Can SGLT2 Inhibitors Limit Acute Kidney Injury in Type 2 Diabetes?

Mitchel L. Zoler, PhD

March 07, 2023

Adults with type 2 diabetes treated with an SGLT2 inhibitor had roughly a third fewer episodes of acute kidney injury (AKI) compared with matched people with type 2 diabetes treated with a DPP4 inhibitor in an analysis of health insurance data from more than 100,000 Taiwan residents in 2016-2018.

The findings add to, and expand on, prior evidence that treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class cuts the incidence of AKI, say the authors of the report, which was recently published in JAMA Network Open.

The long-term risk for AKI among people with type 2 diabetes treated with an SGLT2 inhibitor "appears to be quite low" compared with adults who received an agent from the dipeptidyl peptidase 4 (DPP4) inhibitor class.

Treatment with an SGLT2 inhibitor — such as canagliflozin (Invokana), dapagliflozin (Farxiga), or empagliflozin (Jardiance) — causes a transient drop in kidney function that manifests as a temporary dip in estimated glomerular filtration rate, which caused concerns about AKI when the drugs were first introduced.

Indeed canagliflozin and dapagliflozin had warnings strengthened 7 years ago by the US Food and Drug Administration in a Drug Safety Communication for accumulating reports of AKI linked to their use.

More recent experience has calmed AKI concerns, however.

Commenting on the new study, F. Perry Wilson, MD, a nephrologist at Yale School of Medicine in New Haven, Connecticut, said: "It's a nice piece of data to demonstrate that the long-term risk from SGLT2 inhibitor treatment is low." Wilson was not involved with the new study.

The Taiwan study found a cumulative incidence of AKI events during about 2.5 years of follow-up of 5.55 events/1000 patient-years among adults with type 2 diabetes receiving an SGLT2 inhibitor and 7.88 events/1000 patient-years among those taking a DPP4 inhibitor such as sitagliptin (Januvia).

Main Barrier to SGLT2 Inhibitor Use Is Unfamiliarity, Not AKI Risk

"My impression is that the main barrier to wider use of the SGLT2 inhibitor class is not a perceived risk for causing AKI, but rather ongoing unfamiliarity with the class," said Wilson in an interview.

Although he sees "relatively broad comfort with and enthusiasm for the class among nephrologists and cardiologists," routine prescribing does not seem to have caught on nearly as much among primary care physicians, he said.

Clinicians in primary care "still perceive the SGLT2 inhibitor class as something of a 'specialty drug,' and they defer initiating it on that basis," Wilson observed. "That's probably not a good thing," as many people with type 2 diabetes do not have access to a specialized clinician who might be more amenable to prescribing an SGLT2 inhibitor.

One example of the lag in SGLT2 inhibitor uptake for people with type 2 diabetes in practice was a recent report from the US Centers for Disease Control and Prevention published in Annals of Internal Medicine. Researchers identified a representative US sample of 1330 adults with type 2 diabetes studied in depth in 2017-2020, of whom 82% fulfilled criteria published in 2022 for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of those with a recommended indication actually received an agent from this class.

Early AKI Concern Has Diminished

Results from more recent studies, such as a 2019 meta-analysis of more than 100 randomized studies and four large observational studies that together included about 180,000 people receiving SGLT2 inhibitor treatment, showed the opposite of SGLT2 inhibitor treatment triggering AKI.

In the trials, people taking an SGLT2 inhibitor had a relative 25% lower rate of AKI events, while in the observational studies, SGLT2 inhibitor treatment was linked with a 60% relative reduction in AKI. The study also found that SGLT2 inhibitor use in the trials was linked with a significant 20% relative increase in the incidence of low fluid volume.

Despite accumulated evidence exonerating AKI risk, US labels for canagliflozin, dapagliflozin, and empagliflozin continue to cite AKI as a potential adverse reaction, especially in patients who undergo volume depletion while on SGLT2 inhibitor treatment.

The new Taiwan study used data from the country's National Health Insurance Research Database. Out of more than 250,000 adults with type 2 diabetes in the system from May 2016 to December 2018, the researchers identified 52,231 propensity-score matched pairs of people where one was on treatment with an SGLT2 inhibitor and the other with a DPP4 inhibitor.

During follow-up, 856 of these people (0.8%) had an AKI event, including 102 people with AKI that required dialysis.

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment linked with a significant 34% reduction in AKI events compared with DPP4 inhibitor treatment, as well as with a significant 44% relative risk reduction in the incidence of AKI events requiring dialysis, report the authors from several medical institutions in Taiwan.

The study's main limitation was its reliance on "quite insensitive" administrative coding data to identify AKI cases, commented Wilson.

He also noted that although concern about AKI events secondary to SGLT2 inhibitor treatment is uncommon among US clinicians they do worry about the potential risk for fungal infections, urinary tract infection, or gangrene in people with diabetes who receive an agent from this class.

The study received no commercial funding, and none of the authors had disclosures. Wilson has reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Vifor, and Whoop.

JAMA Netw Open. Published on February 22, 2023. Full text

Mitchel L. Zoler is a reporter for Medscape and MDedge based in the Philadelphia area. @mitchelzoler

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