In agreement with expectations expressed in the comment letter by Heyman et al. (1), most of the patients (72%) included in the Diabetes and Lifestyle Cohort Twente used agents that exert renin angiotensin aldosterone system (RAAS) blockade (2). None of the included patients used an inhibitor of sodium–glucose cotransporter 2 (SGLT2). Of note, medication use was assessed at baseline, and there is no information regarding either initiation of an SGLT2 inhibitor or changes in usage and/or dosage of RAAS blockade during follow-up.
As requested, we performed a subgroup analysis in patients without use of RAS blockade at baseline. Like in the overall analyses, higher dietary protein intake was also associated with a lower hazard for renal function deterioration (univariable analysis: hazard ratio [HR] 0.61, 95% CI 0.35–1.05, P = 0.08; multivariable analysis: HR 0.47, 95% CI 0.23–0.94, P = 0.034) in these patients. Our findings suggest that renal protection is achieved by high dietary protein intake independent of use of RAS blockade, which is the opposite of what was suggested by Heyman et al. (1).
We also performed a subgroup analysis in patients with use of RAS blockade. In these patients, the point estimate for the association between dietary protein intake and renal function deterioration was in a direction similar to that of the point estimate in patients without use of RAS blockade, although it was not statistically significant (univariable analysis: HR 0.76, 95% CI 0.54–1.08, P = 0.12; multivariable analysis: HR 0.75, 95% CI 0.51–1.10, P = 0.14). Although the point estimate is consistent with less effect than that in the patients without use of RAS blockade, our finding in this subgroup is inconsistent with earlier descriptions of an additive effect of low-protein diet and ACE inhibition on reduction of proteinuria (3), as the insignificance in our study could well be the consequence of lack of power due to the small group size.
In conclusion, our main finding that unrestricted dietary protein intake was not associated with an increased hazard for renal function deterioration is not biased by the use of RAS blockade.
Duality of Interest. G.D.L. reports grants and personal fees from Sanofi, AstraZeneca, Astellas, and Novo Nordisk and personal fees from Janssen outside the submitted work. No other potential conflicts of interest relevant to this article were reported.