Previous large cardiovascular outcome trials of sodium–glucose cotransporter 2 (SGLT2) inhibitors in people with type 2 diabetes have demonstrated improvements in adverse renal outcomes such as albuminuria and requirement of renal replacement therapy. These data also suggest that the renal benefits of SGLT2 inhibitors are independent of their glucose-lowering effects. Other studies have shown that these antiproteinuric effects are reversible after cessation of SGLT2 inhibitor treatment, suggesting a haemodynamic mechanism of action. Additionally, the CREDENCE trial, the first dedicated renal outcomes trial for an SGLT2 inhibitor, was published in 2019. CREDENCE demonstrated significant improvements in cardiorenal outcomes with canagliflozin in people with type 2 diabetes and chronic kidney disease (CKD) irrespective of baseline HbA1c. Whether we can replicate these cardiorenal benefits in people without type 2 diabetes remains to be proven.
DIAMOND was a small, short-term (53 participants over 6 weeks), multicentre, randomised, double-blind, placebo-controlled trial primarily exploring the effects of SGLT2 inhibition (using dapagliflozin) on albuminuria in people with proteinuric CKD but without diabetes. Secondary outcomes included changes in glomerular filtration rate (GFR), body weight and blood pressure.
The study demonstrated that 6 weeks of treatment with dapagliflozin did not reduce proteinuria compared with placebo. As has been observed in previous SGLT2 inhibitor trials, an acute decline in GFR of 6.6 mL/min/1.73 m2 was seen, which completely reversed after discontinuation of dapagliflozin. Additionally, dapagliflozin reduced body weight by 1.5 kg and increased haematocrit and haemoglobin levels compared with placebo. Blood pressure was not affected by dapagliflozin treatment and there was no impact on HbA1c or fasting plasma glucose levels in these study participants without a diagnosis of diabetes. No difference in adverse events was noted between the groups.
As discussed above, this was a short-term, 6-week study, which may explain why no significant reduction in proteinuria was seen. However, previous SGLT2 inhibitor studies in people living with type 2 diabetes have demonstrated reductions in albuminuria within this timescale. The authors postulate whether differences in underlying disease pathophysiology may account for the lack of an antiproteinuric response, but a lack of effect in people without type 2 diabetes cannot be fully excluded. This seems unlikely, however, as the DAPA-HF study demonstrated significant improvements in heart failure and renal outcomes irrespective of diabetes status. Furthermore, the Phase 3 DAPA-CKD trial exploring the effect of dapagliflozin on adverse CKD outcomes, in which over 30% of the study cohort did not have type 2 diabetes, was stopped early in March 2020 due to overwhelming efficacy. We await detailed results to see whether there was any discordance in renal benefits between people with and without diabetes.
The similarly designed EMPA-KIDNEY renal outcomes trial will also add to the evidence base as it is recruiting individuals with and without type 2 diabetes. The trial is due to complete in 2022.
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