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For adults with obesity, or with overweight in the presence of at least one weight-related comorbid condition, in combination with a reduced-calorie diet and increased physical activity. 1

Clinical Data: Weight Reduction

Zepbound is proven to help adults with obesity achieve significant weight loss and maintain it long term1

For adults with obesity, or with overweight in the presence of at least one weight-related comorbid condition, in combination with a reduced-calorie diet and increased physical activity. 1

Clinical Data: Weight Reduction

Zepbound is proven to help adults with obesity achieve significant weight loss and maintain it long term1

SURMOUNT-1

Powerful reductions in body weight1

Zepbound 15 mg provided weight reductions ~7x more powerful than placebo1

TODO

Adults lost an average of

20.9%

of their body weight with Zepbound 15 mg vs 3.1% with placebo1

Zepbound should not be used for cosmetic weight loss.

OVERALL PERCENTAGE CHANGE IN BODY WEIGHT FROM BASELINE AT 72 WEEKS1,2

Treatment and placebo included a reduced-calorie diet and increased physical activity.1

P<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1

Studied in adults with obesity (BMI of ≥30 kg/m2), or with overweight (BMI of ≥27 kg/m2) with at least 1 weight-related comorbidity, excluding type 2 diabetes.1

The percentage change in body weight by dose (Zepbound 10 mg and 15 mg) was a coprimary endpoint.3

ITT population includes all randomly assigned patients. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data from the same treatment group assuming missing at random (for missing solely due to COVID-19). Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.1

The proportions of patients who discontinued treatment in SURMOUNT-1 were 14.3%, 16.4%, and 15.1% for the 5 mg, 10 mg, and 15 mg Zepbound-treated groups, respectively, and 26.4% for the placebo-treated group.1

The proportions of patients who discontinued treatment in SURMOUNT-2 were 9.3% and 13.8% for the 10 mg and 15 mg Zepbound-treated groups, respectively, and 14.9% for the placebo-treated group.1

In a separate weight-reduction study of adults with a BMI of ≥27 kg/m2 and type 2 diabetes, the overall percentage change in body weight from baseline at 72 weeks was -12.8% (10 mg), -14.7% (15 mg), and -3.2% (placebo). Mean baseline weights were 222.4 lb (10 mg), 219.6 lb (15 mg), and 224.2 lb (placebo).1,4

ANCOVA=analysis of covariance; BMI=body mass index; COVID-19=coronavirus disease 2019; ITT=intent-to-treat.

Select Important Safety Information

Zepbound is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with known serious hypersensitivity to tirzepatide or any of the excipients in Zepbound. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with tirzepatide.

SURMOUNT-1

Proven efficacy at multiple doses1

91% of adults taking Zepbound 15 mg achieved clinically meaningful weight loss of ≥5% at 72 weeks

of adults taking Zepbound 15 mg achieved clinically meaningful weight loss of ≥5% at 72 weeks1

PERCENTAGE OF ADULTS WHO ACHIEVED ≥5% WEIGHT LOSS AT 72 WEEKS1,2

Treatment and placebo included a reduced-calorie diet and increased physical activity.1

P<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1

Studied in adults with obesity (BMI of ≥30 kg/m2), or with overweight (BMI of ≥27 kg/m2) with at least 1 weight-related comorbidity, excluding type 2 diabetes.1

ITT population includes all randomly assigned patients. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). Analyzed using logistic regression adjusted for baseline value and other stratification factors.1

The proportions of patients who discontinued treatment in SURMOUNT-1 were 14.3%, 16.4%, and 15.1% for the 5 mg, 10 mg, and 15 mg Zepbound-treated groups, respectively, and 26.4% for the placebo-treated group.1

The proportions of patients who discontinued treatment in SURMOUNT-2 were 9.3% and 13.8% for the 10 mg and 15 mg Zepbound-treated groups, respectively, and 14.9% for the placebo-treated group.1

In a separate weight-reduction study of adults with a BMI of ≥27 kg/m2 and type 2 diabetes, the percentage of patients achieving the primary endpoint of body weight reduction ≥5% at 72 weeks was 79.2% (10 mg), 82.8% (15 mg), and 32.5% (placebo). Mean baseline weights were 222.4 lb (10 mg), 219.6 lb (15 mg), and 224.2 lb (placebo).1,4

BMI=body mass index; COVID-19=coronavirus disease 2019; ITT=intent-to-treat.

