By: Katelyn Hoosein, PharmD Candidate c/o 2025 and My Tram (Sophie) Le, PharmD Candidate c/o 2028

In recent years, there has been an increase in the prevalence of obesity in the United States. According to the National Heart, Lung, and Blood Institute (NHLBI), nearly 3 in 4 adults aged 20 years or older in the United States are either overweight or obese, and nearly 1 in 5 children and teens ages 2 to 19 years are obese.¹ The World Health Organization (WHO) defines obesity as a body mass index (BMI) greater than or equal to 30 kg/m² in adults, weight-for-height greater than 3 standard deviations above the WHO Child Growth Standards median for children under 5 years of age, and greater than 2 standard deviations above the WHO Growth Reference median for children aged 5 to 19 years old.² Obesity results from energy imbalance as the body takes in more energy than it consumes, causing fat accumulation over time.¹ Obesity puts patients at risk for many conditions, including cardiovascular disease, stroke, diabetes, and osteoarthritis.²

Current treatment guidelines set by the American Association of Clinical Endocrinologists (AACE) and American College of Endocrinology (ACE) promote lifestyle modifications, such as reduced caloric intake, eating nutritious meals, and increasing physical activity, as first-line therapy for obesity. Lifestyle modifications combined with pharmacotherapy were seen to increase and sustain weight loss for individuals with a BMI greater than or equal to 27 kg/m², and in individuals with obesity stage 2, with a BMI greater than or equal to 25 with a comorbidity.³ Current medications approved by the Food and Drug Administration (FDA) for weight loss include Alli (orlistat), Qsymia (phentermine-topiramate), Contrave (naltrexone-bupropion), and injectables Saxenda (liraglutide) and Wegovy (semaglutide).

On November 8, 2023, the FDA approved Eli Lilly’s Zepbound (tirzepatide) for weight management in adults with a BMI of 30 kg/m² or greater or 27 kg/m² or greater with at least one comorbidity (i.e., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease). It is indicated to be used in addition to lifestyle modifications, such as a reduced calorie eating pattern and increased physical activity.⁴ Tirzepatide activates glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. GLP-1 hormone reduces appetite and increases satiety or feeling of fullness. GIP hormone is responsible for regulating food intake when combined with GLP-1.⁵ Activating both receptors helps target weight loss in patients taking the medication. 

Tirzepatide, as Zepbound, comes in a pre-filled single-dose injection pen in doses 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg per 0.5 mL. The pen must be stored in the refrigerator, but if left unrefrigerated, it must be discarded after 21 days.⁴ It is administered as a once-weekly subcutaneous injection. It can be injected at any time of day, without regard to meals. The recommended starting dose is 2.5 mg, and after 4 weeks, the dose may be increased in 2.5 mg increments. The recommended maintenance doses are 5 mg, 10 mg, and 15 mg. The maximum dose is 15 mg weekly.⁴

Common side effects of tirzepatide are nausea, vomiting, diarrhea, stomach pain, and injection site reactions. Adverse reactions include hypersensitivity reactions, severe stomach issues, acute pancreatitis, depression and suicidal ideation, hypoglycemia, and gallbladder issues including jaundice, fever, and abdominal pain.⁴ These reactions require monitoring and immediate management if they do occur. Tirzepatide carries a risk of thyroid C-cell tumors, which was observed in a 2-year study involving rats. It is uncertain if this risk carries over to humans; however, tirzepatide is contraindicated in patients with past medical history or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia type 2 (MEN 2).⁴ Patients who are pregnant should not use tirzepatide and the drug should be discontinued once pregnancy is identified.

Prior to the approval of Zepbound, the FDA approved Eli Lilly’s Mounjaro in 2022. Mounjaro has the same active ingredient, tirzepatide, as Zepbound; however, Mounjaro is indicated only for improvement of blood sugar levels in patients with type 2 diabetes mellitus, not for weight management. Because Mounjaro contains the same active ingredient as Zepbound, both have the similar dosage forms, dosing, administration recommendations, side effects, warnings, and contraindications.^4,6

