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Diuretics and Risk of Lower Limb Amputation in People Who Have Type 2 Diabetes

Dec 1, 2018
Editor: David L. Joffe, BSPharm, CDE, FACA

Author: Angela Reyes, Pharm.D. Candidate, LECOM College of Pharmacy

New study shows diuresis, canagliflozin use nearly doubled risk of complications.

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 in Berlin, Germany. 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, a sodium glucose cotransporter-2 inhibitor (SGLT-2). 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.

Data came from SURDIAGENE, a French observational cohort. There were 1,459 participants in the study and 670 of them were taking a diuretic. The study follow-up was around 7 years and ended when either the patient had onset of a lower limb event, death, or trail end date of Dec. 2015.

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.


LOUIS POTIER, KAMEL MOHAMMEDI, ABDUL K. MOUTAIROU, ANISOARA BUMBU, ODETTE MATAR, FABRICE SCHNEIDER, MICHEL MARRE, PIERRE SAULNIER, GILBERTO VELHO, RONAN ROUSSEL, SAMY HADJADJ. 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

Angela Reyes, Pharm.D. Candidate, LECOM College of Pharmacy