptor agonists.^1,6,9-12

As with other GLP-1 receptor agonists, the tirzepatide prescribing information includes a boxed warning regarding the risk of medullary thyroid carcinoma. The boxed warning states that tirzepatide caused thyroid C-cell tumors in rats; it is unknown whether tirzepatide causes thyroid C-cell tumors, including MTC, in humans. The boxed warning also refers to the contraindication regarding a personal or family history of MTC and patients with MEN2; patients should be counseled regarding the potential risk of MTC and symptoms of thyroid tumors.^1,6,9-12

The manufacturer is required to conduct a medullary thyroid carcinoma registry-based case series study of at least 15 years’ duration to systematically monitor the annual incidence of MTC in the United States and to identify any increase related to the introduction of tirzepatide to the market. The draft protocol for this study needs to be submitted to the FDA by November 2022, with the final protocol submitted by May 2023. The first interim report is due by March 2024, the study must be completed by June 2039, and the final report is due by June 2040. ³⁹

Acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis, has been associated with GLP-1 receptor agonists. If pancreatitis is suspected (eg, persistent severe abdominal pain, radiating pain to the back, vomiting), tirzepatide should promptly be discontinued, and appropriate management should be initiated. If pancreatitis is confirmed, tirzepatide should not be restarted.^1,6,9-12

In tirzepatide clinical trials (SURPASS-1 and SURPASS-3), an increase from baseline in lipase and pancreatic amylase concentrations was observed in tirzepatide-treated patients, but the values remained in the normal range.^8,15 In SURPASS-2, there were 4 cases of pancreatitis, but none were classified as serious. ²⁹ In SURPASS-3, there were no reports of pancreatitis. ⁸ The tirzepatide product labeling indicates that 14 adjudicated events occurred in 13 tirzepatide-treated patients enrolled in clinical studies. The estimated event rate is 0.23 patients per 100 years of exposure to tirzepatide compared to 0.11 patients per 100 years of exposure with the study comparators. Patients with a history of pancreatitis were excluded from clinical studies; therefore, it is unknown whether patients with a history of pancreatitis are at higher risk of developing pancreatitis when treated with tirzepatide. ¹

Signs and symptoms of hypoglycemia should be monitored. Use of tirzepatide or GLP-1 receptor agonists with an insulin secretagogue or insulin may increase the risk of hypoglycemia, including severe hypoglycemia.^1,6,8-12 If tirzepatide therapy is added to the drug regimen for a patient receiving an insulin secretagogue (eg, sulfonylurea) or insulin, the risk of hypoglycemia may be decreased by lowering the dose of the insulin secretagogue or insulin. ¹

Acute kidney injury is a potential risk with tirzepatide or GLP-1 receptor agonist therapy. GI adverse reactions (eg, nausea, vomiting, diarrhea) may cause dehydration and may worsen renal function. Some acute kidney injury cases with GLP-1 receptor agonists occurred in patients receiving multiple pharmacologic agents, and some events occurred in patients who had experienced nausea, vomiting, or diarrhea with or without dehydration.^1,6,9-12 Monitoring of renal function is advised in patients with renal impairment reporting severe GI adverse reactions, especially during initiation of therapy or after a dosage increase. ¹

Hypersensitivity reactions, including anaphylaxis and angioedema, may occur with GLP-1 receptor agonists and have been reported in patients in tirzepatide clinical studies; some hypersensitivity reactions were severe.^1,6,8-12,29 If a hypersensitivity reaction occurs, tirzepatide should be discontinued, and appropriate medical measures should be implemented. If tirzepatide is prescribed for a patient with a history of angioedema or anaphylaxis with GLP-1 receptor agonist use, it is unknown whether the patient will be predisposed to similar hypersensitivity-type reactions. ¹

The safety of tirzepatide or GLP-1 receptor agonists has not been studied in patients with severe GI disease, including severe gastroparesis. Because these drugs can cause nausea, vomiting, and diarrhea, they are not recommended for patients with severe GI disease.^1,6,11,12

