A significant proportion of adults who meet the FDA's criteria for weight loss treatment with GLP-1 receptor agonists are excluded from clinical trials evaluating these drugs, raising concerns about the generalizability of trial results to the broader population. The study, published in JAMA Internal Medicine, found that up to 33.1% of eligible adults are excluded from trials due to various medical and psychiatric conditions.
Exclusion Criteria Impact
Researchers from the University of Pittsburgh, Lily G. Bessette and Timothy S. Anderson, analyzed data from the National Health and Nutrition Examination Survey (NHANES) to determine the proportion of U.S. adults with overweight or obesity who met FDA label criteria for weight loss treatment but were excluded from GLP-1 receptor agonist trials. The analysis, representing 110.3 million U.S. adults, revealed that a substantial number of individuals were ineligible for trial participation due to pre-existing conditions.
"It struck me that a third of treatment-eligible patients may not have been represented in these pivotal clinical trials, yet little attention is given to how the exclusion criteria of trials may impact a trial’s generalizability," said Bessette.
Common Exclusion Factors
The most common exclusion criteria identified in the study included major depressive disorder, uncontrolled hypertension, malignant neoplasms, and liver disease (specific to tirzepatide). These conditions are often present in individuals who could benefit from weight loss medications, highlighting a potential gap in the evidence base for these populations.
Specifically, the study found that 33.1% (95% CI, 31.4-34.8), 28.1% (95% CI, 26.4-29.8) and 26.2% (95% CI, 24.6-27.9) of the cohort met the exclusion criteria for tirzepatide, liraglutide and semaglutide, respectively.
Implications for Clinical Practice
The researchers emphasize the importance of screening for these conditions before prescribing GLP-1 receptor agonists. "Primary care providers should consider screening for depression, liver function, and concomitant use of medications that delay gastric emptying before prescribing medications like GLP-1 receptor agonists," Bessette advised.
Furthermore, caution should be exercised when prescribing these medications to populations excluded from clinical trials. The study also noted that 23.5% of people meeting FDA indications for tirzepatide reported using medications that may slow gastrointestinal motility, which could increase gastrointestinal adverse effects when combined with any GLP-1 receptor agonist.
Need for Further Research
Bessette called for more real-world evidence to study the safety and effectiveness of GLP-1s and GLP-1/gastric inhibitory polypeptides in these underrepresented and previously excluded populations to guide treatment decisions. This would help to address the current lack of data and ensure that treatment decisions are based on a more comprehensive understanding of the risks and benefits in diverse patient populations.
