Abstract
BACKGROUND: Cardiometabolic disease is a leading cause of pulmonary hypertension (PH), a progressive condition that increases the risk of death and heart failure hospitalization. Preventive therapies are lacking, and Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a promising intervention due to their broad cardiometabolic benefits. Therefore, this study was designed to determine whether GLP-1 RA exposure is associated with reduced risk for developing PH. METHODS: We conducted a retrospective cohort study using data from the Veterans Health Administration. Patients with diabetes and an echocardiogram without PH who initiated a GLP-1 RA or Dipeptidyl Peptidase 4 inhibitor (DPP-4i) between January 1, 2007 and December 31, 2021 were included in the study. We used the active comparator, new user design to emulate a pragmatic clinical trial and employed inverse probability weighting (IPW) to adjust for confounding. GLP-1 RA new users were compared to DPP-4i new users. Patients were followed from first prescription date (baseline) until PH diagnosis, death, or medication cessation (latest date April 30, 2022). The primary outcome was development of PH, defined by an echocardiographic estimated right ventricular systolic pressure of 35 mmHg or greater. RESULTS: We identified 4,109 GLP-1 RA users and 7,384 DPP-4i users without PH at baseline. In comparison to DPP4i users, GLP-1 RA users were younger (median [Q1-Q3], 69 [63-73] vs 70 [65-74]) and similar in sex distribution (94.6% vs 95.6% male). Unadjusted incidence rates of PH for GLP-1 RA compared to DPP-4i were 54.8 vs 69.7 cases per 1000 person-years. IPW achieved covariate balance between groups (all standardized mean differences <0.10). In Cox regression models on the IPW cohort, GLP-1 RA exposure compared to DPP-4i exposure was associated with a 28% reduced risk of developing PH (HR, 0.72; 95%CI 0.61-0.84). Reduced risk of PH associated with GLP-1 RA use was consistent across sensitivity and subgroup analyses, including when stratified by obesity and diabetes severity. CONCLUSIONS: GLP-1 RA use was associated with a reduced risk of developing PH. This finding supports the need for clinical trials and mechanistic studies to evaluate the potential role of GLP-1 RA therapy in the prevention of PH.