Canagliflozin may protect against hyperkalemia in type 2 diabetes with CKD
medwireNews: Canagliflozin may reduce the risk for hyperkalemia, without increasing hypokalemia, in people with type 2 diabetes and chronic kidney disease (CKD) receiving renin–angiotensin–aldosterone system (RAAS) inhibitors, shows a CREDENCE post-hoc analysis.
Hiddo Heerspink (University of Groningen, the Netherlands) and co-investigators say “[t]he lower risk of hyperkalaemia with canagliflozin is notable since it was observed on a background of near-universal use of ACE [angiotensin-converting enzyme] inhibitors or ARBs [angiotensin-receptor blockers],” which are known to increase hyperkalemia risk.
Indeed, 99.9% of participants were receiving a RAAS inhibitor at baseline, when the mean serum potassium level was 4.5 mmol/L and the mean estimated glomerular filtration rate was 56 mL/min per 1.73 m2.
Heerspink et al found that, during a median 2.6 years of follow-up, investigator-reported hyperkalemia or initiation of potassium binders occurred in 8.1% of the 2202 individuals randomly assigned to receive the sodium-glucose cotransporter (SGLT)2 inhibitor canagliflozin 100 mg/day as part of the international CREDENCE trial.
This was significantly lower than the rate of 10.3% recorded among the 2199 participants assigned to receive placebo, resulting in a significant 22% lower risk for the composite outcome with canagliflozin.
Similarly, the risk for laboratory-determined hyperkalemia (serum potassium ≥6.0 mmol/L) was a significant 23% lower with canagliflozin versus placebo.
“Importantly, the effects of canagliflozin on hyperkalaemia outcomes did not appear to be explained by the differential concomitant use of potassium-sparing diuretics or mineralocorticoid receptor antagonists during the trial, which were similar in both treatment arms,” write Heerspink and co-authors in the European Heart Journal.
“Indeed, the reduction in risk of hyperkalaemia with canagliflozin was observed despite more frequent initiation of potassium binders, use of loop diuretics, and discontinuation of RAAS blockade over time in the placebo arm, which would be expected to lower serum potassium and limit our ability to detect effects on hyperkalaemia,” they add.
Conversely, the researchers found that canagliflozin had no significant impact on the risk for hypokalemia. They also observed that mean serum potassium levels increased during the course of the trial in both the canagliflozin and placebo arms, with no significant different between the two at any time point.
Heerspink and team conclude that their analysis “has important implications for the care of people with [type 2 diabetes] and CKD.” They suggest that “[t]he effect of canagliflozin on hyperkalaemia may make combined treatment with [SGLT2 inhibitors, RAAS blockade and finerenone] more feasible.”
The researchers add: “For individuals unable to tolerate RAAS blockade due to hyperkalaemia, treatment with an SGLT2 inhibitor alone may be a reasonable alternative, given the lower risk of hyperkalaemia with these agents.”
In an accompanying editorial, Ileana Piña, from the Central Michigan University College of Medicine in Midlands, USA, says “the implications of this study for clinicians caring for patients with diabetes mellitus and CKD should enhance confidence in the use of SGLT2 [inhibitors] not just to prevent hyperkalaemia, but also to allow the maintenance of renally protective drugs.”
The study data were also presented as an eposter at the virtual ESC Congress 2021.
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