Measuring GLP-1 Efficacy in the Real World
Does real-world evidence show that GLP-1s are as effective as results reported in randomized controlled clinical trials? Insights from real-world clinical data paint a picture of who responds – and who does not – to GLP-1s outside of clinical trials.
Glucagon-like peptide 1 receptor agonists (GLP-1s) are on track to become one of the largest drug classes in history, driven by demand for weight loss alternatives and the potential of GLP-1s to treat a range of conditions such as diabetes, cardiovascular risk, liver disease, and dementia.
While the clinical impact of GLP-1s on approved indications (e.g., obesity, diabetes, cardiovascular risk) and adjacent indications is being studied extensively in clinical trials, there is limited scientific literature on GLP-1 use, efficacy or persistence outside of clinical trial settings.
Using Dandelion Health’s GLP-1 Data Library, we conducted a study to compare outcomes for patients who have taken a GLP-1 and a matched cohort of patients who have never taken a GLP-1, but were very similar clinically, to evaluate whether GLP-1 use in the real world is as effective as results reported in clinical trials.
Results
We assessed the same outcomes reported in the key GLP-1 clinical trials: weight loss and HbA1c. We tracked each measure over time at 3-, 6-, 9- and 12-months post-GLP-1 initiation.
A greater number of patients in the treatment cohort also reached the weight loss thresholds of 5%, 10%, and 20% weight reduction from baseline weight throughout the 12-month period of the study as compared to the control group.
The greatest difference in glycemic control between groups was observed in the first 3-6 months of GLP-1 use, but the difference in the proportion of patients achieving HbA1C < 7% between these two groups continued to increase over time, suggesting sustained and improved glycemic control among patients taking GLP-1s.
Efficacy
We found that GLP-1s have a significant impact on weight loss and managing HbA1c, but the magnitude of the effects varied for GLP-1 users as compared to controls based on whether patients were diagnosed with type 2 diabetes only, obesity or overweight only, or both type 2 diabetes and obesity or overweight/obesity.
We also found that certain demographic groups – older adults and self-reported females – saw greater treatment benefit over time as compared to their matched controls.
There was a clear continuum of responsiveness to GLP-1s, suggesting a high degree of variation in terms of patient benefit from GLP-1s depending on patients’ demographic and medical context.
The top 10% of the treatment cohort had lost up to 15% of their weight by 12 months, as compared to almost 5% average weight gain in the bottom 10% of respondents. We also saw a dramatic reduction from average HbA1C at baseline (10.5%) to well-managed glycemic control (HbA1C <7%) for the top 10% of respondents by 12 months, while the bottom 10% of respondents maintained or slightly increased HbA1C in the 12-month period.
Persistence and Adjacent Indications
Persistence – or the length of time patients stayed on GLP-1s – also varied by patients’ overall disease burden, weight loss and HbA1c measures at initiation.
Patients initiating GLP-1 therapies had many other targetable comorbidities at baseline, and patients who had a higher rate of comorbidities at baseline tended to stay on GLP-1s longer.
GLP-1 discontinuation was also associated with lower HbA1c and higher weight at time of initiation.
Patients initiating GLP-1 therapies had many other targetable comorbidities at baseline, that may or may not also be impacted by the use of GLP-1s.
The denominator for each bar is patients who have been on GLP-1s for that duration. The green bars represent those who were on GLP-1s for over 6 months, while the gray bars represent those who were on GLP-1s for under 6 months. Of those on GLP-1s for >6 months, 78% had diabetes, whereas only 47% of those in the short-term use group had this diagnosis. In addition, patients had multiple comorbidities, which is why the percentages for all green bars across the chart add up to >100, and all gray bars across the chart add up to >100.
Discussion
Aside from the top 10% of responders in our real-world study, we found that GLP-1s resulted in smaller reductions in both weight loss and HbA1c, respectively. There are a few reasons why real-world use and efficacy may differ from observed impacts in GLP-1 clinical trials.
Dose trajectory and other interventions. In this study, we did not restrict either the GLP-1 treatment cohort or the control cohort to any specific medication regimen, dosage trajectory or adjunctive interventions, as the intent was to capture the full range of possible real-world medication usage that is occurring. There is evidence that titrating GLP-1 dosage and switching between GLP-1 medications can occur in clinical practice due to factors such as lack of desired impact, patient preference, insurance coverage and side effects. There is also evidence of the opposing phenomenon – therapeutic inertia – where there is a delay in intensifying treatment despite the availability of effective options. The degree to which these factors impacted weight loss or glycemic control outcomes is a topic for future research.
Patient population selection. Clinical trials are composed of carefully selected patients who meet stringent inclusion and exclusion criteria that are specific to the indication and medication being evaluated, such that they are the best candidates to test a new therapy. This is by design, and reflects the necessity of clinical trials to assess clinical impact for a specific therapeutic and indication. In our study, we evaluated efficacy for a wider range of patients. The treatment differences by diagnosis, age, sex, and race/ethnicity present an opportunity to take precision medicine approaches to clinical care for obesity and diabetes, so the right patients receive the right therapeutics at the right times.
Adherence rates and monitoring. Strict monitoring in clinical trials – which enhance medication efficacy and patient compliance – are generally not replicated in real-world settings. The high variability in adherence and patient management in real-world scenarios likely dilutes the potential maximum efficacy seen under controlled clinical trial conditions. The role of adherence and persistence is beyond the scope of this study, but a promising area of further research is to explore which patients may benefit from this medication class, and how to ensure that the benefits of GLP-1 medications are fully realized in a real-world setting by addressing adherence challenges.
Given our findings, future research with Dandelion data will focus on (i) investigating the heterogeneity in treatment response to GLP-1s, (ii) modeling predictors of patient responsiveness, and (iii) analyzing unstructured clinical data to understand the impact of GLP-1s on measures beyond weight loss and HbA1c (e.g., loss or preservation of lean body mass).
Conclusion
As a starting point to inform deeper investigations into real-world variation and patient profiles for responsiveness to therapies, our research bridges the gap between clinical trials and GLP-1 use in the real world, where a broader, more diverse population is using GLP-1s in a variety of settings and personal contexts. Read our preprint for a deeper discussion of our study design and results, or fill out the form to download our white paper.