A safety update on sodium glucose co-transporter 2 inhibitors

Sodium glucose co-transporter 2 inhibitors (SGLT2is) are the first class of glucose lowering agent to be shown to reduce cardiovascular events. They are generally well tolerated with infrequent serious adverse events. The most frequent side effect is genital mycotic infections with candida species that are usually mild to moderate in severity, easily treated and infrequently recur. Urinary tract infections, although common in patients with diabetes, have not been shown to be increased in controlled studies with SGLT2i. Hypoglycaemia can occur when an SGLT2i is added to agents that cause hypoglycaemia, such as insulin or sulphonylureas. Volume depletion and hypotension is infrequent and can be minimized by adjusting diuretic and antihypertensive treatment in patients at risk. Acute renal failure or kidney injury was observed in early observational studies. However, in randomized controlled trials (RCTs) and in more recent observational studies a decreased incidence of acute kidney injury was observed in SGLT2-treated patients compared to those receiving either placebo or another class of glucose lowering agents. An increased incidence of amputation (largely feet and toes) was observed in the RCT with canagliflozin but not with the other SGLT2i. Observational studies have shown either an increased risk of amputation with other agents whereas another study showed no increase. Although the increased risk of amputation is very low, avoidance of SGLT2i in patients at high risk seems prudent. Increased incidence of fractures was observed with canagliflozin but not with SGLT2i nor in a meta-analysis that included canagliflozin, empagliflozin and dapagliflozin. No increased incidence of cancer has been observed in either RCTs or observational studies.