Maintaining Weight Loss: The Efficacy of Long-Term Tirzepatide Therapy

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Obesity is the most prevalent chronic condition worldwide, affecting more than 13% of the adult population. Excessive adiposity, along with its associated complications such as cardiovascular disease and type 2 diabetes, imposes a substantial economic burden and is a leading cause of global morbidity and mortality.2, 3

Historically, the management of obesity has focused on lifestyle interventions such as diet and exercise. However, recent evidence has revealed that these approaches often trigger physiological counterregulatory mechanisms that may potentially complicate weight loss and its maintenance. This recognition has led to a redefinition of obesity as a complex metabolic disorder involving both central mechanisms, such as disruptions in hypothalamic function that regulates appetite and energy, and peripheral mechanisms, including hormonal and metabolic factors that affect fat storage. Consequently, while lifestyle modifications are crucial, sustaining weight reduction through these methods alone proves to be a significant challenge. As such, several clinical guidelines now advocate for the use of adjunctive anti-obesity medications (AOMs) in individuals with obesity, as well as those who are overweight and experiencing weight-related complications (e.g., hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease).  While most approved AOMs achieve a modest weight reduction of 3% to 9% compared to placebo, randomized withdrawal studies have revealed that discontinuing AOMs often leads to regaining weight. Nevertheless, evidence also suggests antiobesity medications such as long-acting GLP-1 receptor agonists, naltrexone/bupropion, phentermine/topiramate, and orlistat can assist in maintaining weight reduction. 1-6

Tirzepatide, a U.S. Food and Drug Administration (FDA)-approved once-weekly subcutaneous injectable peptide for type 2 diabetes, is a 39-amino acid synthetic peptide with agonist activity at both GIP and GLP-1 receptors. Preclinical studies reveal that tirzepatide binds to GIP receptors with the same affinity as native GIP, but has about five times weaker affinity for GLP-1 receptors. As a dual agonist for GIP and GLP-1 receptors, tirzepatide may provide superior weight reduction compared to selective GLP-1 agonists by targeting additional tissues and integrating signals from both receptor pathways in the brain.8,9

The efficacy of tirzepatide was evaluated in a phase 3 randomized withdrawal clinical trial (NCT04660643) with a 36-week, open-label tirzepatide lead-in period, followed by a 52-week, double-blind, placebo-controlled period, conducted at 70 sites in Argentina, Brazil, Taiwan, and the United States. Conducted from March 29, 2021, to May 18, 2023, the trial aimed to investigate the effect of continued treatment with the maximum tolerated dose (ie, 10 or 15 mg) of once-weekly tirzepatide, compared with placebo, on the maintenance of weight reduction following an initial open-label lead-in treatment period in participants with obesity or overweight.

Participants were eligible if they were 18 years or older with a body mass index (BMI) of 30 or above, or a BMI of 27 or above with at least one weight-related condition, such as hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. Major exclusion criteria included having diabetes, a history or planned surgical treatment for obesity, and the use of weight loss medications within three months before enrollment. In the open-label lead-in phase, patients received a once-weekly subcutaneous injection of tirzepatide for 36 weeks. At week 35, patients were randomized 1:1 to either continue tirzepatide or switch to a placebo for the subsequent 52 weeks. During the 36-week open-label lead-in phase, tirzepatide was initially administered at 2.5 mg, increased by 2.5 mg every 4 weeks up to a maximum tolerated dose of 10 or 15 mg. Gastrointestinal symptoms were managed with dietary counseling, symptomatic medications, or skipping a dose as per protocol. If these measures were ineffective, dose adjustments of tirzepatide by 2.5 mg increments were permitted during the lead-in phase. At the end of the lead-in phase, participants who reached the maximum tolerated dose of tirzepatide were randomly assigned to continue with tirzepatide or switch to placebo for an additional 52 weeks, with no dose adjustments during the double-blind treatment period. 

During the tirzepatide lead-in period (week 0 to 36), randomized participants achieved a mean weight reduction of 20.9%, along with reductions in BMI and waist circumference, and improvements in blood pressure, glycemic parameters, lipid levels, and patient-reported outcomes. From week 36 to 88, the mean percent weight change was −5.5% with tirzepatide versus 14.0% with placebo. Overall, tirzepatide resulted in a 25.3% weight reduction from weeks 0 to 88 compared to 9.9% with placebo. At week 88, 89.5% of tirzepatide patients maintained at least 80% of their weight loss, compared to 16.6% with placebo. 

Most participants reported at least one treatment-emergent adverse event during the lead-in phase, primarily mild to moderate gastrointestinal issues. In the subsequent double-blind period, 60.3% of participants continuing tirzepatide and 55.8% of those switched to placebo reported at least one adverse event, with gastrointestinal disorders more prevalent in the tirzepatide group. For further trial details and pertinent results, please refer to Table 1. 

While this study provides valuable data on tirzepatide's efficacy and safety, it also has distinct strengths and limitations. The study’s large sample size and randomized withdrawal design enhance the validity of its results. The prolonged open-label lead-in phase allowed for a comprehensive assessment of weight maintenance and provided insights into dose escalation strategies. However, the study did not permit dose adjustments post-randomization and did not evaluate the impact of intensive behavioral therapy on sustained weight reduction. Furthermore, the cohort of participants who tolerated initial treatment with 10mg or 15 mg tirzepatide may not be fully representative of the general population, as many patients may experience side effects at lower doses, or have preexisting conditions that may affect their tolerance.

