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26-06-2020 | Diabetes | News | Article

SGLT2 inhibitor effects on nondiabetic CKD remain unclear

Eleanor McDermid

medwireNews: Treatment with dapagliflozin for 6 weeks has no effect on proteinuria in people with nondiabetic chronic kidney disease (CKD), show the findings of a randomized crossover trial.

Results obtained with canagliflozin in the CREDENCE trial showed that the medication reduced the risk for renal outcomes in people with type 2 diabetes and CKD, and that this was unlikely to be wholly due to canagliflozin’s glucose-lowering effect.

In this current study, Hiddo Heerspink (University Medical Centre Groningen, the Netherlands) and colleagues therefore looked at the effects of the sodium-glucose cotransporter (SGLT)2 inhibitor dapagliflozin on CKD in 53 people without diabetes. They were an average age of 51 years, 68% were male, and the majority were White (55%) or Asian (32%).

The primary outcome of change in 24-hour proteinuria did not significantly differ with dapagliflozin versus placebo treatment, the team reports in The Lancet Diabetes & Endocrinology.

Proteinuria fell by an average 15.8%, from a geometric mean baseline of 1088.1 mg per 24 h, during 6 weeks of treatment with dapagliflozin 10 mg/day and by 15.0%, from a baseline of 1029.8 mg per 24 h, during 6 weeks of placebo treatment. The study participants undertook these treatment phases in a randomly assigned order, with a 6-week washout period between.

There was also no significant difference between the treatment phases in change in 24-hour albuminuria or protein-to-creatinine ratio.

In a linked commentary, Hillel Sternlicht (Wayne State University Medical Center, Detroit, Michigan, USA) and George Bakris (University of Chicago Medicine, Illinois, USA) propose a number of explanations for the lack of effect on proteinuria, contrary to that seen in trials of people with diabetic kidney disease. These include variability in urine albumin assays, the small number of study participants, variable kidney disease etiologies, and the low baseline blood pressure.

Measured glomerular filtration rate significantly decreased during the dapagliflozin treatment phase, by an average of 6.3 mL/min per 1.73 m2 from a baseline of 59.3 mL/min per 1.73 m2. But the researchers stress that this was “completely reversible,” with values returning to baseline levels during the 6-week washout period.

Dapagliflozin treatment resulted in a significant 1.5 kg reduction in average bodyweight versus placebo, but there were no changes in blood pressure, heart rate, or levels of neurohormonal biomarkers such as N-terminal pro B-type natriuretic peptide and prostaglandin markers.

But Sternlicht and Bakris caution that changes in neurohormonal biomarkers are “very fast and can only be detected within the nephron, therefore these data do not provide information about the contribution of these markers to albuminuria reduction.”

The commentators conclude: “These data from a well performed physiological study leave us awaiting the results of the DAPA-CKD outcome trial. If DAPA-CKD reports a discordance of renal outcomes independent of albuminuria reduction, mechanistic studies will be required to understand this dissociation in chronic kidney disease progression in individuals without diabetes.”

medwireNews is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature Group

Lancet Diabetes Endocrinol 2020; doi:10.1016/S2213-8587(20)30162-5
Lancet Diabetes Endocrinol 2020; doi:10.1016/S2213-8587(20)30185-6

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