Letter Regarding "Moderating Effects in Randomized Trials-Interpreting the P Value, Confidence Intervals, and Hazard Ratios".

To the Editor:

We have read with great interest the commentary of Agarwal et al. titled “Moderating Effects in Randomized Trials—Interpreting the P Value, Confidence Intervals, and Hazard Ratios” published in this issue of the KI Reports, where the authors comment on the article published by Provenzano et al. and expose the evidence of the renal and cardiovascular benefits of 2 groups of drugs—SGLT2 inhibitors and mineralocorticoid receptor antagonists—in the setting of diabetic kidney disease (DKD) and their combined use. They perform a statistical analysis of clinical trials conducted to date and conclude that the current evidence is not strong for combination therapy. We consider it relevant to share additional information that must be considered when covering said topic.

Evidence has revealed and emphasized that renal function trajectories in patients with diabetes differ., Several phenotypes associated with DKD have been described. To date, 4 different phenotypes of DKD have been reported, the classic or albuminuric and 3 nonclassic phenotypes.

Although the classic DKD phenotype remains the most important, current evidence suggests that the nonclassic phenotypes are becoming common. Approximately 20% to 40% of DKD belong to the nonclassic phenotypes. Furthermore, cohort studies have suggested that renal and cardiovascular outcomes may vary between different DKD phenotypes. Therefore, it is necessary to classify and approach patients with DKD according to phenotype.

Important studies such as CREDENCE,S1 DAPA-CKD,S2 and FIDELIO-DKDS3 only include patients with a classic or albuminuric phenotype. The same happens with the combined therapy of SLGT2 inhibitor + mineralocorticoid receptor antagonists, which, although the current evidence is not solid for patients with DKD of the albuminuric phenotype, it is far less in patients with DKD of the nonalbuminuric phenotype.

The first trial that will reveal evidence in patients with nonalbuminuric phenotype DKD is EMPA-KIDNEY (The Study of Heart and Kidney Protection With Empagliflozin).S4

We make a call not to generalize the patient with DKD, but to classify it according to its phenotype and from this approach guide the design of new clinical trials, build solid evidence, and achieve a positive impact on the management of these patients. Phenotype in the patient with DKD is important.

Disclosure

All the authors declared no competing interests.