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Beware: Diuretics Can Increase Risk of Amputations

May 4, 2019

Author: Steve Freed, R.PH., CDE

Study found diuretics can increase risk, and adding a SGLT-2 inhibitor which acts as a diuretic can also increase the risk.

Recently, safety data signaled an increased risk of amputations in people taking canagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor. If this side effect is due to drug-induced hypovolemia, diuretics should also increase that risk. The aim of this study was to analyze the association between diuretic use and the risk of lower limb events (LLEs) in people with type 2 diabetes.


The SURDIAGENE Study is a prospective observational cohort that includes people with type 2 diabetes and followed-up until onset of LLE, death or 31 December 2015, whichever came first. Primary outcome was the first occurrence of LLE, a composite of lower limb amputation (LLA) and lower limb revascularization (LLR). The rates of primary outcome were compared between participants taking and not taking diuretics at baseline..

The results showed that, at baseline, of the 1,459 participants included, 670 were taking diuretics. In participants with and without diuretics, the mean ages were 67.1 and 62.9 years and 55.8% and 59.8% were men, respectively. During a median follow-up of 7.1 years, the incidence of LLE was 1.80 per 100 patient-years in diuretic users vs 1.00 in non-users (p < 0.001). The HR for LLE in users vs non-users was 2.08, p < 0.001. This association remained significant in a multivariable-adjusted model and similar after considering death as a competing risk.

From the results it was concluded that, among people with type 2 diabetes treated with diuretics, there was a significant increase in the risk of LLE, predominantly in the risk of LLA, and the use of an SGLT-2 can increase that risk.

New research on diuretic use and amputation risk in people who have type 2 diabetes was presented at the European Association for the Study of Diabetes. It concluded that diuretic use almost doubled the risks for serious complications like lower limb amputations. This potential association between diuretic use and amputations came as a hypothesis from a previous study involving canagliflozin. SGLT-2 mechanism of action blocks glucose reabsorption in the kidneys, thereby increasing renal glucose excretion and lowering blood glucose levels.

According to the CANVAS study done in 2017, lower limb amputations were doubled in people with type 2 who were taking canagliflozin compared with placebo. SGLT-2 inhibitors have a mild diuretic effect due to osmotic diuresis as seen similarly with loop diuretics. The diuresis causes volume depletion or hypovolemia and that leads to reduced lower extremity perfusion. The findings from the CANVAS trial led to the new study just released that aimed to see if the hypovolemic effects of canagliflozin could be responsible for the increased risk of lower limb amputations. But to test this hypothesis, researchers examined diuretic use in people with type 2 and risk for amputations.

Results showed a lower limb event such as an amputation or revascularization (angioplasty or the bypassing of blocked or damaged blood vessels to prevent amputations) occurred in 13% of diuretic users and only 7% of non-users.

Propensity score matching was done to account for the different characteristics of participants. Each patient taking a diuretic was matched to a comparable patient not on a diuretic. The matched cohort included 1,074 participants and the results were similar.  Those on a diuretic had almost double the risk of lower limb events than non-users. Amputation risk was 2.3 times greater among diuretic users versus non-users.

Looking further into the data, higher risk for amputations were seen in men, those with high systolic blood pressure, and high albuminuria. Lower risk was associated with fibrate use.

The use of diuretics was by far the highest risk factor for lower limb amputations. Patients with type 2 diabetes who are being treated with diuretics should be cautious about risk of amputation. It is unclear if canagliflozin has an increased risk of amputations because of its diuretic effect, but it could be a possible explanation. Patients with type 2 diabetes and peripheral neuropathy should be cautious of diuretic use and choose appropriate therapy to mitigate severe complications like lower limb amputations.

Practice Pearls:

  • Among people with type 2, lower limb amputations rates were double that of canagliflozin users compared to non-users.
  • Similar results were found among diuretic use. The risk of lower limb amputations in people with type 2 who were using diuretics was double that of non-diuretic users.
  • Patient education on peripheral neuropathy signs and symptoms as well as monitoring for ulcers on the lower extremities will help reduce the risk of amputations, but caution should be highest when patients are on diuretics or an SGLT-2 inhibitor.


Diabetologia, First Online: 26 February 2019

Association of Diuretics Use and Amputations in Patients with Type 2 Diabetes—A Hypothesis Driven from Canvas Warning? Diabetes (2018), 67:Supp.1, 2221-PUB; DOI: 10.2337/db18-2221-PUB