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Peripheral artery disease and amputations with Sodium-Glucose co-Transporter-2 (SGLT-2) inhibitors: A meta-analysis of randomized controlled trials

      Highlights

      • SGLT-2 inhibitors demonstrated to reduce cardiovascular morbidity and, for empagliflozin, mortality.
      • Some concerns have been raised for an increased risk of amputations with SGLT-2 inhibitors.
      • The possibility that SGLT-2 inhibitors can also increase the risk of peripheral artery disease cannot be excluded.
      • Individual SGLT-2 inhibitors could have differential effects on amputations and peripheral artery disease.

      Abstract

      Background

      Concerns have been raised on the risk of lower limb amputations with SGLT-2 inhibitors. Aim of the present metanalysis is the assessment of the effect of SGLT-2inhibitors on peripheral artery disease and lower limb amputations in randomized controlled trials performed in patients with type 2 diabetes.

      Methods

      A Medline and Embase search for “Canaglifozin” OR “Dapaglifozin” OR “Empaglifozin” OR “Ertuglifozin” OR “Ipraglifozin” OR Tofoglifozin” OR “Luseoglifozin” was performed, collecting randomized clinical trials (duration > 12 weeks) up to December 1st, 2018, comparing SGLT-2i at approved dose with placebo or other active comparators different from SGLT-2 inhibitors. Furthermore, unpublished studies were searched in the www.clinicaltrials.gov register. Separate analyses were performed for individual molecules of the class. In addition, a separate analysis was performed for placebo-controlled trials. Mantel-Haenszel odds ratio with 95% Confidence Interval (MH-OR) was calculated for all outcomes defined above.

      Results

      A total of 27 trials fulfilling the inclusion criteria was identified. The overall incidence of peripheral artery disease was increased with SGLT-2 inhibitors (MH-OR: 1.26 [1.04, 1.52]). The increase of risk was statistically significant only with canagliflozin. MH-OR for amputation in the three cardiovascular safety trials with SGLT-2 inhibitors was 1.22 [0.59–2.52].

      Conclusions

      At present, there is no reason to believe that empagliflozin or dapagliflozin increase the risk of either peripheral artery disease of lower limb amputations. Canagliflozin could be associated with a specific risk, which needs to be further investigated.

      Keywords

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