For many seeking effective weight management, medications like Wegovy (semaglutide) and Zepbound (tirzepatide) – both belonging to the GLP-1 receptor agonist class – have offered significant hope based on impressive results seen in clinical trials. However, new research suggests that the real-world experience for many patients falls short of those trial outcomes.
A recent study analyzing electronic health records (EHR) from nearly 7,900 adults treated for overweight or obesity within the Cleveland Clinic health system between 2021 and 2023 revealed a notable difference. On average, patients in this real-world setting experienced less overall weight loss compared to participants in the tightly controlled clinical trials that led to the drugs’ approvals.
Key Factors Behind the Discrepancy
The primary reasons identified for this gap between clinical trial promise and real-world results boil down to two main factors:
- Higher rates of medication discontinuation.
- The prevalent use of lower maintenance dosages.
- Unmet Expectations: Patients may discontinue if their weight loss doesn’t match potentially inflated expectations based on trial data or media hype.
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Unlike trials where patients are typically highly adherent and often titrate up to target doses, real-world use presents several barriers.
The Impact of Stopping Treatment Early
The Cleveland Clinic study found that discontinuation rates were substantially higher in routine clinical practice than in trials. Within the first year, over 50% of patients stopped taking their medication – either early (within 3 months) or later (within 3-12 months). This is a significant contrast to pivotal trials where discontinuation rates were typically below 20%.
Patients who discontinued treatment saw markedly less weight loss. Those who stopped within 3 months achieved an average weight reduction of only 3.6% at one year. Even those who stopped later still only saw an average loss of 6.8%.
The Unexpected Role of Dosage
Another surprising finding from the study was the widespread use of lower maintenance doses. Over 80% of patients were using doses below the typical highest maintenance doses seen in trials (below 1.7 mg for semaglutide and below 10.0 mg for tirzepatide).
This significantly impacted outcomes. The mean overall weight loss at one year for the entire group was 8.7% (7.7% for semaglutide, 12.4% for tirzepatide). This is considerably lower than the average weight loss of 15% to 21% reported in Phase 3 trials.
However, the study provided a crucial insight: patients who continued taking the medication for a full year and used higher maintenance doses achieved weight loss figures much closer to trial results, averaging 14.7% reduction (13.7% for semaglutide, 18.0% for tirzepatide). This underscores that achieving significant weight loss often requires both persistence and adequate dosing.
Multivariate analysis confirmed that continuing treatment, using higher doses, being female, and using tirzepatide (compared to semaglutide) were all associated with a greater likelihood of achieving at least 10% weight loss at one year.
Why Patients Stop: Real-World Barriers
While the study authors are conducting further research into the specific reasons for discontinuation, external research and expert commentary highlight common real-world challenges, including:
High Cost: The significant price of these medications can be a major barrier.
Insurance Coverage Issues: Lack of or inadequate insurance coverage makes treatment unaffordable for many.
Side Effects: Gastrointestinal side effects are common and can lead patients to stop.
Supply Shortages: Ongoing issues with medication availability can disrupt treatment.
These factors create a complex environment where maintaining consistent treatment at effective doses is challenging for many.
Beyond Weight: Metabolic Benefits
Despite the lower average weight loss compared to trials, the study did show positive metabolic outcomes, particularly for patients with prediabetes. Among this group, significant improvements in A1c levels were observed.
Persistence with treatment was linked to better metabolic results: 67.9% of those who continued treatment normalized their A1c, compared to 41.0% of late discontinuers and 33.1% of early discontinuers. Continuing treatment also significantly lowered the risk of progressing to type 2 diabetes (1.7% risk for continuers vs. 4.4-6.5% for discontinuers). This confirms the medications’ benefit in preventing type 2 diabetes, while also stressing the importance of persistence for maximal effect.
An Unexpected Finding After Discontinuation
One surprising observation was that patients who discontinued the medication early did not experience the rapid weight regain often seen in clinical trials after stopping the drug. Their weight trajectories remained relatively stable throughout the follow-up period. Researchers are investigating potential reasons, such as adopting lifestyle changes, trying other treatments, or simply finding it easier to maintain a smaller amount of lost weight compared to the larger losses often achieved and then potentially regained in trials.
Expert Commentary and the Future
Experts acknowledge the study’s value in illustrating the realities of GLP-1 use outside controlled settings. They note that current pharmacotherapy faces challenges in treating obesity as a chronic disease, pointing to the need for future medications that are better tolerated, more accessible, and more affordable to help patients achieve and maintain significant weight loss long-term. Researchers are actively working to understand predictors of success and discontinuation to better support patients starting treatment.
In conclusion, while GLP-1 medications remain powerful tools for weight loss and metabolic health, real-world outcomes highlight the critical role of treatment persistence and adequate dosing. Addressing the practical barriers patients face – from cost and coverage to side effects and supply – is essential to help more individuals achieve the life-changing health benefits demonstrated in clinical trials.