Select Important Safety Information

Risk of Thyroid C-cell Tumors: Counsel patients regarding the potential risk for MTC with the use of Zepbound and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Zepbound. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

SURMOUNT-1

More than half of adults taking Zepbound 10 and 15 mg lost ≥20% of their body weight1,3

SECONDARY ENDPOINT: PERCENTAGE OF ADULTS WHO ACHIEVED ≥10% AND ≥20% WEIGHT REDUCTION FROM BASELINE TO WEEK 721-3

Treatment and placebo included a reduced-calorie diet and increased physical activity.1

P<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1

The percentage of adults who had ≥10% and ≥20% weight loss in the SURMOUNT-1 trial for 5 mg was 68.5%, and 30% respectively. Not controlled for type I error.1

Studied in adults with obesity (BMI of ≥30 kg/m2), or with overweight (BMI of ≥27 kg/m2) with at least 1 weight-related comorbidity, excluding type 2 diabetes.1

ITT population includes all randomly assigned patients. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). Analyzed using logistic regression adjusted for baseline value and other stratification factors.1

The proportions of patients who discontinued treatment in SURMOUNT-1 were 14.3%, 16.4%, and 15.1% for the 5 mg, 10 mg, and 15 mg Zepbound-treated groups, respectively, and 26.4% for the placebo-treated group.1

The proportions of patients who discontinued treatment in SURMOUNT-2 were 9.3% and 13.8% for the 10 mg and 15 mg Zepbound-treated groups, respectively, and 14.9% for the placebo-treated group.1

In a separate weight-reduction study of adults with a BMI of ≥27 kg/m2 and type 2 diabetes, the percentage of participants achieving reductions ≥10% was 60.5% (10 mg), 64.8% (15 mg), and 9.5% (placebo). The percentage of participants achieving reductions ≥20% was 21.5% (10 mg), 30.8% (15 mg), and 1.0% (placebo). Mean baseline weights were 222.4 lb (10 mg), 219.6 lb (15 mg), and 224.2 lb (placebo).1,4

BMI=body mass index; COVID-19=coronavirus disease 2019; ITT=intent-to-treat.

Select Important Safety Information

Severe Gastrointestinal Adverse Reactions: Use of Zepbound has been associated with gastrointestinal adverse reactions, sometimes severe. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), severe gastrointestinal adverse reactions were reported more frequently among patients receiving Zepbound (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than placebo (1.0%). Similar rates of severe gastrointestinal adverse reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound clinical trials for obstructive sleep apnea (OSA). Zepbound has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

AR=adverse reaction; GI=gastrointestinal.

SURMOUNT-1

Improvements in cardiometabolic parameters at 72 weeks3,5

At 72 weeks, participants in the pooled Zepbound arm had a mean pulse rate increase of 1.8 beats/minute compared to a mean baseline of 72.2 beats/minute. The placebo arm has a mean pulse rate increase of 0.1 beats/minute compared to a mean baseline of 72.9 beats/minute. Results were not adjusted for type I error.1,6

Changes in HDL cholesterol, systolic blood pressure, and triglycerides for pooled Zepbound were significant at P<0.001 for superiority vs placebo.3

Treatment and placebo included a reduced-calorie diet and increased physical activity.1

Studied in adults with obesity (BMI of ≥30 kg/m2), or with overweight (BMI of ≥27 kg/m2) with at least 1 weight-related comorbidity, excluding type 2 diabetes.1

ITT population includes all randomly assigned patients. The missing values were imputed by a hybrid approach using retrieved dropouts from the same treatment group (if missing not due to COVID-19) or using all non-missing data assuming missing at random (for missing solely due to COVID-19). Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.1

ANCOVA=analysis of covariance; BMI=body mass index; COVID-19=coronavirus disease 2019; HDL=high-density lipoprotein; ITT=intent-to-treat; LDL=low-density lipoprotein.

SURMOUNT-4

Participants on Zepbound maintained weight loss through 88 weeks versus weight regain for those switched to placebo at week 361

PERCENTAGE CHANGE IN BODY WEIGHT OVER TIME1,7-9

Treatment and placebo included a reduced-calorie diet and increased physical activity.1

The mean percentage change in body weight for Zepbound MTD (10 mg or 15mg) versus placebo was the primary endpoint.1

aHybrid imputation least-square mean values at week 88 were -25.3% for Zepbound MTD and -9.9% for those who switched to placebo at week 36.

bZepbound MTD was either 10 mg or 15 mg.

