Clinical Context

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are known to improve outcomes in chronic kidney disease, even among patients without a history of diabetes, but can they improve the risk for acute kidney injury (AKI)? A previous meta-analysis by Menne and colleagues, which was published in the December 9, 2019 issue of PLOS Medicine,^[1] sought an answer to this question.

Researchers found 112 clinical trials and 4 observational studies that examined SGLT2 inhibitors with at least 1 renal outcome. In the prospective trials, the odds ratio (OR) of AKI was 0.64 (95% CI: 0.53, 0.78) in comparing SGLT2 inhibitors and control treatment. Empagliflozin, dapagliflozin, and canagliflozin all appeared to reduce the risk for AKI. In observational studies, the OR for AKI associated with SGLT2 inhibitors was 0.4 (95% CI: 0.33, 0.48).

The current study by Chung and colleagues uses a national database in Taiwan to further analyze the potential value of SGLT2 inhibitors in the prevention of AKI.

Study Synopsis and Perspective

Adults with type 2 diabetes (T2D) treated with an SGLT2 inhibitor had roughly a third fewer episodes of AKI compared with matched people with T2D treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor in an analysis of health insurance data from more than 100,000 Taiwan residents in 2016 to 2018.

The findings added to, and expanded on, prior evidence that treatment with an agent from the SGLT2 inhibitor class cuts the incidence of AKI, said the authors of the report, which was recently published in JAMA Network Open.^[2]

The long-term risk for AKI among persons with T2D treated with an SGLT2 inhibitor "appears to be quite low" compared with adults who received an agent from the DPP-4 inhibitor class.

Treatment with an SGLT2 inhibitor -- such as canagliflozin, dapagliflozin, or empagliflozin -- 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^[3] 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 (PY) among adults with T2D receiving an SGLT2 inhibitor and 7.88 events/1000 PY among persons taking a DPP-4 inhibitor, such as sitagliptin.

"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 [T2D] 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 T2D in practice was a recent report from the Centers for Disease Control and Prevention (CDC) published in the Annals of Internal Medicine.^[4] Researchers identified a representative US sample of 1330 adults with T2D studied in depth in 2017 to 2020, of whom 82% fulfilled criteria published in 2022^[5] for receiving treatment with an SGLT2 inhibitor. Despite this high prevalence of medical appropriateness, a scant 5.3% of persons with a recommended indication actually received an agent from this class.^[4]

Results from more recent studies, such as a 2019 meta-analysis^[1] of more than 100 randomized studies and 4 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, whereas 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^[2] used data from the country's National Health Insurance Research Database.^[6] Of more than 250,000 adults with T2D 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 DPP-4 inhibitor.^[2]

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

A logistic regression analysis that adjusted for 16 potential confounders showed that SGLT2 inhibitor treatment was linked to a significant 34% reduction in AKI events compared with DPP-4 inhibitor treatment, as well as to a significant 44% relative risk reduction in the incidence of AKI-D, reported 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 relevant financial relationships.

Clinical Implications

• A previous meta-analysis found that SGLT2 inhibitors were associated with lower risks for AKI in both clinical trials and observational studies. Empagliflozin, dapagliflozin, and canagliflozin all appeared to reduce the risk for AKI.
• The current study by Chung and colleagues comparing SGLT2 inhibitors and DPP-4 inhibitors among adults with diabetes found that SGLT2 inhibitors can reduce the risk for AKI and AKI-D. Specifically, SGLT2 inhibitors were significantly associated with reductions in the risk for AKI in the settings of respiratory failure and shock, but SGLT2 inhibitors had insignificant results for AKI related to heart disease and sepsis.
• Members of the healthcare team should become familiar with the mechanism of action and potential adverse events of SGLT2 inhibitors in order to facilitate shared decision-making discussions with patients who have Type 2 diabetes.

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