The effect of tirzepatide on weight loss maintenance was studied by the SURMOUNT-4 trial, which was a phase 3 randomized withdrawal study with a 36-week, open-label tirzepatide lead-in period followed by a 52-week, double-blind, placebo-controlled period.⁷ The participants included adults that were overweight or obese with at least 1 complication (hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease). The study did not include patients with diabetes, previous or planned surgical intervention for weight loss or treatment with medication for weight loss 3 months prior to the study. The study was conducted at 70 sites in Argentina, Brazil, Taiwan, and the United States. A reduced calorie eating pattern and increased physical activity was maintained throughout the trial. The 36-week, open-label lead-in period consisted of administering the starting dose of tirzepatide (2.5 mg) and increasing the dose by 2.5 mg every 4 weeks until a tolerated dose of 10 or 15 mg was achieved. At the end of the lead-in period, participants who received and tolerated the maximum dose of tirzepatide (10 or 15 mg) were randomized into 2 groups: continue receiving the maximum tolerated dose of tirzepatide or switch to matching placebo for an additional 52 weeks.⁷ 783 participants were going into the open-label, lead-in period, but 670 participants were able to tolerate the maximum dose and be randomized at week 36.⁷

The study’s primary endpoint was the mean percent change in weight from the time of randomization (week 36) to the end of the trial (week 88). The secondary endpoint was the number of patients in week 88 who kept at least 80% of the weight lost during the 36-week lead-in period. The results showed that a mean weight reduction of 20.9% was observed during the 36-week lead in period.⁷ Also, tirzepatide was seen to have a more significant mean percent change in weight. The mean percent weight change from week 36 to week 88 was −5.5% with tirzepatide compared to 14.0% with placebo (group difference, −19.4% [95% confidence interval (CI), −21.2% to −17.7%]; P < .001).⁷ Regarding the secondary endpoint, the results showed that 89.5% of patients who continued receiving tirzepatide vs. placebo maintained at least 80% of the body weight loss, compared to 16.6% with placebo [P < 0.001].⁷ The results from this study showed that tirzepatide helps lose weight and maintain weight loss. 

The SURMOUNT-4 trial also measured the side effects and tolerability of tirzepatide use for weight loss. In this study, 634 patients (81%) reported at least one or more adverse events during the tirzepatide lead-in period (weeks 0-36), with 16 patients (2%) reporting a serious adverse event and 1 death occurred due to coronavirus disease 2019 (COVID-19) related pneumonia. The most common side effects were gastrointestinal-related issues, including nausea (35.5%), diarrhea (21.1%), constipation (20.7%), and vomiting (16.3%). Other side effects reported include decreased appetite (9.5%) and injection site reactions (8.2%).⁷ During the double-blind period (weeks 36 to 88) and safety follow-up period, 202 out of 335 participants (60.3%) in the tirzepatide group and 187 out of 335 participants (55.8%) in the placebo group experienced one or more adverse event.⁷ In each group, 10 patients (3%) of participants experienced serious adverse events. There was 1 death observed in the tirzepatide group due to congestive heart failure and 1 death in the placebo group due to adenocarcinoma of the colon. The most common adverse effects in the tirzepatide and placebo group were COVID-19 (14% vs 14.9%) and gastrointestinal related issues including diarrhea (10.7% vs 4.8%), nausea (8.1% vs 2.7%), and vomiting (5.7% vs 1.2%).⁷ During the lead-in period, treatment discontinuation due to an adverse event occurred with 55 participants (7%). During the double-blind period, treatment discontinuation due to an adverse event occurred in 6 participants (1.8%) in the tirzepatide group and 3 participants (0.9%) in the placebo group.⁷ These results show that tirzepatide has tolerable side effects with most participants who took the drug, with treatment discontinuation being minimal. 

Obesity has been a rising concern in the United States in recent years among adults and children. According to WHO, obesity poses numerous health risks including cardiovascular disease, diabetes, and osteoarthritis. Obesity treatment involves lifestyle changes and may include medication. Approval from the FDA of Zepbound marks a significant advancement in obesity management.

References

1. National Heart, Lung and Blood Institute. What are Overweight and Obesity?. Updated March 24, 2022. Accessed January 15, 2024. https://www.nhlbi.nih.gov/health/overweight-and-obesity. 
2. World Health Organization. Obesity and Overweight. Published June 9, 2021. Accessed January 15, 2024. https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight
3. Cornier, Marc-André. American Journal of Managed Care. A Review of Current Guidelines for the Treatment of Obesity. Published December 14, 2022. Accessed January 18, 2024.  https://www.ajmc.com/view/review-of-current-guidelines-for-the-treatment-of-obesity
4. Zepbound (tirzepatide). Prescribing information. Eli Lilly; 2022. Accessed January 30, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217806s000lbl.pdf
5. How Zepbound Works. Eli Lilly; 2023. Accessed January 30, 2024. https://www.zepbound.lilly.com/hcp/how-zepbound-works
6. Mounjaro (tirzepatide). Prescribing Information. Eli Lilly; 2022. Accessed January 30, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/215866s000lbl.pdf
7. 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. doi:10.1001/jama.2023.24945

Published by Rho Chi Post