P<0.001 for superiority of Zepbound vs placebo, controlled for type I error.1

Studied in adults with obesity (BMI of ≥30 kg/m2), or with overweight (BMI of ≥27 kg/m2) with at least 1 weight-related comorbidity (excluding type 2 diabetes) as an adjunct to a reduced-calorie diet and increased physical activity.1

During the open-label period (week 0 to week 36, including a 20-week dose escalation period), 783 participants were enrolled and received Zepbound. At week 36, 670 participants were randomized to receive either a maximum tolerated dose of Zepbound or placebo.1

Data represent observed mean values from week 0 to week 88 for the full analysis set. The -5.5% and +14% reflect least-squares mean from ANCOVA adjusted for baseline (randomization) values and other stratification values.9

Of the 783 patients who started Zepbound at week 0, 113 patients (14.4%) discontinued treatment before randomization at week 36, and adverse events were the most common reason for discontinuation (n=53, 6.8%).1

The proportions of patients who discontinued study drug after randomization (Week 36) in SURMOUNT-4 were 10.4% for the Zepbound-treated group and 17.9% for the placebo-treated group.1

ANCOVA=analysis of covariance; BMI=body mass index; ITT=intent-to-treat; MTD=maximum tolerated dose.

Select Important Safety Information

Acute Kidney Injury: Use of Zepbound has been associated with acute kidney injury, which can result from dehydration due to gastrointestinal adverse reactions to Zepbound, including nausea, vomiting, and diarrhea. In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function in patients reporting adverse reactions to Zepbound that could lead to volume depletion.

In SURMOUNT-5, an open-label, head-to-head trial comparing Zepbound® to Wegovy® (semaglutide), Zepbound demonstrated superior percentage reduction in body weight10,11

At 72 weeks, adults taking Zepbound (n=374) experienced superior body weight reduction of 20.2% vs 13.7% compared with those taking Wegovy (n=376)11*

-50.3 lb in adults taking Zepbound 15 mg or MTD (10 mg or 15 mg) and -33.1 lb in those taking Wegovy 2.4 mg or MTD (1.7 mg or 2.4 mg)12,13†

Both Zepbound and Wegovy treatment arms included a reduced-calorie diet and increased physical activity.12

The proportion of adults who discontinued the study drug due to adverse events were 6.1% for the Zepbound-treated group and 8.0% for the Wegovy-treated group.14

Zepbound should not be used for cosmetic weight loss.1

Studied in a randomized, open-label, phase 3b trial of adults who had obesity (BMI ≥30 kg/m2), or overweight (BMI ≥27 kg/m2) with at least 1 weight-related comorbidity, excluding type 2 diabetes. The study included a 2-week screening period and a 72-week treatment period. Mean baseline weight was 248.4 lb for Zepbound 15 mg or MTD (10 mg or 15 mg) and 250.0 lb for Wegovy 2.4 mg or MTD (1.7 mg or 2.4 mg). 10,12,15

Limitations of an open-label study may be related to a bias in evaluation of the outcomes, efficacy and/or safety, and the study did not have a comparison with placebo.

mITT population includes all randomly assigned participants exposed to at least 1 dose of study intervention. The missing values were imputed using retrieved dropouts from the same treatment group. Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors.11

*P<0.001 for superiority of Zepbound vs Wegovy, controlled for type I error.11,12
Not controlled for type I error.13

ANCOVA=analysis of covariance; BMI=body mass index; mITT=modified intent-to-treat; MTD=maximum tolerated dose.

Select Important Safety Information

Acute Gallbladder Disease: Treatment with Zepbound and GLP-1 receptor agonists is associated with an increased occurrence of acute gallbladder disease. In a pool of two clinical trials of Zepbound (SURMOUNT-1 and SURMOUNT-2), cholelithiasis was reported in 1.1% of Zepbound-treated patients and 1.0% of placebo-treated patients, cholecystitis was reported in 0.7% of Zepbound-treated patients and 0.2% of placebo-treated patients, and cholecystectomy was reported in 0.2% of Zepbound-treated patients and no placebo-treated patients. Acute gallbladder events were associated with weight reduction. Similar rates of cholelithiasis were reported in Zepbound clinical trials for weight reduction and in Zepbound trials for OSA. If cholecystitis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Adverse reactions pooled from the SURMOUNT-1 and SURMOUNT-2 trials1

ADVERSE REACTIONS (≥2% AND GREATER THAN PLACEBO) IN ZEPBOUND-TREATED ADULTS1

Studied in adults with obesity (BMI of ≥30 kg/m2), or with overweight (BMI of ≥27 kg/m2) with at least 1 weight-related comorbidity, as an adjunct to a reduced- calorie diet and increased physical activity.1

In a trial of adults with type 2 diabetes mellitus and BMI ≥27 kg/m2, hypoglycemia (plasma glucose <54 mg/dL) was reported in 4.2% of Zepbound-treated adults versus 1.3% of placebo-treated adults.1

In a trial of Zepbound in adults with obesity/overweight without type 2 diabetes mellitus, there was no systematic capturing of hypoglycemia, but plasma glucose <54 mg/dL was reported in 0.3% of Zepbound-treated adults versus no placebo-treated adults.1

This table shows common adverse reactions associated with the use of Zepbound in two phase 3 placebo-controlled trials. Percentages reflect the number of adult patients who reported at least 1 treatment-emergent occurrence of the adverse reaction.1,3,16

All participants in the clinical trials received Zepbound via the single-dose pen.

