EASD 2018: Diuretics Linked With Greater Amputation Risk in Type 2 Diabetes

October 2, 2018—Berlin, Germany—The use of diuretics among patients with type 2 diabetes is associated with an increased risk of having a lower limb event, particularly one requiring an amputation, according to a presentation made at the 54th Annual Meeting of the European Association for the Study of Diabetes, taking place here from Oct 1 – 5, 2018.

“This study was based on the hypothesis that amputation warnings found in the CANVAS trial could be driven by the diuretic effect of SGLT-2 inhibitors,” Louis Potier, MD, with Assistance Publique - Hôpitaux de Paris (AP- HP) in France told Elsevier’s PracticeUpdate. “This is, to our knowledge, the first study so far to propose a mechanistic explanation for this unexpected outcome.”

For the prospective, observational cohort study known as SURDIAGENE, 1074 patients with type 2 diabetes were enrolled between 2002 and 2012 and followed-up until the onset of lower-limb events, death, or December 31, 2015. The primary outcome measure was the first occurrence of a lower-limb event, defined as a composite of lower-limb amputation and lower-limb revascularization.

Patients were divided into those who were using diuretics at baseline and those who were not, with 537 patients in each group. The two groups of patients were matched. The mean age in each group was 65.9 years and 66.3 years, respectively. The proportion of males in each group was 57.2% and 57.4%, respectively.

During a median follow-up of period of 7.2 years, the incident rate of lower-limb events was 0.81 per 100 patient years among those using diuretics and 0.54 per 100 patient years among non-users. The hazard ratio for lower-limb events in users vs non-users of diuretics was 1.75 (95% confidence interval 1.19 - 2.58; P = .005).

Looking at lower-limb amputation and revasculariation separately revealed that diuretic use was associated with a greater risk of amputations (hazard ratio 2.34; 95% confidence interval 1.35 - 4.05; P = .003), but not revascularizarions (hazard ratio 1.28; 95% confidence interval 0.82 - 2.01; P = .28).

“In the light of our primary hypothesis of diuretic-induced effect for amputations observed in CANVAS, we assume that volume depletion could lead to hypoperfusion of the distal extremities and then trigger amputations,” said Dr. Potier. “However, this assumption remains speculative; we do not have enough data in our study to support this hypovolemia hypothesis. … Further studies with careful assessment of volemic status are needed to address this question.”

He also noted important limitations to the study. Only baseline exposure to diuretics was evaluated without considering duration of therapy or introductions and interruptions of these drugs during the study period.

While he recommended that clinical implications be addressed with caution, given the ongoing uncertainty about what drives this observed link, Dr. Potier suggested that, “clinical implications might be to use diuresis-inducing drugs with caution and with careful assessment of the volemia in patients at highest risk of amputations (ie, those with peripheral arterial disease or foot ulcers).”