Association of Diuretics Use and Amputations in Patients with Type 2 Diabetes—A Hypothesis Driven from Canvas Warning?

Abstract

Clinical trials in patients with type 2 diabetes (T2D) showed that the incidence of lower limb amputations (LLA) was doubled in patients in canagliflozin arm compared with placebo. Whether hypovolemia favored by SGLT2 inhibition-induced diuresis could be associated with a reduced lower extremity perfusion is a potential explanation. Although we cannot test this hypothesis directly, a similar side-effect of diuretics would be a supportive argument. We tested the association between use of diuretics (recorded at baseline) and risk of LLA (any LLA occurring during follow-up) in patients with T2D from the SURDIAGENE French cohort. Unadjusted and adjusted cox models were used. Among 1468 participants (Male 58%, age 65±11 years, known diabetes duration 15±10 years), 670 (46%) were on treatment with diuretics. LLA occurred in 79 (5.4%) patients during 5.8±3.2 years of follow-up: 51 (3.5%) among diuretics users and 28 (1.9%) in non-users (p<0.001). In the unadjusted model, the risk of amputation was higher in diuretics users (hazard ratio (HR), 2.52; 95% CI, 1.59-4.02; P<0.0001). The risk remained significantly higher after adjustment for confounding variables (age, sex, BMI, HbA1c at baseline, systolic blood pressure, diabetes duration, current smoking status, cholesterol-lowering drugs use and urinary albumin to creatinine ratio): HR 2.51 (95% CI, 1.50-4.22; P=0.0005). Higher risk of LLA during follow-up was also independently associated with male sex (HR 1.80; 95% CI, 1.1-1.41; P<0.0001), higher systolic blood pressure (HR 1.02; 95% CI, 1.00-1.03; P=0.01), and higher albuminuria (HR 1.33; 95% CI, 1.18-1.50; P<0.0001). Lower risk of LLA was associated with the use of fibrate (HR 0.23; 95% CI, 0.06-0.95; P=0.04). In our prospective observational study, the use of diuretics was the highest risk factor for LLA in patients with T2D. The result supports the role of hypovolemia in the amputation risk in T2D, a potential under-recognized effect of canagliflozin. Disclosure L. Potier: Consultant; Self; Sanofi, Novo Nordisk A/S, Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp. K. Mohammedi: Speaker's Bureau; Self; Novo Nordisk Inc.. Other Relationship; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Sanofi. Other Relationship; Self; Sanofi, Takeda Development Centre Europe Ltd., Boehringer Ingelheim Pharmaceuticals, Inc.. A.K. Moutairou: None. A. Bumbu: Other Relationship; Self; Sanofi, Novo Nordisk A/S. O. Matar: None. F. Schneider: None. M. Marre: Board Member; Self; Abbott. Consultant; Self; AstraZeneca. Board Member; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Eli Lilly and Company. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. Research Support; Self; Sanofi. Board Member; Self; Servier. P. Saulnier: None. G. Velho: None. R. Roussel: Advisory Panel; Self; AbbVie Inc., Abbott, Eli Lilly and Company, Sanofi, Novo Nordisk A/S, AstraZeneca. Speaker's Bureau; Self; Servier. Consultant; Self; Bayer AG. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Amgen Inc., Sanofi, Novo Nordisk A/S, Danone Research. Stock/Shareholder; Self; Iriade. Advisory Panel; Self; Physiogenex S.A.S. S. Hadjadj: Consultant; Self; Abbott, Novo Nordisk A/S, Servier, AstraZeneca, Merck Sharp & Dohme Corp.. Board Member; Self; Valbiotis. Consultant; Self; Sanofi, Eli Lilly and Company.

Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis

“…Studies that evaluate the biological mechanisms that could account for any such risk of SGLT2i's are also needed. For example, it is unclear whether any increased risk of amputation, should it be present, is due to the diuretic effect of SGLT2i's; some studies have suggested that diuretics may increase the risk of amputations in patients with type 2 diabetes [48] [49].…”