Cleveland Clinic Study Reveals Injectable Obesity Medications Yield Less Weight Loss in Real-World Use Than in Clinical Trials

A recent comprehensive study conducted by researchers at the Cleveland Clinic sheds light on the real-world effectiveness of two prominent injectable GLP-1 receptor agonists, semaglutide and tirzepatide, widely prescribed for obesity management. While controlled randomized clinical trials have consistently demonstrated the considerable weight loss benefits of these medications, the new findings suggest that in everyday clinical practice, the outcomes are considerably more modest. This discrepancy has been attributed to significant rates of treatment discontinuation and the prevalent use of lower maintenance dosages by patients outside the tightly regulated environment of clinical trials.

The retrospective cohort study analyzed data from nearly 8,000 adults with severe obesity, defined by an average body mass index exceeding 39, treated with either semaglutide or tirzepatide between 2021 and 2023. A substantial proportion of the cohort also had prediabetes, a condition characterized by elevated blood glucose levels that often precedes the onset of type 2 diabetes. The investigators followed these patients through December 2024, documenting patterns of medication adherence, dosing strategies, and associated clinical outcomes relating to both weight reduction and glycemic control.

One of the pivotal observations emerging from the research was the notable prevalence of early discontinuation, with over 20% of patients ceasing treatment within the first three months. An additional 32% halted therapy later, within one year of initiation. Such persistence rates contrast sharply with those typically reported in clinical trials, where adherence is rigorously supported and monitored. Furthermore, more than 80% of patients who remained on treatment were maintained on dosages equal to or lower than 1 mg daily for semaglutide and 7.5 mg weekly for tirzepatide, respectively. This dosage pattern diverges from the higher maintenance doses commonly employed in trials, thereby potentially limiting therapeutic efficacy.

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When examining weight loss outcomes, the study revealed a graded relationship between treatment persistence, dosage, and the extent of body weight reduction. Participants who discontinued therapy early lost an average of just 3.6% of their body weight after one year, while those who discontinued late experienced a 6.8% reduction. In stark contrast, individuals who maintained treatment throughout the year achieved an average weight loss of 11.9%. Among this subset, those on high maintenance doses attained even more pronounced decreases, with semaglutide recipients losing approximately 13.7% and tirzepatide recipients achieving an impressive 18.0% reduction. These figures underscore the crucial role of both continued therapy and appropriate dosing in realizing the full potential of these pharmacologic agents.

The heterogeneity in patient response also aligned with other demographic and medication-specific factors. The data indicated that female patients had higher likelihoods of achieving significant weight loss, defined as a reduction of 10% or more, compared to their male counterparts. Moreover, tirzepatide was more effective than semaglutide at inducing such clinically meaningful weight reductions. These findings hint at possible sex-related physiological differences in drug metabolism or responsiveness, as well as intrinsic differences between the two agonists’ mechanisms of action.

Beyond weight parameters, the study turned attention to glycemic control, particularly among the subgroup of patients with prediabetes. In this vulnerable population, medication adherence was closely linked to the normalization of blood sugar levels, measured by the biomarker hemoglobin A1c (HbA1c). Only one-third of those who discontinued treatment early reverted to normal glycemic ranges, compared to nearly 42% of late discontinuers. However, a significant 67.9% of patients who continued treatment throughout achieved HbA1c levels consistent with normoglycemia. As type 2 diabetes constitutes one of the most common and severe complications of obesity, these findings emphasize the dual metabolic benefits of sustained GLP-1 receptor agonist therapy.

The study’s lead author, Dr. Hamlet Gasoyan of the Cleveland Clinic’s Center for Value-Based Care Research, emphasized the real-world implications of these conclusions, noting that despite robust efficacy demonstrated in clinical trials, the effectiveness of semaglutide and tirzepatide in everyday settings is undermined by factors such as medication discontinuation and suboptimal dosing. He highlighted the necessity for clinicians and patients to collaboratively address these issues to maximize therapeutic outcomes.

Further exploration of the reasons underpinning widespread discontinuation revealed a constellation of barriers common to medications for chronic conditions. Cost emerged as a paramount concern, with insurance coverage limitations frequently cited. Patients also reported adverse side effects and challenges related to medication supply shortages. In response, the research team is planning follow-up investigations to quantitatively and qualitatively dissect these drivers, aiming to inform policy changes and support mechanisms that could enhance treatment continuity.

An intriguing observation was that despite the significant differences in weight loss related to discontinuation, the trajectories of weight among patients who ceased treatment were relatively stable over time. This stability suggests that individuals may be employing additional weight management strategies post-discontinuation — a hypothesis that will be a focus of future studies. Understanding these compensatory behaviors could provide insights into holistic approaches combining pharmacotherapy with lifestyle or alternative interventions.

This investigation provides critical evidence on how the promising benefits of GLP-1 receptor agonists for obesity management translate outside the controlled environment of trials. It serves as a reminder that clinical effectiveness hinges not only on drug pharmacodynamics but also on factors like adherence, dosing regimens, economic considerations, and patient support systems. In the context of a global obesity epidemic and its interlinked metabolic diseases, optimizing the real-world use of agents like semaglutide and tirzepatide could have substantial public health implications.

The foundational importance of this research is heightened by the prevalence of severe obesity and prediabetes among the studied population — groups at markedly elevated risk for diabetes and cardiovascular disease. As the obesity and type 2 diabetes crises intensify worldwide, these findings advocate for more nuanced, patient-centered management strategies that anticipate and mitigate obstacles to sustained treatment.

In conclusion, Cleveland Clinic’s retrospective analysis throws into sharp relief the challenges of translating clinical trial success into real-world benefits for patients battling obesity and its metabolic sequelae. It challenges healthcare providers, payers, and policymakers to consider how best to support patients in maintaining high-dose, long-term GLP-1 receptor agonist therapy while addressing logistical and financial barriers. Through such multifaceted efforts, the promise of these innovative therapies might be fully realized, curbing obesity’s immense toll and improving quality of life for millions.

Subject of Research: The real-world effectiveness of semaglutide and tirzepatide in weight loss and glycemic control among patients with severe obesity, focusing on medication discontinuation and maintenance dosage impact

Article Title: Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status

News Publication Date: 10-Jun-2025

Web References:

Cleveland Clinic Center for Value-Based Care Research
Obesity Journal DOI

References:
Gasoyan H, et al. Changes in weight and glycemic control following obesity treatment with semaglutide or tirzepatide by discontinuation status. Obesity. 2025 Jun 10. DOI: 10.1002/oby.24331

Keywords: Weight loss, Medical treatments, Semaglutide, Tirzepatide, Obesity, GLP-1 receptor agonists, Glycemic control, Prediabetes, Type 2 diabetes, Medication adherence, Maintenance dosage, Real-world evidence

Tags: Cleveland Clinic obesity studyGLP-1 receptor agonists effectivenessglycemic control weight lossinjectable obesity medications researchmedication adherence in obesity treatmentobesity management clinical trialspatients with severe obesityprediabetes and obesity correlationreal-world weight loss outcomesretrospective cohort study findingssemaglutide tirzepatide comparisontreatment discontinuation rates