Adverse reactions from the SURMOUNT-5 trial: The overall safety profile of Zepbound in SURMOUNT-5 was similar to previously reported SURMOUNT trials.14*

*Studied in a randomized, open-label, phase 3b trial of adults who had obesity (BMI ≥30 kg/m2), or with overweight (BMI ≥27 kg/m2) with at least 1 weight-related comorbidity, excluding type 2 diabetes.10,12

Treatment discontinuation rates pooled from the SURMOUNT-1 and SURMOUNT-2 trials1

TREATMENT DISCONTINUATION RATES1

  • The majority of adults who discontinued Zepbound due to adverse reactions did so during the first few months of treatment due to gastrointestinal adverse reactions1
  • The most common adverse reactions occurring more frequently with Zepbound than with placebo were GI related1
  • The majority of reports of nausea, vomiting, and/or diarrhea occurred during dose escalation and decreased over time1

Studied in adults with obesity (BMI of ≥30 kg/m2), or with overweight (BMI of ≥27 kg/m2) with at least 1 weight-related comorbidity.1

In Zepbound clinical trials, gastrointestinal adverse reactions occurred more frequently among patients receiving Zepbound (5 mg 56%, 10 mg 56%, 15 mg 56%) than placebo (30%).1

Select Important Safety Information

Severe Gastrointestinal Adverse Reactions: Use of Zepbound has been associated with gastrointestinal adverse reactions, sometimes severe. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), severe gastrointestinal adverse reactions were reported more frequently among patients receiving Zepbound (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than placebo (1.0%). Similar rates of severe gastrointestinal adverse reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound clinical trials for obstructive sleep apnea (OSA). Zepbound has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

Study Designs

SURMOUNT-1

SURMOUNT-1 was a 72-week, double-blind, placebo-controlled, phase 3 trial that randomized 2539 adult patients with a body mass index (BMI) of ≥30 kg/m2 or ≥27 kg/m2 and at least 1 weight-related comorbid condition (study excluded patients with type I diabetes or type 2 diabetes), to receive once-weekly subcutaneous Zepbound 5 mg, 10 mg, 15 mg, or placebo (1:1:1:1 ratio), including a 20-week dose-escalation period. Treatment was an adjunct to a reduced-calorie diet and increased physical activity.* Mean baseline body weight for Zepbound 5 mg was 226.8 lb, for Zepbound 10 mg 233.3 lb, for Zepbound 15 mg 232.8 lb, and for placebo 231.0 lb.1-3

Coprimary endpoints were to demonstrate that Zepbound 10 mg and/or 15 mg are superior to placebo for mean percent change in body weight from baseline and percentage of study participants who achieved ≥5% body weight reduction at 72 weeks.1,3

Secondary endpoints were assessed at 72 weeks: superiority of Zepbound 5 mg to placebo for mean percent change in body weight and percentage of participants who achieved ≥5% body weight reduction; superiority of Zepbound 10 mg and/or 15 mg to placebo for percentage of participants who achieved ≥10% body weight reduction, ≥15% body weight reduction, and/or ≥20% body weight reduction.3

*Reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended to a minimum of 150 min/week).1

QW=once weekly.

Select Important Safety Information

Acute Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists or tirzepatide. In clinical trials of tirzepatide for a different indication, 14 events of acute pancreatitis were confirmed by adjudication in 13 tirzepatide-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 0.2% of Zepbound-treated patients had acute pancreatitis confirmed by adjudication (0.14 patients per 100 years of exposure) versus 0.2% of placebo-treated patients (0.15 patients per 100 years of exposure). The exposure-adjusted incidence rate for treatment-emergent adjudication-confirmed pancreatitis in the pooled clinical studies for OSA was 0.84 patients per 100 years for Zepbound and 0 for placebo-treated patients. Observe patients for signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, discontinue Zepbound and initiate appropriate management. Continuation of Zepbound after a confirmed diagnosis of pancreatitis should be individually determined in the clinical judgment of a patient's health care provider.

