SGLT2 inhibitors and lower limb amputations

SGLT2 inhibitors (SGLT2i) and lower limb amputations

• a systematic review and meta-analysis concluded that (1):
  • there was no consistent evidence of SGLT2i exposure and increased risk of amputation. The increased risk of amputation seen in the large, long-term Canagliflozin Cardiovascular Assessment Study (CANVAS) trial for canagliflozin, and select observational studies, merits continued exploration
    
    
• a Korean database study (n=219900) concluded that (2)
  • initiating SGLT2is against dipeptidyl peptidase-4 inhibitors (DPP-4i) did not increase the risk of amputation across patient populations of varying vulnerability
    
    
• a review (51 RCTs; n=97,589) found that overall, SGLT-2 inhibitors were associated with an increased risk of peripheral arterial disease (OR 1.20, 95% CI 1.01–1.43, p=0.04), but not amputation (1.18, 0.78–1.79, p=0.43) (3)
  • however, risk was increased for treatment duration >100 weeks
  • the study authors caution that their research has various limitations, and the data therefore need to be interpreted carefully
    • findings emphasise the importance of patient and clinical vigilance in monitoring foot infections and other conditions that can precede amputation
      
      
• in a retrospective cohort study (76,072 SGLT-2 inhibitor vs. 75,833 DPP-4i use episodes) SGLT-2 inhibitor as add-on to metformin +/- sulfonylurea +/- insulin for diabetes was associated with an increased cause-specific hazard of peripheral arterial disease surgeries vs DPP-4i (adjusted hazard ratio 1.18 [95% CI 1.08–1.29])
  • study authors concluded:
    • SGLT2i as an add-on therapy was associated with increased cause specific hazard of PAD surgeries compared to DPP4i

Reference:

1. Heyward J, Mansour O, Olson L, Singh S, Alexander GC. Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis. PLoS One. 2020 Jun 5;15(6):e0234065. doi: 10.1371/journal.pone.0234065. PMID: 32502190; PMCID: PMC7274434.
2. Park, S, Jeong, HE, Bea, S, et al. Safety of sodium-glucose co-transporter-2 inhibitors on amputation across categories of baseline cardiovascular disease and diuretics use in patients with type 2 diabetes. Diabetes Obes Metab. 2023; 1-11. doi:10.1111/dom.15221
3. Geng L, Sun B, Chen Y. A meta-analysis of randomized controlled studies examining the effects of sodium-glucose co-transporter-2 inhibitors on peripheral artery disease and risk of amputations. Diabetes Obes Metab. 2024; 1-14
4. Griffin KE et al. Use of SGLT2i Versus DPP-4i as an Add-On Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery): A Cohort Study in Veterans With Diabetes. Diabetes Care 2024; dc241546