People with type 2 diabetes treated with sodium-glucose cotransporter 2 inhibitors (SGLT2) inhibitors show a significantly reduced risk of developing kidney stones compared with those treated with other commonly used diabetes drugs.
“To our knowledge, this study is the first and largest to assess the association between SGLT2 inhibitors use and risk of nephrolithiasis [kidney stones] in patients with type 2 diabetes in routine US clinical practice,” said the authors of the study, published in JAMA Internal Medicine.
they wrote.
The prevalence of kidney stones has been on the rise, and the problem is especially relevant to those with type 2 diabetes, which is known to have an increased risk of kidney stones, potentially causing severe pain and leading to kidney function decline.
With SGLT2 inhibitors showing renoprotective, in addition to cardiovascular benefits, first author Julie Paik, MD, MPH, an associate professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics and the Division of Renal (Kidney) Medicine at Brigham and Women’s Hospital in Boston, Massachusetts, and colleagues conducted an active comparator cohort study using data from three nationwide databases on patients with type 2 diabetes in routine clinical practice.
In the study’s two arms of propensity score-matched patients, 358,203 pairs of patients with type 2 diabetes were matched 1:1 to either those who were new users of SGLT2 inhibitors or glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), with patients in those groups having a mean age of 61 and being about 51% female.
In addition, 331,028 pairs matched new SGLT2 inhibitor users 1:1 with didpeptidyl peptidase-4 (DPP4) inhibitor users, who also had a mean age of about 61.5 years and were about 47% female.
Over a median follow-up of 192 days, those treated with SGLT2 inhibitors had about a 31% significantly lower risk of kidney stones than GLP-1RA users (14.9 vs 21.3 events per 1000 person-years; hazard ratio [HR], 0.69).
And the SGLT2 group also had a 26% lower kidney stone risk vs DPP4 inhibitor users (14.6 vs 19.9 events per 1000 person-years; HR, 0.74).
There were no differences in the results with either groups of pairs based on sex, race, ethnicity, a history of chronic kidney disease, or obesity.
Of note, the magnitude of the risk reduction observed with SGLT2 inhibitors was greater in adults aged < 70 years than in those aged ≥ 70 years (HR, 0.85; P for interaction < .001).
The age-related difference could possibly be due to changes in stone composition that occurs with aging, which may influence SGLT2 inhibitor response, Dr Paik told this news organization.
“However, we did not have information on stone composition in our study.”
In the study, patients were taking, on average, more than two antidiabetic medications upon entrance to the study, with 13% taking thiazides and 12% taking loop diuretics. In addition, approximately half of patients discontinued SGLT2 inhibitors (52.6%) and DPP4 inhibitors (53.2%).
However, the results remained consistent after adjusting for those factors, Dr. Paik noted.
Mechanisms: Urinary Citrate Excretion?
Among key possible explanations for the lower risk of kidney stones with SGLT2 inhibitors is that the drugs have increased urinary citrate excretion, with one study showing a nearly 50% increase in urinary citrate excretion among patients treated with empagliflozin vs placebo over 4 weeks and other studies also showing similar increases.
“This increased urinary citrate excretion may play a pivotal role in decreasing stone risk by inhibiting supersaturation and crystallization of calcium crystals,” the authors explained.
In addition, the urinary citrate excretion could further play a role by “forming complexes with calcium and thus lowering urinary calcium concentration, and raising urinary pH, thereby reducing the risk of uric acid stones,” they added.
SGLT inhibitors’ anti-inflammatory effects could also reduce stone formation by “suppressing the expression of a stone core matrix protein, osteopontin, and markers of kidney injury, inflammation, and macrophages that promote stone formation,” the authors noted.
Ultimately, however, “while we found a lower risk of kidney stones in our study, we don’t fully understand how they lower the risk,” Dr. Paik said. The potential explanations “remain to be studied further.”
Either way, “the risk of kidney stones in a patient might be one additional consideration for a clinician to take into account when choosing among the different glucose-lowering agents for patients with type 2 diabetes,” Dr. Paik said.
The study was funded by the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, the National Institute of Aging the Patient-Centered Outcomes Research Institute, the US Food and Drug Administration, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.
A version of this article appeared on Medscape.com .