SURMOUNT-2

SURMOUNT-2 was a 72-week, double-blind, placebo-controlled, phase 3 trial that randomized 938 adult patients with a body mass index (BMI) of ≥27 kg/m2 and type 2 diabetes to receive once-weekly subcutaneous Zepbound 10 mg, 15 mg, or placebo (1:1:1 ratio), including a 20-week dose-escalation period. Treatment with Zepbound or placebo was an adjunct to a reduced-calorie diet and increased physical activity.* Patients included in the trial were treated with diet and exercise alone or with any oral anti-hyperglycemic agent except DPP-4 inhibitors or GLP-1 receptor agonists. Patients taking injectable therapies for type 2 diabetes were excluded from the study. Mean baseline body weight was 222.4 lb for Zepbound 10 mg, 219.6 lb for Zepbound 15 mg, and 224.2 lb for placebo.1,4,16

Coprimary endpoints were to demonstrate that Zepbound 10 mg and/or 15 mg are superior to placebo for mean percent change in body weight from baseline and percentage of study participants who achieved ≥5% body weight reduction at 72 weeks.1

Some key secondary endpoints assessed at 72 weeks were superiority of Zepbound 10 mg and/or 15 mg to placebo for percentage of participants who achieved ≥10%, ≥15%, and/or ≥20% body weight reduction: mean change in A1C (%); percentage of participants who achieved A1C <7%; and mean change in fasting glucose.1,16

*Reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity counseling (recommended to a minimum of 150 min/week).1


DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; QW=once weekly.

SURMOUNT-3

SURMOUNT-3 was an 84-week, placebo-controlled, phase 3 trial that enrolled 806 patients with a body mass index (BMI) of ≥30 kg/m2, or ≥27 kg/m2 and at least 1 weight-related comorbid condition (excluding type 2 diabetes). Following a 12-week lead-in period that included intensive lifestyle intervention*, participants achieving ≥5% weight reduction (n=579) were randomized 1:1 to either Zepbound maximum tolerated dose (10 mg or 15 mg) or to placebo once-weekly for 72 weeks. Treatment in both groups included a reduced-calorie diet and increased physical activity.1†

Coprimary endpoints were mean percentage change in weight from randomization to week 72 and percentage of participants achieving weight reduction ≥5% from randomization (week 0) to week 72.1

*Intensive lifestyle intervention during the lead-in period included a diet of approximately 1200 kcal/day for women and 1500 kcal/day for men and at least 150 minutes of moderate intensity exercise per week.

During the randomized treatment period, exercise requirements were 150 minutes of moderate activity per week and maintenance of daily energy intake to 500 kcal below individual energy requirements as calculated by the Food and Agriculture Organization of the United Nations/World Health Organization/United Nations University (FAO/WHO/UNU) estimates of human energy requirements, using a sedentary physical activity level (PAL) of 1.3.17

SURMOUNT-4

SURMOUNT-4 was an 88-week phase 3 withdrawal trial that enrolled 783 adults with a body mass index (BMI) ≥30 kg/m2, or with a BMI 27 to <30 kg/m2 with at least one weight-related comorbid condition (excluding type 2 diabetes). All participants received Zepbound once weekly during the 36-week lead-in period, which included a 20-week dose escalation period. At week 36, 670 participants were randomized 1:1 to a maximum tolerated dose of Zepbound (10 mg or 15 mg) or placebo once weekly for 52 weeks. Treatment throughout the 88-week period included a reduced-calorie diet (approximately 500 kcal/day deficit) and increased physical activity (recommended minimum of 150 min/week) for both arms of the study.1

Mean baseline (week 0) weight for all participants was 236.6 lbs.8 The primary endpoint was mean percent change in body weight from randomization (week 36) to week 88.1 Some key secondary endpoints* included mean change in body weight (kg) from week 36 to week 88, mean change in waist circumference from week 36 to week 88, percentage of participants maintaining at least 80% of body weight lost during the 36-week open-label lead-in period at week 88, percentage of patients achieving body weight reduction (≥5%, ≥10%, ≥15%, ≥20%) from week 0 to week 88, and time during the double-blind treatment period (week 36 to 88) to first occurrence of participants returning to >95% baseline body weight for those who lost at least 5% body weight during the lead-in period.9

*Controlled for type I error and tested for superiority.

