Higher Hyperkalemia Risk with DPP-4i Compared with Alternatives

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In patients with chronic kidney disease (CKD) and type 2 diabetes, treatment with dipeptidyl peptidase-4 inhibitors (DPP-4is) is associated with a greater risk of hyperkalemia compared with sodium-glucose cotransporter-2 inhibitors (SGLT2is) or glucagon-like peptide-1 receptor agonists (GLP-1RAs), reports a recent paper in Kidney International.

The study used large datasets of patients with stages 3 to 4 CKD and type 2 diabetes, drawn from Medicare and commercial insurance claims data. The analysis included three cohorts of patients initiating treatment with differing classes of diabetes medications: 141,671 patients receiving SGLT2i versus DPP-4i therapy, 159,545 receiving GLP-1RA versus DPP-4i, and 93,033 receiving SGLT2i versus GLP-1RA.

Diagnosis of hyperkalemia in an outpatient or inpatient setting was compared among groups, along with secondary outcomes. Analyses included adjustment for more than 140 potential confounders by propensity score matching.

Patients initiating SGLT2i therapy were less likely to develop hyperkalemia compared with those receiving DPP-4i (hazard ratio [HR], 0.74) or GLP-1RA (HR, 0.92). Hyperkalemia risk was lower with GLP-1RA compared with DPP-4i (HR, 0.80). Absolute rate differences per 1000 person-years were −24.8 for SGLT2i versus DPP-4i, −5.0 for SGLT2i versus GLP-1RA, and −17.7 for GLP-1RA versus DPP-4i. Two-year absolute risk differences were −4.3%, −1.8%, and −2.3%, respectively.

Similar patterns were noted for secondary outcomes, including inpatient or emergency department diagnoses of hyperkalemia and serum potassium levels of 5.5 mmol/L or higher. Findings were also similar across demographic and clinical subgroups and on analysis of individual SGLT2i and GLP-1RA agents.

In patients with type 2 diabetes and CKD, hyperkalemia may limit the use of guideline-recommended renin-angiotensin system inhibitors. There are limited data comparing the effects of SGLT2i, GLP-1RA, and DPP-4i in this clinical situation. Reports have suggested that SGLT2i may have a protective effect against hyperkalemia.

The authors discuss the study implications for antihyperglycemic medication choices in patients with type 2 diabetes and CKD. Treatment with SGLT2i or GLP-1RA “may enable the use of other guideline-recommended medications that improve clinical outcomes but increase serum potassium, such as renin-angiotensin system inhibitors” [Fu EL, et al. A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes. Kidney Int, published online December 13, 2023. doi: 10.1016/j.kint.2023.11.025].