Rapid improvement in glucose control may be associated with a temporary worsening of diabetic retinopathy in patients treated with GLP-1 receptor agonists. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.^1,9-12 Tirzepatide was not studied in patients with nonproliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Therefore, patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy if tirzepatide is added to their drug regimen. ¹

Acute gallbladder disease (eg, cholelithiasis, cholecystitis) has been associated with exenatide therapy and occurred in both treatment groups in SURPASS-2. If cholelithiasis is suspected, appropriate diagnostic studies and clinical follow-up are recommended.^6,28 Acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was reported by 0.6% of tirzepatide-treated patients and 0% of placebo-treated patients in clinical studies. ¹

Development of antidrug antibodies may be possible with tirzepatide and GLP-1 receptor agonists. Patients with a higher tier of drug-related antibodies may have an attenuated HbA_1c response. If worsening of glycemic control occurs, a change in therapy may be necessary.^1,6,8-12

Information on the safety of tirzepatide use in pregnant patients is insufficient to evaluate for drug-related risks of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. However, poorly controlled diabetes during pregnancy is associated with increased maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, and delivery complications; increased fetal risks include major birth defects, stillbirth, and macrosomia-related morbidity. ¹ Caution is recommended if GLP-1 receptor agonist therapy is continued during pregnancy and breastfeeding.^6,9-12

There are no data regarding the presence of tirzepatide in human milk, or its effects on breastfeeding infants or milk production. ¹ The manufacturer is required to conduct a milk-only lactation study in lactating patients who have received a dose of tirzepatide to assess concentrations of tirzepatide in breast milk; the study must be completed by July 2024, and the final report must be submitted by July 2025. ³⁹

Safety and effectiveness of tirzepatide have not been established in pediatric patients (younger than 18 years). ¹ The requirement for studies in children younger than 10 years has been waived because necessary studies are impossible or highly impracticable. The manufacturer is still required to complete a 30-week, randomized, double-blind, placebo-controlled, multicenter, parallel-arm study of the safety and efficacy of tirzepatide for the treatment of type 2 diabetes mellitus in pediatric patients 10 to 17 years of age, followed by a 22-week open-label extension study. This study needs to be completed by December 2027, and the final report needs to be submitted by September 2028. ³⁹

Safety and efficacy in pediatric patients have not been established with other GLP-1 receptor agonists, except for exenatide, which is approved for use in pediatric patients 10 years and older.^6,9-12

No overall differences in safety or efficacy of tirzepatide have been detected between older and younger patients, but greater sensitivity of some older individuals cannot be ruled out. The clinical studies included patients 65 years and older (30.1%) and some patients 75 years and older (4.1%). ¹

See Table 2 for a comparison of the contraindications, warnings, and precautions associated with the use of tirzepatide and select long-acting GLP-1 receptor agonists.^1,6,9-12

Table 2.

Comparison of Contraindications, Warnings, and Precautions Associated with Tirzepatide and Select Long-acting GLP-1 Receptor Agonists.^1,6,9-12

	Tirzepatide	Dulaglutide	Exenatide ER	Semaglutide
Contraindications
Personal or family history of MTC	X	X	X	X
Patients with MEN2	X	X	X	X
Serious hypersensitivity to drug or any of its excipients	X	X	X	X
History of drug-induced immune-mediated thrombocytopenia			X
Warnings and precautions
Risk of thyroid C-cell tumors	X	X	X	X
Pancreatitis	X	X	X	X
Hypoglycemia with concomitant use of insulin secretagogues	X	X	X	X
Hypoglycemia with concomitant use of insulin	X	X	X	X
Hypersensitivity reactions	X	X	X	X
Acute kidney injury	X	X	X	X
Severe GI disease	X	X	X
Diabetic retinopathy complications	X	X		X
Acute gallbladder disease	X		X	X
Injection-site reactions	X a	X a	X	X a
Immunogenicity	X a	X a	X	X a
Drug-induced thrombocytopenia			X

^aNot listed in the Warnings and Precautions section of the prescribing information, but included as a potential adverse reaction.

