Risk of amputation under diuretics in patients with or at risk of lower extremity arterial disease: A systematic review and meta-analysis

Background: Recently, increased risk of amputation under sodium glucose cotransporter-2 inhibitors has been debated. Similar concerns have been raised with other "traditional" diuretics, more particularly in patients with or at risk of lower extremity arterial disease (LEAD).

Aim: To collect all available data on any potential risk of amputation associated with diuretics in patients with or at risk of LEAD. Additionally, we looked for other limb-related events in these patients.

Methods: We searched in PubMed, Embase and Scopus databases up to February 2021 for references, using peripheral or lower extremity arterial disease, diuretics and amputation keywords, excluding case reports, experimental animal studies and non-English reports.

Results: Among the 1376 hits identified in the databases, six studies were finally included in this review, including one cross-sectional and five longitudinal studies (total of 47,612 participants). One study was limited to thiazide diuretics, one focused on loop diuretics and the remainder mixed all diuretics. All studies reported a significant association between diuretic use and amputation risk in patients with or at high risk of LEAD. Despite some limitations in several studies, the meta-analysis showed an increased risk of amputation associated with diuretics (odds ratio: 1.75, 95% confidence interval: 1.53-1.99; P<0.001). Beyond amputation, patients with or at risk of LEAD under diuretics appeared to be at increased risk of other lower limb events, mostly in the presence of other comorbidities, including diabetes.

Conclusions: Although the amount of data in the literature is scarce, this first systematic review and meta-analysis favours an increased risk of amputation in patients with or at risk of LEAD under diuretics. Further prospective studies must be conducted to provide a better understanding of the mechanisms. Meanwhile, the use of diuretics in these patients should be parsimonious, considering alternatives whenever possible.