Association of Antidiabetic Medication Classes With Survival Outcomes in Pulmonary Hypertension Patients With Diabetes

Aaron W. Trammell, Divya Verma, Alyssa R. Cruse, Xiangqin Cui, Matthew Ryan Smith, Charles Michael Hart

https://doi.org/10.1002/pul2.70313 
 

Abstract

Pulmonary hypertension (PH) and diabetes frequently coexist, and metabolic dysregulation plays a role in PH pathogenesis. While preclinical studies indicate that certain antidiabetic therapies may beneficially impact the pulmonary vasculature and right heart function in PH, clinical data remain limited. We conducted a retrospective cohort study of veterans with PH and diabetes using Veterans Health Affairs data (2003–2015). The associations between exposure to antidiabetic medications at the time of PH diagnosis and survival were analyzed using Cox proportional hazards regression. We identified 41,670 veterans with PH and diabetes, largely older men (median age 69, 97% male). Average survival from PH diagnosis was 3.5 years. After adjustment for demographics, comorbid conditions, renal function, and hemoglobin A1c, metformin and thiazolidinedione (TZD) exposure were associated with lower mortality (HR 0.828, 95% CI 0.799–0.857 and HR 0.838, 95% CI 0.793–0.885, respectively). Conversely, insulin use was associated with higher mortality. These associations remained consistent across multiple analytical approaches and were independent of baseline hemoglobin A1c levels. Interactions were observed between drug effects and both renal function and PH comorbidities, with metformin's protective effect enhanced in patients with lower eGFR but attenuated in those with lung disease. In conclusion, metformin and TZD use were associated with improved survival in veterans with PH and diabetes, while insulin use was associated with reduced survival. These findings suggest that metabolic modulation may represent a viable therapeutic strategy in PH, though could be context dependent. Prospective trials are needed to evaluate therapeutic approaches targeting the metabolic pathobiology of PH.

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