A case for screening real-world data for collateral drug benefits: Glucagon-like peptide 1 receptor agonists and bile acid diarrhea

Purpose: Collateral drug benefits are hitherto unknown beneficial effects that might lead to repurposing of already marketed drugs. A randomized controlled trial has found liraglutide to be non-inferior to colesevelam in reducing bile acid diarrhea. We hypothesized that this collateral drug benefit of liraglutide could have been detected using observational data. Methods: We performed a sequence symmetry analysis (SSA). In the SSA, we indexed individuals on the date of the first prescription of GLP1-RA and restricted the analysis to all individuals who had a first prescription of bile acid sequestrants between 365 days prior to until 365 days after the index date. Sequence ratios (SR), that is, the ratio between counts of persons initiating GLP1-RA first versus last, were calculated, and 95% confidence intervals were obtained. We adjusted for prescribing trends using null-effect SR adjustment. Results: We included 158 individuals, with a median age of 58 years. The trend-adjusted SR was 0.96 (95% confidence interval 0.70–1.31). When stratifying on the type of GLP1-RA (liraglutide or semaglutide), we found results compatible with the previous trial (SR_liraglutide 0.75, 0.51–1.10 and SR_semagltuide 1.23, 0.80–1.89). Since BAS also can be used as a cholesterol lowering drug, we repeated the main analysis while excluded statin users, resulting in a stronger association (SR 0.56, 0.33–0.96). Conclusion: Using the SSA methodology, we obtained estimates of a collateral drug benefit that were compatible with trial results. These results support the use of epidemiological analyses of observational data as instrument for detecting collateral drug benefits.