GLP-1 Receptor Agonists Reduce Hyperkalemia and Enhance RASi Use in Type 2 Diabetes

This is of important concern for T2D patients, especially those who use RAS inhibitors to manage blood pressure and preserve kidney function as part of their treatment. The risk of developing hyperkalemia could lead to underutilization of these guideline-recommended medications. Of interest, recent evidence has suggested that GLP-1RAs—a newer class of diabetes medications—may increase urinary potassium excretion, thereby decreasing the risk of developing hyperkalemia.

This was a cohort study of data from adults with T2D newly initiated on either GLP-1RAs or DPP-4is in Stockholm, Sweden, from January 1, 2008, to December 31, 2021. Data analysis took place from October 1, 2023, to April 29, 2024. A total of 33,280 participants were used, including 13,633 users of GLP-1RA and 19,647 users of DPP-4i. Rates of hyperkalemia, defined as potassium above 5.0 mEq/L, and moderate-to-severe hyperkalemia, defined as a potassium level above 5.5 mEq/L, were the measured major outcomes. The secondary outcome measured was the rate of discontinuation of RASi therapy among users at baseline. Inverse probability of treatment weight was applied to balance over 70 confounders, and marginal structural models were used to estimate hazard ratios.

Key Findings

• The use of GLP-1RAs was associated with a lower rate of any hyperkalemia compared to DPP-4is (HR, 0.61; 95% CI, 0.50-0.76).

• For moderate to severe hyperkalemia, GLP-1RAs also showed a significant reduction (HR, 0.52; 95% CI, 0.28-0.84).

• Among the 21,751 participants who were on RASis at the start of the study, 1,381 discontinued this therapy.

• GLP-1RA use was linked to a lower rate of RASi discontinuation compared to DPP-4i use (HR, 0.89; 95% CI, 0.82-0.97).

• The results were consistent across different age groups, sexes, cardiovascular comorbidities, and baseline kidney function.

The findings suggest that GLP-1RAs could be expected to lower the likelihood of hyperkalemia and thereby enable the continued administration of RAS inhibitors, which play a key role in managing blood pressure and preserving kidney function in T2D patients. This being the case, in reducing the rate of hyperkalemia and promoting continued RAS use, GLP-1RAs might also optimize the total control of diabetes and hence improve patient outcomes in a more general way.

Finally, as compared to DPP-4is, GLP-1RAs were associated with lower rates of hyperkalemia and better persistence with RASi therapy. It became even more speculative in this analysis whether GLP-1RAs played such a critical role in T2D treatment since they could overcome barriers to a certain level and possibly improve clinical outcomes.

Reference:

Huang, T., Bosi, A., Faucon, A.-L., Grams, M. E., Sjölander, A., Fu, E. L., Xu, Y., & Carrero, J. J. (2024). GLP-1RA vs DPP-4i use and rates of hyperkalemia and RAS blockade discontinuation in type 2 diabetes. JAMA Internal Medicine. https://doi.org/10.1001/jamainternmed.2024.3806