Obesity Treatment With Tirzepatide And Semaglutide
Overview
The aim of this study was to compare the effectiveness of obesity treatment with tirzepatide at doses of 10 mg and 15 mg with semaglutide at a dose of 2.4. The comparison was conducted using an indirect treatment comparison method.
The study utilized data from the SURMOUNT-1 and STEP 1 trials to evaluate the mean percentage change in body weight from baseline and the odds ratio (OR) of achieving a 5% or greater weight loss. These outcomes were compared between tirzepatide at 10 mg and 15 mg at week 72 and semaglutide at 2.4 mg at week 68, employing a matching-adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were also performed, employing various methods, estimands, and time points.
The results indicated that tirzepatide at both 10 mg and 15 mg led to more significant reductions in the percentage change in body weight compared to semaglutide at 2.4 mg. Specifically, the mean differences were as follows: tirzepatide 10 mg had a mean difference of -4.67% (95% CI -5.91% to -3.43%), and tirzepatide 15 mg had a mean difference of -5.92% (95% CI -7.16% to -4.68%), with both differences being statistically significant (P < .001).
Likewise, a higher proportion of participants achieved a 5% or greater weight loss with tirzepatide at 10 mg (OR 2.61, 95% CI 1.48 to 4.57, P < .001) and 15 mg (OR 2.75, 95% CI 1.57 to 4.81, P < .001) in comparison to semaglutide at 2.4 mg.
The study conducted various sensitivity analyses, all of which provided consistent results, except for the analysis of the OR of achieving a 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyze the treatment regimen estimand (P = .074).
In conclusion, this analysis revealed that there are currently no direct comparisons available between tirzepatide and semaglutide for weight management. However, using the matching-adjusted indirect treatment comparison method, the study demonstrated that tirzepatide at both 10 mg and 15 mg resulted in greater weight loss compared to semaglutide at 2.4 mg for chronic weight control.
Introduction
Obesity has reached pandemic levels over the past 50 years, posing a significant health challenge. Its pathogenesis is intricate, involving various factors such as sociocultural, environmental, genetic, physiological, and behavioral influences. Obesity is now recognized as a disease, and effective treatments are needed to address its complexities, including hormonal, metabolic, and neurochemical adaptations, adherence issues, and long-term persistence challenges.
Semaglutide 2.4 mg is a once-weekly glucagon-like peptide-1 (GLP-1) receptor agonist approved in June 2021 for chronic weight management. The phase 3 STEP 1 trial demonstrated that, in individuals with obesity or overweight (without diabetes), treatment with semaglutide 2.4 mg resulted in substantial body weight loss of 16.9% or 14.9%, using different estimation methods, after 68 weeks of treatment. The most commonly reported adverse events were gastrointestinal in nature.
Tirzepatide is a once-weekly glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist recently approved in the United States for people with type 2 diabetes (T2D) and is being studied for chronic weight management. In the phase 3 SURMOUNT-1 study involving individuals with obesity or overweight (without diabetes), tirzepatide treatment led to mean body weight reductions of up to 22.5% or 20.9%, depending on the estimation method, at week 72. Similar to semaglutide, the most frequently reported adverse events were gastrointestinal in nature.
Presently, there are no direct head-to-head studies comparing tirzepatide and semaglutide for chronic weight management. This study employed indirect treatment comparisons (ITCs), using a placebo as a common reference point, to evaluate the relative efficacy of tirzepatide at doses of 10 mg and 15 mg versus semaglutide at 2.4 mg. Given the potential influence of baseline characteristics like gender, baseline body weight, and prediabetes on treatment outcomes, a population-adjusted indirect comparison was utilized to account for differences in study populations.
Method
This study utilized a systematic literature review to identify trials suitable for an indirect treatment comparison (ITC) between tirzepatide and semaglutide 2.4 mg, using a placebo as a common comparator. Three studies were initially identified for inclusion: SURMOUNT-1, STEP 1, and STEP 8. However, STEP 8 was excluded from the analysis due to variations in the placebo arm’s administration schedules, rendering it incomparable to SURMOUNT-1 and STEP 1.
To minimize bias and ensure a valid treatment comparison across trials, the matching-adjusted indirect comparison (MAIC) approach was employed. Individual patient data were available for SURMOUNT-1, whereas aggregate published data were used for STEP 1. The primary characteristic balanced between the two studies was gender, with other baseline characteristics being quite similar. The MAIC aimed to align the patient data in SURMOUNT-1 with the aggregate data in STEP 1, mainly focusing on gender, which exhibited meaningful differences.
The primary outcomes under scrutiny were based on the efficacy estimand and included the percentage change in body weight from baseline to week 72 (SURMOUNT-1) or week 68 (STEP 1) and the percentage of participants achieving at least 5% weight reduction at those respective time points. The study conducted various sensitivity analyses to assess the robustness of the findings, including evaluations of different estimands, analysis time points, and methods.
In summary, this study employed an ITC methodology to compare tirzepatide and semaglutide 2.4 mg, using a placebo as a reference, addressing the challenge of the absence of head-to-head comparisons between these treatments for chronic weight management. The analyses aimed to provide valuable insights into their comparative efficacy, accounting for potential effect modifiers and differences in study populations.