Overall, after achieving clinically significant weight loss during the 36-week tirzepatide lead-in phase, adults with obesity or overweight who continued with the maximum tolerated dose of tirzepatide for an additional 52 weeks experienced superior weight maintenance and further reductions in weight compared to those who switched to placebo. This finding represents a novel discovery in obesity management, demonstrating that sustained treatment with tirzepatide not only maintains but also enhances weight loss over a longer period. This is crucial for clinical practice as it highlights the long-term efficacy of tirzepatide in achieving and maintaining weight reduction, providing a significant therapeutic option for patients struggling with obesity. 

References: 

[1] 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.

[2] 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.

[3] le Roux CW, Zhang S, Aronne LJ, et al. Tirzepatide for the treatment of obesity: Rationale and design of the SURMOUNT clinical development program. Obesity. 2023;31(1):96-110.

[4] Apovian CM, Aronne LJ, Bessesen DH, et al. Pharmacological management of obesity: an endocrine Society clinical practice guideline [published correction appears in J Clin Endocrinol Metab. 2015 May;100(5):2135-6. doi: 10.1210/jc.2015-1782]. J Clin Endocrinol Metab. 2015;100(2):342-362. doi:10.1210/jc.2014-3415

[5] Wharton S, Lau DCW, Vallis M, et al. Obesity in adults: a clinical practice guideline. CMAJ. 2020;192(31):E875-E891. doi:10.1503/cmaj.191707

[6] Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404(6778):661-671. doi:10.1038/35007534

[7] Garvey WT, Mechanick JI, Brett EM, et al. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY COMPREHENSIVE CLINICAL PRACTICE GUIDELINES FOR MEDICAL CARE OF PATIENTS WITH OBESITY. Endocr Pract. 2016;22 Suppl 3:1-203. doi:10.4158/EP161365.GL

[8] Coskun T, Sloop KW, Loghin C, et al. LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Mol Metab. 2018;18:3-14. doi:10.1016/j.molmet.2018.09.009

[9] Baggio LL, Drucker DJ. Biology of incretins: GLP-1 and GIP. Gastroenterology. 2007;132(6):2131-2157. doi:10.1053/j.gastro.2007.03.054

 

Table 1: Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity

Design

Phase 3, randomized withdrawal clinical trial with a 36-week, open-label lead-in period (N= 783) followed by a 52-week, double-blind, placebo-controlled period (N= 670)

Objective

To assess the effect of tirzepatide, with diet and physical activity, on the maintenance of weight reduction

Study Groups

Tirzepatide (n= 335) Placebo (n= 335)

Inclusion Criteria

≥18 years old; body mass index (BMI) of ≥ 30; or  BMI ≥ 27 with at least one weight-related condition (ie. hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease)

Exclusion Criteria

Patients with diabetes, a history or planned surgical treatment for obesity, and the use of weight loss medications within three months before enrollment

Methods

Participants (n= 783) in the open-label lead-in period received weekly subcutaneous tirzepatide (10 or 15 mg) for 36 weeks. At week 36, 670 participants were randomized 1:1 to either continue tirzepatide (n = 335) or switch to placebo (n= 335) for 52 weeks.

Duration

Trial: March 29, 2021  to May 18, 2023 Intervention: 88 weeks

Outcome Measures

Primary: mean percent change in weight from week 36 to week 88 Secondary: proportion of participants at week 88 who maintained at least 80% of the weight loss during the lead-in period

Baseline Characteristics

Week 0 of lead-in period

Week 36

Tirzepatide  (N= 607)

Tirzepatide (n= 335)

Placebo (n= 335)

Age, years

48 (13%)

49 (13%)

48 (12%)

Female

473 (70.6%)

236 (70.4%)

237 (70.7%)

Duration of obesity, years

15.5 ± 11.8

15.9 ± 12.1

15.2 ± 11.4

Race Asian Black White Native Multiple

48 (7.2%) 75 (11.2%) 537 (80.1%) 2 (0.3%) 8 (1.2%)

26 (7.8) 39 (11.6) 264 (78.8%) 1 (0.3%) 5 (1.5%)

22 (6.6%) 36 (10.7%) 237 (81.5%) 1 (0.3%) 3 (0.9%)

Body weight, kg

107.3 ± 22.3

84.6 ± 19.8

85.8 ± 22.3

BMI

38.4 ± 6.6

30.3 ± 6.0

30.7 ± 6.8

Waist circumference, cm

115.2 ± 14.5

96.8 ± 14.1

98.2 ± 16.0

Fasting glucose, mg/dL

94.8 ± 10.9

85.1 ± 7.4

85.0 ± 7.8

Results

Least-squares mean (95% CI)

Absolute difference (95% CI)

p-Value

Tirzepatide (n= 335)

Placebo (n= 335)

Change in body weight from week 36 to 88, %

-5.5 (-6.8 to -4.2)

14.0 (12.8 to 15.2)

-19.4 (-21.2 to -17.7)

<.001

Patients maintaining ≥80% of weight lost from wk 36 to 88

300 (89.5%)

55 (16.6%)

44.0 (24.9 to 77.5)

<.001

Abbreviations: CI= Confidence Interval

Adverse Events

Common Adverse Events: mild to moderate gastrointestinal events (nausea (35.5%), diarrhea, (21.1%), constipation (20.7%), and vomiting (16.3%) Serious Adverse Events: 2.0% during the lead in period; 3.0% during the double-blind period, with similar percentages across treatment groups Adverse Events that Led to Discontinuation: 7.0% of patients during lead-in treatment period mainly due to gastrointestinal events; during the double-blind period, 1.8% of participants in the tirzepatide group and 0.9% in placebo group

Study Author Conclusions

After achieving clinically meaningful weight reduction during a 36-week tirzepatide lead-in treatment period, adults with obesity or overweight who continued treatment with maximum tolerated dose tirzepatide for an additional 52 weeks demonstrated superior weight maintenance and continued weight reduction compared to those who switched to placebo.

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