SGLT2 inhibitors reduce serious hyperkalemia

SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk and/or with CKD, without increasing the risk of hypokalemia.

The findings, published in Circulation, contrast with other disease modifying therapies such as RAAS inhibitors and MRAs, which increase the risk of hyperkalemia and consequently limit their utility.

The meta-analysis of nearly 50,000 participants from six RCTs and across four SGLT2 inhibitors has found the drugs consistently reduced the risk of serious hyperkalemia (serum potassium ≥6.0 mmol/L) about 16% overall (HR 0.84).

“In an additional sensitivity analysis, the incidence of mild hyperkalemia (central laboratory determined serum potassium ≥5.5 mmol/L) was also modestly lower with SGLT2 inhibitors (HR 0.92, 95% CI 0.86-0.98, P-heterogeneity=0.03),” the study said.

SGLT2 inhibitors also consistently reduced the risk of investigator-reported hyperkalemia events by 20% (HR 0.80).

“The relative effect of SGLT2 inhibitors on serious hyperkalemia was consistent across different levels of HbA1c, eGFR, UACR, history of heart failure, and use of MRAs and diuretic therapy,” it said.

“Additionally, no increased risk of hypokalemia [serum potassium ≤3.5 mmol/L] was observed.”

The study, led by Dr Brendon Neuen, an academic nephrology registrar and NHMRC Postgraduate Scholar at The George Institute Australia, said the study extends previous work – including a Cochrane Review – that suggested SGLT2 inhibitors might reduce the risk of hyperkalemia.

“However, whether benefits for hyperkalemia are similar for different agents within the SGLT2 inhibitor class and consistent across heterogenous populations with varying background risk and concomitant therapies has been uncertain.”

The researchers said the study provides substantive evidence that SGLT2 inhibition reduces the risk of serious hyperkalemia across diverse subgroups of individuals with type 2 diabetes, without increasing the risk of hypokalemia.

“These findings have important implications for the care of people with type 2 diabetes with CKD and/or heart failure, given that hyperkalemia is a major factor limiting the optimal use of RAAS inhibitors, which form the basis of disease modifying therapy in these populations.”

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