Lower-limb amputations in patients treated with SGLT2 inhibitors versus DPP-4 inhibitors: A meta-analysis of observational studies

Background: An increased risk of lower limb amputations (LLA) has been suspected with the use of sodiumglucose cotransporter type 2 inhibitors (SGLT2is) in the CANVAS programme with canagliflozin and in pharmacovigilance reports with all SGLT2is. Even if reassuring observations were reported in several large prospective
placebo-controlled cardiovascular outcome trials, real-life conditions in more frailty patients might be associated with a higher risk.
Methods: This work analyses the incidence of LLA events in retrospective observational studies that compared SGLT2i users with patients treated with dipeptidyl peptidase-4 inhibitors (DPP-4is), a pharmacological class with an excellent safety profile. A meta-analysis of 12 comparative cohort studies (9 of them using a propensity score matching) worldwide has been performed.
Results: The relative risk of LLA tended to be slightly lower in SGLT2i users (1228 LLA events/711159 patients) versus DPP-4i users: 2167 LLA events/1121914 patients, with a hazard ratio 0.91, 95% CI 0.85-0.98, p=0.01).
However, a high between-study heterogeneity was observed (I2 = 79%, P<0.00001), which could not be explained by differences across countries, between studies with/without propensity score matching, between cohorts treated with/without canagliflozin or between patients with/without peripheral artery disease.
The incidence rate expressed as a number of LLA events per 1000 patient.years was almost similar among SGLT2i users and DPP-4i users (2.48§1.45 versus 2.67§3.09, p=0.849).
Conclusion: Physicians should not fear an increased risk of LLA with SGLT2is compared with DPP-4is in daily clinical practice, even if caution may be advised in some patients exposed to special conditions.