Toe amputations with SGLT-2 inhibitors: data from randomized clinical trials

Excerpt

The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recently issued a warning on a possible risk of lower limb amputation associated with canagliflozin [http://​www.​fda.​gov/​Drugs/​DrugSafety/​ucm500965.​htm; http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Referrals_​document/​SGLT2_​inhibitors_​Canagliflozin_​20/​Procedure_​started/​WC500204901.​pdf], based on the interim results of the Canagliflozin Cardiovascular Assessment Study (CANVAS). In that trial, the incidence of toe amputation was 5–7 and 3 cases/1000 patient*years in active treatment and comparator groups, respectively. EMA reports that a smaller increase in the incidence of toe amputation was also found in another study with canagliflozin, CANVAS-R (7 versus 5 cases/1000 patient*years with canagliflozin and placebo, respectively), whereas no cases were reported in 12 further trials with the same molecule [http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Referrals_​document/​SGLT2_​inhibitors_​Canagliflozin_​20/​Procedure_​started/​WC500204901.​pdf]. Analyses on the risk of amputation with other SGLT-2 inhibitors are currently ongoing [http://​www.​ema.​europa.​eu/​docs/​en_​GB/​document_​library/​Referrals_​document/​SGLT2_​inhibitors_​Canagliflozin_​20/​Procedure_​started/​WC500204901.​pdf]. A similar signal of risk has been reported with thiazide diuretics, and it could be related to reduced volemia and increased hematocrit and blood viscosity; there is, therefore, a biological plausibility. …