The DPP-4 inhibitor alogliptin was associated with the lowest risk for kidney disease compared with other agents in the same class among adults with type 2 diabetes (T2D) and moderate cardiovascular risk, according to an analysis of claims data from approximately 170,000 adults.

The increasing use of GLP-1 receptor agonists has changed glucose-lowering pharmacotherapy, but many patients, especially older adults, continue to receive DPP-4 inhibitors, said senior study author Rozalina G. McCoy, MD, an endocrinologist and associate professor of medicine at the University of Maryland School of Medicine in Baltimore.

DPP-4 inhibitors are commonly prescribed when GLP-1 receptor agonists or SGLT2 inhibitors are not feasible. However, head-to-head comparisons within the DPP-4 inhibitor class are lacking, and available kidney outcome data have largely come from secondary endpoints, McCoy told Medscape Medical News.

“Using a target trial emulation approach with a large, multi-payor, longitudinal claims dataset allowed us to fill that gap and examine kidney-related outcomes with the different available DPP-4 inhibitor drugs,” she explained.

The findings were published in Diabetes, Obesity, and CardioMetabolic CARE.

Comparing DPP-4 Inhibitors

McCoy and colleagues reviewed data from adults aged 21 years or older with T2D, moderate cardiovascular risk, and no chronic kidney disease (CKD) of stage 3 or worse. Participants initiated alogliptin, linagliptin, saxagliptin, or sitagliptin between 2014 and 2021. The study included 3026 patients who started alogliptin, 38,213 who started linagliptin,14,934 who started saxagliptin, and 115,091 who started sitagliptin.

The primary outcome was a composite of incident stages 3-5 CKD, kidney failure, or kidney replacement therapy.

At 1 year, the primary outcome occurred in 1.4% of patients receiving alogliptin, 2.7% receiving linagliptin, 2.2% receiving saxagliptin, and 2.4% receiving sitagliptin. At 3 years, the corresponding rates were 3.2%, 6.2%, 5.0%, and 5.4%, respectively.

Overall, alogliptin was associated with a lower risk for stage 3 or worse CKD than linagliptin (hazard ratio [HR], 0.50; 95% CI, 0.37-0.69), saxagliptin (HR, 0.63; 95% CI, 0.45-0.86), and sitagliptin (HR, 0.58; 95% CI, 0.42-0.79).

Saxagliptin was also associated with a lower risk for CKD than linagliptin (HR, 0.80; 95% CI, 0.73-0.87), whereas linagliptin was associated with a higher risk than sitagliptin (HR, 1.15; 95% CI, 1.10-1.21).

Unexpected Differences Between Agents

“We initially expected to see no difference between the agents, just as we found no difference in their cardiovascular effects examined in an earlier study,” McCoy said. However, clear differences emerged in kidney-related effects.

Alogliptin’s apparent advantage was unexpected, particularly because it was the least frequently prescribed DPP-4 inhibitor in US practice and in the study cohort, she noted.

“Because alogliptin was so infrequently used, we ran a sensitivity analysis excluding it, and saxagliptin and sitagliptin still separated out as more favorable than linagliptin,” McCoy said. “That reinforced that the linagliptin finding wasn’t just an artifact of the alogliptin comparison.”

The findings support favoring alogliptin or saxagliptin when a DPP-4 inhibitor is needed and GLP-1 receptor agonists or SGLT2 inhibitors are not options and perhaps avoiding linagliptin when reducing kidney risk is a priority, she said.

“That said, the absolute differences in outcomes across all four agents were very modest, so this isn’t a signal that any DPP-4 inhibitor is unsafe or should not be used,” McCoy added. “Our data should be considered as a tiebreaker for clinicians and patients choosing among otherwise similar options in patients without baseline CKD.”

Study limitations included the inability to incorporate laboratory values and the inclusion of only patients who did not have stage 3 or worse CKD. Comparable analyses are therefore needed in patients with more advanced disease, McCoy said.

“We don’t yet know the mechanism behind the linagliptin finding, and it is worth exploring given the pharmacokinetic differences across these agents despite their shared mechanism of action,” she added.

Data May Help Inform Treatment Decisions

If the DPP-4 inhibitors studied are equally effective for the treatment of diabetes, then determining whether any has greater impact on kidney or cardiovascular outcomes is valuable, said Jeffrey S. Berns, MD, professor of medicine in pediatrics and associate chief of the Division of Renal, Electrolyte, and Hypertension at the Hospital of the University of Pennsylvania in Philadelphia.

However, “as the authors note, this class of drugs is not known to have any real benefit on kidney outcomes generally, and they do not delineate why there might be a clinical difference among these agents,” said Berns, who was not involved in the study.

Consequently, the findings should be considered preliminary, he said.

“A1c levels, estimated glomerular filtration rate, urine albuminuria, weight, and blood pressure were not known, but are vitally important baseline and on-study information to ensure comparability,” Berns emphasized. Trends in estimated glomerular filtration rate would also be more informative than CKD stage alone, he added.

Although the observed differences were statistically significant, they were small, and several baseline comorbidities appeared to favor alogliptin, Berns noted.

“I would like to see this study repeated with different populations and research approaches,” he said.

Whether any of the drugs were themselves reno-protective when added to therapies such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, SGLT-2 inhibitors, mineralocorticoid receptor antagonists, or GLP-1 receptor agonists remain unknown, he added.

The study was supported by the Patient-Centered Outcomes Research Institute. The researchers reported no financial conflicts to disclose. Berns also reported no relevant financial conflicts.