Result
In this analysis, a total of 1,909 participants were included from the tirzepatide 10 mg, tirzepatide 15 mg, and placebo arms of the SURMOUNT-1 study, with 1,961 participants included from the STEP 1 study, comprising semaglutide 2.4 mg and placebo groups. To ensure comparability, matching-adjusted indirect comparison (MAIC) was employed, balancing baseline characteristics such as age, gender, body weight, BMI, prediabetes, and waist circumference between the reweighted SURMOUNT-1 and STEP 1 populations.
The primary analysis focused on percentage change in body weight and the percentage of participants achieving 5% or greater body weight reduction from baseline. It revealed that both tirzepatide 10 mg and 15 mg resulted in significantly greater reductions in percentage change in body weight compared to semaglutide 2.4 mg. The mean difference in percentage change in body weight was -4.67% (95% CI -5.91% to -3.43%) for tirzepatide 10 mg and -5.92% (95% CI -7.16% to -4.68%) for tirzepatide 15 mg, both statistically significant.
Sensitivity analyses, including those examining the treatment regimen estimand, SURMOUNT-1 data at week 68, the Bucher method, and adjustments for gender, baseline prediabetes status, and baseline body weight, consistently supported the primary analysis findings. Particularly, sensitivity analysis 1, which considered the treatment regimen estimand, showed substantial mean differences between tirzepatide 10 mg and semaglutide 2.4 mg (-5.56%, 95% CI -6.90% to -4.22%) and tirzepatide 15 mg and semaglutide 2.4 mg (-6.80%, 95% CI -8.14% to -5.46%).
Regarding participants achieving 5% or greater weight loss, the primary analysis indicated that significantly more participants achieved this with tirzepatide 10 mg and 15 mg compared to semaglutide 2.4 mg. The odds ratios (OR) were 2.61 (95% CI 1.48 to 4.57) for tirzepatide 10 mg and 2.75 (95% CI 1.57 to 4.81) for tirzepatide 15 mg, both highly significant.
The results from sensitivity analyses supported these findings, with sensitivity analysis 1 indicating ORs of 3.71 (95% CI 2.39 to 5.70) for tirzepatide 10 mg and 4.14 (95% CI 2.66 to 6.49) for tirzepatide 15 mg compared to semaglutide 2.4 mg. However, sensitivity analysis 4, which employed the Bucher method for the treatment regimen estimand using week-72 SURMOUNT-1 data, did not show a significant OR for participants achieving 5% or greater weight loss (P = .074).
In conclusion, this analysis demonstrated that both tirzepatide 10 mg and 15 mg were associated with significantly greater reductions in body weight and higher rates of participants achieving 5% or greater weight loss compared to semaglutide 2.4 mg. These findings were consistent across various sensitivity analyses, underscoring the robustness of the results.
Conclusion
This analysis provides a first-of-its-kind comparison between two novel antiobesity medications, semaglutide 2.4 mg and tirzepatide at 10 mg and 15 mg, with a focus on their effects on body weight and weight reduction in individuals with obesity or overweight and no diabetes.
The results indicate that both tirzepatide 10 mg and 15 mg exhibit substantial efficacy, leading to additional weight reduction ranging from 4.0% to 5.6% and 5.4% to 6.8%, respectively, when compared to semaglutide 2.4 mg. Moreover, participants treated with tirzepatide 10 mg and 15 mg were significantly more likely to achieve a 5% or greater reduction in body weight than those on semaglutide 2.4 mg. These findings were consistent across various sensitivity analyses, underscoring the robustness of the results.
The clinical implications of these differences in weight loss are noteworthy, as greater weight loss can result in meaningful improvements in metabolic health and weight-related complications. However, further research will be needed to determine the specific clinical benefits associated with these varying degrees of weight loss.
The mechanisms behind tirzepatide’s superior weight loss efficacy compared to semaglutide 2.4 mg remain unclear. Both medications act on glucagon-like peptide-1 (GLP-1) receptors, but tirzepatide also activates glucose-dependent insulinotropic polypeptide (GIP) receptors. Future research may shed light on the mechanisms responsible for this difference.
These findings align with previous research in individuals with type 2 diabetes, where tirzepatide consistently demonstrated greater reductions in body weight compared to semaglutide. However, it’s important to note that the trials analyzed here were not originally designed as weight loss trials, and the doses of the medications differed, which may impact the interpretation of the results.
While this analysis provides valuable insights into the comparative efficacy of these medications for weight management, it does not address safety and tolerability differences due to variations in safety data collection methods. Nonetheless, the results may assist healthcare providers in making informed clinical decisions and inform pharmacoeconomic assessments, particularly once both treatments are approved for chronic weight management.
Despite the strengths of this study, including systematic review, matching-adjusted indirect comparison (MAIC) methodology, and consideration of baseline characteristics, it has limitations. Only two studies were eligible for inclusion, and individual participant data were not available for one of them. Furthermore, differences in study durations and a focus on the regulatory framework of achieving greater than 5% weight loss limit the scope of the findings. Additionally, indirect treatment comparisons cannot account for unmeasured variables and do not replace direct head-to-head trials.
In conclusion, this analysis underscores the greater weight loss potential and improved odds of achieving significant body weight reduction associated with tirzepatide 10 mg and 15 mg in comparison to semaglutide 2.4 mg. These findings, supported by sensitivity analyses, may guide clinical decisions and pharmacoeconomic assessments in the realm of chronic weight management for individuals without diabetes, pending approval of these treatments.
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