Study compared SGLT2 inhibitors with GLP-1 agonists and DPP-4 inhibitors

One class of glucose-lowering agent may help lower the risk of kidney stones in adults with type 2 diabetes, a cohort study suggested.

Adults who newly started on an SGLT2 inhibitor had a 31% lower risk of nephrolithiasis compared with those starting on a GLP-1 receptor agonist (HR 0.69, 95% CI 0.67-0.72), found Julie M. Paik, MD, ScD, MPH, of Brigham and Women’s Hospital in Boston, and colleagues. This equated to 14.9 versus 21.3 nephrolithiasis events per 1,000 person-years for new SGLT2 and GLP users over a median 192-day follow-up, respectively.

New SGLT2 users also had a significantly lower risk of nephrolithiasis when compared with new initiators of a DPP-4 inhibitor (HR 0.74, 95% CI 0.71-0.77), the group reported in JAMA Internal Medicineopens in a new tab or window. This equated to 14.6 versus 19.9 nephrolithiasis events per 1,000 person-years for SGLT and DPP-4 users, respectively.

These findings didn’t come as much of a surprise to the researchers, Paik told MedPage Today, given what is already known about SGLT2 inhibitors and their renoprotective benefits. According to the study, the reduced kidney stone risk with SGLT2 inhibitor use could be explained by the drugs’ ability to increase urinary citrate excretion or urinary bicarbonate excretion, their anti-inflammatory properties, or by increasing urine flow.

Currently, a few FDA-approved SGLT2 inhibitors have diabetes, kidney, and cardiovascular protection indications on their labels, including empagliflozin (Jardiance)opens in a new tab or window, dapagliflozin (Farxiga)opens in a new tab or window, and canagliflozin (Invokana).

“However, there had been no prior studies looking at the association between the use of this newer class of diabetes medication and the risk of kidney stones in a U.S. population receiving routine care,” she said. “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.”

That being said, she pointed out that their study only included patients with type 2 diabetes and therefore it’s still unclear how this class of medications might modify risk in patients without type 2 diabetes but at risk for kidney stones.

In subgroup analyses, Paik’s group found that kidney stone risk was still significantly lower with SGLT2 inhibitors across various age groups, sex, race, and BMI. The only subgroup that didn’t have a lower nephrolithiasis risk were those falling into early chronic kidney disease (CKD) stages (1 to 2), but those in higher stages (3 to 4) had a significantly lower risk.

While all ages had significantly lower nephrolithiasis risk with SGLT2 inhibitors, the magnitude of the risk reduction was greater among those under 70 years.

The researchers pulled data on 716,406 adults with type 2 diabetes from Optum’s deidentified Clinformatics Data Mart Database (2013-2020), IBM MarketScan (2013-2019), and Medicare Fee-for-Service Parts A, B, and D (2013-2018). For inclusion, all patients had to be new adult users of an SGLT2 inhibitor, GLP-1 agonist, or DPP-4 inhibitor between 2013 and 2020. Those with a prior history of kidney or urinary tract stones were excluded. Nephrolithiasis was diagnosed by ICD codes in the inpatient or outpatient setting.

New SGLT2 users were propensity-score matched 1:1 to new users of GLP agonists and DPP-4 inhibitors.

Prior to matching, patients starting GLP agonists were more likely to be female and to have seen an endocrinologist or nephrologist; were more likely to have a higher combined comorbidity score, obesity, or CKD stage 3 to 4; and were more likely to be on insulin or a loop diuretic but less likely to be taking metformin.

The group initiating DPP-4 inhibitors were more likely to be older, to have seen a nephrologist, and to be taking a loop diuretic or an antihypertensive agent. They were also more likely to have a higher combined comorbidity score, CKD stage 3 to 4, heart failure, cerebrovascular disease, or a history of a urinary tract infection or acute kidney injury. This group was also less likely to have obesity, to be taking insulin, and to have seen an endocrinologist.

In the SGLT2- and GLP-matched cohort, the average age was 61 years, 51% were women, 71% were white, 40% had obesity, 7% had CKD stage 3 to 4, and 4% had a history of gout. In the cohort matched with DPP-4 inhibitors, the average age was 62 years, 47% were women, 62% were white, 34% had obesity, 6% had CKD stage 3 to 4, and 4% had a history of gout.

Because nephrolithiasis occurrence was measured with diagnostic codes, Paik’s group warned there was the potential for some outcome misclassification. Also, they couldn’t tell if kidney stones were new or recurrent, nor tell the composition of the stones.