Effects of SGLT-2 inhibitors on diabetic ketoacidosis: A meta-analysis of randomised controlled trials


      • SGLT-2 inhibitors stimulate ketone reabsorption, increasing the risk of ketoacidosis.
      • Ketoacidosis with SGLT2 inhibitors is a relevant acidosis with mild hyperglycemia.
      • If the drug is properly prescribed, the risk of DKA is negligible in type 2 diabetes.



      Diabetic ketoacidosis (DKA) associated with SGLT-2 inhibitors (SGLT-2i) is a possible adverse event. In fact, SGLT-2i are capable of stimulating the release of glucagon and ketone re-absorption in the renal tubuli, thus increasing the concentration of ketone bodies.


      A Medline search for SGLT2i (dapagliflozin, empagliflozin, canagliflozin, ipragliflozin, ertugliflozin, luseogliflozin) was performed, collecting all randomized trials with a duration of treatment ≥ 12 weeks, enrolling patients with type 2 diabetes, and comparing a SGLT2i with placebo or other comparators. The principal outcome was the effect of SGLT2i on ketoacidosis as serious adverse event.


      Out of 72 trials reporting information on DKA, 9 reported at least one event of ketoacidosis; those eight trials enrolled 10,157 and 5396 in SGLT-2 inhibitors and comparator groups, respectively. No signal of increased risk for ketoacidosis was observed for SGLT2 inhibitors as a class (MH-OR [95% CI] 1.14 [0.45–2.88], p = 0.78) or as individual molecule. The sensitivity analysis with continuity correction (inputing one event each in drug and comparator arms of each trial with zero events) suggested a reduced incidence of ketoacidosis in patients treated with SGLT-2 inhibitors (MH-OR 0.65 [0.47–0.90]; p = 0.01).


      The results of clinical trials summarized in the present meta-analysis reassure us that, when the drug is properly prescribed, the risk of DKA is negligible.


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