Recently, an increased risk of lower extremity amputation (LEA) was observed with canagliflozin, a SGLT2 inhibitor, in the CANVAS trial although observational studies showed conflicting results. This association could be related to the contraction of plasma volume induced by SGLT2 inhibition. In this case, copeptin, a surrogate marker of vasopressin, should be associated with LEA. Our aim was to analyze the association between LEA and plasma copeptin in 4 cohorts of patients with type 1 and type 2 diabetes (T1D, T2D). Analysis were done in 2 pooled cohorts of patients with type 2 diabetes (DIABHYCAR, SURDIAGENE, n=4532) and 2 pooled cohorts of patients with type 1 diabetes (GENESIS, GENEDIAB, n=712). Cox regression model was fitted to compute hazard ratio (HR) and 95% CI for incident LEA by tertiles of copeptin at baseline. C-statistic, integrated discrimination improvement (IDI) and continuous net reclassification improvement (cNRI) were used to assess the prognostic value of copeptin in LEA discrimination. Mean follow-up was 5.3 years for DT2 and 6.3 for DT1. Incidence of LEA was 1.6% (T1), 2.6% (T2) and 3.3% (T3) for DT2 (p<0.001) and 3.9% (T1), 3.3% (T2) and 10% (T3) for DT1 (p=0.003). In a Cox multivariable analysis model (adjusted for cohort, sex, diabetes duration, hypertension, previous cardiovascular and peripheral arterial disease and glomerular filtration rate), HR for LEA was 1.91 (1.13-3.24; p=0.016) in DT2 and 2.76 (1.05-7.66; p=0.04) in DT1, both for T3 vs. T1. Plasma copeptin yielded incremental information for the risk of LEA in DT2: C-statistic change 0.012 (p=0.005), IDI: 0.007 (0.005-0.025, p=0.05), cNRI: 0.13 (0.03-0.29, p=0.03). Plasma copeptin is significantly associated with an increased risk of LEA in patients with T1D and T2D. Mechanisms underlying this association are not known but could be related to hydration status. Our results suggest a potential role of contraction volume effect of SGLT2 inhibitor in the higher risk of LEA possibly associated with this class.


L. Potier: Advisory Panel; Self; Merck Sharp & Dohme Corp. Consultant; Self; Sanofi. R. Roussel: Advisory Panel; Self; Merck Sharp & Dohme Corp., Sanofi. Consultant; Self; Abbott, AstraZeneca, Eli Lilly and Company, Medtronic, Novo Nordisk A/S, Physiogenex. Research Support; Self; Janssen Pharmaceuticals, Inc. K. Mohammedi: None. P. Saulnier: None. M. Marre: Advisory Panel; Self; Servier. Board Member; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. S. Hadjadj: Consultant; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk A/S, Sanofi, Servier. Research Support; Self; Bayer AG, Janssen Research & Development. Speaker's Bureau; Self; Abbott, Valbiotis. G. Velho: None.

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