SURMOUNT-5

SURMOUNT-5 was a 72-week, phase 3b, parallel-design, open-label, randomized active-controlled study that evaluated the safety and efficacy of Zepbound 15 mg or MTD (10 mg or 15 mg) compared with Wegovy (semaglutide) 2.4 mg or MTD (1.7 mg or 2.4 mg) in adults with obesity (BMI ≥30 kg/m2), or with overweight (BMI ≥27 kg/m2) with at least 1 weight-related comorbidity, excluding type 2 diabetes. Treatment was an adjunct to a reduced-calorie diet and increased physical activity. The study included a 2-week screening period. Mean baseline weight was 248.4 lb for Zepbound 15 mg or MTD (10 mg or 15 mg) and 250.0 lb for Wegovy 2.4 mg or MTD (1.7 mg or 2.4 mg).10,12,15

Primary endpoint was to demonstrate that Zepbound 15 mg or MTD (10 mg or 15 mg) is superior to Wegovy 2.4 mg or MTD (1.7 mg or 2.4 mg) for mean percent change in body weight from baseline at 72 weeks.10,12

Key secondary endpoints were assessed at 72 weeks to demonstrate that Zepbound 15 mg or MTD (10 mg or 15 mg) is superior to Wegovy 2.4 mg or MTD (1.7 mg or 2.4 mg) for12:

  • Body weight reductions of ≥10%, ≥15%, ≥20%, and ≥25% from baseline
  • Change in waist circumference (cm) from baseline

Primary and key secondary endpoints were controlled for multiplicity.12

Zepbound is indicated in combination with a reduced-calorie diet and increased physical activity.1

BMI=body mass index; MTD=maximum tolerated dose.

References
  1. Zepbound. Prescribing Information. Lilly USA, LLC.
  2. Data on File. DOF-ZP-US-0001. Lilly USA, LLC.
  3. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med. 2022;387(3):205-216. doi:10.1056/NEJMoa2206038
  4. Data on File. DOF-ZP-US-0005. Lilly USA, LLC.
  5. Data on File. DOF-ZP-US-0004. Lilly USA, LLC.
  6. Data on File. DOF-ZP-US-0019. Lilly USA, LLC.
  7. Data on File. DOF-ZP-US-0022. Lilly USA, LLC.
  8. Data on File. DOF-ZP-US-0024. Lilly USA, LLC.
  9. Aronne LJ, Sattar N, Horn DB, et al. Continued treatment with tirzepatide for maintenance of weight reduction in adults with obesity: the SURMOUNT-4 randomized clinical trial. JAMA. 2024;331(1):38-48 (incl suppl 2). doi:10.1001/jama.2023.24945
  10. A study of tirzepatide (LY3298176) in participants with obesity or overweight with weight related comorbidities (SURMOUNT-5). ClinicalTrials.gov identifier: NCT05822830. Updated August 28, 2024. Accessed November 21, 2024. https://clinicaltrials.gov/ct2/show/NCT05822830
  11. Data on File. DOF-ZP-US-0034. Lilly USA, LLC.
  12. Data on File. DOF-ZP-US-0038. Lilly USA, LLC.
  13. Data on File. DOF-ZP-US-0036. Lilly USA, LLC.
  14. Data on File. DOF-ZP-US-0037. Lilly USA, LLC.
  15. Data on File. DOF-ZP-US-0035. Lilly USA, LLC.
  16. Garvey WT, Frias JP, Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): a double-blind, randomised, multicentre, placebo-controlled, phase 3 trial. Lancet. 2023;402(10402):613-626. doi:10.1016/S0140-6736(23)01200-X
  17. Wadden TA, Chao AM, Machineni S, et al. Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: the SURMOUNT-3 phase 3 trial. Nat Med. 2023;29(11)(suppl mat):2909-2918. doi:10.1038/s41591-023-02597-w

Important Safety Information for Zepbound® (tirzepatide) injection

Warning:

WARNING: RISK OF THYROID C-CELL TUMORS

In rats, tirzepatide causes dose-dependent and treatment-duration-dependent thyroid C-cell tumors at clinically relevant exposures. It is unknown whether Zepbound causes thyroid C-cell tumors, including medullary thyroid carcinoma (MTC), in humans as human relevance of tirzepatide-induced rodent thyroid C-cell tumors has not been determined.

Zepbound is contraindicated in patients with a personal or family history of MTC or in patients with Multiple Endocrine Neoplasia syndrome type 2 (MEN 2). Counsel patients regarding the potential risk for MTC with the use of Zepbound and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Zepbound.

Contraindications:
Zepbound is contraindicated in patients with a personal or family history of MTC or in patients with MEN 2, and in patients with known serious hypersensitivity to tirzepatide or any of the excipients in Zepbound. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with tirzepatide.

Risk of Thyroid C-cell Tumors: Counsel patients regarding the potential risk for MTC with the use of Zepbound and inform them of symptoms of thyroid tumors (e.g., a mass in the neck, dysphagia, dyspnea, persistent hoarseness). Routine monitoring of serum calcitonin or using thyroid ultrasound is of uncertain value for early detection of MTC in patients treated with Zepbound. Such monitoring may increase the risk of unnecessary procedures, due to the low test specificity for serum calcitonin and a high background incidence of thyroid disease. Significantly elevated serum calcitonin values may indicate MTC and patients with MTC usually have calcitonin values >50 ng/L. If serum calcitonin is measured and found to be elevated, the patient should be further evaluated. Patients with thyroid nodules noted on physical examination or neck imaging should also be further evaluated.

