Phenome-Wide Risk Evaluation of GLP-1 Receptor Agonist Use in Type 2 Diabetes with Real-World Data Across Multiple Healthcare Systems

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), widely used for managing type 2 diabetes (T2D) and weight, are gaining attention for treatment of a broad set of conditions. Large-scale, real-world evidence of their broader clinical impact is needed. We assessed the phenome-wide risks and benefits of new users of GLP-1RA versus sulfonylureas, SGLT-2 inhibitors (SGLT-2i), and DPP-4 inhibitors (DPP-4i) in adults with T2D in a multi-healthcare center, 1:1 high-dimensional propensity score matched new user cohort study utilizing principles of target trial emulation with electronic health records (EHRs) of over 9 million patients followed up to 730 days. Primary outcomes included 239 clinical endpoints across 14 organ systems. Among 86,790 patients, mean age was 58-66 years and 44-62% were female across cohorts. Compared to DPP-4i, GLP-1RA use was associated with a reduced risk of acute myocardial infarction (sHR 0.61, 95% CI 0.43-0.85) and chronic kidney disease (sHR 0.71, 95% CI 0.62-0.81). Compared to sulfonylurea, GLP-1RA use was associated with reduced acute renal failure risk (sHR 0.77, 95% CI 0.65-0.90). GLP-1RA use was associated with reduced heart failure risk compared to SGLT-2i (sHR 0.66, 95% CI 0.55-0.80). GLP-1RA also was associated with lower epilepsy risk versus DPP-4i (sHR 0.49, 95% CI 0.32-0.76). GLP1RA was associated with elevated risks of nausea/vomiting: sHR 1.37 vs SGLT2i, 95% CI 1.15-1.62; sHR 1.46 vs sulfonylureas, 95% CI 1.24-1.71). Head-to-head real-world comparisons with established T2D therapies confirmed the broad cardiorenal and metabolic benefits and known on-target adverse effects of GLP-1RAs -consistent with randomized clinical trials - but also suggest potential risks for musculoskeletal and genitourinary adverse events, warranting continued real-world post-market surveillance.

Figure-1:

Overview of the study design. (A) Real-World data source across UC Health B) Treatments considered in this study c) Cohort identification following inclusion and exclusion criteria (D) High-dimension propensity score estimation of treatment assignment at each site individually (E) Matched cohorts of each comparator and treatment at each site (F-G) Phenome-wide outcome analysis of matched cohort at each site independently (H) Random-effect meta-analysis with leave-one-medical-center-out stability analysis of each effect estimate across UC Health (I) Analysis of the robustness of the summary estimates with respect to un-measured confounding (J) Evidence landscape at varying degree of statistical certainty, significance and un-measured confounding.

Figure-2:. Propensity score distribution and balance diagnostics.

Distribution of propensity scores before and after matching as well as covariate balance diagnostic across UC Health for sulfonylurea vs GLP1-RA comparison. A) (top panel) propensity score distribution before matching, (middle panel) propensity score distribution after matching, and (bottom panel) covariate balance in terms of standardized mean difference of 5,286 covariates used in the propensity score estimation at UC-1.

Figure-3:. Phenome-wide associations.

Elevated or reduced risk of 239 clinical phenotypes on treatment GLP-1RA compared with sulfonylurea, DPP-4i or SGL-2i across 5 UCs. The outermost ring delineates phenotypic categories (clinical endpoints, n = 239) stratified by body system (n = 14). Concentric rings represent hazard ratios for increased or reduced risk of corresponding clinical endpoints within each organ system for sulfonylurea, DPP-4i and SGLT-2i compared with treatment GLP-1RA at each of the UC.

Figure-4:. Real-world evidence landscape at varying degree of statistical significance.

Evidence landscape of comparative risk profiles at varying degree of statistical certainty, significance and un-measured confounding comparing GLP-1RA (treatment) and sulfonylurea, SGLT-2i, or DPP-4i (controls). A) Outcomes with reduced risk B) outcomes with increased risk.