Safety and tolerability of sodium glucose cotransporter-2 inhibitors in children and young adults: A systematic review and meta-analysis.

PURPOSE: Sodium glucose co-transporter-2 inhibitors (SGLT2i) have been evaluated in children with type-2 diabetes (T2DM), Type-1 diabetes (T1DM) and several other non-diabetic conditions. Potential tolerability issues have been preventing us from routinely using SGLT2i in children with diabetes. No meta-analysis till date has evaluated the safety and tolerability of SGLT2i in children. This systematic review and meta-analysis aimed to address this knowledge-gap.

METHODS: Databases were searched for randomized controlled trials (RCTs), case-control and cohort studies involving children receiving SGLT2i in intervention-arm. Primary outcome was occurrence of treatment-emergent adverse events (TAEs). Secondary outcomes were evaluation of glycaemic efficacy and occurrence of severe adverse-events (SAEs), hypoglycaemia, ketosis, genital or urinary infections and any other adverse-events.

RESULTS: From initially screened 27 articles, data from 4 RCT (258 children) was analyzed. In children with T2DM, occurrence of TAEs [OR 1.77(95%CI:0.93-3.36);P=0.08;I2=0%], SAEs [OR 0.45(95%CI:0.08-2.54);P=0.37;I2=0%], ketoacidosis [OR 0.33(95%CI:0.01-8.37);P=0.50], urinary tract infections [OR 2.34(95%CI:0.44-12.50);P=0.32;I2=0%] and severe hypoglycaemia [OR 4.47(95%CI:0.21-96.40);P=0.34] were comparable among SGLTi group and placebo. Compared to placebo, T2DM children receiving SGLTi had significantly lower HbA1C at 24-26 weeks [MD -0.79%(95%CI:-1.33--0.26);P=0.004;I2=0%]. In T1DM children, ß-hydroxybutyrate levels were significantly higher in SGLTi group compared to placebo [MD 0.11mmol/L(95%CI:0.05-0.17);P=0.0005;I2=53%]. In T1DM, there was not a single report of SAE, ketoacidosis, severe hypoglycaemia among both groups, with time in range considerably greater in SGLT2i group (68%±6% vs. 50%±13%;P<0.001).

CONCLUSION: This study provides us with reassuring data on safety of use of SGLT2i in children and young adults.