Adverse Reactions

Adverse reactions reported in 5% or more of patients treated with tirzepatide included nausea, diarrhea, decreased appetite, vomiting, constipation, dyspepsia, and abdominal pain. ¹

In clinical studies, GI-related adverse reactions with tirzepatide, including mild to moderate nausea, vomiting, and diarrhea, tended to be dose dependent and decreased over time.^{1,15,28,35,40}

Animal carcinogenicity studies (6 months in duration) have not shown development of thyroid hyperplasia or neoplasia signals. No reports of MTC occurred in SURPASS-1, SURPASS-2, or SURPASS-3.^{8,15,28,35,40}

Table 3 shows the frequency of commonly reported adverse events from the SURPASS-2 study, which compared tirzepatide and semaglutide. ²⁸ Table 4 shows the frequency of commonly reported adverse events from the SURPASS-3 study, which compared tirzepatide and insulin degludec. ⁸

Table 3.

Comparison of Adverse Events Occurring in Tirzepatide- and Semaglutide-treated Patients with Type 2 Diabetes (SURPASS-2 Trial). ²⁹

	Tirzepatide 5 mg (n = 470) (%)	Tirzepatide 10 mg (n = 469) (%)	Tirzepatide 15 mg (n = 470) (%)	Semaglutide (n = 469) (%)
Any GI adverse events	40	46.1	44.9	41.2
Nausea	17.4	19.2	22.1	17.9
Diarrhea	13.2	16.4	13.8	11.5
Decreased appetite	7.4	7.2	8.9	5.3
Dyspepsia	7.2	6.2	9.1	6.6
Constipation	6.8	4.5	4.5	5.8
Vomiting	5.7	8.5	9.8	8.3
Abdominal pain	3	4.5	5.1	5.1
Injection-site reactions	1.9	2.8	4.5	0.2
Hypersensitivity	1.9	2.8	1.7	2.3
Cholelithiasis	0.9	0.9	0.9	0.4
Hypoglycemia (blood glucose <54 mg/dL)	0.6	0.2	1.7	0.4

Table 4.

Comparison of Adverse Events Occurring in Tirzepatide- and Insulin Degludec-treated Patients with Type 2 Diabetes (SURPASS-3 Trial). ⁸

	Tirzepatide 5 mg (n = 358) (%)	Tirzepatide 10 mg (n = 360) (%)	Tirzepatide 15 mg (n = 359) (%)	Insulin degludec (n = 360) (%)
Nausea	12	23	24	2
Diarrhea	15	17	16	4
Decreased appetite	6	10	12	1
Vomiting	6	9	10	1
Dyspepsia	4	9	5	0
Hypersensitivity	3	3	3	1
Injection-site reactions	<1	2	2	2
Cholelithiasis	1	<1	<1	0
Increased lipase	6	4	6	2
Hypoglycemia (blood glucose ≤70 mg/dL)	8	14	14	48
Hypoglycemia (blood glucose <54 mg/dL)	1	1	2	7

Drug Interactions

Tirzepatide influences weight reduction and may interact with medications used for weight loss.^15,28 Patients taking weight loss medications were excluded from clinical trials. Additionally, GLP-1 receptor agonists, including tirzepatide, delay gastric emptying and may impact absorption of orally administered medications.^1,6,9-12 Tirzepatide may alter C_max and/or efficacy of oral drugs with narrow therapeutic indexes (eg, warfarin); patients taking tirzepatide with these drugs should be monitored. ¹

Females using oral hormonal contraceptives should be encouraged to switch to nonoral contraceptive method(s) or to add a barrier method of contraception for 4 weeks after initiation of tirzepatide therapy and for 4 weeks after each dose escalation. ¹

GLP-1 receptor agonists, including tirzepatide, are associated with an increased risk of hypoglycemia when combined with insulin secretagogues or insulins.^1,6,9-12

Recommended Monitoring

The ADA recommends routine diabetic monitoring of serum glucose and HbA_1c to validate drug efficacy. ⁵

