Encourage Further SGLT2 Inhibitor Treatment for Diabetes, Kidney Disease, Expert Says


New data from the CREDENCE trial shows that the sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin may reduce hyperkalemia risk in people with type 2 diabetes and chronic kidney disease who are using RAAS inhibitors.

New data from the CREDENCE trial shows the sodium glucose co-transporter 2 (SGLT2) inhibitor canagliflozin may reduce the risk of hyperkalemia in certain patients with type 2 diabetes (T2D) and chronic kidney disease, and an editorial1 published alongside the new results2 suggests the findings call for additional research to learn whether this effect is shared across this ground-breaking class of medication.

SGLT2 inhibitors have made a huge positive impact in clinical care—offering benefits in T2D, heart failure, and chronic kidney disease—and should be further studied based on the post-hoc data presented from CREDENCE, which first showed cardiovascular and renal benefits for canagliflozin (Invokana, Janssen) in 2019. The study and editorial appeared in European Heart Journal as the findings were presented during last month's virtual meeting of the European Society of Cardiology.

The post-hoc data from CREDENCE showed the effects of canagliflozin on serum potassium in people with T2D and CKD. According to the findings, canagliflozin may reduce the risk of hyperkalemia in people with T2D and CKD without increasing the risk of hypokalemia among patients treated with renin–angiotensin–aldosterone system (RAAS) inhibitors.

Hyperkalemia is a condition where someone has too much potassium in their blood, while hypokalemia is a result of extremely low potassium in their blood. Patients with T2D and CKD are at a higher risk of developing hyperkalemia and must have their potassium levels closely monitored.

Multiple studies have shown that hyperkalemia is the most common reason for decreased dosage or complete withdrawal of RAAS inhibitors among people with T2D and CKD. However, more recent studies have suggested that RAAS inhibitor removal led to hospitalization and death.

In the past, clinicians faced the choice between risking consequences of incident hyperkalemia, adding another medication in the form of a potassium binder, or having to withdraw the drugs protecting the kidney. Other studies on SGLT2 inhibitors have shown a decrease in serum potassium levels in patients with intact kidneys, but did not necessarily study populations with T2D and CKD already present.

Ileana L. Piña, MD, MPH, clinical professor at Central Michigan University College of Medicine, wrote that newer potassium binders—medications that prevent intestinal absorption of potassium by binding potassium ions in the gastrointestinal tract, such as patiromer—have an acceptable safety profile. However, she also said prescribing a potassium binder adds additional costs and another pill burden to patients whose medical regimens are already complex.

“The impetus for the study was the contradictory findings of canagliflozin and potassium levels,” she said.

She argues that the researchers used an “ideally treated population” of patients with both T2D and CKD. More than 99% of included patients were already on RAAS inhibitors and the mean baseline potassium was 4.5, meaning it was clinically acceptable.

“The overall results reported are impressive, in that canagliflozin reduced the risk of investigator-reported hyperkalaemia or the initiation of potassium binders compared with placebo, and extend the findings of other SGLT2i studies in patients without CKD at entry,” Piña said.

The study authors defined hyperkalemia as K > 6.0 mmol/L and tracked changes in serum potassium as well as other drugs that could potentially alter potassium levels above or below baseline. They also tracked RAAS inhibitor removal or reduction.

“In addition, although exploratory, but given the large number of enrolled patients, Neuen and colleagues assessed the association between baseline potassium and both renal and cardiovascular outcomes,” she said. “The collection of data allowed adjustment for a multitude of factors including age, sex, and history of cardiovascular disease, among others.”

Both the canagliflozin and placebo groups saw an increase in potassium levels throughout the trial, showing that kidney function continues to deteriorate, especially in this group with baseline abnormal kidney function.

The results of the study showed a U-shaped curve for kidney and cardiovascular outcomes that reflect the findings of other trials, supporting the need for potassium regulation and the role of SGLT2 inhibitors in that process.

“Finally, the implications of this study for clinicians caring for patients with diabetes mellitus and CKD should enhance confidence in the use of SGLT2is not just to prevent hyperkalaemia, but also to allow the maintenance of renally protective drugs, now with a new one on the shelf,” Piña concluded.


  1. Piña IL. SGLT2 inhibitors: the story continues to unfold. Eur Heart J. Published online August 23, 2021. doi:10.1093/eurheartj/ehab561
  2. Neuen BL, Oshima M, Perkovic V, et al. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial. Eur Heart J. Published online August 23, 2021. doi.org/10.1093/eurheartj/ehab497

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