GLP-1 Agonists for Diabetes Tied to Lower Hyperkalemia Rates

Hyperkalemia in type 2 diabetes occurred less often with GLP-1 receptor agonists in routine care than dipeptidyl peptidase-4 (DPP-4) inhibitors, a large observational study in Sweden showed.

Over a median 3.9-month treatment time, GLP-1 agonists were linked with a 39% reduced risk for hyperkalemia — a potassium level greater than 5.0 mEq/L — compared with DPP-4 inhibitor use (HR 0.61, 95% CI 0.50-0.76), reported Yang Xu, Pharm, PhD, of the Peking University Health Science Center in Beijing, and colleagues.

GLP-1 receptor agonists also were associated with a 48% reduced risk for moderate-to-severe hyperkalemia, defined as a potassium level greater than 5.5 mEq/L (HR 0.52, 95% CI 0.28-0.84), the researchers wrote in JAMA Internal Medicine.

The 12-month absolute risk of a first hyperkalemia event was 2.9% in the GLP-1 agonist group and 4.6% in the DPP-4 inhibitor group (weighted risk difference -1.7%, 95% CI -2.4% to -1.1%), Xu’s group noted.

“Treatment with GLP-1RAs[receptor agonists] may enable wider use of the guideline-recommended cardioprotective and renoprotective medications and contribute to improving clinical outcomes in this population,” the researchers suggested.

This study “provides credible observational evidence supporting mechanistic evidence on the pleiotropic effects of GLP-1RAs on potassium homeostasis,” they noted. GLP-1 receptor agonists boost the flow of tubular fluid and the sodium load delivered to the distal nephron, which then induces an increase in urinary potassium excretion by the collecting duct, Xu and colleagues explained.

Besides hyperkalemia reduction, GLP-1 agonists were associated with a lower rate of renin-angiotensin system (RAS) inhibitor discontinuation compared with DPP-4 inhibitors (HR 0.89, 95% CI 0.82-0.97), which the researchers said was a novel finding.

Of 21,751 participants using RAS inhibitors, 1,381 discontinued therapy. Incidence rates for discontinuation were 146.2 per 1,000 person-years among GLP-1 agonist users and 170.2 per 1,000 person-years for DPP-4 inhibitor users.

“Although the observational nature of our study does not allow us to determine whether the lower hyperkalemia rates causally explain this finding, many studies show that hyperkalemia often leads to dose reduction or discontinuation of RAS inhibitor use in clinical practice and that this clinical decision is associated with worse clinical outcomes,” Xu and co-authors said.

The findings were consistent across subgroups and various sensitivity analyses.

The cohort study focused on 33,280 Swedish adults with type 2 diabetes who started treatment with a GLP-1 receptor agonist or a DPP-4 inhibitor from 2008 through 2021. Of these, 13,633 were GLP-1 receptor agonist initiators and 19,647 were initiators of DPP-4 inhibitors. The average age of participants was 63.7 years and 59.7% were male.

Patients who filled a GLP-1 agonist or DPP-4 inhibitor prescription prior to 2008 were excluded. GLP-1 agonists included exenatide (Byetta, Bydureon), liraglutide (Victoza), lixisenatide (now discontinued), dulaglutide (Trulicity), and semaglutide (Ozempic). DPP-4 inhibitors included the agents sitagliptin (Januvia), vildagliptin (not FDA-approved), linagliptin (Tradjenta), and saxagliptin (Onglyza).

Prior to starting one of these agents, participants were using metformin (79.3%), sulfonylureas (22.1%), insulin (20.9%), and SGLT2 inhibitors (7.4%).

GLP-1 agonist users tended to be younger (mean age 60.4 vs 66 years), had a higher HbA1c (mean 8.2% vs 7.9%), higher eGFR (median 92.9 vs 86.5 mL/min/ 1.73 m²), and lower urinary albumin-creatinine ratio (median 10.8 vs 12.9 mg/g).

They also had a higher prevalence of chronic obstructive pulmonary disease (10.5% vs 7.3%), psychiatric disorders (15.1% vs 9.9%), more often used antidepressants (17.2% vs 13.5%), and less often used platelet inhibitors (22.6% vs 30.3%). GLP-1 agonist users had a higher frequency of outpatient visits to the diabetologist (33.1% vs 25%) in the year prior as well.

Xu’s group said some limitations were a lack of data about confounders like dietary potassium or the use of potassium-containing supplements. The study was also underpowered to explore an interaction between GLP-1 receptor agonists with SGLT2 inhibitors.

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