Sodium glucose cotransporter 2 (SGLT2) inhibitors not only are effective in lowering blood glucose levels and reducing cardiovascular risks in type 2 diabetes, but a new study asserts the drugs also could be helpful in lowering the risks of serious renal events.

The report in The BMJ argues for greater use of SGLT2 inhibitors in a wide range of patients with type 2 diabetes, according to authors from the Karolinska Institutet and colleagues. A linked editorial and another article in the same issues didn’t go that far, however.

The research article points out that T2D is the leading cause of kidney failure. Although past trials have suggested a protective effect on renal function in those patients, researchers point out that the drugs’ effect on serious renal events in patients in "real-world" clinical practice had remained uncertain.

To help resolve questions about effectiveness, the international team of researchers sought to assess the association between use of SGLT2 inhibitors and risk of serious renal events using data from routine clinical practice. Their cohort study used an active comparator, new user design and nationwide register data.

The study was conducted in Sweden, Denmark, and Norway from 2013-18. Participants included 29, 887 new users of SGLT2 inhibitors, including dapagliflozin, empagliflozin and canagliflozin. Those patients were compared to  29,887 new users of dipeptidyl peptidase-4 inhibitors. The two groups were, matched 1:1 on the basis of a propensity score with 57 variables over a mean follow-up time of 1.7 (SD 1.0) years.

The study population had a mean age of 61.3 (SD 10.5) years, with 11,108 (19%) having cardiovascular disease and 1,974 (3%) diagnosed with chronic kidney disease

The researchers tracked use of SLT2 inhibitors vs. dipeptidyl peptidase-4 inhibitors using data on filled prescriptions and analyses of intention to treat. Defined as the main outcome was serious renal events, a composite including renal replacement therapy, death from renal causes, and hospital admission for renal events.  Individual components of the main outcome were considered secondary outcomes.

Study results indicate that use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a reduced risk of serious renal events (2.6 events per 1000 person years vs. 6.2 events per 1000 person years; for a hazard ratio 0.42 (95% confidence interval 0.34 to 0.53) and an absolute difference of −3.6 (–4.4 to −2.8) events per 1000 person years). 

Researchers determined that, in secondary outcome analyses, the hazard ratio for use of SGLT2 inhibitors vs. dipeptidyl peptidase-4 inhibitors was 0.32 (0.22 to 0.47) for renal replacement therapy, 0.41 (0.32 to 0.52) for hospital admission for renal events, and 0.77 (0.26 to 2.23) for death from renal causes. 

The authors explain that their results equate to a difference of 3.6 fewer events per 1000 person-years or a 58% lower relative risk of serious renal events with SGLT2 inhibitors. The further analysis points to greater risk reduction in patients with underlying cardiovascular disease and chronic kidney disease (CKD), they add.

The study team also performed sensitivity analyses in each of the Swedish and Danish parts of the cohort, further adjusting the model for glycated hemoglobin and estimated glomerular filtration rate (Sweden and Denmark) and for blood pressure, body mass index, and smoking (Sweden only). Based on those analyses, the hazard ratio moved from 0.41 (0.26 to 0.66) to 0.50 (0.31 to 0.81) in Sweden and from 0.42 (0.32 to 0.56) to 0.55 (0.41 to 0.74) in Denmark, according to the report.

“In this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with dipeptidyl peptidase-4 inhibitors, was associated with a significantly reduced risk of serious renal events,” the authors conclude.

This is an observational study, so can't establish cause, and the researchers point to some study limitations, such as relying on prescription data and hospital records, which may have affected the accuracy of their results.

What's more, because the study was conducted in Scandinavia, findings may not apply to other populations and healthcare systems.

However, they say that in this analysis using nationwide data from three countries, use of SGLT2 inhibitors, compared with DPP-4 inhibitors, was associated with a significantly reduced risk of serious renal events.

Steven M. Smith, PharmD, MPH, of the Department of Pharmacotherapy and Translational Research at the University of Florida, writes in a linked editorial that, while the study has some strengths, caution should be urged in interpreting the results. 

Additional trials in real world settings and more diverse populations "could add further support for broader access to these drugs, not just in high income countries, but also in lower income countries where the burden of kidney disease is disproportionately high," Smith concludes.

In an analysis article also published in The BMJ, researchers point out that several serious safety warnings related to SGLT2 inhibitors have been issued since approval of the drugs, although U.S., Australian, Canadian, and European regulators have differed in the types and strengths of the warning. The authors from the University of Sydney in Australia, the University of British Columbia, in Canada and Brigham and Women’s Hospital and Harvard Medical School in the United States suggest that greater transparency in decision making is needed to  increase the accountability of both regulators and industry and allow for more informed treatment choices.