By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
Dr. Elliott is Assistant Clinical Professor of Medicine, University of California San Francisco. Dr. Chan is Associate Clinical Professor, School of Pharmacy University of California San Francisco.
The U.S. Food and Drug Administration (FDA) has approved tirzepatide for chronic weight management. The drug previously was approved for the treatment of type 2 diabetes (T2D) under the trade name Mounjaro. This is the third incretin-based drug to be approved for treatment of T2D and then subsequently for weight loss following semaglutide, which initially was marketed as Ozempic for T2D, then later approved for weight loss as Wegovy, and liraglutide as Victoza (T2D) and Saxenda (weight loss). Tirzepatide is a first-in-class dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonist (twincretin). Tirzepatide for chronic weight management was given a priority review and a fast-track breakthrough therapy designation and is marketed by Lilly USA, LLC, as Zepbound.
INDICATIONS
Tirzepatide is indicated as an adjunct to a reduced-caloric diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of 30 kg/m2 or greater, or 27 kg/m2 or greater in the presence of at least one weight-related comorbidity (e.g., hypertension, dyslipidemia, type 2 diabetes mellitus, obstructive sleep apnea, or cardiovascular disease).1
DOSAGE
The recommended starting dose is 2.5 mg given subcutaneously once weekly.1 After four weeks, the dose is increased to 5 mg once weekly. The dose should be increased at 2.5-mg increments after at least four weeks to a recommended maintenance dose of 5 mg, 10 mg, or 15 mg weekly. Recommended injection sites include abdomen, thigh, or back of the upper arm. The site should be rotated weekly. Tirzepatide is available as 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, or 15 mg as 0.5 mL single-dose pens.
POTENTIAL ADVANTAGES
Tirzepatide combines dual action on GLP-1 and GIP receptors, theoretically providing greater effectiveness in weight reduction than solely a GLP-1 agonist (e.g., semaglutide, liraglutide). These two nutrient-stimulated hormones act synergistically to reduce appetite and food intake, producing more fat mass loss over lean mass loss.1
POTENTIAL DISADVANTAGES
As with GLP-1 agonists, tirzepatide carries a Boxed Warning for the risk of thyroid C-cell tumors and is contraindicated in patients with a personal or family history of medullary thyroid carcinoma or in patients with multiple endocrine neoplasia syndrome type 2.1 The most frequent (vs. placebo) adverse reactions include nausea (25% to 28% vs. 8%), diarrhea (19% to 23% vs. 8%), vomiting (8% to 13% vs. 2%), constipation (11% to 17% vs. 5%), increase in pancreatic amylase (20% to 25% vs. 2%), and increase in serum lipase (28% to 35% vs. 5.8%).1 Tirzepatide may reduce the effectiveness of oral contraceptives. Switching to a non-oral contraceptive method or adding a barrier method is recommended for four weeks after initiation of tirzepatide and for four weeks after each dose escalation.1
COMMENTS
Tirzepatide’s efficacy for chronic weight management was established in two randomized, double-blind, placebo-controlled, 72-week trials.1-3 Trial 1 (SURMONT-1) enrolled participants with a body mass ≥ 30 kg/m2 or ≥ 27 kg/m2 with at least one weight-related complication excluding diabetes (however, about 40% of participants were prediabetic). At baseline the mean body weight was 104.8 ± 22.1 kg, mean BMI of 38.0 ± 6.8 kg/m2, with 94.5% of participants with BMI ≥ 30 kg/m2. More than two-thirds were female and 71% were white. They were randomized to tirzepatide 5 mg (n = 630), 10 mg (n = 636), 15 mg (n = 630), or placebo (n = 643) once weekly for 72 weeks after a 20-week dose escalation period. Participants also received lifestyle interventions and adherence to healthful balanced meals. The coprimary endpoints were the percentage change in weight from baseline and percentage with a weight reduction of 5% or more at week 72. The percentage changes in body weight were -15.0%, -19.5%, and -20.9% for the three doses of tirzepatide compared to -3.1% for placebo. The percentages with ≥ 5% weight reduction were 85.1%, 88.9%, 90.9%, and 34.5%, respectively.
Trial 2 (SURMONT-2) enrolled participants with a BMI ≥ 27 kg/m2 and diabetes (HbA1c 7% to 10%). The mean body weight was 100.7 ± 21.1 kg, BMI of 36.1 ± 6.6 kg/m2, and HbA1c of 8.02 ± 0.89%. Seventy-six percent were white, and sex was roughly evenly distributed. Those on insulin or GLP-1 agonists were excluded. Participants were randomized to 10 mg (n = 312), 15 mg (n = 311), and placebo (n = 315). The percentage changes in body weight were -12.8%, -14.7%, and -3.2%, respectively for tirzepatide 10 mg, 15 mg, and placebo. The percentages with ≥ 5% weight loss were 79.2%, 82.8%, and 32.5%, respectively. In both studies, tirzepatide 10 mg and 15 mg significantly reduced waist circumference compared with placebo.2,3
CLINICAL IMPLICATIONS
Approximately 70% of Americans are obese or overweight.4 Losing 5% to 10% of body weight could be associated with a reduced risk of cardiovascular disease.4 Tirzepatide is demonstrated to be a potent agent to reduce body weight, with 79.2% to 90.9% of study participants losing ≥ 5% compared to about 33% with placebo.1 Sixty percent to 83.5% lost ≥ 10% of body weight and 40% to 71% lost ≥ 15% of body weight.1 In contrast, 67% to 85% of patients lost ≥ 5% with semaglutide compared to 31% to 48% for placebo, and 44% to 62% for liraglutide compared to 16% to 34% for placebo.5,6 A trial comparing tirzepatide and semaglutide in participants with obesity or overweight with weight-related comorbidities without T2D is in progress (NCT0582283) and is estimated to be completed in November 2024.
Liraglutide requires daily injection, while both tirzepatide and semaglutide are dosed once weekly. The GLP-1 agonists, and now with a twincretin, have the potential to revolutionize treatment of obesity and overweight.
Tirzepatide, a potent first-in-class medication approved for weight loss, may be more effective than the two GLP-1 agonists in this category. In addition to affecting weight loss, these incretin-based drugs improve blood sugar and reduce the risk of cardiovascular disease in T2D individuals.5-7 They also are being investigated in the treatment of alcohol and substance abuse disorders.8,9 The cost for tirzepatide as Zepbound is $1,059.87 for four weeks, compared to semaglutide (as Wegovy), which is $1,349.02 for four weeks.
REFERENCES
- Zepbound Prescribing Information. Eli Lilly and Company. November 2023. https://pi.lilly.com/us/zepbound-uspi.pdf
- Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide once weekly for the treatment of obesity. N Engl J Med 2022;387:205-216.
- 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, randomized, multicentre, placebo-controlled, phase 3 trial. Lancet 2023;402:613-626.
- Food and Drug Administration. FDA approves new medication for chronic weight management. Nov. 8, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-new-medication-chronic-weight-management
- Wegovy Prescribing Information. Novo Nordisk. December 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215256s000lbl.pdf
- Saxenda Prescribing Information. Novo Nordisk June 2022. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/206321s016lbl.pdf
- Marx N, Husain M, Lehrke M, et al. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation 2022;146:1882-1894.
- Klausen MK, Thomsen M, Wortwein G, Fink-Jensen A. The role of glucagon-like peptide 1 (GLP-1) in addictive disorders. Br J Pharmacol 2022;179:625-641.
- Leslie M. Hot weight loss drugs tested as addiction treatments. Science. Aug. 28, 2023. https://www.science.org/content/article/hot-weight-loss-drugs-tested-addiction-treatments