Plasma glucose; GI adverse reactions (eg, nausea, vomiting, diarrhea); kidney function (at baseline and following dose increases in patients with kidney impairment reporting severe GI adverse reactions); signs/symptoms of pancreatitis (eg, persistent severe abdominal pain, which may radiate to the back and that may or may not be accompanied by vomiting); signs/symptoms of gallbladder disease; worsening of diabetic retinopathy (particularly in those with a history of the disease). ¹

Dosing

The recommended starting dosage of tirzepatide is 2.5 mg injected subcutaneously once weekly. After 4 weeks, increase the dosage to 5 mg subcutaneously once weekly. If additional glycemic control is needed, additional tirzepatide dosage adjustments should occur at 4-week intervals in 2.5 mg increments. The maximum recommended dosage is 15 mg subcutaneously once weekly. ¹

Tirzepatide can be given at any time of day, without regard to meals. The site of the subcutaneous injection (abdomen, thigh, or upper arm) should be rotated with each dose. ¹

See Table 5 for a comparison of dosing recommendations for tirzepatide and select long-acting GLP-1 receptor agonists.^1,6,9,11

Table 5.

Comparison of Dosing Recommendations for Tirzepatide and Select Injectable Long-acting GLP-1 Receptor Agonists for Treatment of Type 2 Diabetes Mellitus.^1,6,9,11

	Tirzepatide	Dulaglutide	Exenatide ER	Semaglutide a
Initial dosage	2.5 mg subcutaneously once weekly for 4 week	0.75 mg subcutaneously once weekly	2 mg subcutaneously once weekly	0.25 mg subcutaneously once weekly for 4 week
Dosage adjustment	Increase to 5 mg once weekly; if additional glycemic control needed, increase in 2.5 mg increments after ≥4 week on current dose	If additional glycemic control needed, increase to 1.5 mg once weekly; if additional glycemic control is needed after ≥4 week on 1.5 mg/week dosage, may further increase in 1.5 mg increments (ie, 3 mg once weekly, then 4.5 mg once weekly) after ≥4 week on current dose	—	Increase to 0.5 mg once weekly; if additional glycemic control needed after ≥4 week on 0.5 mg/week dosage, may increase to 1 mg once weekly; if additional glycemic control needed after ≥4 week on 1 mg/week dosage, may increase to 2 mg once weekly
Maximum dosage	15 mg once weekly	4.5 mg once weekly	2 mg once weekly	2 mg once weekly
Special populations
Renal impairment	No dosage adjustment necessary	No dosage adjustment necessary	No dosage adjustments provided in labeling; not recommended in patients with eGFR < 45 mL/min/1.73 m2	No dosage adjustment necessary
Hepatic impairment	No dosage adjustment necessary	No dosage adjustments provided in labeling	Has not been studied	No dosage adjustment necessary

^aOzempic product.

Product Availability and Storage

Tirzepatide was approved by the FDA on May 13, 2022. ⁴⁰ Tirzepatide is available as a prefilled single-dose pen in strengths of 2.5, 5, 7.5, 10, 12.5, and 15 mg per 0.5 mL. Each carton contains 4 single-dose pens. ¹

Store tirzepatide in a refrigerator at 2°C to 8°C (36-46°F) in the original carton to protect from light. Each tirzepatide pen can be stored unrefrigerated at temperatures not to exceed 30°C (86°F) for up to 21 days. The pens should not be frozen; if the solution is frozen, it should not be used. ¹

Drug Safety/REMS

No REMS is required for tirzepatide. ³⁹

Conclusion

Tirzepatide is a dual-mechanism GIP/GLP-1 receptor agonist approved for use as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. Clinical trials have demonstrated significant HbA_1c and weight reductions in patients receiving tirzepatide compared with placebo and active comparators. Current therapy options are clinically effective at lowering HbA_1c and promoting weight loss; however, there is still a significant proportion of patients not reaching ADA-recommended HbA_1c target value of less than 7.5%, and the majority of these patients are overweight or obese. Positive results with tirzepatide regarding lowering of HbA_1c to target and promoting substantial weight loss indicate it will be beneficial in the management of diabetes.