Severe Gastrointestinal Adverse Reactions: Use of Zepbound has been associated with gastrointestinal adverse reactions, sometimes severe. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), severe gastrointestinal adverse reactions were reported more frequently among patients receiving Zepbound (5 mg 1.7%, 10 mg 2.5%, 15 mg 3.1%) than placebo (1.0%). Similar rates of severe gastrointestinal adverse reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound clinical trials for obstructive sleep apnea (OSA). Zepbound has not been studied in patients with severe gastrointestinal disease, including severe gastroparesis, and is therefore not recommended in these patients.

Acute Kidney Injury: Use of Zepbound has been associated with acute kidney injury, which can result from dehydration due to gastrointestinal adverse reactions to Zepbound, including nausea, vomiting, and diarrhea. In patients treated with GLP-1 receptor agonists, there have been postmarketing reports of acute kidney injury and worsening of chronic renal failure, which may sometimes require hemodialysis. Some of these events have been reported in patients without known underlying renal disease. A majority of the reported events occurred in patients who had experienced nausea, vomiting, diarrhea, or dehydration. Monitor renal function in patients reporting adverse reactions to Zepbound that could lead to volume depletion.

Acute Gallbladder Disease: Treatment with Zepbound and GLP-1 receptor agonists is associated with an increased occurrence of acute gallbladder disease. In a pool of two clinical trials of Zepbound (SURMOUNT-1 and SURMOUNT-2), cholelithiasis was reported in 1.1% of Zepbound-treated patients and 1.0% of placebo-treated patients, cholecystitis was reported in 0.7% of Zepbound-treated patients and 0.2% of placebo-treated patients, and cholecystectomy was reported in 0.2% of Zepbound-treated patients and no placebo-treated patients. Acute gallbladder events were associated with weight reduction. Similar rates of cholelithiasis were reported in Zepbound clinical trials for weight reduction and in Zepbound trials for OSA. If cholecystitis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated.

Acute Pancreatitis: Acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, has been observed in patients treated with GLP-1 receptor agonists or tirzepatide. In clinical trials of tirzepatide for a different indication, 14 events of acute pancreatitis were confirmed by adjudication in 13 tirzepatide-treated patients (0.23 patients per 100 years of exposure) versus 3 events in 3 comparator-treated patients (0.11 patients per 100 years of exposure). In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 0.2% of Zepbound-treated patients had acute pancreatitis confirmed by adjudication (0.14 patients per 100 years of exposure) versus 0.2% of placebo-treated patients (0.15 patients per 100 years of exposure). The exposure-adjusted incidence rate for treatment-emergent adjudication-confirmed pancreatitis in the pooled clinical studies for OSA was 0.84 patients per 100 years for Zepbound and 0 for placebo-treated patients. Observe patients for signs and symptoms of pancreatitis, including persistent severe abdominal pain sometimes radiating to the back, which may or may not be accompanied by vomiting. If pancreatitis is suspected, discontinue Zepbound and initiate appropriate management. Continuation of Zepbound after a confirmed diagnosis of pancreatitis should be individually determined in the clinical judgment of a patient’s health care provider.

Hypersensitivity Reactions: There have been postmarketing reports of serious hypersensitivity reactions (e.g., anaphylaxis, angioedema) in patients treated with tirzepatide. In a pool of two Zepbound clinical trials (SURMOUNT-1 and SURMOUNT-2), 0.1% of Zepbound-treated patients had severe hypersensitivity reactions compared to no placebo-treated patients. Similar rates of severe hypersensitivity reactions were observed in Zepbound clinical trials for weight reduction and in Zepbound trials for OSA. If hypersensitivity reactions occur, advise patients to promptly seek medical attention and discontinue use of Zepbound. Do not use in patients with a previous serious hypersensitivity reaction to tirzepatide or any of the excipients in Zepbound. Use caution in patients with a history of angioedema or anaphylaxis with a GLP-1 receptor agonist because it is unknown if such patients will be predisposed to these reactions with Zepbound.

