Cardiovascular risk of gabapentin and pregabalin in patients with diabetic neuropathy
Authors: Pan Yiheng , Davis Pamela B. , Kaebler David C. , Blankfield Robert P. , Xu Rong 
Published: September 2022

Abstract
Background
Gabapentin and pregabalin are commonly prescribed medications to treat pain in patients with diabetic neuropathy. Gabapentin and pregabalin can cause fluid retention, which is hypothesized to be associated with cardiovascular diseases. However, whether long-term use of gabapentin and pregabalin is associated with adverse cardiovascular diseases remains unknown. This study aims to examine the association between gabapentin use, pregabalin use and several adverse cardiovascular events.

Methods
This retrospective cohort study used propensity score matching within patient electronic health records (EHRs) from a multicenter database with 106 million patients from 69 health care organizations in the US. The study population comprised 210,064 patients who had a diagnosis of diabetic neuropathy and were prescribed diabetic neuropathy medications in their EHRs. The exposure cohort comprised patients who were prescribed gabapentin or pregabalin to treat diabetic neuropathy. The comparison cohort comprised patients who were not prescribed either gabapentin or pregabalin but were prescribed other drugs to treat diabetic neuropathy. The outcomes of interest were myocardial infarcts, strokes, heart failure, peripheral vascular disease, and venous thromboembolic events. We calculated hazard ratios (HRs) and 95% confidence intervals (CIs) for 3-month and 5-year risk for adverse cardiovascular events between the propensity score-matched cohorts.

Results
Both gabapentin and pregabalin were associated with increased risk of 5-year adverse cardiovascular events compared with the comparison group. In patients prescribed gabapentin, the highest risk was observed for deep venous thrombosis (HR: 1.58, 95% CI 1.37–1.82), followed by pulmonary embolism (HR: 1.5, 95% CI 1.27–1.76), peripheral vascular disease (HR: 1.37, 95% CI 1.27–1.47), stroke (HR: 1.31, 95% CI 1.2–1.43), myocardial infarction (HR: 1.25, 95% CI 1.14–1.38) and heart failure (HR: 1.14, 95% CI 1.07–1.21). In patients prescribed pregabalin, the highest risk was observed for deep venous thrombosis (HR: 1.57, 95% CI 1.31–1.88), followed by peripheral vascular disease (HR: 1.35, 95% CI 1.22–1.49), myocardial infarction (HR: 1.29, 95% CI 1.13–1.47), pulmonary embolism (HR: 1.28, 95% CI 1.04–1.59), stroke (HR: 1.26, 95% CI 1.12–1.42), and heart failure (HR: 1.2, 95% CI 1.11–1.3). There were significant associations between short-term (3 month) gabapentin use and heart failure, myocardial infarction, peripheral vascular disease, deep venous thrombosis, and pulmonary embolism. Short-term (3 month) pregabalin use was associated with deep venous thrombosis, peripheral vascular disease.

Conclusion
In patients with diabetic neuropathy who were prescribed gabapentin and pregabalin, there is an increased risk for heart failure, myocardial infarction, peripheral vascular disease, stroke, deep venous thrombosis, and pulmonary embolism with long-term use. Our findings suggest that increased risk for adverse cardiovascular events, along with other side effects, the efficacy of pain control and the degree of tolerance of the patient, should be considered when prescribing gabapentin and pregabalin long-term in patients with diabetic neuropathy.