Sodium Glucose Cotransporter 2 Inhibitors and Amputation Risk

Bonaca, Marc P.; Beckman, Joshua A.

doi:10.1161/circulationaha.118.032745

Cited by 10 publications

(3 citation statements)

References 17 publications

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“…Apart from RCTs, three US observational cohort studies14, 24, 60 and two disproportionality analyses of international spontaneous reporting systems, namely, the FDA Adverse Event Reporting System (FAERS) and the WHO Vigibase,61, 62 provided conflicting results as to whether or not this adverse effect concerns all SGLT2‐Is 63. Another critical issue is the mechanistic basis of this side effect,64 and the multifactorial role of disease and comorbidities. The mechanistic basis is unclear: while gliflozins are presented as selective inhibitors of SGLT2, canagliflozin causes a substantial inhibition of other SGLTs (including SGLT1, SGLT3 and SGLT6), but the biological effect is still uncertain 65.…”

Section: Observational Findings: What's Missing?mentioning

confidence: 99%

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

Raschi

Poluzzi

Fadini

et al. 2018

Diabetes Obesity Metabolism

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Sodium glucose co‐transporter‐2 inhibitors have attracted the interest of the scientific community following the results from dedicated cardiovascular outcome trials, which demonstrated remarkable reduction in all‐cause mortality and other cardiovascular (CV) endpoints with empagliflozin and canagliflozin. These impressive results raised further expectations on real world data from large observational cohort studies. They were designed to address the possible existence of a class effect, and the uncertainty on whether this benefit can be extended from secondary to primary CV prevention of patients with type 2 diabetes. In this review, we collated data from existing observational studies (including the celebrated CVD‐REAL cohorts) and critically appraised results and methodological issues with the aim of providing clinical insight, including unsettled aspects, and proposing a research agenda for future investigations.

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Section: Observational Findings: What's Missing?mentioning

confidence: 99%

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

Raschi

Poluzzi

Fadini

et al. 2018

Diabetes Obesity Metabolism

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“…Evidence from observational studies, including some comparing SGLT-2i with GLP-1RA ( Chang et al, 2018 ; Ueda et al, 2018 ; Fralick et al, 2020 ; Hsiao et al, 2021 ; Patorno et al, 2021 ; Paul et al, 2021 ), was divergent and conflicting ( Chang et al, 2018 ; Ryan et al, 2018 ; Ueda et al, 2018 ; Fralick et al, 2020 ; Caparrotta et al, 2021 ; Hsiao et al, 2021 ; Li et al, 2021 ; Patorno et al, 2021 ; Paul et al, 2021 ), probably due to heterogeneity in terms of study design and analysis, specific types of SGLT-2i, characteristics of the included populations, and the choice of comparator drugs. Given complex and multifactorial reasons that drive diabetes patients toward amputation instead of revascularization procedures, few studies had evaluated comprehensively the safety of SGLT-2i, as compared with GLP-1RA, on the composite major adverse limb outcome: CLI, which was at the late stage of the broad spectrum of PAD ( Bonaca and Beckman, 2018 ). Moreover, based on the signal warning about the risk of using canagliflozin from the CANVAS trial, questions remain regarding to whether this is restricted to a specific drug or a class effect that also applies to other SGLT-2i ( Khouri et al, 2018 ).…”

Section: Introductionmentioning

confidence: 99%

Risk of major adverse limb events in patients with type 2 diabetes mellitus receiving sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists: A population-based retrospective cohort study

et al. 2022

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Background: Both sodium glucose cotransporter 2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) have cardiovascular protective effects in patients with type 2 diabetes mellitus. However, the comparative risk of GLP-1RA versus SGLT-2i for major adverse limb events remains unknown.Materials and methods: We studied a nationwide cohort involving 123,048 diabetes patients 20–100 years of age who initiated a SGLT-2i or GLP-1RA during 2012 and 2017. The patients in the two groups were matched by propensity score (PS), and incidence rates for hospitalization for major adverse limb events, critical limb ischemia (CLI) and lower extremity amputation (LEA), were assessed. Cox proportional hazards regression was applied to estimate hazard ratios (HRs) between patients receiving SGLT-2i as compared with GLP-1RA. The modification effects of age, a history of established cardiovascular disease, and chronic kidney disease were examined. In addition, use of dipeptidyl peptidase-4 inhibitor (DPP-4i) was chosen as a second active comparator.Results: After PS-matching, a total of 13,378 SGLT-2i and 13,378 GLP-1RA initiators were identified. Use of SGLT-2i was not associated with an increased risk for hospitalization for CLI and LEA, either compared with GLP-1RA (HR, 1.13; 95% CI, 0.77–1.65 and 1.27; 95% CI, 0.63–2.55, respectively) or compared with DPP-4i use (HR, 1.06; 95% CI, 0.75–1.50 and HR, 0.80; 95% CI, 0.42–1.53, respectively). Although the study was underpowered to explore potential effect modification, a trend of higher risks for LEA was noted among SGLT-2i users with cardiovascular disease as compared with either GLP-1RA or DPP-4i.Conclusion: Use of SGLT-2i was not associated with higher risks for hospitalization for CLI and LEA as compared with reference drugs. Further large-scale studies are needed for a precise risk estimation.

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“…Although there is a need to identify the underlying causes associated with amputations in SGLT-2 inhibitors. Theoretically, using these drugs in people with peripheral vascular disease could cause high tissue hypoperfusion, contributing to the onset of amputations [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Amputation Risk in Type II Diabetes Mellitus Patients Treated with SGLT-2 Inhibitors: A Systematic Literature Review of Randomized Clinical Trials

Hoda,

Jamali,

Arshad

et al. 2024

Drug Res (Stuttg)

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Background SGLT-2 inhibitors, prescribed for type 2 diabetes, have a heightened risk of amputation. The FDA issued a warning in May 2017, leading to the inclusion of a cautionary label. Vigilance is essential for patients and healthcare providers to promptly identify and address potential limb complications associated with the use of SGLT-2 inhibitors. Method A comprehensive search of electronic databases was conducted, covering the period from inception to May 2024. This systematic literature review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of the included studies was assessed using the Cochrane risk of bias (ROB) tool. Inclusion and exclusion criteria were predefined, and data extraction was performed to summarize the findings. Result A total of 12 randomized control trial (RCT) studies were included in the present systematic review. 37,657 (54.89%) participants were randomly assigned to receive the different interventions of SGLT-2 inhibitor, whereas 30,959 (45.11%) received a placebo. Overall, 618 events were reported in the treatment group, whereas 396 events were reported in the placebo group. Conclusion In conclusion, patients treated with SGLT-2 inhibitors did not have any significant difference in amputation occurrences compared to placebo across various studies. However, canagliflozin usage has led to higher amputation events in certain trials.

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Sodium Glucose Cotransporter 2 Inhibitors and Amputation Risk

Cited by 10 publications

References 17 publications

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

Observational research on sodium glucose co‐transporter‐2 inhibitors: A real breakthrough?

Risk of major adverse limb events in patients with type 2 diabetes mellitus receiving sodium glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists: A population-based retrospective cohort study

Amputation Risk in Type II Diabetes Mellitus Patients Treated with SGLT-2 Inhibitors: A Systematic Literature Review of Randomized Clinical Trials

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