Real‐world risk of lower‐limb amputation associated with sodium–glucose cotransporter 2 inhibitors versus metformin: A propensity score‐matched model analysis in Japan

Abstract

Aims/Introduction We aimed to clarify the real‐world risk of lower‐limb amputation and identify factors related to increased risk in Japanese patients with type 2 diabetes using sodium–glucose cotransporter 2 inhibitors (SGLT2is). Materials and Methods We carried out a retrospective observational cohort study utilizing the Japanese Medical Data Vision, a diagnosis procedure combination database. We identified 107,296 patients with type 2 diabetes who were initiated on SGLT2is or metformin (control; n = 53,648 per group) using 1:1 propensity score matching from April 2014 to October 2019. The hazard ratio (HR) for the risk of lower‐limb amputation was analyzed using a Cox proportional hazards model adjusted for patients' baseline characteristics and use of concomitant medical agents. Results Of the 107,296 patients, 66 (0.06%); that is, 41 (0.08%) in the SGLT2is group and 25 (0.05%) in the metformin group, underwent amputation, with no significant difference in the proportions between the groups. There was no significant difference in the risk of amputation between the SGLT2is and metformin groups (HR 1.34, 95% confidence interval [CI] 0.80–2.24). However, female sex (HR 2.78, 95% CI 1.12–6.94) and use of strong statins (HR 2.68; 95% CI 1.18–8.20) were significantly associated with a higher risk of amputation in the SGLT2is group than in the metformin group. Conclusions SGLT2is might not be related to an increased risk of lower‐limb amputation in patients with type 2 diabetes in real‐world clinical practice. The possible increased risk of SGLT2is‐associated amputation in female patients with type 2 diabetes and patients with type 2 diabetes requiring strong statins is notable.

Comparative safety of different recommended doses of sodium–glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systematic review and network meta-analysis of randomized clinical trials

“…In terms of amputation, based on the assessment of recent new clinical data and large-scale real-world studies, although the subgroup analyses suggest that the risk of amputations, although still increased with canagliflozin, is lower than previously described. Furthermore, overall analyses have not shown a significantly increased risk of amputations associated with SGLT-2i (63)(64)(65)(66)(67), thus, the boxed warning about e risk of amputations for canagliflozin was removed from the prescribing information by the FDA in 2020.…”

Effectiveness and safety of sodium–glucose cotransporter 2 inhibitors in Asian populations

“…Furthermore, these incidence rates are relatively low in Asian people compared with those in other countries 13 . In real‐world clinical practice settings, the initiation of SGLT2i therapy did not result in an increased risk of fracture in South Korea or lower‐limb amputations in Japan 15,16 . In older adults aged ≥65 years in South Korea, the initiation of SGLT2i therapy did not increase the risk of diabetic ketoacidosis, fracture or severe hypoglycemia.…”

The role of sodium-glucose cotransporter type 2 inhibitors on the path to cardiovascular well-being in type 2 diabetes mellitus and chronic kidney disease

“…пациентов с СД 2 типа, которым была начата терапия иНГЛТ-2 или метформином (контроль n=53648), с апреля 2014г по октябрь 2019г. Из 107296 пациентов 66 (0,06%) : 41 (0,08%) в группе иНГЛТ-2 и 25 (0,05%) в группе метформина подверглись ампутации без существен-ной разницы между группами (ОР 1,34, 95% ДИ: 0,80-2,24) [25].…”