Hypoglycemia: Zepbound lowers blood glucose and can cause hypoglycemia. In a trial of patients with type 2 diabetes mellitus and BMI ≥27 kg/m2 (Study 2), hypoglycemia (plasma glucose <54 mg/dL) was reported in 4.2% of Zepbound-treated patients versus 1.3% of placebo-treated patients. In this trial, patients taking Zepbound in combination with an insulin secretagogue (e.g., sulfonylurea) had increased risk of hypoglycemia (10.3%) compared to Zepbound-treated patients not taking a sulfonylurea (2.1%). There is also increased risk of hypoglycemia in patients treated with tirzepatide in combination with insulin. Hypoglycemia has also been associated with Zepbound and GLP-1 receptor agonists in adults without type 2 diabetes mellitus. Inform patients of the risk of hypoglycemia and educate them on the signs and symptoms of hypoglycemia. In patients with diabetes mellitus, monitor blood glucose prior to starting Zepbound and during Zepbound treatment. The risk of hypoglycemia may be lowered by a reduction in the dose of insulin or sulfonylurea (or other concomitantly administered insulin secretagogue).

Diabetic Retinopathy Complications in Patients with Type 2 Diabetes Mellitus: Rapid improvement in glucose control has been associated with a temporary worsening of diabetic retinopathy. Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema. Patients with a history of diabetic retinopathy should be monitored for progression of diabetic retinopathy.

Suicidal Behavior and Ideation: Suicidal behavior and ideation have been reported in clinical trials with other weight management products. Monitor patients treated with Zepbound for the emergence or worsening of depression, suicidal thoughts or behaviors, and/or any unusual changes in mood or behavior. Discontinue Zepbound in patients who experience suicidal thoughts or behaviors. Avoid Zepbound in patients with a history of suicidal attempts or active suicidal ideation.

Pulmonary Aspiration During General Anesthesia or Deep Sedation: Zepbound delays gastric emptying. There have been rare postmarketing reports of pulmonary aspiration in patients receiving GLP-1 receptor agonists undergoing elective surgeries or procedures requiring general anesthesia or deep sedation who had residual gastric contents despite reported adherence to preoperative fasting recommendations. Available data are insufficient to inform recommendations to mitigate the risk of pulmonary aspiration during general anesthesia or deep sedation in patients taking Zepbound, including whether modifying preoperative fasting recommendations or temporarily discontinuing Zepbound could reduce the incidence of retained gastric contents. Instruct patients to inform healthcare providers prior to any planned surgeries or procedures if they are taking Zepbound.

Most Common Adverse Reactions: The most common adverse reactions reported in ≥5% of patients treated with Zepbound are nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, and gastroesophageal reflux disease.

Drug Interactions: Zepbound lowers blood glucose. When initiating Zepbound, consider reducing the dose of concomitantly administered insulin or insulin secretagogues (e.g., sulfonylureas) to reduce the risk of hypoglycemia. Zepbound delays gastric emptying and thereby has the potential to impact the absorption of concomitantly administered oral medications. Caution should be exercised when oral medications are concomitantly administered with Zepbound. Monitor patients on oral medications dependent on threshold concentrations for efficacy and those with a narrow therapeutic index (e.g., warfarin) when concomitantly administered with Zepbound.

Pregnancy: Advise pregnant patients that weight loss is not recommended during pregnancy and to discontinue Zepbound when a pregnancy is recognized. Available data with tirzepatide in pregnant patients are insufficient to evaluate for a drug-related risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Based on animal reproduction studies, there may be risks to the fetus from exposure to tirzepatide during pregnancy. There will be a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Zepbound (tirzepatide) during pregnancy.

Pregnant patients exposed to Zepbound and healthcare providers are encouraged to contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979).

Lactation: There are no data on the presence of tirzepatide or its metabolites in animal or human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Zepbound and any potential adverse effects on the breastfed infant from Zepbound or from the underlying maternal condition.

Females and Males of Reproductive Potential: Use of Zepbound may reduce the efficacy of oral hormonal contraceptives due to delayed gastric emptying. This delay is largest after the first dose and diminishes over time. Advise patients using oral hormonal contraceptives to switch to a non-oral contraceptive method, or add a barrier method of contraception, for 4 weeks after initiation with Zepbound and for 4 weeks after each dose escalation.

Pediatric Use: The safety and effectiveness of Zepbound have not been established in pediatric patients.

Please see accompanying Prescribing Information, including Boxed Warning about possible thyroid tumors, including thyroid cancer, and Medication Guide.

Please see Instructions for Use.

Zepbound is available as a 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg and 15 mg injection.

ZP HCP ISI 20DEC2024

INDICATIONS

Zepbound is indicated in combination with a reduced-calorie diet and increased physical activity:

  • to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition.
  • to treat moderate-to-severe obstructive sleep apnea (OSA) in adults with obesity.

Limitations of Use

Zepbound contains tirzepatide. Coadministration with other tirzepatide-containing products or with any glucagon-like peptide-1 (GLP-1) receptor agonist is not recommended.