Use of Sodium-Glucose Co-Transporter-2-Inhibitors (SGLT2-Is) and Risk of Lower Limb Amputation

Abstract

Background: Treatment with sodium-glucose co-transporter-2-inhibitors (SGLT2-Is), such as canagliflozin, has been associated with an increased risk of lower limb amputations (LLAs) in type 2 diabetes mellitus (T2DM). However, conflicting results have been reported for different SGLT2-Is and the underlying mechanism is unclear. Objective: To investigate the risk of LLA and diabetic foot ulcer with SGLT2-I use compared to other anti-diabetic drugs and to explore hypovolemia as a potential underlying mechanism. Methods: A cohort study was conducted using data from the Clinical Practice Research Datalink GOLD (2013-2019). The study population (N=51,847) consisted of T2DM patients over 18 years of age with at least one prescription of a noninsulin anti-diabetic drug. Concomitant diuretic use and the presence of signs of hypovolemia were determined to assess the potential underlying mechanism. Cox proportional hazard models were used to estimate the hazard ratio (HR) for LLA in current SGLT2-I use versus current sulphonylurea (SU) use. Analyses were adjusted for life-style variables, comorbidities and concomitant drug use. Results: Current SGLT2-I use was not associated with an increased risk of LLA compared to current SU use (fully adjusted HR 0.70; 95% confidence interval 0.38-1.29). Concomitant use of diuretics and the presence of signs of hypovolemia were not associated with an increased risk of LLA. Conclusion: Use of SGLT2-Is, with or without signs of hypovolemia, was not associated with an increased risk of LLA or DFU versus current SU use. Future studies powered to detect potential differences between individual SGLT2-Is are required to rule out a canagliflozin-specific effect.

Safety of sodium-glucose transporter 2 (SGLT-2) inhibitors in patients with type 2 diabetes: a meta-analysis of cohort studies

“…1.61 per 1,000 person-years; HR: 0.87; 95% CI: 0.72–1.06; p = 0.18; I 2 = 79.8%; Supplementary Appendix S5.5 ). The prevalence of PVD in these studies ranged from 0% to 8.1% ( Ryan et al, 2018 ; Yang et al, 2019 ; Yuan et al, 2018; Fralick et al, 2020 ; Yu et al, 2020 ; Paul et al, 2021 ; Werkman et al, 2021 ; Patorno et al, 2022 ). Similarly, when the baseline PVD prevalence was greater than 10% (768 events among 264,885 patients vs .…”

Effect of Sodium-Glucose Cotransporter Type 2 Inhibitors on Clinical Outcomes in Patients With Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials

“…SGLT-2s reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with T2DM, with or without basic renal disease, and provided protection against acute kidney injury [45][46][47]. The use of SGLT-2s was not associated with an increased risk of fracture and amputation compared with other antidiabetics [44,[48][49][50]. Volume depletion is another major concern, not consistent with recent studies, which showed signi cant differences between SGLT-2s and other oral hypoglycaemic agents in volume depletion events [51][52][53], perhaps because of individualised dosing of SGLT-2s.…”

Effects of SGLT2 inhibitors and GLP1-receptor agonists on cardiovascular and limb events in peripheral artery disease: A review

“…56 However, a cohort study using data from the Clinical Practice Research Datalink GOLD (2013–2019) demonstrated using SGLT2i drugs in 51,847 patients, with or without signs of hypovolemia, was not associated with an increased risk of lower-limb amputation. 57…”

“…56 However, a cohort study using data from the Clinical Practice Research Datalink GOLD (2013-2019) demonstrated using SGLT2i drugs in 51,847 patients, with or without signs of hypovolemia, was not associated with an increased risk of lower-limb amputation. 57 Six observational studies using the Truven MarketScan health claims database from the USA were conducted to investigate the effect of SGLT2i drugs use on amputation risk. The results vary from no difference in amputation risk with canagliflozin compared with non-SGLT2i glucose-lowering agents in three studies [58][59][60] and lower amputation risk with SGLT2i drugs (where canagliflozin therapy comprised 70% of SGLT2i use) compared with sulfonylurea agents, but not compared to DPP-4 inhibitors in two studies 61,62 and only one study that showed a higher amputation risk with SGLT2i drugs compared with DPP-4 inhibitors, but not compared with sulfonylurea agents or non-metformin, non-SGLT2i glucose-lowering agents.…”